BOUGHT WITH THE [NCOME OF THE SAGE ENDOWMENT FUND THE GIFT OF HENRY W. SAGE IS9I Cornell University Library 3 1924 031 251 691 olin.anx Cornell University Library The original of this book is in the Cornell University Library. There are no known copyright restrictions in the United States on the use of the text. http://www.archive.org/details/cu31 924031 251 691 The Pharmacology of Useful Drugs by ROBERT A. HATCHER Professor of Pharmacology, Cornell University Medical College, New York and MARTIN I. WILBERT Technical Assistant, Division of Pharmacology, Hygienic Laboratory, U. S. Public Health Service CHICAGO American Medical Association Five Hundred and Thisty-Five North Dearborn Street 1915 Copyright, 1915 BY THE American Medical Association PREFACE This book is a reprint, with numerous additions, of the matter presented in The Journal of the American Medical Association under the heading "Practical Pharmacology." It is an attempt to present, in simple language, the pharmacology of those drugs with which the practitioner is mostly concerned. The new advances in pharmacology are stated and their prac- tical application to the treatment of disease is indi- cated. Under each subject are given the pharmacology, therapeutics, dosage, and materia medica of the drugs discussed. For the convenience of the practitioner it has been issued in a handy pocket size. It is hoped that this work will prove of service to those who prac- tice modern scientific medicine. A H-sT^y Abbreviations a The following abbreviations occur in the text: U. S. P. — ^The Pharmacopeia of the United States of America, Eighth Revision. N. F. — ^The National Formulary of Unofficial Preparations, Third Edition. N. N. R. — New and Nonofficial Remedies, 1913. w/v — The relation of the weight of active constituents to the volume of liquid preparations. Statement of Solubility For ease of reference, the solubility , of oi^cial articles is indicated -in approximate terms in accordance with the following equivalents: Substances that are soluble in: Less than 1 part of solvent = very soluble. From 1 to 10 parts of solvent = freely soluble. From 10 to 100 parts of solvent = soluble. From 100 to 1,000 parts of solvent — slightly soluble. From 1,000 to 10,000 parts of solvent = very slightly soluble. From 10,000 to 100,000 parts of solvent = nearly insoluble. More than 100,000 parts of solvent = practically insoluble. TABLE OF CONTENTS PAGE Chapter I. — Drugs Which Act on the Central Nervous System 13 A. Stimulants 14 Chapter II. — Drugs Which Act on the Central Nervous System (Continued) 53 B. Depressants , S3 General Anesthetics 103 Hypnotics US Chapter III. — Local Anesthetics 128 Chapter IV. — Antiseptics and Disinfectants 141 Derivatives of Benzene 143 Urinary Antiseptics and Disinfectants 163 General Disinfectants 166 Disinfectants Used in Skin Diseases 178 Chapter V. — Drugs Which Stimulate Sympathetic End- ings 184 Chapter VI.— Drugs Which Act Mainly On the Heart. .. 214 The Digitalis Group 214 Chapter VII. — Circulatory Depressants, Diuretics and Diaphoretics 236 Circulatory Depressants 236 Diuretics 249 Diaphoretics 260 Chapter VIII.— Evacuants 266 1. Evacuants Acting Mainly on the Small Intestine. . . . 272 2. Evacuants Acting Mainly on the Large Intestine. . . . 279 3. Evacuants Acting on the Small and the Large Intestines 287 4. Evacuants Acting on the Rectum 302 Miscellaneous Evaciiants 304 Chapter IX. — Emetics, Anti-Emetics and Expectorants . . 308 Emetics 308 Anti-Emetics — Gastric Sedatives 321 Expectorants 325 Chapter X. — Arsenic, Antimony and Phosphorus 330 4 TABLE OF CONTENTS PAGE Chapter XI.— The Heavy Metals and Their Salts 354 Chapter XII. — Demulcents, Emollients, Astringents, Irri- tants and Caustics 383 Demulcents, Emollients and Other Protectives 383 Astringents 390 Rubefacients 399 Vesicants 402 Caustics or Corrosives 402 Chapter XIII.— Miscellaneous Salts, Acids and Alkalies. . 405 Miscellaneous Salts 405 Thyroid ; 424 Antithyroid 428 Chapter XIV.— Suhstances Used to Influence the Appetite and Digestion 428 Chapter XV.— Anthelmintics 437 Chapter XVI. — Serums, Vaccines and Viruses 445 THE PHARMACOLOGY OF USEFUL DRUGS INTRODUCTORY The greater part of the material comprising the present volume was published in a series of articles in The Journal of the American Medical Association. In the following pages we will discuss the pharma- cology/ the chief therapeutic uses and the materia medica of those drugs which have been accepted by the Council on Pharmacy and Chemistry for inclusion in the "Handbook of Useful Drugs." * Several years ago The Joi,trnal published a some- what similar volume under the title "The Pharmacopeia and the Physician," and while the same general plan will be followed in the present volume, the discussions will be limited almost entirely to the really essential drugs of the materia medica, as indicated in the title. It is evident that the therapeutic use of drugs requires some knowledge of their pharmacologic actions, but many physicians fail to appreciate the true value of pharmacology. Frequently, too, it is impossible to distinguish the literature of the disinter- ested investigator from that issued by those who are commercially interested in the products which they discuss. We trust that the present treatment of the subject, so far from satisfying the reader, may stimulate him to further inquiry and the perusal of the larger works on pharmacology and therapeutics. 1. The terms ''materia medica" and "pharmacology" are often used somewhat loosely. Materia medica treats of the physical and chemical properties of drugs and of their pharmaceutical preparations. Pharma- cology, or pharmacodynamics^ treats of the actions which drugs exert on .normal animal tissues or organs. For example, the paralysis of vagus endings in the heart by atropin is one of its pharmacologic actions. 2. The Council has made a careful selection of all drugs and preparations, irrespective of their nature, whether official or unofficial, proprietary or non-proprietary, which seem to be the best for the treat- ment of diseases, and these have been included in the little volume entitled, "A Handbook of Useful Drugs." 6 INTRODUCTION The pharmacology of the different drugs will be discussed very briefly in some cases, somewhat more comprehensively in others, but sufficiently in each case to afford a basis for the best therapeutic use of the drug under consideration. The discussion of quinin and digitalis, respectively, illustrates the prin- ciple followed. Quinin finds its greatest use in the treatment of malaria, in which its value depends on its killing the organisms which are found in the blood, and the secret of the successful employment of quinin is to get the requisite amount in the blood at the proper time ; hence dosage and methods of administration are of greater importance in that case than a knowledge of the various other pharmacologic actions of quinin, beyond the mere fact that it is a general protoplasm poison, and consequently injurious to all tissues with which it comes in contact in sufficient concentra- tion. Digitalis, on the other hand, does more harm than good in the hands of those who, use it without a pretty accurate knowledge of its pharmacologic actions; it becomes necessary, therefore, to devote more attention to the pharmacology of digitalis than to that of quinin. Drugs produce their effects by increasing or decreas- ing the normal functions of the structures on which they act, and in so doing they do not themselves pro- duce an appreciable amount of energy. The failure of a drug to produce its expected therapeutic effects may often be explained by the condition of the organ on which it acts. A grasp of this relationship between drugs and the organism will serve to simplify the understanding of their uses and" limitations, and will often prevent disappointment. Every drug exerts a variety of actions, but only a few of the actions of any drug are of benefit in any given condition; the others are negligible or detri- mental. _ Thus, in the treatment of night sweats, atropin is used on account of only one of its many actions, namely, its power of limiting secretion. The therapeutic usefulness of a drug depends on the fact that it exerts a far greater action on certain organs or tissues than on others. Strychnin, for ABSORPTION AND ELIMINATION 7 example, is capable of combining with certain cells in the central nervous system and affecting them pro- foundly, while leaving the other cells of the body prac- tically unaffected. The influences of age, sex, weight, diet and many other factors which modify the actions of drugs are generally recognized and do not call for detailed dis- cussion here, but every physician encounters occasional disappointment in the use of a drug on which he has come to rely, and we shall point out some of the most common causes of the variability of action, which are frequently overlooked because they are deemed of too little importance to merit careful consideration. ABSORPTION AND ELIMINATION The intensity of the action of a given drug usually depends largely on the total amount which acts at one time, and this is determined to some extent by the ratio between the rate of absorption on the one hand and that of elimination or destruction in the body on the other. A large dose of a drug may produce less effect at one time than a small dose administered in the same way at another time, the difference in the inten- sity of action being due to differences in the rates of absorption and elimination. The degree of dilution in which a salt is adminis- tered not only influences the intensity of a given action, but may even determine its nature. A concentrated solution of magnesium sulphate may cavise nausea, whereas the same amount of the salt in dilute solution will cause purgation. Magnesium sulphate usually causes only watery diarrhea when it is adminis- tered orally, but it has been known to cause death when administered in this way, because of its rapid absorption and slow elimination. A common cause of disappointment is the want of exact knowledge concerning the absorption of drugs. It is often asserted, and accepted without question, that because a given substance is very soluble in water, it must necessarily be absorbed readily from the ali- mentary canal. Disregarding the relatively slow absorption of soluble purgative salts, we may call 8 ABSORPTION AND ELIMINATION attention to the fact that for some unknown reason, some of the very soluble glucosids are absorbed slowly and irregularly from the gastro-intestinal tract; also that certain glucosids or resins which are wholly insoluble in water are absorbed fairly rapidly from the gastro-intestinal tract. In other words, we must recog- nize the fact that every drug is a law unto itself in regard to its rates of absorption and elimination. Most drugs are not absorbed readily from the stomach, but must pass into the duodenum before absorption begins ; it may follow, therefore, that when the gastric movements are interfered with by disease or drugs, and especially when the pylorus remains in tonic contraction, as it does at times after large doses of morphin have been taken, drugs may remain unab- sorbed in the stomach for hours after oral administra- tion. Drugs should be administered subcutaneously or by the rectum when it is suspected that the gastric con- tents will be prevented from passing into the duo- denum in the usual manner. Comparatively few drugs are absorbed from the unbroken skin, and the use of ointments and plasters containing active alkaloids is irrational in the main; the good results which may follow their use in most instances are not due to the alkaloids. For example, in the case of opium and lead wash — a most unscien- tific mixture, since the morphin in that case is value- less — the beneficial results are due to the astringent action of the lead water. A few substances which are readily miscible with oils and fats penetrate the skin sufficiently to act on the sensory nerve-endings, but our knowledge of this subject is far from complete. Another cause of disappointment lies in the fact that physicians sometimes forget that locally acting drugs may fail to exert an effect after absorption similar to that observed in the alimentary canal. Tannin, for example, acts as an astringent on the mucous membrane of the gastro-intestinal tract after its oral administration, but it is not absorbed in the free state and after absorption it does not exert an astringent action. Antiseptics are sometimes recom- mended for their action on micro-organisms in the MODES OF ADMINISTRATION 9 circulating blood, but such misleading advice occurs chiefly in the literature distributed by the exploiters of nostrums. We are not so well informed as we should be even on the subject of dosage; it is often stated as a rule that the oral dose of a given drug is about twice as large as the subcutaneous dose, and that the rectal is about twice the oral. These ratios apply to very few drugs indeed; the attempt to regulate the dosage of some drugs by this rule would result disastrously. In fact, death has resulted from the subcutaneous injec- tion of an amount of strophanthin equal to one-half of the oral dose. This illustrates the necessity for a better acquaintance with a few drugs, rather than a superficial knowledge of a large number. At best drugs are like two-edged swords capable of doing harm if used improperly, and if we assume the respon- sibility of using them we owe it to our patients to know as much as possible about their actions. SYNERGISTIC ACTIONS It was formerly customary to use mixtures of many drugs having supposedly related actions without any clear idea of their synergistic effects, but such mix- tures are not used at present by educated physicians, for we are coming to have a better understanding of the synergistic actions of drugs which are useful in some cases and harmful in others. Some of these S3niergistic actions will be discussed when we consider the drugs exhibiting them. MODES OF ADMINISTRATION Drugs should be administered by the mouth except in those cases in which the oral method is contraindi- cated. While the others methods advocated from time to time may be suitable for special cases, and in the hands of those who have developed a special technic, the oral administration will suffice in the vast majority of cases. The intravenous injection of a variety of drugs has been advised, but this method is distinctly dangerous 10 MULTIPLICATION OF PREPARATIONS in the hands of any one who is not skilled in its use, and it is often disappointing even with the best technic. Compressed tablets of insoluble drugs do not always disintegrate rapidly in the stomach, and such drugs are preferably given in the form of mixtures or as dry powders, which may be enclosed in capsules. Many of the ready-made pills tend to become harder and less readily disintegrated when long kept. Freely soluble salts, such as potassium bromid, taken in doses of 0.3 gm. (5 grains) or more, may give rise to gastric irritation with nausea, when they are administered in concentrated solution, or in the form of compressed tablets, which form concentrated solutions on dissolv- ing in the stomach. Such salts should be dissolved in about thirty times their weight of fluid before being administered. Nausea and vomiting sometimes follow the admin- istration of various drugs. When this symptom arises from local irritation of the stomach it may be avoided either by dilution or by a dififerent mode of adminis- tration. In other cases, as in members of the digitalis group, the nausea and vomiting, being due to a stimu- lation of the vomiting center in the medulla, are not influenced by the mode of administration. In such cases, nausea is to be avoided only by regulation of the dose. Before resorting to inconvenient methods of administration, therefore, one should be certain that the method proposed will actually give relief from the disagreeable symptom. Idiosyncrasy, tolerance and cumulation, so called, will be discussed in connection with those drugs in the use of which they are important factors. MULTIPLICATION OF PREPARATIONS The present era of pharmacy and therapeutics is marked by the multiplicity of alleged remedies urged on the attention of the prescriber. This multiplica- tion of preparations is attributable largely to the influ- ence of commercial interests, which have often had more weight than considerations of pharmacologic and medical science and have overshadowed the interests of the sick. CHOICE OF AGENTS II In this confusion physicians will often find them- selves at a loss how to choose wisely the most efficient agent. A careful study of the new remedies offered will show that few present any new therapeutic action or are specifics for particular diseases. Most of those which are worthy of consideration claim advantage over the older remedies in the avoidance of disagree- able side effects. In a considerable number of cases these claims have not been realized, and the prepara- tions are nothing but encumbrances to our materia medica. Before accepting a manufacturer's claim that his preparation is preferable because it avoids unde- sirable by-effects, one should make sure that this free- dom from disagreeable effects is not accomplished by lack of therapeutic effciency. In choosing therapeutic agents, the practitioner will gladly welcome the help extended by the Council on Pharmacy and Chemistry in sifting the mass of evi- dence presented and commending for use the remedies listed in the new volume, "Useful Drugs." In admit- ting preparations to the book New and Nonofficial Remedies, the Council has adopted a liberal policy ; it has admitted any drug which has probable value if exploited in an unobjectionable manner. Though the Council has been in existence for more than ten years and though during that time manufacturers have been afforded ample opportunities for submitting evidence of any advantages which their preparations possess, among the thousands of these advertised to physicians, only about 250 are enumerated in New and Non- official Remedies, and of this number not more than a score have been found of sufficient importance to merit inclusion in the "Handbook of Useful Drugs," for admission to which evidence of merit is essential. It is obviously impossible to discuss any considerable number of popular nostrums in this volume. A few of them, however, will be mentioned, chiefly to show the methods of misrepresentation employed in their exploi- tation, and the necessity of fostering the use of stand- ard drugs of proved value and well-known side actions for which proper allowance may be made in the admin- istration. 12 CLASSIFICATION OF DRUGS These side actions deserve more attention than they usually receive. We have been prone to consider unfavorable symptoms in patients as unavoidable manifestations of the diseases from which they suffer in many cases in which the drugs were contributing causes at least. We must face the question squarely and recognize the fact that there is no such thing as an ideal drug. When a manufacturer asserts that his preparation possesses all the advantages of a given drug with none of its disadvantages, his excessive optimism is obvious. CLASSIFICATIONS OF DRUGS Buchheim classified drugs about sixty years ago according to their more prominent pharmacologic actions, and this classification has been retained with some modifications to the present time, despite the fact that it has many disadvantages. No strict classifica- tion is possible, because every drug has a variety of actions, and no two have exactly the same range of activities. We shall make no effort to classify the drugs in any rigid way in the following pages, and it is understood that any grouping attempted is merely suggestive and intended to facilitate the convenient discussion of the various drugs. CHAPTER I.— DRUGS WHICH ACT ON THE CENTRAL NERVOUS SYSTEM We may consider the drugs of these groups with reference to the dominant action, whether it be stimu- lation or depression, and with reference to the part of the nervous system on which they exert the most pronounced effect. The action of a drug is never limited to one part of the central nervous system; though in a given case it may be exerted mainly on the brain, medulla or cord. Few drugs produce stimulation without some subsequent depression, or depression without at least fleeting stimulation. Drugs which act mainly on the central nervous system will be classified as follows: A. Stimulants: 1. Drugs acting mainly on the spinal cord, but having important actions on the medulla (strychnin group). 2. Drugs acting mainly on the medulla, but having important actions on the brain or cord (atropin group). 3. Drugs acting mainly on the brain, but with important actions on the medulla or cord (caffein and theobromin). B. Depressants: 1. Drugs which act on the brain first, then on the medulla (morphin group). 2. Drugs which act mainly on the heat and pain cen- ters (antipyretics and analgesics). 3. Drugs which depress first the great brain, then the cord and the medulla last (hydrocarbon narcotics). (Order of involvement of first importance.) This classification (like others used in this volume) is only approximate, and no attempt will be made to adhere to it rigidly. A. STIMULANTS STRYCHNIN There are several drugs which act on the spinal cord much as strychnin acts. While this is of some impor- tance as a side action, strychnin and nux vomica are virtually the only drugs which are used therapeutically for increasing the reflex activity of the cord. Thebain (an alkaloid occurring in opium) has an almost pure strychnin-like action on the cord, and caffein, morphin and codein possess the action to some extent, though they rarely exhibit it in man. Caffein and codein are seldom given in doses large enough to cause any increased reflex excitability. In morphin poisoning in man death results from paral- ysis of the respiratory and other centers before the action on the cord has time to develop. In view of the subsidiary importance of reflex stimulation in the action of those drugs, the present article deals almost entirely with strychnin. Strychnin^ acts on the spinal cord of vertebrates in such a way that the reflexes are increased, the effect increasing with the size of the dose, so that with the largest therapeutic doses in man there is distinct twitching of the voluntary muscles, and with larger doses any slight stimulus, such as touching, induces a convulsive movement involving the closely related groups of muscles. If an excessive dose has been given, a stimulus which induces any reflex movement at all suffices to cause a convulsion involving all the voluntary muscles of the body. The intensity and duration of the convulsions increase with the size of the dose. The convulsion is followed by a period of 1. In practically all cases, the actions of alkaloids are so nearly like those of their salts that they are discussed together. It is understood that the salts contain a small amount of acid, which is negligible so far as the pharmacologic actions of the alkaloids are concerned, but for which allowance mflst sometimes be made in calculating the dose. The principal reason for using salts of the alkaloids is that the salts are more soluble than the alkaloids themselves. STRYCHNIN IS depression varying from a few seconds to some min- utes, and usually becoming longer with successive con- vulsions; but death may follow the first convulsion. Strychnin convulsions are typical; there is at first a sudden contraction of the voluntary muscles, and if the dose has been very large this is immediately followed by tetanus with opisthotonos, the convulsion terminating with a few clonic jerks, followed by the pause during which the reflexes are actually depressed. If the first convulsion was brief, the depression may be followed almost immediately by a second con- vulsion if any stimulus is applied, or after an interval the length of which depends on various circumstances. The succeeding convulsions are almost exactly like the first in character, but they may be of shorter or longer duration. ACTIONS OF STRYCHNIN ON THE MEDULLA The actions of strychnin on the respiratory and vasomotor centers in the medulla probably differ only in degree from those on the cord, but it is difficult to determine the precise nature of this action on the medullary centers, and opinions differ as to the value of strychnin in conditions of circulatory depression. When a normal animal is anesthetized and strych- nin is injected into the circulation, no appreciable effect on the blood-pressure is produced until an amount is given equal to that which causes a distinct increase in the reflexes in a normal animal. Touch- ing or pinching then causes a sudden rise of blood- pressure and a rapid return to normal. If a convul- sive dose is injected, the rise in blood-pressure corre- sponds in duration to the convulsion. This rise of blood-pressure is wholly independent of any spasm of the voluntary muscles, for it occurs in exactly the same way in curarized (motionless) animals. It is impossible to state whether or not therapeutic doses of strychnin affect the vasomotor centers so as to increase the blood-pressure when this is abnor- mally low, but it seems probable that in pathologic conditions with low blood-pressure, strychnin may render the vasomotor centers more susceptible to stimulation, and it is certain that it affects the circula- 16 STIMULANTS OF CENTRAL NERVOUS SYSTEM tion indirectly by increasing the tone of voluntary muscles through its action on the spinal cord in suit- able cases. The action of strychnin on the respiratory center is probably analogous to that on the cord, rendering it more responsive to stimuli, which normally play such an important role in the rate and depth of respiration, and under the influence of therapeutic doses of strychnin the carbon dioxid of the blood causes an increased respiratory movement, this being more pronounced when the respiratory center has been previously depressed by a narcotic. With excessive (convulsive) doses of strychnin the respiratory center is first stimulated and later depressed. During the convulsions the respiration ceases, owing to the rigidity of the muscles of the chest; this causes an extraordinarily rapid increase in the carbon dioxid in the blood, which stimulates the respiratory center. Nevertheless, there is an interval, following the cessation of the convulsion and before the reinstatement of respiration, during which the center is evidently depressed, but this depression is much briefer than is the depression of the cord, as a rule, and the respiration begins shortly and is then deeper or more rapid than before the convulsion. Following large doses the respiration fails to be reinstated after one of the convulsions, it may be the first, but usually after the second or third. Though opinions differ concerning the value of strychnin as a stimulant to the vasomotor centers, there is little doubt about its being an active stimulant for the respiratory center. Strychnin stimulates the vagus center in the medulla, causing some slowing of the heart, but the rate of the heart depends on so many factors that this effect is not pronounced with therapeutic doses. ACTIONS OF STRYCHNIN ON THE BRAIN Strychnin increases the reflexes in the brain, espe- cially those of the special senses, so that vision, smell, hearing, touch and taste are rendered more acute. The effects on the eye and ear are utilized therapeu- tically. Strychnin sometimes exerts a marked psychic STRYCHNIN 17 efifect, causing a feeling of exaltation and relief from fatigue. This action is quite variable, and it is impos- sible to state when it may be expected. ABSORPTION AND EXCRETION OF STRYCHNIN Strychnin exerts a much greater action when administered intravenously than when administered in any other way, but it may be absorbed fairly rapidly from the gastro-intestinal tract and exert as great an effect after oral administration as after subcutaneous injection. The full effects of the oral dose are seen usually in about half an hour; the effects of poison- ous intravenous doses are exhibited almost immedi- ately. An extract of nux vomica, or a pill contain- ing strychnin and some colloidal substance, is com- monly employed when slow absorption is desired with prolonged action on the local nervous mechanism in the walls of the intestine. Strychnin probably leaves the blood-stream very rapidly, and the larger part of a therapeutic dose is almost certainly eliminated from the body within a few hours, for fairly large doses may be administered several times daily for many days without causing toxic symptoms. Cushny states that elimination is not complete for a period varying from two to eight days. Strychnin appears in the urine soon after its absorption into the blood, and an amount equal to sev- eral times the normally fatal dose has been recovered from the urine of a dog in a period of five hours, dur- ing which large amounts of solution of sodium sul- phate were injected intravenously in order to induce copious diuresis. (Unpublished experiments of R. A. Hatcher.) TOXICOLOGY Strychnin is among the most poisonous of the com- monly used alkaloids, and as little as 0.03 gm. (% grain) has proved fatal to a man. It is probable that the average fatal dose for a previously healthy adult is about 0.10 gm. (1^^ grains). With appropriate treatment patients have survived much larger doses. One should never abandon hope of saving life until it is extinct, whatever the dose taken. 18 STIMULANTS OF CENTRAL NERVOUS SYSTEM Death in strychnin poisoning usually results from respiratory paralysis, but a previously weakened heart may stop as the result of the sudden excessive rise in blood-pressure. The method to be followed in the treatment of strychnin poisoning will depend on a number of fac- tors, including the following : The total amount of the poison taken ; the amount which remains unabsorbed (in case of its oral administration) ; the presence or absence of hyperexcitability or convulsions. Hence the following remarks are only intended by way of sug- gestion, and the treatrhent must always be adapted to the needs of the case in hand. The physician' will rarely be called on to treat strych- nin poisoning after the administration of the drug in any way except by the mouth, because death usually follows so swiftly after the subcutaneous injection of a massive dose that no opportunity is afforded for effective interference. So promptly does death usually follow the absorption of a fatal dose of strychnin into the circulation, that the mere fact that the patient is alive affords proof that at most but little more than the normally fatal dose has been absorbed, and when there is reason to sup- pose that any poison remains in the stomach, the chief efforts should be directed toward its removal or destruction. If there is no increased reflex excitability, one should proceed to empty the stomach as quickly as possible. It may be washed with water to which strong tea^ or half a pint or more of a 1 per cent, solution of potas- sium permanganate has been added, or with water alone if the tea or potassium permanganate is not readily available. If the means for washing the stomach are lacking, an intramuscular injection of 6 mg. (%o grain) of 2. While the tannin of tea is useful as a precipitant of strychnin (SoUmann), it should be remembered that the beverage varies enormously in its tannin content. Some teas contain little tannin, and are prac- tically useless for preparing an alkaloidal precipitant. While the physi- cian is preparing to iwash the stomach of the patient, he may have tea prepared as follows: Hot water is poured on the leaves and allowed to stand about one_ minute; this infusion is thrown ^away, because it con- tains caffein, which is synergistic with strychnin, but little of the tannin. Boiling water is then poured on the leaves and allowed to stand about five minutes. This infusion contains most of the tannin and little caffein. STRYCHNIN 19 apomorphin may be given at once, and strong tea or a pint of 0.5 per cent, solution of potassium perman- ganate may be swallowed by the patient. Should it become necessary to abolish vomiting, this may be done by inducing anesthesia with chloroform and maintain- ing it with ether. If hyperexcitability has been induced while there is reason to believe that the stomach still contains a notable amount of strychnin, the treatment is not so simple. It is imperative to remove or destroy any of the poison which remains in the stomach when it is practically certain that its absorption would prove fatal despite any treatment, but the washing of the stomach or emesis would be dangerous at a time when such measures are liable to cause convulsions. Emesis is then contra-indicated, and anesthesia must be induced before the stomach-tube is passed. An especially difficult question arises when it is known that much more than the average fatal dose of strychnin has been swallowed, and when, owing to the length of time which has elapsed since it was taken, and the severity of the symptoms present, it seems probable that much of the poison has passed into the duodenum. In such a case the poison cannot be removed by gastric lavage, and it probably cannot be precipitated or destroyed by chemical agents, yet its complete absorption must almost inevitably prove fatal. The procedure, however, in such cases must be much the same as in those in which some of the drug is sup- posed to remain in the stomach, and in addition, it is necessary to empty the bowel as quickly as possible, preferably by means of a copious saline cathartic. The measures so far discussed are concerned with the prevention of the absorption of strychnin; apart from this are the questions of antagonizing its action after absorption and of hastening its elimination, both of which enter into consideration after absorption occurs, whatever the channel of administration. Strychnin is eliminated by the kidneys, and what- ever physiologic antidote is employed it should not interfere with diuresis, which should be promoted to the utmost. Hot tea or other hot liquids will induce 20 STIMULANTS OF CENTRAL NERVOUS SYSTEM diuresis, but the action is. somewhat slow, and unnec- essary loss of time should be avoided; hence a large amount of hot fluid should be introduced into the stomach, while as much should be introduced into the rectum and lower bowel as can be retained with com- fort. In urgent cases it would seem to be justifiable to inject a quart or more of a sterile 2 per cent, solu- tion of sodium sulphate into the veins, under suitable precautions, of course. The value of ether in strychnin poisoning is shown by the fact that an animal under its influence — it must be anesthetized completely — will survive an amount of strychnin equal to more than twice the fatal dose for a normal animal. Chloroform may be used to hasten the induction of anesthesia, but this should be continued with ether so long as may be necessary. Special stress is placed on the use of ether, for while hydrated chloral is commonly advised as an antidote to strychnin, pharmacologic experiments show that hypnotic doses of it are nearly, or quite, useless, and narcotic doses are dangerous in various ways. The dosage cannot be regulated so as to produce only the desired action; it is injurious to the heart; it lowers blood-pressure to the point that the respiratory center must sufifer, while the elimination of the poison is seriously hindered. Anesthesia may be maintained with ether without any of these disadvantages. Artificial respiration should be employed when severe convulsions indicate that the respiratory cen- ter will suffer depression. One should not wait until actual respiratory failure occurs before instituting this measure. Unless the dose has been excessive, the convulsions can be controlled by this means. The inhalation of oxygen is an aid in hastening the destruction of strychnin. The treatment of strychnin poisoning may be summarized then as follows: removal of the drug from the stomach; precipitation by tannin; destruction by potassium permanganate; control of convulsions by ether; artificial respiration; elimination by copious diuresis, and avoidance of all stimuli, including touching the patient, noise and STRYCHNIN 21 flashes of light. The chief reliance must be placed in efforts to prevent the absorption of large amounts into the circulation, if the patient is seen in time. THERAPEUTIC USES Strychnin is probably not directly curative in any disease, but its capacity for increasing the activity of the reflex centers in the cord, medulla and brain sug- gest its employment in various conditions in which these centers are depressed, and its action on the vasomotor and respiratory centers indicates its use in various conditions attended with lowered blood- pressure and interference with respiration. It is used in many forms of incomplete motor paral- ysis, but it should not be used when the paralysis results from a lesion in the cord, or in the presence of inflammation of the nerve centers; it is especially contra-indicated in the inflammatory stage of infantile paralysis (anterior poliomyelitis). Opinions diflfer concerning its value after the paralysis has developed. In motor paralysis due to lesions in the brain, it is useful, in moderate doses, to maintain the tone of voluntary muscles through the increased reflexes. Respiratory stimulants are useful when the center is depressed by narcotics, including alcohol, chloro- form, ether, hydrated chloral and morphin, and in diseases of the respiratory passages and the lungs, including bronchitis and pneumonia, when there is a tendency toward respiratory- depression. Strychnin can be used, but it must be remembered that large doses of strychnin depress the respiratory center, after first stimulating it. Such large doses are therefore contra-indicated, especially in narcotic poisoning, in which the stimulant action of the strychnin might be entirely masked by the narcotic, and yet the late depres- sion due to strychnin would be added to that of the nar- cotic. Caifein would seem to deserve the preference as a respiratory stimulant in narcotic poisoning at least. Strychnin is often used for increasing the blood- pressure, despite the fact that no essential increase follows the administration of non-toxic doses to nor- mal animals or men. It is quite possible that its 22 STIMULANTS OF CENTRAL NERVOUS SYSTEM effects in pathologic conditions attended with abnor- mally low blood-pressure may be beneficial, and, indeed, Osborne states that it is the sheet-anchor when all of the vital centers are depressed in pneumonia. It is often used in shock, but opinions vary con- cerning its value in that condition. The mechanism of shock is so little understood that it is impossible to state positively what the effects of strychnin are likely to be. Crile believes that it has no value in that condition, but that, on the contrary, it is decidedly harmful, actually increasing the danger. In cases in which respiratory depression is the primary cause of shock, it seems probable that strychnin may be of value, but we have no satisfactory evidence that thera- peutic doses are capable of increasing the blood- pressure directly to any notable degree in shock. Strychnin is often used with occasional benefit in disturbances of vision (amblyopia, amaurosis) when there is no anatomic change or only incipient optic atrophy, and in impairment of hearing of central origin. It is often used to improve the tone of the weakened sphincters (in enuresis), but when there is spasm of the vesical sphincter it is contra-indicated; atropin should be used instead. The use of strychnin as a simple bitter for improv- ing the appetite and digestion and as an addition to cathartics will be discussed in connection with other drugs belonging to those groups. It is often used mofe or less empirically in many different conditions, in some of which it is certainly useful, but in others probably useless. It is often recommended as a "cardiac tonic," but we have no evidence of its direct action on the heart. It may slow the heart through vagus stimulation at times; it may improve the circulation through its actions on the vasomotor and respiratory centers — for one cannot wholly separate the influence of the respiration and circulation — and thus through the circulatory changes it may improve the nutrition of the heart, much as it causes improvement in the voluntary muscles and other tissues of the body, when STRYCHNIN 23 it improves the circulation by increasing the muscular activity. Cecil Wall states that nux vomica has been termed the best hypnotic in the treatment of chronic bronchitis. DOSAGE The average single dose of strychnin, sulphate or nitrate, for oral administration is 0.001 gm. (%o grain), but the dose varies so widely that the statement of the average dose does not convey much information unless the purpose for which it is to be used is indi- cated. As Httle as 0.00065 gm. (%oo grain) is often used as a bitter tonic, and as much as 0.010 gm. (% grain) may be given daily for short periods. Much larger doses have been used, but there is no satisfactory evidence, that they are necessary, and their use is attended with danger. The dose, whatever it may be, should be reduced or discontinued for a few days when the appearance of muscular twitching indicates that the therapeutic limits are reached. The treatment of partial paralysis calls for the administration of doses of 0.003 gm. (%o grain) three or four times a day for ten days, with an inter- val of a week before continuing it. Halsey states that at least that amount must be given to overcome depression of the central nervous system, especially in infectious diseases. Poisoning by hydrated chloral, alcohol, chloroform and other narcotics may be treated with an initial intramuscular injection of 0.004 gm. (%6 grain) ; if this causes an improvement in the respiration the dose may be repeated in about two hours if necessary, but if the strychnin adds to the depression, or if there is no improvement with that dose, caffein should be used, and, as stated previously, it probably should be used from the beginning. Morphin interferes with the movements of the stomach, and since strychnin is probably not absorbed readily from the human stomach, it should not be administered orally in the treatment of morphin poisoning, but intramuscularly, to secure quick action, and later by the rectum if desired. 24 STIMULANTS OF CENTRAL NERVOUS SYSTEM Strychnin salts are absorbed readily from the gastro-intestinal tract under normal conditions, and from the subcutaneous tissues, the dose being approxi- mately the same whether it be given by mouth, rectum or subcutaneously. In emergencies its action may be elicited almost instantaneously after intravenous injection, but the dose by this method of administra- tion is only about half the oral dose. Some authors state that large doses of strychnin may lead to toxic symptoms through cumulation, because of the slow elimination, but there is no danger of serious poisoning to be feared when the daily dos- age is limited to 0.010 gm. (% grain), and the admin- istration stopped on the appearance of increased reflexes. MATERIA MEDICA Nux Vomica, U. S. P., the seed of Strychnos Nux- vomica, an oriental tree, at present comes chiefly from India and Ceylon. The fruit, a berry, is of the size and appearance of an orange, and contains usually from two to five of the flat circular seeds embedded in a mucilaginous pulp. The seeds are hard and extremely tough. The drug is probably the most widely used (and abused) article in our materia medica, and with its alkaloid, strychnin, it is prescribed more frequently even than opium and its alkaloids and derivatives. Nux vomica contains about 1.25 per cent, of strych- nin. It also contains brucin, an alkaloid which resem- bles strychnin somewhat in its actions, but which is of little importance, as it contributes little to the action of the crude drug. Nux vomica also contains an unim- portant glucosid, loganin, and tannin similar to that occurring in coifee. Nux vomica is seldom administered in substance, one of the galenical preparations being usually pre- ferred. Extractum Nucis Vomicae, U. S. P., a powdered extract which contains 5 per cent, of strychnin, is usually employed in the form of a pill or capsule. 4 gr.vi U gr. XXX U gr. XXX STRYCHNIN 25 frequently combined with iron and quinin, as a bitter tonic. It may be prescribed somewhat as follows: gm. R Extracti nucis vomicae 014 gr.vi Ferri reducti 2|S gr. xl M. et fac pilulas xx. One pill 3 or 4 times a day. Or as follows: gm. 3 Extracti nucis vomicae Quininae stllphatis 2 Ferri reducti 2 M. et fac capsulas xx. One capsule to be given 3 times a day. Tinctura Nucis Vomicae, U. S. P., is the more gen- erally useful of the preparations of nux vomica, and is administered preferably diluted with water, or with water and syrup or fruit-juice at the time the dose is taken. Tincture of nux vomica represents 10 w/v per cent, of the drug in a mixture of alcohol and water. Strychnina, Strychninae Nitras and Strychninae Sulphas, U. S. P., are the three fonns in which strych- nin is official. They are colorless crystals or white powders, having an intensely bitter taste, which is perceptible in solutions containing 1 part of the alka- loid or its salt in 700,000 parts of water. Strychnin and its salts may be administered in the form of pills, capsules or cachets, when the bitter taste is not desired. It is seldom administered by the rectum, but it is absorbed readily and may be given in the form of suppositories. It may be given hypodermically when for any reason the oral or rectal administration is contra-indicated, or when rapidity of action is essential; and in urgent cases it may be given intravenously in physiologic salt solution, of course, with the proper technic. The sulphate is soluble in 31 parts of water and in 65 parts of alcohol ; the nitrate in 42 parts of water, and in 120 of alcohol; the alkaloid is only slightly soluble in water, requiring 6,400 parts for solution; it is soluble in 110 parts of alcohol. 26 STIMULANTS OF CENTRAL NERVOUS SYSTEM The salts are precipitated by the usual precipitants of alkaloidal salts, including alkalies, alkali carbonates, and by the bromids and iodids. Combinations of strychnin salts with precipitants in solution should be avoided, as the precipitate might escape detection and nearly the whole amount be taken in the last dose. ATROPIN Atropin is much the most important member of its group, which includes scopolamin and homotropin and the crude drugs, belladonna, hyoscyamus and stramonium, together with their preparations. The alkaloids of this group are commonly called the mydriatic alkaloids, because dilatation of the pupil is the most characteristic action which they possess in common. While they exhibit individual differences in their actions, they form a fairly well-defined group. The action of atropin will be discussed in some detail, and the special uses of others will be mentioned, but in the main it is to be understood that the several drugs are used for the same purposes, with the excep- tion of scopolamin. This drug occupies a special field of usefulness because of the fact that while it resem- bles the other members in a general way, its stimulant action on the central nervous system is so much less pronounced than theirs, while the depression it pro- duces is so much more prominent, that it is used to produce depression, while atropin is used to cause stimulation. This illustrates the difficulty of classi- fying drugs satisfactorily. The chemical investigation of the drugs which yield the mydriatic alkaloids presents many difficulties, and some confusion has resulted from the application of the same name to different substances, and of dif- ferent names to the same substance in slightly differ- ent degrees of purity. It is recognized at present that the substance first described as hyoscin was nothing but an impure form of the alkaloid which in pure form was first described correctly under the name of "scopolamin;" hence the two terms are purely synonymous, and only the name "scopolamin" should be used. ATROPIN 27 Therapeutic doses of atropin exert a greater action on the medulla than on the brain, but with toxic doses the effects on the cerebrum become more pronounced. Atropin stimulates the respiratory center in the medulla, causing a marked increase in the amount of air breathed in a given period of time. Poisonous doses cause depression of the respiratory and other centers. This action on the respiratory center is of great importance, atropin being one of the most active of the respiratory stimulants which we have. Mid brain Bulb Vertebral gcvneiioa. Oculomotor aerve ^^^^^DSolivoiy gjonds Vasomotor jHeori Bronchi Stomach Liver Pancreas Intestine Kidneys ffelvic ganglion Colon- rectum _ Blactder 6 Genitals taitonomle ympoiKctie- — - Diagram of the anatomic relations of the autonomic and sympathetic systems (from Meyer and Gottlieb, Experimentelle Pharmakologie, 1911, p. 128). The vasomotor centers are stimulated by moderate doses of atropin, which cause a scarlet appearance of the face and upper part of the body, due to a dila- tation of the vessels of those regions simultaneously with a constriction of the vessels of the splanchnic region. There may be merely a redness of the skin, or there may be a rash, followed by desquamation, but usually the rash disappears within a short time. The vasoconstriction tends to raise the blood- pressure, but the effects of atropin on the circulation 28 STIMULANTS OF CENTRAL NERVOUS SYSTEM are complex and changes in the blood-pressure with small doses depend on the heart-rate rather than on any vasconstriction. The vagus center is stimulated somewhat with the respiratory and vasomotor centers, but this is soon overshadowed by the depression or paralysis of the vagus endings in the heart, which is one of the char- acteristic actions of all of the mydriatic alkaloids. Nausea and vomiting are mentioned among the symptoms of poisoning by atropin; dogs, however, do not show these symptoms after the intravenous injec- tion of large or small doses of the drug, but on the contrary, only very small doses are required to inhibit the emetic action of pilocarpin and, probably, other centrally acting drugs. The actions on the brain cannot be described in detail, and it need only be said that larger doses cause stimulation of certain areas, resulting in increased coordinated movements, talkativeness, excitement and delirium, followed by depression and coma. Atropin in moderate doses does not affect the psychic areas so much as caffein does. It is not used therapeutically for its actions on the brain. Atropin depresses or paralyzes the endings of the parasympathetic' nerve throughout the body, includ- ing the oculomotor, chorda tympani, vagus and erigens, and also the sympathetic endings in the sweat-glands in the skin. It will be observed that the sympathetic endings in the sweat-glands behave toward several drugs like the parasympathetic end- ings (Fig. 1). A discussion of the peripheral actions of atropin is largely a discussion of the functions of the para- sympathetic nerves, for atropin simply abolishes those functions, but it acts on these endings in different parts of the body with varying degrees of intensity. 3. Reference to Figure 1, taken from Myer and Gottlieb's Pharma- cology, Ed. 2, will show the relationship between the sympathetic and parasympathetic nerves. Epinephrin stimulates the myoneural junctions of all of the sympathetic nerves (except those to the vessels and sweat- glands of the skin), while it leaves those of the parasympathetic unaf- fected. Atropin, on the other hand, paralyzes the endings of those nerves which epinephrin does not affect while it has no influence on those which epinephrin stimulates. Many other drugs show similar selective actions with reference to these nerves. ATROPIN 29 Hence a given dose does not have the same relative effect on all organs which the nerves supply. Atropin can be brought into contact with the oculo- motor endings by dropping a solution into the eye, without inducing its systemic actions, but its actions on other parasympathetic endings cannot be elicited so conveniently. Depression of the oculomotor endings causes dila- tation of the pupil through the unopposed actions of the radiating fibers, and it also causes paralysis of the muscle of accommodation. These actions are pro- longed after repeated applications, or after the use of strong solutions, and it may be a week or more before the eye becomes quite normal. The action of homatropin on the pupil is quali- tatively like that of atropin, but the effect is not so lasting. Homatropin is often preferred when an examination of the eye is to be made, but it is not so dependable as atropin, which many oculists con- tinue to use even for the examination of the eye. Dilatation becomes maximal in a period usually vary- ing from half an hour to an hour. Scopolamin acts as a mydriatic in the same way as atropin. The actions of atropin on the pupil and on accom- modation may be counteracted with physostigmin, but this renders the muscles of accommodation hyper- excitable, so that efforts at accommodation result in spasm of the muscles, and reading is attended with discomfort. Paralysis of the chorda tympani endings interferes with the secretion of the salivary glands, rendering the mouth and throat dry, the voice hoarse, and swal- lowing difficult. The mucous glands in the nose and respiratory passages and the gastric, pancreatic and biliary secretions, and possibly the secretion of milk, are also inhibited by atropin. The action on the sym- pathetic endings in the sweat-glands causes the skin to become dry, these being the only sympathetic end- ings which behave toward a number of drugs like the parasympathetic. The paralysis of the vagus endings in the heart causes the heart to beat more rapidly; in the stomach and intestine it overcomes the motor influence of the vagus. 30 STIMULANTS OF CENTRAL NERVOUS SYSTEM The lower part of the colon, the rectum and the uterus are innervated by the erigens, the endings of which atropin paralyzes. The intestinal effects will be discussed in connection wil^h the evacuants. Depression of the vagus endings in the bronchi result in muscular relaxation, when the muscles are spasmodically contracted in asthma. Atropin depresses the sensory endings in the skin with which it may be brought into contact in the form of an oleate, or of an ointment of belladonna extract. Atropin and the other mydriatic alkaloids are absorbed promptly from the gastro-intestinal tract and from the subcutaneous tissues. Some absorption occurs even from the unbroken skin when suitable application is made; at least the drug may reach the sensory endings in sufficient amount to cause analgesia. The mydriatic alkaloids are excreted in the urine for the greater part, and scopolamin is said to be excreted in human milk to a slight extent.. The fatal dose of atropin is supposed to be about 125 mg. (2 grains), but much smaller amounts give rise to unpleasant and even alarming symptoms of poisoning. These symptoms may be enumerated somewhat in the order of their occurrence with increasing doses as follows: Even the larger thera- peutic doses induce redness, or rash of the skin, which results in desquamation; the skin, as well as the nose, mouth, throat and bronchi become dry; the voice becomes hoarse, swallowing difficult; the heart becomes rapid with rise of blood-pressure, and some motor unrest. Talkativeness, and dilatation of the pupils from systemic action occur only with very large doses ; these symptoms may be succeeded by coma and respiratory failure ending in death, or there may be convulsions; nausea and vomiting are reported as common symptoms, and these must be of central origin. Small doses of atropin, however, prevent nausea when given with morphin, and even the largest doses of atropin do not cause vomiting after intra- venous injections in dogs. ATROPIN 31 There is an extraordinary difference in the degree to which different patients react to atropin. Qne will respond to the smallest therapeutic dose with dryness of the throat and redness of the skin, while another may take the maximum dose usually advised with little inconvenience. An instance has been reported in which a woman took about an ounce of a 15 per cent, tincture of belladonna, in a mixture containing half as much fluidextract of hyoscyamus, daily for several days with no other symptoms than slight dryness of the throat. If the preparations used were of full strength, the patient must have received approximately half a grain (30 mg.) of mydriatic alkaloids daily. Incom- plete absorption probably explains the want of toxic symptoms in this case. Poisoning by atropin may occur through the acci- dental taking of a solution intended for external use, or the use of strong solutions in the eye. Belladonna berries are attractive in appearance and are not infre- quently eaten by children. Fortunately, they are indi- gestible and may result in vomiting before a fatal dose has been absorbed. The symptoms of poisoning by atropin or one of the members of the group are usually so typical as to direct attention to the cause, but where the earlier symptoms are obscure, suspected poisoning may be confirmed by testing the urine for atropin. For this purpose a few drops of the urine are dropped into the eye of a cat; if atropin or any other of the mydriatic alkaloids is present the pupil will dilate widely within about half an hour. The test should be made within thirty-six hours after the poison has been swallowed. In case of poisoning by the berries, or when one suspects that a poisonous dose of one of these alka- loids remains in the stomach, recourse should be had at once to the stomach-tube. Tannin or potassium permanganate may be added to the water used in washing the stomach, but the use of alkaloidal pre- cipitants or of potassium permanganate does not obvi- ate the necessity of emptying the stomach, for the precipitated alkaloid would be absorbed, though more 32 STIMULANTS OF CENTRAL NERVOUS SYSTEM slowly than the soluble salt, and one cannot be certain that the potassium permanganate has been brought into contact with all of the alkaloid. Excretion should be hastened through the use of diuretics, hot water and tea, and in urgent cases the intravenous injection of normal salt solution under suitable precautions would be justified. Excessive doses of atropin or the other mydriatic alkaloids may prove fatal in a short time, but such amounts are seldom taken, and the physician is more frequently called on to treat the alarming symptoms which yield to treatment. Pilocarpin stimulates the salivary and mucous glands, and relieves the dryness of the mouth and throat; morphin is useful only in the early stages of poisoning by atropin, not at all in scopolamin poison- ing, in which it is directly contra-indicated. If depression has already begun in atropin poison- ing, or if the dose taken was sufficient to lead one to expect severe depression later, morphin is contra- indicated, or at most small doses should be used in the stage of excitement. Application of cold water or of the ice-bag to the head is useful during delirium. Respiratory failure demands artificial respiration, and in such cases vigorous means should be adopted to secure rapid elimination by intravenous injections of normal salt solution. THERAPEUTIC USES Atropin is useful as a respiratory stimulant in various conditions. It is often recommended in the treatment of morphin poisoning, but authorities differ widely in' their views concerning the wisdom of this measure, and to a greater extent in regard to the dose which should be employed in any event. Atropin and morphin in small doses are antagonistic in their actions on the respiratory center, but they are syner- gistic in large doses, both causing depression. The difference in opinion results from the question whether atropin is capable of causing stimulation without subsequent 'depression, and if this be pos- sible, the next question concerns the amount which can be given without causing severe depression. ATROPIN 33 It seems probable that moderate doses of atropin are useful in combating the action of a poisonous dose of morphin on the respiratory center, because there seems to be little danger of serious depression from such doses of atropin. The amount which can be given in such cases can hardly be stated in exact figures. If used for this purpose, it is best given in doses of about 1 mg. (%o grain). This is repeated every hour until three doses are given if each of the first two doses is followed by improvement in the respiration. This probably represents the maximum that can be given with safety, within a period of six hours. Caffein is safer than atropin and probably deserves the preference in all cases in which respira- tory stimulation is required. Atropin probably deserves to be used more fre- quently than it is in shock, because it is capable of increasing the heart-rate, when this is unduly slow, and this, with the action on the vasomotor centers, tends to increase the blood-pressure, and the stimula- tion of the respiratory center should further improve the condition. It would appear to be useful in res- piratory and circulatory failure during anesthesia, for, according to Hewitt, cardiac failure during anes- thesia is frequently secondary to interference with respiration. Its use before the administration of chloroform will prevent the dangerous inhibition of the heart which sometimes occurs early in the course of the admin- istration, before the heart is seriously injured by the direct action of the chloroform. The therapeutic use of atropin as a mydriatic has been indicated in discussing its action on the pupil. It appears to be more certain than homatropin in causing complete paralysis of accommodation, but the latter is preferable as a mydriatic when there is reason to fear glaucoma, because it does not increase the intra-ocular tension so much as atropin. The pro- longed action of atropin is preferred in iritis to pre- vent adhesions and to break up those already formed. Excessive salivation, sweating from various causes, such as the use of large doses of the antipyretics, and 34 STIMULANTS OF CENTRAL NERVOUS SYSTEM the night sweats of phthisis may be controlled by very small doses of atropin. The application- of ointment of atropin or belladonna does not appear to relieve local sweating. Its continued local application to the breast diminishes the flow of milk. Atropin is used to increase the heart-rate, especially where this is abnormally slow (bradycardia) owing to overactivity of the vagus, but it has much less influence on the rate when this is due to cardiac dis- ease, and when slow rhythm is due to heart-block atropin will not influence the rate. Certain forms of cardiac irregularities due to vagus control are abol- ished by atropin. Its action on the vagus is much less effective at the extremes of life because the vagus itself has less control over the heart-rate in the young and the aged than during the remainder of life. Bronchial asthma resulting from spasm of the muscles is often relieved by atropin or one of the crude drugs of this group. Atropin abolishes spasmodic contraction of the pylorus, and is useful in the treatment of lead colic in which spasm of the muscles of the intestine occurs, and in the same way it is useful in spasm of the muscles of the ureter and of the bile-ducts due to the irritation of calculi. Atropin is useful in relieving certain neuralgias for which it is commonly applied locally. Belladonna is used in whooping-cough, in which Cushny suggests that it may allay the excitability of the respiratory center. Atropin is the physiologic antagonist of those poi- sons which exert their actions through stimulation of the parasympathetic (vagus, oculomotor, chorda, erigens) nerves, such as physostigmin, pilocarpin and muscarin, but it is not feasible to discuss in detail its actions in antagonizing these poisons. It has been found that animals survive a larger dose of aconitin if atropin be administered than without it. The cardiac effect of aconitin is attributable to vagus influence in part. Drugs of the atropin group have long enjoyed a special reputation in the treatment of ,nocturnal enuresis in children, but there is no doubt that they ATROPIN 35 have been used with little discrimination in many cases. Unfortunately, the causes of this condition are not sufficiently understood to enable one to say just when atropin will be useful. Under the circumstances it may be tried when hygienic measures have proved unavailing, but it should not be employed for any considerable period when it does not prove unmistak- ably useful. There is no reason to suppose that all cases of nocturnal enuresis arise from the same cause, or that they can be relieved by the same treatment; but it is probable that when it results from an abnormally active reflex operating through the parasympathetic nerve to the bladder, atropin, or one of the other mem- bers of the group, may afford relief. Hyoscyamus is sometimes preferred, probably act- ing better than belladonna in those cases in which nervousness plays an important role. Occasional wetting of the bed by children probably results in some cases from delayed absorption of fluids from the alimentary canal and increased secre- tion of urine at such time as the sweat-glands of the skin are less active than usual. Atropin would prob- ably aggravate the trouble in such cases. The recommendation of drugs with such diverse actions as ergot, cantharides, buchu, rhus aromatica, strychnin and arsenic by a prominent writer serves to indicate the vagueness of our knowledge of this con- dition. If belladonna or other drug of this group is used it is preferable to employ fairly large doses at once and abandon it if it does not afford prompt relief. Hyoscyamus is generally reputed to be more useful than belladonna and stramonium as a sedative to the nervous system; stramonium is little used except as an ingredient of asthma powders, used for smoking. Scopolamin hydrobromid has a special field of use- fulness in quieting the excitement of the insane and producing sleep. It is more effective when given at night than during the day. Some ophthalmologists prefer it to atropin as a mydriatic, because it is said to be less irritating and 36 STIMULANTS OF CENTRAL NERVOUS SYSTEM to produce a brief but complete dilatation of the pupil with paralysis of accommodation. Its use with morphin in producing narcosis will be discussed after morphin has been considered. Extract of belladonna is sometimes applied to the skin in the form of an ointment for the relief of neuralgic pain and for acute inflammatory conditions ; the commercial belladonna plaster is widely used by the laity, but it is doubtful whether the belladonna contributes anything to the effect. It is probable that all of the crude drugs and galen- ical preparations of this group are superfluous, and that with a better knowledge of the actions of atropin and scopolamin these alkaloids will replace the crude drugs and their galenical preparations as completely as quinin has displaced cinchona and its galenicals. DOSAGE The average dose of atropin sulphate is stated to be 0.4 mg. (%5o gi'ain), but there are many condi- tions for which this dose would be insufficient and others for which it would be too large. The dose should be carefully graduated for the specific purpose for which the drug is intended, as one can then accomplish the desired effect with a minimum of side actions. The smallest therapeutic doses of atropin commonly used are probably those which are added to the laxa- tives. The official compound laxative pill contains 8 mg. (Ya grain) of extract of belladonna, or approxi- mately %o i"g- iVeso grain) of atropin. The largest doses commonly used internally are employed for relieving spasm of the intestinal muscle, in which case as much as 3 mg. (%o grain) may be needed. To lessen sweating the dose is ^ mg. (%5o grain) ; to paralyze the vagus endings in the heart, 1 mg. (%o grain) ; to antagonize morphin poisoning, 1 to 3 mg- (%o to %o grain); but, as previously stated, there is considerable diversity of opinion concerning the advisability of the larger dose given here; to antagonize other poisons, such as aconite, pilocarpin, and other drugs which stimulate the autonomic nerves. ATROPIN 37 the dose required will depend on the action elicited by the poison ; since aconite stimulates the vagus, this should be paralyzed by atropin, and about 1 to 1.5 ™g- (%o to Yio grain) should be used. Pilocarpin induces excessive secretion of the bronchial and salivary glands, the excessive bronchial secretion con- stituting a danger with overdoses of pilocarpin, and to antagonize this, 0.5 mg. (%25 grain) atropin should be used. Atropin is more eflfefctive in antagonizing pilocarpin than is pilocarpin in antagonizing atropin. Some per- sons appear to be remarkably susceptible to the action of atropin in inducing skin rashes. Dryness of the throat is commonly induced by doses of 1 mg. (%o grain) or over. A dose of 0.2 mg. (%oo grain) is said to stop the vomiting which small doses of morphin cause in sus- ceptible persons. Asthma resulting from spasm of the bronchial muscle, whatever the exciting cause, may be relieved by atropin in doses of 0.25 to 0.5 mg. (%5o to %25 grain), repeated several times daily if necessary. Belladonna and other members of the group are used in the form of cigarets for the relief of asthma. It is stated that the smoke of 4 gm. (60 grains) of stramonium in the form of a cigaret contains 0.4 mg- iViso grain) atropin. Children bear atropin fairly well, and relatively large doses are frequently recommended in the treat- ment of whooping-cough, and such large doses are required if the depression of the respiratory center is the object to be attained. As little as 1 drop of a 1: 1,000 solution of atropin dropped into the eye will cause dilatation of the pupil, but stronger solutions are required to paralyze the muscles of accommodation, and 1 per cent, solutions are commonly employed for this purpose. The average dose of scopolamin hydrobromid is 0.5 mg. (H25 grain) ; much larger doses are some- times required for quieting the insane, but even here caution must be shown for it may cause depression of respiration and a rapid fall in the blood-pressure, resulting in collapse. 38 STIMULANTS OF CENTRAL NERVOUS SYSTEM For use as a mydriatic alone solutions of from 1 : 500 to 1 : 1,000 suffice, but where paralysis of accommodation is required, somewhat stronger solu- tions are necessary (from 1 : 100 to 1 : 250). The average doses of the galenical preparations of the drugs of this group will be given in the discussion of the materia medica. English authorities advise doses of the drugs of this group which we are accustomed to consider enormous ; for example, Leonard Guthrie states that in the treat- ment of habitual nocturnal enuresis tincture of bella- donna should be pushed to full doses, that is, to from 10 to 40 minims for a child of 10 to 12 years. The British tincture of belladonna is required to contain from 0.048 to 0.052 per cent, of alkaloid, or about 50 per cent, more than is required by the U, S. P. Such doses may prove beneficial in cases of hab- itual nocturnal enuresis when the treatment in vogue in this country would fail, but such heroic treatment will certainly result in dryness of the throat, rashes and other disagreeable side actions and should not be used except in persistent cases when milder treat- ment has failed. One will find formulas prescribing the drugs of this group in text-books which do not take into account the fact that the alkaloids of this group are prone to undergo changes and that we cannot fore- tell what changes will take place when one of the galenical preparations is mixed with alkaline salts and allowed to stand. A prescription of this nature found in a standard work on therapeutics includes tincture of belladonna, potassium iodid, ammonium carbonate, potassium bicarbonate, camphor water and water. Any tincture of this group is prescribed preferably alone except that it should be diluted (and flavored, if desired) so that the dose may be measured con- veniently. The following illustrates the method of prescribing tincture of belladonna: 3 Tincturae belladonnae 4 Syrupi aurantii IS Elixiris aromatici q. s. ad 30 M. Dose: a teaspoonful. c.c. flSi flSiv fiSi ATROPIN 39 The smoke of burning belladonna and stramonium leaves has been widely used by inhalation for the relief of asthma. The leaves are ground or granulated in order to prevent their burning with a flame, and a little potassium nitrate is commonly added to secure more uniform combustion. The mixture is burned on a plate, smoked in a clean pipe, or used in the form of cigarets. W. J. Hadley advised the use of a mixture of equal parts of belladonna, hyoscyamus, and stramonium leaves and potassium nitrate as a fumigation, but there is no advantage in using a mixture of drugs contain- ing such similar constituents, and any one of the leaves may be used with the addition of from one- eighth to one-fourth its weight of potassium nitrate. Half a teaspoonful of the mixture is used at each fumigation. MATERIA MEDICA Atropina. — Atropin, U. S. P. An alkaloid obtained from Atropa belladonna and from other solanaceous plants. It occurs as colorless crystals or as a white crystalline powder, odorless and having a bitter nau- seating taste. Atropin in all its forms is usually contaminated with a small amount of optically active hyoscyamin. The alkaloid is only slightly soluble (1:450) in water but freely soluble (1: 1.5) in alco- hol. It is usually prescribed in the form of: Atropinae Sulphas. — Atropin Sulphate, U. S. P. This salt occurs as a white crystalline powder that is odorless and has a very bitter and nauseating taste. It is permanent in air and very soluble (1:0.4) in water, and (1:4) in alcohol. Scopolaminae Hydrobromidum. — S copolamin Hydrobromid, U. S. P. This is sometimes called "hyoscin hydrobromid," though the latter name was originally applied to an impure product. Scopolamin hydrobromid occurs as colorless crystals, odorless and having an acrid slightly bitter taste. It is freely soluble (1 : 15) in water and (1: 16) in alcohol. Homatropinae Hydrobromidum. — Homatropin Hydrobromid, U. S. P. The hydrobromid of an alka- 40 STIMULANTS OF CENTRAL NERVOUS SYSTEM loid, tropin mandelate, produced synthetically. The alkaloid was discovered in 1879 by Ladenberg in the course of his researches on the constitution of atropin. It is used extensively in ophthalmologic practice and appears to be more stable than atropin in aqueous solution. It is seldom given internally, though it has been used in doses of from 0.5 to 3 mg. (%oo *o Yzo grain). Belladonnae Folia. — Belladonna Leaves, U. S. P. The dried leaves of Atropa Belladonna, which are required to yield by the pharmacopeial process not less than 0.3 per cent, of mydriatic alkaloids. Bella- donna leaves are rarely administered as such; the more widely used preparations of this drug are: Tinctura Belladonnae Foliorwm. — Tincture of Bel- ladonna Leaves, U. S. P. Each 100 c.c. of this preparation represents the soluble constituents of 10 gm. of the drug in diluted alcohol and should contain 0.03 gm. of the alkaloids from belladonna leaves. The average dose is 0.5 c.c. (8 minims). Extractum Belladonnae Foliorum. — Extract of Bel- ladonna Leaves, U. S. P. A hydro-alcoholic extract of belladonna leaves which should contain 1.4 per cent, of mydriatic alkaloids. The average dose is 0.01 gm. (% grain). The average doses of the tincture and the extract of belladonna represent only about % mg. (%oo grain) of total alkaloids, which is much less than the average dose of atropin for many of the purposes for which it is used. Unguentum Belladonnae. — Belladonna Ointment, U. S. P. An ointment containing 10 per cent, of extract of belladonna leaves in a mixture of hydrous wool fat and benzoinated lard. Emplastrum Belladonnae. — Belladonna Plaster, U. S. P. Represents approximately 30 per cent, of extract of belladonna leaves, and should contain not less than 0.38 per cent, and not more than 0.42 per cent, of mydriatic alkaloids. All plasters of belladonna and allied drugs are necessarily of doubtful utility because the drug itself is probably effectually sealed and prevented from being absorbed LOBELIA 41 by the rubber with which it is mixed. The use of rubber base plasters for any other purpose than sup- port is not justified by experimental observations. Hyoscyamus. — Hyoscyamus, U. S. P. This drug, commonly called henbane, consists of the dried leaves and flowering tops of Hyoscyamus niger. The only preparation of it that is at all extensively used is: Tinctura Hyoscyami. — Tincture of Hyoscyamus, U. S. P. One hundred c.c. of this tincture represent the soluble constituents of 10 gm. of hyoscyamus in dilute alcohol and should contain approximately 0.007 gm. of mydriatic alkaloids, chiefly hyoscyamin and scopolamin. It is usually given in doses of from 0.5 to 2.0 c.c. (10 to 30 minims). Stramonium. — Stramonium, U. S. P. The leaves of Datura Stramonium, commonly called Jamestown or jimson weed. Its constituents are much the same as those of belladonna. LOBELIA The action of lobelia is practically that of its alka- loid, lobelin, which resembles nicotin closely in its physical properties and actions. Tobacco was used formerly in a great variety of conditions, but owing to its careless use and the great toxicity of its alkaloid, many accidents resulted, and it fell into disuse in therapeutics. If the drug which has been studied more frequently should now be con- sidered of little value, it is difficult to explain the advantages to be derived from lobelia. Lobelia itself is no longer used as an emetic as it was formerly, but it would seem that physicians are loath to give up a drug which has been so long in use. Those who wish a detailed description of lobelia, or lobelin, are referred to the larger text-books of pharmacology, for its actions are very complex. The peripheral actions of lobeHn, like those of nicotin, may be summarized as consisting of stimulation of the ganglia of the sympathetic and parasympathetic sys- tems throughout the body after small doses, followed by depression or paralysis of these ganglia with large doses. It will thus be seen that lobelin acts on the 42 STIMULANTS OF CENTRAL NERVOUS SYSTEM organs innervated by the sympathetic and parasympa- thetic systems in opposite directions, depending on the dose, and the complex nature of its effects may be appreciated when one remembers that the actions of these two sets of nerves are commonly antagonistic. Stimulation and depression of the ganglia induce the same effect on the organ supplied as stimulation and depression of the nerve endings; hence lobelin combines in itself the peripheral actions of a number of drugs including atropin, pilocarpin, epinephrin and others. In addition to these actions it stimulates and later depresses various parts of the central nervous system. The emetic action, for which lobelia was formerly used, points toward the medullary centers as the seat of this stimulation, and it also stimulates the vagus, vasomotor and respiratory centers. The action on the vagus ganglia results in cardiac slowing, which is augmented by the stimulation of the vagus center, but this is soon followed by an increased heart-rate due to the depression of the ganglia. The rise of blood-pressure of peripheral origin is also augmented by the central actions. Lobelia is not used for these effects, and it is now sought to avoid more than slight stimulation of the vomiting center, because dangerous collapse is fre- quent with large doses. The treatment of poisoning is symptomatic, severe poisoning with lobelia being rare since its use as an emetic has been abandoned. Nicotin is excreted by the kidneys in part, and the same is probably true of lobelin. THERAPEUTIC USES The principal therapeutic use of lobelia is in asthma, in which it is sought to utilize the paralysis of the vagus in the bronchi. It is not apparent that it has any decided advantages over the mydriatic alkaloids for this purpose, especially as the action of atropin has been found to be more lasting. Lobelia is some- times used as an expectorant, in which case the nause- ant stage should not.be exceeded. So-called cardiac CAMPHOR 43 asthma, or the presence of severe cardiac disease com- plicating spasmodic asthma, is a contra-indication for lobelia. DOSAGE The herb is seldom employed as such, the tincture being used in doses of 0.5 to 1.5 c.c. (10 to 20 minims). MATERIA MEDICA Lobelia. — Lobelia, U. S. P. The dried leaves and tops of Lobelia inflata. It is still widely used in eclectic practice. Tinctura Lobelia. — Tincture of Lobelia, U. S. P. Each 100 c.c. represents the soluble constituents of 10 gm. of the drug in diluted alcohol. CAMPHOR We are unable to offer a rational basis for all the therapeutic uses to which camphor is put, its exact mode of action being unknown, but it is often used as a stimulant of the vasomotor centers, partly as a result of clinical experience and partly on the basis of the results of experiments on animals. The effects of very large doses of camphor resemble those of picrotoxin so far as the stimulant actions on the medulla are concerned, but there is an essen- tial difference in that even moderate doses of the drugs of the picrotoxin group tend to cause depression after the stimulation has passed, whereas with cam- phor, depression becomes of importance only after extremely large amounts. The convulsions which are seen after massive doses of camphor have been administered to animals ( cats or dogs) are usually attributed to the action on the medulla, but it is probable that other parts of the cen- tral nervous system are also concerned in this action, especially in young animals. The convulsions are epileptiform in character. Moderate doses of camphor stimulate the respira- tory center, and while doses comparable to those used in therapeutics have little influence on the respiratory and vasomotor centers, in normal animals, it is quite possible that those centers may be influenced more 44 STIMULANTS OF CENTRAL NERVOUS SYSTEM easily by camphor, as in other drugs, when they have been previously depressed. It will be recalled that doses of strychnin less than those causing marked hyperexcitability have little influence on the normal blood-pressure, and that even convulsive doses cause only a brief, though high, rise of pressure in the nor- mal animal. Clinical experience seems to. show that camphor is sometimes useful in improving the respirattion and circulation when collapse is impending, and that it also acts beneficially on the heart, but there are many diametrically opposed observations recorded concern- ing its clinical value. Camphor is widely used in Europe for its circu- latory actions, especially in threatened cardiac failure, but on the other hand, certain English observers have recently reported that they were unable to detect any constant influence on the circulation after the subcu- taneous injection of much larger doses than those commonly used. It seems probable that camphor may cause some change in the distribution of the blood by constriction of the vessels in one area and simultaneous dilatation of those in another, without increasing the pressure. It is quite possible that much of the diversity of opinion arises from differences in the methods of employing the drug, both as to the selection of cases in which it is to be used and in the mode of admin- istration. Camphor resembles the drugs of the picrotoxin group further in that it is absorbed somewhat irregu- larly, or at least, the actions are elicited to a variable degree after the administration of a given dose, and this probably depends on differences in the ratio of absorption and excretion. It has been observed in laboratory experiments that the results were somewhat more nearly uniform after the oral administration* of camphor dissolved in olive oil than when it was given subcutaneously, but the two modes of administration gave only slightly dif- ferent results. It is probable that the effects may be elicited most" rapidly by means of the intraperitoneal CAMPHOR 45 injection of camphor dissolved in ether, but there are mechanical difficulties involved in the injection, because of the extreme volatility of ether. The method is not recommended. THERAPEUTIC USES Camphor is used like other respiratory stimulants, and in collapse for its action on the respiration and circulation, and, as stated, in impending cardiac col- lapse. It has long been popular in combination with other drugs to promote sweating, and enjoys a cer- tain degree of popularity in the treatment of "colds." It is not commonly used now in this way by physi- cians. DOSAGE Camphor is frequently administered internally in doses of from 0.1 to 0.3 gm. (2 to 5 grains) prefer- ably in the form of capsules, cachets, mixtures or solutions. Camphor water, a comparatively weak solution, is given in doses of 15 c.c. (4 fluidrams). Spirit of camphor, a 10 per cent, alcoholic solution, which is the most frequently used preparation of camphor, can be given on sugar, cracked ice or mixed with cold water in doses of from 0.5 to 1.5 c.c. (7 to 20 minims). The liniment of camphor, which as its name indicates is primarily intended for external use, though it is double the strength of the foregoing, can be given in approximately the same dose. It may be directed in the form of an emulsion. It is frequently used for hypodermic administration. A more limpid preparation for the latter purpose can be made by directing the use of oil of sweet almond or olive oil in place of the cotton-seed oil used in the official preparation. MATERIA MEDICA Camphora. — Camphor, U. S. P. The official product is described as the dextrogyrate modification of the saturated ketone obtained from Cinnamomum Camphora, purified by sublimation. The drug occurs in commerce as white, translucent masses of a tough consistency and crystalline structure; it may be pow- dered readily with the aid of a small amount of alcohol. Camphor has a characteristic odor and pungent taste. 46 STIMULANTS OF CENTRAL NERVOUS SYSTEM It is very slightly soluble (1 : 700) in water, but freely soluble (1:3) in alcohol and (1:4) in olive oil and other fatty oils of this type. The several official solu- tions include : Aqua Camphorae. — Camphor Water, U. S. P. The saturated solution of camphor and distilled water. This is a weak preparation used chiefly as a vehicle for coUyria. Spiritus Camphorae. — Spirit of Camphor, U. S. P. An alcoholic solution of camphor (10 gm.) in alcohol (to make 100 c.c). Linimentum Camphorae. — Camphor Liniment, U. S. P. Popularly known as camphorated oil. It is a solution of camphor (20 gm.) in cottonseed oil (enough to make 100 c.c). CAFFEIN AND THEOBROMIN Caffein and theobromin belong to a group of sub- stances which are commonly known as the purins, from the fact that they contain a purin nucleus. Xan- thin is dioxypurin, and theobromin and caffein are dimethylxanthin and trimethylxanthin, respectively. Another dimethylxanthin, theophyllin, occurs in the leaf of the tea ; it has been prepared synthetically and called theocin. Comment has often been made on the extraordinary extent to which plants which contain caffein are used among nearly all civilized peoples and even among savages, which is all the more remarkable in view of the fact that there is nothing in the taste of these plants which serves to direct attention to them. It is well known that savage tribes are constantly on the alert for new poisons, and when a caffein-bearing plant is tested the psychic effects of caffein on any one who has not used it previously could hardly fail to attract attention, and lead to the further use of the plant. Caffein does not increase the functions of the nor- mal brain under the best conditions for mental work, that is, after sound and refreshing sleep and sufficient rest with freedom from worry, but when small doses are used after severe physical or mental effort it CAFFEIN AND THEOBROMIN 47 causes fatigue to disappear, and the perception of sensory stimuli and the association of ideas are pro- moted. A good illustration of the inability of caffein, or other drug, to improve the best of normal conditions is afforded by the experience of athletes who find that caffein tends to lessen, rather than increase, their performances. Large doses of caffein interfere with the proper association of ideas ; for example, students are unable to study so effectively after large doses as without them. With very large amounts there is actual con- fusion of thought with ringing in the ears, flashes of light and other signs of mental disturbance. There is also restlessness due to stimulation of the motor areas, and to heightened reflexes in the brain and cord, and with excessive doses there are convulsions similar to those seen in fatal poisoning with strychnin, and death follows from respiratory or cardiac failure. Caffein stimulates the medullary centers, causing increased respiration and rise of blood-pressure, due to stimulation of the vasomotor centers, but this is complicated by cardiac and vascular effects, and slow- ing of the heart from stimulation of the vagus center, which is also complicated by the direct, and indirect, cardiac actions. Obviously, the effects on the circu- lation are complex and variable. Wakefulness is one of the most frequently observed effects of caffein in those who are unaccustomed to its use, especially when it is taken shortly before bedtime, but it may promote sleep when sleeplessness is due to fatigue. Caffein relieves certain forms of neuralgia, the eti- ology of which, and the mechanism of relief are obscure. It appears to enhance the antineuralgic actions of antipyretic drugs, such as antipyrin, with which it is sometimes administered. Theobromin induces much less psychic stimulation than caffein, but it is convenient to consider them together because of the general similarity in most of their other actions. The effect of caffein on cardiac muscle is important, but the muscular action is observed more conveniently 48 STIMULANTS OF CENTRAL NERVOUS SYSTEM on skeletal muscle. Extremely small amounts of caffein, such as are utilized when solutions of 1 : 100,000 or weaker are employed in laboratory experiments, increase the force, efficiency and rapidity of contraction of voluntary muscle, but when more concentrated solutions are used, the muscle contracts less efficiently, less forcibly and more slowly, and finally goes into rigor. Nearly all doses of caffein that produce any per- ceptible effect on the heart increase the rate, without increasing the force, and this effect with the stimula- tion of the vasomotor center results in at least a temporary rise of pressure, unless it is prevented by the antagonistic dilator action on the vessels them- selves. Occasionally the force of the heart-beat is increased without any notable influence on the rate. The continued use of tea or coffee in large amounts gives rise to intermissions, extrasystoles or other forms of cardiac irregularity, which usually disappear when the beverage is discontinued or taken in greater moderation; but it is not certain that these cardiac irregularities are due exclusively to the caffein pres- ent in the tea and coffee, for indigestion may play a part in the symptoms. German clinicians employ caffein in cardiac dis- ease much as they use digitalis, but while these two drugs have a certain degree of synergistic action, the total effect is quite different. The effects of caffein on the circulation are of importance with reference to its diuretic action. The vasoconstriction which at first affects the vessels of the splanchnic region, causing a rise of blood-pressure, also constricts the renal vessels, so that the secretion of urine may actually show a temporary diminution; but this renal vasoconstriction soon gives place to dila- tation while the pressure in the general circulation remains high, thus securing the best circulatory con- ditions for diuresis. There are many persons in whom caffein and theobromin do not induce active diuresis. Caffein and theobromin are absorbed fairly readily from the gastro-intestinal tract. Theobromin is rela- tively insoluble, but there is vastly more fluid in the gastro-intestinal tract than is required to dissolve the CAFFEIN AND THEOBROMIN 49 largest therapeutic dose. When it is desired to inject these drugs subcutaneously it is necessary to use them in combination with an alkaline salt such as sodium salicylate or sodium benzoate, to produce soluble preparations. Caffein is probably broken down in the organism to dimethylxanthin before it acts on the kidney, and it and theobromin are excreted partly as dimethyl- xanthin, and partly as uric acid, but they do not cause any important increase in the output of uric acid under ordinary conditions. A small amount of unchanged caffein may appear in the urine after the administration of very large doses. It is a matter of common experience that a certain degree of habituation on the part of the central ner- vous system occurs toward caffein on continued use, but the heart becomes more susceptible if large amounts are taken daily. Very few fatal cases of poisoning by caifein have been recorded, and in view of the enormous use of the beverages containing it we must suppose that it is not a dangerous drug so far as the immediate peril to life is concerned; but minor toxic symptoms, including nervousness, cardiac irregularities, sleepless- ness, lassitude, ill humor and headache are common; these usually call for no other treatment than the dis- continuance of the beverage which is causing the trouble. THERAPEUTIC USES Caffein is used therapeutically for its diuretic action, especially in dropsical conditions and in nephritis, and also in cardiac disease. Aside from its diuretic action it is not easy to suggest a logical basis for its use in cardiac disease. Caffein is one of the best of respiratory stimulants, because the stimulation has little tendency to pass into depression even with large doses. The antagonistic action of caffein to that of mor- phin and other narcotics is strikingly illustrated in a well-known laboratory experiment. If a cat or dog be given alcohol until completely anesthetized, and caffein be then injected subcutaneously, the animal so STIMULANTS OF CENTRAL NERVOUS SYSTEM will speedily regain consciousness and make coordi- nated voluntary movements, often rising to its feet, or at least, to a sitting position. If anesthetized with ether previous to the administration of the caflfein, it may regain consciousness and not pass under the anesthetic again, as it does with alcohol, owing to the slowness with which the alcohol is eliminated. Caffein has an equally important, though not so striking, effect in animals under the influence of mor- phin, and on theoretical grounds should be given in preference to atropin as a respiratory stimulant in the treatment of poisoning by morphin and other narcotics. Caffein in the form of tea or coffee is often useful for the relief of headache due to overexertion and nervousness. DOSAGE Caffein and theobromin or the several combina- tions of these bases with other substances may be administered in doses of from 0.1 to 0.5 gm. (2 to 8 grains). Caffein, the citrated caffein and theo- bromin are preferably given enclosed in a capsule or cachet or in the form of dry powder to be washed down with a copious draught of cold water. The combinations of caffein and of theobromin with sodium benzoate and sodium salicylate are readily soluble in water and are usually administered in the form of simple solutions. The intravenous injection of caffein is not without its dangers; under no circumstances should it be injected rapidly into the blood-stream. The follow- ing experiments illustrate the danger : A cat required 150 mg. (2^4 grains) per kilogram of weight to cause death, when a dilute solution was injected very slowly, but in. another experiment the heart was stopped at once by the rapid injection of as little as 5 mg. (Ka grain) of caffein per kilogram. It should be remembered that this dose corresponds to about 0.30 gm. (5 grains) of caffein for a man, or less than is commonly taken habitually by many persons daily in the form of tea and coffee without perceptible effects. When one recalls what was said regarding the effeH of even fairly dilute solutions of caffein on skeletal CAFFEIN AND THEOBROMIN 51 muscle, he will appreciate the danger of rapid intra- venous injections of even small amounts of caffein. If it is desired to inject the drug directly into the circulation, for which there is no apparent good reason in therapeutics, the dose should not exceed 0.20 gm. (3 grains), which should be dissolved in a fairly large amount of- salt solution, and the injection should be made slowly, so that at least one minute should be consumed in the injection. It is not recommended that caffein be injected intravenously in therapeutic practice, however. MATERIA MEDICA Caffeina. — Caffein, U. S. P. Caffein is identical with thein, guaranin and methyl theobromin. Chem- ically it is trimethylxanthin. It is a feebly basic alkaloid usually obtained from the dried leaves of Thea sinensis or from the dried seeds of Coffea arabica and also found in a number of other plants. It occurs as white, silky, glistening needles or as a white crystalline powder, odorless and having a bitter taste. Caffein is soluble (1 : 70) in water and (1 : 50) in alcohol. For administration in the form of solu- tion one of the more soluble preparations is usually preferred. Caffeina Citrata. — Citrated Caffein, U. S. P. A mixture of equal parts of caffein and citric acid. It is a white odorless powder having an acid and bitter taste and an acid reaction. It is soluble (1:25) in water and in alcohol, but is not at all suited for hypo- dermic . administration. Because of its acid nature it is incompatible in solution with substances like potassium iodid, sodium salicylate, sodium benzoate and the several nitrites. For combination with sali- cylates and benzoates the alkaloid itself should be used or it may be prescribed in the form of : Caffeinae Sodiobenzoas. — Caffein Sodiobenzoate, N. F. A mixture of equal parts of caffein and sodium benzoate. This product is freely soluble (1:2) in water and it, or the corresponding combination with sodium salicylate, is usually used for administration in solution either by mouth or hypodermically. 52 STIMULANTS OF CENTRAL NERVOUS SYSTEM Theobromina. — Theobromin, N. N. R. Chemically known as 3, 7-dimethyIxanthin. A weak alkaloidal base closely related to caffein, that occurs in Theo- broma Cacao, Kola acuminata, and several other plants. It occurs as a white crystalline powder, odor- less and having a bitter taste. It is almost insoluble in water, but readily soluble in alcohol. Because of its comparative insolubility it is usually administered in soluble combination with sodium salicylate or sodium benzoate, preferably the former. Theobrominae Sodium Salicylas. — Theobromin Sodium Salicylate, N. N. R. A double salt of theo- bromin sodium and sodium salicylate first recom- mended by Graham in 1887. The product contains approximately 50 per cent, of theobromin and occurs as a white powder, odorless and having a saline taste. Theobromin sodium salicylate is readily decomposed and therefore incompatible with acids, even carbon dioxid being sufficient to decompose it. Physicians commonly object to using the beverages tea, coffee and cocoa, when the diuretic action of caffein and theobromin is desired, on the ground that too much water is thereby administered. The argu- ment is not always well taken; every patient must have some water, and large doses of caffein and theo- bromin may be given with strong beverages without increasing the minimum of water, and absorption from the gastro-intestinal tract takes place promptly. ) CHAPTER II.— DRUGS WHICH ACT ON THE CENTRAL NERVOUS SYSTEM (Continued) B. DEPRESSANTS MORPHIN Morphin is much the most important member of the group, but others have special fields of useful- ness. Opium depends for its therapeutic value almost exclusively on the morphin which it contains, but the action of morphin in opium is modified to a certain extent by other constituents present, this probably being an advantage in some conditions and a disad- vantage in others. Not enough is known about the actions of narcotin to enable us to state definitely how it modifies the actions of the morphin in opium, but it is probably of no importance in most cases when opium is used therapeutically, though its action may assume some significance when toxic doses of opium are taken. Thebain acts on the spinal cord much like strychnin, but it and codein are present in opium in amounts too small to influence the action of the morphin appre- ciably. Opium contains a caoutchouc-like substance and other colloidal matter which interfere with the absorption of the alkaloids, and thus prolong the local action on the intestine after the oral administra- tion of opium. With this exception we may consider the actions of opium and morphin together, remem- bering, however, that with massive doses of opium the convulsant action of the other alkaloids is prob- ably concerned. The discovery of morphin by Serttirner of Hanover in 1805 has been characterized as the greatest dis- 54 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM covery in the field of materia medica and toxicology of all times, and Robert has called attention to the fact that all subsequent discoveries of alkaloids, or plant bases, since then have resulted from modified repetitions of the work of that apothecary. Until then it had not been supposed that plants might yield prin- ciples capable of combining with acids to form salts. To-day, ho^yever, the alkaloids constitute the most important group of plant principles in the materia medica, one reason being that many of them can be prepared in a high degree of purity. About 1850, Pravaz, a French soldier and surgeon, invented the syringe which is still known by his name and which he used for injecting ferric chlorid into aneurysms; a little later Alexander Wood utilized the syringe for the subcutaneous injection of morphin. Morphin is known to contain two hydroxyl groups, one being phenolic, or united to a benzene ring, and the other alcoholic, or united to a group such as occurs in alcohols. Substitution in one or both of these hydroxyl groups serves to modify the actions of morphin in various ways. Codein, or methyl morphin, differs chemically from morphin only by having a methyl group (CHg) replacing the hydrogen of one of the hydroxyls; ethyl morphin hydrochlorid (dionin) has an ethyl group in one of the hydroxyls of mor- phin; and diacetyl morphin (heroin) differs from mor- phin by having two acetyl groups in the hydroxyls. The number of substances which may be formed in this way is very large, but none of the others has attained any considerable degree of importance in therapeutics. Apomorphin is also derived from morphin, and while it retains the narcotic action to some extent, the specific emetic action which it acquires places it in the group of emetics. Morphin has a variety of actions which are sever- ally of therapeutic or toxicologic importance, and since these different actions cannot be seen to advan- tage in a single species of animal the effects are nec- essarily studied on different species. For example, MORPHIN 55 morphin exerts a strychnin-like action on the spinal cord, which can be observed very conveniently in the frog, but this is masked in the higher mammals as a rule by the more pronounced actions on the cerebrum and respiratory center. Witkowski observed that the depressant effects of large doses of morphin on the central nervous system of the frog were comparable to those resulting after the removal of successive portions of the brain begin- ning above and proceeding downward. These several effects of morphin are not separated sharply, but with appropriate doses they can be made out with some degree of clearness. Following these actions on the higher parts of the central nervous system, the spinal cord is first depressed, and then rendered hyperexcitable so that the later condition is scarcely distinguishable from that induced by strychnin. It is often said that man reacts specifically to mor- phin, but the character of the action is modified materially with the age and sex of the patient and with the size of the dose; thus van Swieten observed that different amounts of the same preparation exerted varying types of action, and he obtained stimulation with small doses, and depression with large. Children occasionally show tetanic convulsions after opium. Binz gives the following graphic description of the action of moderate amounts of morphin on the higher centers in normal man: After some minutes pleasant sensations are usually expe- rienced; the brain seems to be relieved from the confines of the skull; glittering fantastic visions appear; one is indis- posed to move; questions are answered with stammering; beautiful visions appear, but the beauty is short-lived, the eyelids grow heavy, the limbs lie motionless; every impulse sent out to them from the brain dies away; the whole body feels heavy as lead, and soon one sinks into deep sleep which is indistinguishable from the normal, if the dose is not too large. The respiration and heart-beat are slowed, one lies asleep but he can be aroused by a loud noise to a confused condition, but only by stronger stimuli can one be aroused completely. 56 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM This description applies to normal man; hence it does not include the most pronounced action which follows the therapeutic use of small or moderate doses of morphin which lessen or abolish the perception of pain. This analgesic action is exerted on the centers con- cerned with the perception of pain, not in the peri- pheral mechanism, for the effect is no greater in the immediate region of a subcutaneous injection than it is elsewhere. The belief that morphin has a local analgesic action has resulted in a number of irra- tional methods of application, for example, urethral injections and other local applications. Lead and opium wash forms a poultice-like mass which retains the heat of the body while macerating the tissue, and the lead is astringent. Little or none of the morphin in the opium can be absorbed into the skin in such a case, and it is probable that mucilage of acacia could be substituted for the tincture of opium with advantage. A comparison of the analgesic value of morphin and of hydrated chloral is afforded by observing their effects on rabbits. If one animal receives a hypnotic dose of hydrated chloral, and another an analgesic dose of morphin, it may be observed that the first reacts to painful stimuli, but the second remains awake or can be aroused easily. Of course, a massive dose of hydrated chloral will prevent any perception of pain. A further advantage which morphin has over hydrated chloral is that it does not depress the heart and vasomotor centers. It must be remembered, when one speaks of the central actions of morphin and the absence of peripheral effects, that the actions on the gastro-intestinal tract constitute an exception. Morphin is not actively hypnqtic in doses which leave the respiratory center "ttnaffected, the action on that center occurring with doses just larger than the minimal analgesic, but sleep often follows the use of a small dose of morphin when wakefulness is due to pain, which the morphin relieves. The effects of morphin on the medullary centers stand next in importance to those exerted on the cere- MORPHIN 57 brum, the respiratory center being depressed with smaller doses than are required to affect the other centers. On these two actions, the analgesic in the brain, and the respiratory in the medulla, depend the greatest therapeutic uses of morphin, for the relief of pain and for the control of cough. Morphin depresses the respiratory center in such a way that carbon dioxid in the blood no longer increases the rate of respiration, but it does increase the depth of the individual respirations as much as it does in the normal animal. This depression results in lessening the cough reflex. It may be well to remeth- ber that while morphin lessens or prevents cough, it does not cure the condition of which the cough is a symptom and in some cases a necessary result, since it may be necessary to remove the exudate in the air passages. The respiratory center shows a peculiar suscepti- bility to chloroform after morphin has depressed it, and when morphin is used before general anesthesia ether is to be preferred. Small doses of morphin have little influence on the vagus center in man, but somewhat larger doses stimulate it, and with toxic doses it and all the higher centers are depressed. Patients who suffer from cardiac lesions may show a greater response to vagus stimulation than normal man, and as little as 10 mg. (% grain) of morphin has been followed by Cheyne-Stokes respiration in a man suffering with aortic insufficiency. We have here a chain of effects for which Cushny offers this explanation : The respiratory disturbances due to the morphin cause vagus stimulation with decreased heart- rate and disturbed circulation, which in turn causes Cheyne-Stokes respiration. Atropin abolishes the slowing of the heart-rate by paralyzing the vagus end- ings, and the Cheyne-Stokes respiration disappears with the improvement in the circulation. Small doses of morphin cause dilatation of the cutaneous vessels through the action on the vasomotor centers, increasing the actions of diaphoretic drugs which may be administered with it. Dilatation of 58 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM the cutaneous vessels from any cause may cause ery- thema, and this sometimes follows the use of morphin or opium. While small doses cause this cutaneous dilatation, large doses have the opposite effect, the skin appearing pale because of the constriction of the peripheral vessels and dilatation of the splanchnic, due to vasomotor depression. Macht showed that perfusion of the coronaries with morphin and other opium alkaloids induced dilatation, but the amounts to which the coronaries were sub- jected in his experiments were incomparably greater than those which can act on them when opium or morphin is used clinically. Furthermore, alkaloids leave the blood stream very rapidly, and hence any direct action on the arteries would be fleeting at most. Morphin stimulates the centers in the medulla which are concerned with vomiting with varying degrees of intensity. Emesis may result even with moderate doses, or where the narcotic action is delayed after large doses in man. Vomiting cannot be induced during deep narcosis; hence this symptom is commonly absent in the late stages of morphin poisoning, while nausea, at least, is a more common symptom with moderate amounts. This emetic action of morphin is of some importance in connection with its use in strychnin poisoning, in which morphin is sometimes recommended. The convulsant action of morphin is not usually seen in man because he succumbs to the narcotic action before the effect on the cord can be developed, but children occasionally show hjrperexcitability, or even convulsions, after poisonous doses of opium. The convulsant action of codein is more pronounced than is that of morphin relatively to the narcotic effect. Toxic doses of opium probably contain enough narcotin to add materially to the convulsant action of the morphin present. Therapeutic doses of morphin have little direct action on the heart except that they may depress the accelerator mechanism, permitting the vagus to exer- cise increased control over the heart-rate; the action is commonly utilized in therapeutics. The slowing MORPHIN 59 which follows morphin is not always necessarily attributable to this direct action, for it may follow the relief of pain and anxiety, and the resulting rest and sleep. The nauseant action of morphin is accompanied by some increase in the secretion of the bronchial glands, which is probably due in part to the excretion of the drug by them. The pupils are not acted on by morphin directly, the miosis which is seen in morphin poisoning being due to the central action; it appears to be analogous to the miosis which occurs during sleep. This is worthy of attention because it is sometimes stated that the degree of antagonism between morphin and scopolamin can be estimated by changes in the size of the pupil. The actions are so different that little importance should be attached to the state of the pupils when morphin and scopolamin are used together. It is very well known that morphin and opium lessen or abolish peristalsis and relieve pain in the gastro-intestinal tract. In this we have an example of the local analgesic action of morphin, but this is an exception to the rule and it is not seen elsewhere. Even here morphin does not relieve all pain by its local action. It abolishes sensory impulses from the mucous surface of the stomach, but not from the serous. The behavior of the movements of the stomach after morphin depends on the dose and mode of administration, the gastric movements being increased by small doses, and the pylorus caused to contract firmly by somewhat larger ones, administered in such a way that they enter the circulation with a minimum of local action, as with subcutaneous injection, the effect being due to vagus stimulation. Many investigators have endeavored to explain the direct and indirect influence of morphin on the gastro- intestinal tract, but there is still much to be learned on the subject. Morphin does not interfere directly with the secre- tion of urine, but in larger doses it causes the sphincter of the bladder to contract, preventing urina- 60 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM tion ; hence it is often necessary to empty the bladder by means of a catheter during morphin poisoning. Morphin is absorbed readily from the gastro-intes- tinal tract, and more rapidly after subcutaneous injec- tion. Opium is used in the form of a pill when it is desired to retard absorption in order that the local action in the stomach and intestine may be prolonged, the colloidal matter delaying the absorption of the alkaloid. Various explanations have been offered for the alleged greater action of opium than of an amount of morphin equal to that which it contains, but there is no satisfactory evidence that opium has any advan- tages over morphin except those just mentioned, which insure its increased local action. Morphin is fixed in the liver of some animals in considerable amounts, and a small proportion may pass into the urine, though testimony on this subject is conflicting; the kidneys are probably negligible as excretory organs when one is seeking to hasten elimination during morphin poisoning. It is of the first importance that morphin is excreted into the stomach after it has entered the circulation, but it is probable that this excretion is not very active after the first hour following the absorption of the drug into the circulation. It is sometimes stated that the excretion into this organ goes on for many hours, but it is probable that in such cases absorption has been prolonged. It is surprising that we know so little about the rate of elimination of morphin by previously healthy man in .view of its obvious importance in medicolegal cases. Since cumulation does not occur when mor- phin is taken several times daily by habitues, we must suppose that they, at least, are capable of destroying or excreting the drug fairly rapidly. Morphin is not dangerous to the infant in the uterus, since it does not breathe through its lungs, but it is dangerous to administer it to the mother at such a time that it will be in the fetal circulation at the time of birth, as it depresses the respiratory center and may cause death. It is excreted in the MORPHIN 61 milk of the nursing mother, and may give rise to poisoning of the infant in that way. The odoriferous principle of opium is excreted in the urine and may afford a clue in cases of suspected poisoning. TOXICOLOGY Few drugs have assumed greater toxicologic impor- tance than opium and morphin, as the various tables of death by poisoning attest. Habitues become careless and in many instances have taken overdoses with fatal effect. Morphin has been dispensed by error for quinin in many instances. The administration of soothing syrups to infants has been a prolific source of fatal poisoning. Morphin is a favorite method of suicide because of the painless death which it causes, but it is not so frequently used for the murder of adults as some of the more rapidly acting poisons, because the symptoms are apt to attract attention and treatment is so commonly successful. It is more commonly used for the inurder of infants, however, and unfortunately, statistics on this score are probably of little value. The importance of determining from what part of the cadaver any morphin was recovered may be illustrated by the following: A woman was found dead in a bath-tub of water. The person accused of her murder maintained that the dead woman had taken morphin as a preliminary to self-destruction by drowning. Morphin was found in the gastro-intes- tinal tract, but the chemist had not examined the duodenum and the ileum separately, and could give no information as to the source of that part of the recovered morphin. Fortunately, he recovered a notable amount from the gall-bladder, showing con- clusively that it had been absorbed; it seemed so improbable that the woman could have carried out the purpose of drowning herself after the morphin she had taken had been absorbed into the circulation, that the accused was led to confess. The fatal dose of morphin varies so widely with the circumstances attending its administration that it is 62 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM impossible to convey an accurate idea of the fatal dose in a single sentence. It is often stated that infants are extraordinarily susceptible to all opiates, but several pediatrists have recently stated that very small children frequently take opium and morphin very well. It is not advis- able for the general practitioner to disregard the almost universal testimony on this subject until we know more about the conditions under which opium and morphin may be given to infants with safety. Reference to the pages of The Journal during the past few years will disclose the fact that many deaths have followed the administration of soothing-sirups to infants. Morphin is oxidized readily into the harmless oxydimorphin. This change may even take place in old pills of morphin which contain acacia as an excipient; it may occur in solutions which are kept for some time; and it is induced almost instantly by potassium permanganate, which is therefore of great value in destroying any morphin with which it may be brought into contact in the stomach. This change also probably takes place slowly in the body when morphin has been taken. The treatment of morphin poisoning demands the washing of the stomach at frequent intervals as long as the washings give any evidence of containing mor- phin ; the bowels should be emptied by vigorous means in order to remove any of the poison that may have been excreted into the intestine or which reaches it jfrom the stomach. The patient should be kept awake if this is possible without resorting to violent means. Efforts should be directed toward sustaining the respiratory center; this may be so depressed that the respiration is insufficient long before death, and one should not wait for actual paralysis before beginning artificial respiration. Caffein is a valuable stimulant both for the respiratory centers and for the cerebrum. The free use of atropin is sometimes advised, but this is evidently a source of danger. It would be better not to use more than one, or possibly two, therapeutic doses of atropin, and if stimulation still be needed MORPHIN 63 resort should be had to caffein. Since the tonic con- traction of the pylorus may prevent the passage of fluid into the intestine, antidotal drugs should not be administered by mouth, except such as are added to the water for washing the stomach. The treatment of chronic morphinism cannot be detailed here, but it may be stated that other narcotics, such as belladonna, are usually substituted for the morphin until the painful stage of withdrawal has been passed. Relapses are common, but the treatment can be taken repeatedly, and an ultimate complete cure may be effected. Morphin is decomposed at a temperature slightly above that at which it distils, and this is very near the temperature which obtains in the opium pipe. Hence the question has arisen whether the opium-smoker actually absorbs morphin or not; it seems probable that some morphin passes over with the smoke and, being inhaled, is absorbed. THERAPEUTIC USES The celebrated remark attributed to Sydenham, that few physicians would be so callous as to practice medi- cine without opium, suggests the variety of condi- tions in which the opiates are used. Morphin stands first among drugs for the relief of pain. It often gives relief when used in doses which have hardly any other perceptible effect, but intense pain may require the use of the largest doses. Neuralgia affords one of the few examples of con- ditions in which other drugs are to be preferred to morphin as analgesics. Alfred Pearce Gould states that in Middlesex Hos- pital Cancer Charity (London), where from 90 to 100 cancer patients are treated constantly, morphin is now used much less than formerly, and that in a ward having thirty-two patients, months may elapse between the administration of two doses of the drug, reliance being placed on aspirin and phenacetin for the relief of pain. He says that morphin often leads to more suffering than the disease. 64 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM This suggests the inadvisability of resorting to mor- phin and opium unless they become absolutely neces- sary, in the early stages of malignant disease which tends to progress slowly and from which the patient may suffer for years. Morphin -often affords relief to patients suffering with cardiac disease, and while various suggestions have been oft'ered in explanation of its action in such cases, we are unable to say on what actions the relief depends. There are comparatively few conditions in which morphin is indicated as a simple hypnotic, since we now have a series of drugs better adapted for this purpose, but sleep may be afforded by relieving pain which prevented it. Morphin is useful to prevent cough when this is not attended with free expectoration and is of suffi- cient frequency to prove distressing, or when it inter- feres with sleep. When bronchial secretion is free the cough is necessary to remove it, and interference with the cough at this time results in the accumula- tion of fluid in the air passages, making the patient's ultimate condition worse. Marphin and opium are used as diaphoretics, espe- cially in the form of Dover's powder, in which the dilatation of the skin vessels by morphin promotes the diaphoretic action of the ipecac. Morphin allays restlessness, and this is very commonly utilized in the treatment of inaccessible hemorrhage. The vasodilator action of morphin is sometimes used in the treatment of eclampsia, in which no other drug is so valuable, if enough be given, according to H. Oliphant Nicholson. He employes doses of 30 to 45 mg- (% to % grain) and as many as four of such doses in a day. It is said that the dilator action then induces diuresis. Opium acts locally to diminish intestinal peristalsis, and this action is utilized in a variety of conditions, many of which do not require enumeration. Opium in peritonitis serves the double purpose of relieving pain and restlessness and of immobilizing the intes- MORPHIN 65 tine. It is useful in checking the excessive peristalsis in diarrhea. Morphin is frequently used previous to general anesthesia to allay the nervous apprehension of the patient and to secure sleep. It also acts synergetic- ally to chloroform and ether, less of which is required for general anesthesia after morphin than without it. The synergistic action of chloroform and morphin on the respiratory center appears to be a source of dan- ger in their combined use. The depression of the respiratory center prevents, to a certain extent, excessive respiration accompanying variations in the depth of anesthesia. Accidental death from too rapid administration of ether is not common, with dogs, at least, after morphin; in fact, it is sometimes impossible to kill dogs by the ordinary administration of ether when they have previously received large doses of morphin. Codein is now largely prepared synthetically from morphin, and is obtained in a purer form than it was formerly. Codein and ethyl morphin hydrochlorid are much less active than morphin, which they resem- ble otherwise. Codein is said to be only about one- tenth to one-twentieth as active as morphin, and while this may be true so far as the narcotic action is con- cerned, it is not used therapeutically in doses twenty times as large as those of morphin. Its analgesic action is so slight as to make it much less valuable than morphin, but it does dull pain to some extent, and the probable absence of euphoria, which leads to the habit with morphin, is a distinct advantage of codein. It is said to have an especial value for the relief of abdominal and pelvic pain. The actions of ethyl morphin hydrochlorid on the central nervous system are very similar to those of codein, and in addition it is irritant to the mucous membrane of the conjunctiva, this action being util- ized in the treatment of conjunctivitis, iritis and corneal opacity, but it sometimes causes acute edema of the conjunctiva from local vasodilatation. Ethyl morphin hydrochlorid (dionin) has been exploited to some extent as an analgesic and sedative 66 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM but there is no satisfactory evidence that it is equal to morphin for these purposes. Diacetyl-morphin (heroin) differs from morphin to a greater degree than codein and dionin. Diacetyl- morphin and its action in lessening cough have been known for many years, but it was not used thera- peutically until Dreser investigated it in 1898, and stated that it decreased the reflex excitability of the respiratory center toward painful stimuli, such as those which induce cough, more than it does toward carbon dioxid, the normal stimulant of the center. He also stated that it slows the rate of respiration while the depth and force of the individual respirations are increased, and he suggested that the increased force of the respirations would be of value in the treatment of bronchitis, in which the air-passages are narrowed. Dreser experimented with rabbits, but it has been shown that his results do not apply to the use of heroin on man, and Cushny has shown recently that heroin influences the respiration exactly as morphin does; it has, therefore, no evident advantage over the older drug in the treatment of cough. Diacetyl-morphin is much more toxic than morphin and must be used in correspondingly smaller doses. It gives rise to the habit quite as readily as morphin does, and the habit is as difficult to break and fully as injurious. Diacetyl-morphin is said to be less actively narcotic in proportion to its activity on the respiratory center, and it is also less actively analgesic than morphin; its use should be limited, therefore, to the relief of cough, if, indeed, it were not better to use morphin or codein in these cases also. Indian cannabis is usually classified with the mor- phin group, but its action is feeble compared to that of opium, and its effects are so uncertain that it is probable that there is no condition in which opium or morphin does not deserve the preference. Extract of Indian cannabis is said to be a constituent of the extensively advertised proprietary hypnotic Bromidia, and it is probable that the continued belief in the value of Indian cannabis as a hypnotic is due in no small measure to its exploitation in this prepara- tion. MORPHIN 67 DOSAGE Morphin sulphate is analgesic in doses of from 3 to IS mg. (%o to % grain), the smaller doses lessening or abolishing mild pain, (such as may inter- fere with sleep) and intense pain requiring the larger- dose. Even this may require repetition before relief is afforded, but it is preferable to use an insufificient dose and repeat it in half an hour, rather than run the danger of giving too large a dose at once. The dose used for the relief of cough varies widely, dependent on whether it is desired to lessen the fre- quency of a troublesome cough without interfering with its removal of the secretion, or to abolish a severe irritative "dry" cough, which interferes with sleep. The former will require from 1 to 2 mg. (%o to %o grain) and the latter will require somewhat larger doses and more frequent repetition. Eight mg. (% grain) of morphin or 0.06 gm. (1 grain) of opium in the form of Dover's powder is used for its diaphoretic effect. A single dose taken on retiring is a popular treatment for "colds." When morphin is used just prior to gen- eral anesthesia, the dose is from 8 to 16 mg. (Vs to 1/4 grain), and when used some hours previously to secure sleep and allay apprehension, the larger dose will be required usually, or the smaller dose may be used and repeated when the effect begins to pass off. The aim with all narcotic drugs should be to secure the desired action with the absolute minimum of the drug, and it is always best to give a small dose when there is any doubt concerning the amount which will be required and repeat it if necessary. Codein and its salts are given in doses of 0.03 gm. (Vs grain) or more, this dose corresponding to approximately 0.003 gm. (%q grain) of morphin. Its use can be long continued without much fear of giv- ing rise to the habit. Half the dose may be used and repeated with cor- respondingly greater frequency when desired. The average dose of diacetyl-morphin, or heroin hydrochlorid, is 3 mg. (^^o grain). Its use should not be long continued because of its extreme tendency to induce the habit. 68 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM MATERIA MEDICA Morphin, an alkaloid obtained from opium, is the chief therapeutic constituent of the drug. In medical literature the term "morphin" is hab- itually used indiscriminately for the alkaloid and its salts, but the prescriber should not write "morphin" when the sulphate, or other salt, is desired. Morphin and its salts occur in commerce as colorless or white crystals or as a crystalline powder, odorless, and hav- ing a bitter taste. The dose of the several products is comparable and from a practical point of view the only important difference to note is their solubility in water and in alcohol. Morphin is official as : Morphina. — Morphine, U. S. P. Morphinae Hydrochloridum. — Morphine Hydro- chloride, U. S. P. Morphinae Sulphas. — Morphine Sulphate, U. S. P. The solubility of the several constituents varies considerably and suggests the limitation to the pos- sible uses. Water Alcohol Morphin is soluble in 3,330 parts 168 parts Morphin hydrochlorid is soluble in 17.2 parts 42 parts Morphin sulphate is soluble in 15.3 parts 465 parts Several additional salts of morphin have been used, more notably the acetate, but because of its unstable character and the fact that the liberated alkaloid is only slightly soluble in water, this salt has fallen into disuse. Apomorphinae Hydrochloridum. — Apomorphin Hydrochloride, U. S. P. (See under Emetics.) Opium. — Opium, U. S. P. The concrete milky exudation of Papaver somniferum. In medicine it is usually used in the form of: Opii Pulvis. — Powdered Opium, U. S. P. The forthcoming pharmacopeia will require that powdered opium contain 10 per cent, of morphin, or about 20 per cent, less than that required by the U. S. P. VIII. Extractum Opii. — Extract of Opium, U. S. P. A powdered extract which when assayed by the official MORPHIN 69 process should yield 20 per cent, of crystallized mor- phin. For practical purposes this preparation has little or no advantage over the powdered opium and its use should be discouraged. Tinctura Opii. — Tincture of Opium, U. S. P. Laudanum. Tinctura Opii Deodorati. — Tincture of Deodorized Opium, U. S. P. The forthcoming pharmacopeia will require that tincture of opium and the deodorized tincture repre- sent 10 W/V per cent, of the powdered drug, as the U. S. P. VIII does, but since powdered opium will contain only 10 per cent, of morphin, the tinctures will contain only 1 per cent, of morphin. The deodorized tincture of opium is made by remov- ing the volatile oil and its resinous constituents from the aqueous solution by means of purified petroleum benzin and adding alcohol to the filtered solution. The two preparations are otherwise comparable and have practically the same uses. Tinctura Opii Camphorata. — Camphorated Tinc- ture of Opium, U. S. P. This preparation, popularly known as paregoric, represents powdered opium (0.4 gm.), benzoic acid (0.4 gm.), camphor (0.4 gm.), oil of anise (0.4 c.c.) and glycerol (4 c.c.) in diluted alcohol (to make 100 c.c). This mixture is widely used and abused, and its promiscuous administration to children has been the cause of more harm than good. Pulvis Ipecacuanhae et Opii. — Powder of Ipecac and Opium, U. S. P. Dover's powder consists of a mixture of ipecac (10 gm.), powdered opium (10 gm.) and sugar of milk (80 gm.). Codein or methyl-morphin is official in several forms, and as with morphin, the word "codein" is appHed in medical literature to the alkaloid and its salts. The official forms ar.e : Codeina. — Codein, U. S. P. Codeinae Phosphas. — Codein Phosphate, U. S. P. Codeinae Sulphas. — Codein Sulphate, U. S. P. 70 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM These several forms of codein usually occur as crystalline powders, odorless and having a faintly bitter taste. The solubility in water and in alcohol is shown in the following table: Water Alcohol Codein is soluble in 120 parts 1.6 parts Codein phosphate is. soluble in 2.25 parts 261. parts Codein sulphate is soluble in 30. parts 1,035. parts Ethyl-Morphinae Hydrochloridum. — Ethyl-Morphin Hydrochloride, N. N. R. This preparation, commonly known as dionin, usually occurs as a white crystal- line powder, odorless and having only a slightly bit- ter taste. It is freely soluble (1:7) in water and (1:2) in alcohol. Diacetyl-morphin (heroin) is generally used in the form of: Diacetyl-Morphinae Hydrochloridum. — Diacetyl- Morphin Hydrochlorid, N. N. R. This preparation, commonly known as heroin hydrochlorid, is a salt of a base formed by the action of acetyl-anhydrid on water-free morphin. It occurs as a white crystalline powder, odorless and having a bitter taste. It is freely soluble (1:2) in water and in alcohol. MORPHIN AND SCOPOLAMIN Some years ago Schneiderlin, a surgeon connected with an institution for the insane, administered mor- phin and scopolamin to a patient in the institution for the purpose of diminishing the amount of gen- eral anesthetic necessary for a major surgical opera- tion, and was surprised to find that he was able to remove a cancerous breast without administering chloroform or ether to induce general anesthesia. After performing a small nurnber of operations in which morphin and scopolamin were employed in this way, he suggested the use of the combination as a substitute for general anesthetics, or to render more than a few drops of the latter unnecessary for. sur- gical operations. Schneiderlin seems to have been under a misappre- hension concerning the degree to which morphin and scopolamin are antagonistic, and to have supposed that they were synergistic only in their narcotic effects, MORPHIN AND SCOPOLAMIN 71 for he placed much stress on the importance of the antagonisms in their side actions. In truth, the antagonisms between morphin and scopolamin are of minor importance, but they have an extraordinary degree of synergistic action on the respiratory center, sometimes causing paralysis in minute doses of the combination. The morphin-scopolamin narcosis was tried by many surgeons, but the fatalities following its use were so numerous that it was abandoned by the great .majority of operators, but it has been exploited in a sensational manner both in Europe and in the United States as a preliminary to childbirth. Effective doses are not very dangerous to the mother, in the hands of those who have mastered the difficult technic of its use, but labor is frequently prolonged by its use and the death-rate among the new-born from asphyxia is certainly higher than with other methods in the hands of the general practitioner. Under no circumstances should the single dose exceed 0.01 gm. (% grain) of morphin and 0.5 mg. (K25 grain) scopolamin, nor should this be repeated until the effects have passed (several hours). The combination is strongly contra-indicated outside of special institutions, and except in the hands of those who are trained in its use. Morphin and scopolamin do not produce total insensibility to pain when used in doses which are safe, but they induce a peculiar condition — the so-called "twilight sleep" — in which everything is quickly forgotten, so that the mother has no recollec- tion of anything that happened during labor. An American manufacturer combines an extract of cactus, known as caetoid, with scopolamin (or hyoscin), claiming that the danger to the heart is overcome thereby; but it has been shown by several investigators that cactus and all its preparations are inert; hence such combination can have no advantage over the simpler one. Another manufacturer has sought to avoid the decomposition of scopolamin, to which the injurious action is attributed, by the addi- tion of an alcohol, but this is of no practical advan- tage. 72 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM Various combinations of opium alkaloids under trade names, including Omnopon, Pantopium and Narcophin, have been introduced with the claim that they have all the advantages of morphin without the side actions, but independent observers have not found the expensive substitutes preferable to morphin. ANTIPYRETICS AND ANALGESICS The drugs of this group are classified conveniently under this heading, though they are seldom used therapeutically for the reduction of temperature alone. The discussion of their actions will be facili- tated by a brief consideration of the regulation of body temperature in health and in fever. There is no known anatomic center for the direct regulation of the body temperature, but there is cer- tainly a coordinating mechanism, in addition to any local mechanism in the skin, whereby the tempera- ture of the body is maintained both in health and in fever, and reference to this mechanism is made when the heat-regulating centers are mentioned. The efficiency of the heat-regulating mechanism is shown by the fact that the production of heat may be increased 60 per cent, by taking food, or during severe exercise, without causing a rise in the tem- perature of the body. Fever results from a change in the heat-regulating centers whereby they appear to economize the heat loss, so that while with any increase in the heat for- mation there is normally a compensating heat loss, during fever a slight increase in heat formation is attended with some increase in the loss, but not enough to prevent the temperature from rising to a given degree. The centers do not lose control of the regulation, otherwise the temperature would continue to rise indefinitely, and in fact, during fever the centers are more sensitive to external changes in temperature and to the influence of drugs than normally. This increased sensitiveness may be looked on as the effect of stimulation of the centers by drugs or disease products. We may look on the antipyretic actions of the drugs of this group therefore, as depressant to QUININ 12, the heat-regulating centers, preventing them from maintaining the higher temperature, which then returns toward normal. This conception led to Schmiedeberg's classifying the antipyretics of this group as fever narcotics. The antipyretic effect of quinin is due mainly to diminished heat production through its peripheral actions; the other antipyretics of the group lower the body temperature through their central action which increases the elimination of heat, but quinin also has some central action, and the other anti- pyretics lessen heat formation, so that their actions differ mainly in degree. It seems probable that fever may have a protective value in infectious diseases, siijce it appears to favor the formation of antibodies, and it is no longer held that hyperpyrexia is responsible for many of the pathologic changes which are found at necropsy, and which were formerly attributed to the febrile tem- perature which was therefore considered so dan- gerous. It was owing to this erroneous view that the anti- pyretics had an enormous vogue soon after their intro- duction, and for a time there was intense activity in the search for new and better drugs of this type. QUININ It is commonly stated that the therapeutic use of cinchona, from which quinin is prepared, began with •the treatment of the Countess of Chinchon in Peru in 1638, during an attack of malaria. The Jesuits employed it in the treatment of malaria in Europe, and from the foregoing circumstances it was variously called, Chinchona bark, Cinchona, Peruvian bark, Countess' bark, Jesuits' bark or simply "the bark." At present nearly all of the quinin of commerce is obtained from cinchona cultivated in India and Java. Quinin is a protoplasm poison and is capable of destroying various forms of animal and vegetable cells. While it exerts its toxic action on such a variety of structures, it is extraordinarily active in destroying certain low forms of life. In 1867 Binz observed that in weak solutions it killed the para- 74 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM mecium of hay infusion at once, and that in very dilute solutions (1:20,000) it exerted a markedly toxic action on them, though they were much more resistant to the action of other poisonous alkaloids such as morphin and strychnin. These observations led Binz to the conclusion that malaria is due to a parasite which quinin is capable of destroying readily. The correctness of this conclusion has been abund- antly proved, of course. Since the great value of quinin in the treatment of malaria depends on its destructive action on these micro-organisms, it may be worth whjle to present briefly the more important facts concerning their pres- ence in the human body. It is known that when the anopheles mosquito bites a patient suffering with malaria it takes the malarial fever organisms into its stomach with the blood which it draws; that this blood contains asexual forms and smaller numbers of others which take on the sexual form and after passing through a cycle in the body of the mosquito, are injected with the saliva into the body of a person whem the mosquito bites later.. These organisms, known as sporozoites, enter the blood and attack red blood-corpuscles, assuming a form which then multiplies in the blood. The sporozoite undergoes segmentation, and with the breaking up of the red blood-corpuscles and discharge of the young parasites into the blood there occurs a paroxysm of malaria, that is, a chill followed by a hot stage, presumably due to the discharge of toxins into the blood-stream. Quinin is most destructive to the young parasites at the time they are discharged into the blood-stream, and it is important that the administration be so timed as to secure a sufficient concentration in the blood during the time that sporulation occurs. Unfortun- ately, in addition to the forms which quinin destroys readily, there are others which are more resistant and which may survive to become sources of infec- tion through the anopheles. The testimony of eminent authorities appears to be contradictory concerning the capacity of quinin to prevent an oncoming paroxysm. Thus Osier states QUININ 75 that quinin has no power to prevent an oncoming paroxysm which attends segmentation ; Ricketts states that quinin given some hours before the time of an expected paroxysm prevents segmentation and thus prevents the paroxysm. This is in accordance with the teaching prevalent in some malarial districts, and there can be little doubt that a large dose of quinin given four hours before the time of the expected paroxysm may prevent it, but it has no influence on a paroxysm which is just beginning-. The action of quinin on the blood and its capacity for causing hemoglobinuria have been the subject of much discussion. Quinin even in dilute solution is known to be capable of destroying both the red and the white cells of the blood in vitro. Hemoglobin- uria has been observed frequently after the adminis- tration of quinin, which was therefore believed to be its cause. Hemoglobinuria may occur during malarial fever, however, without the administration of quinin, and the view now held by the most eminent authori- ties is that quinin is not the cause of the hemoglobin- uria which sometimes follows its use in malaria. It should be remembered that washed corpuscles behave differently toward various drugs in vitro from the way they behave when those drugs are injected directly into the blood-stream. For example, saponin destroys red blood-cells suspended in normal salt solution, but when a solution of saponin is injected into the blood-stream directly, the saponin is fixed by the cholesterin present in the blood and the red blood- cells escape injury. Binz states that 1 gm. (15 grains) of quinin hydrochlorate in 10 per cent, solution may be injected intravenously without causing injury to the blood. There would then be 1 part of quinin to about 5,000 parts of blood. Very small amounts of quinin are capable of increasing the force of muscular contraction, but slightly larger amounts decrease the force and effici- ency. This is of interest with regard to the action of quinin on the heart when large doses are given, and also with reference to the action on the uterus when quinin is used to increase the force of uterine con- tractions during labor. One can understand why it 16 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM should sometimes have the desired effect and why it should sometimes fail, owing to the difficulty of adjusting the dose with precision. It seems probable that the action of quinin will be useful when induced at such a period that a few powerful contractions will suffice to expel the fetus; but if labor is not nearly terminated the induction of a few powerful contrac- tions may be followed by weaker ones, and labor may be prolonged through its depressant action. Fortun- ately, it does not cause spasm of the uterus as many of the oxytocics do. Quinin is not used for its action on the muscu- lature of the heart, but it is of toxicologic importance. It is also of interest to note that cinchonidin is more poisonous to the heart and much less actively destruc- tive to the malarial fever parasites. Cinchonidin was formerly much cheaper than quinin, which it resem- bles closely in appearance and in physical properties, and for which it was often fraudulently sold. Quinin lessens the action of enzymes and of oxida- tion and it causes a diminution in the amount of heat formed in the body through its lessening metabolism by its action on muscles and glands. With small doses this diminution in the amount of heat formed does not cause a fall in the body temperature during health, because the heat-regulating centers compen- sate for the change by causing a diminished loss of heat. During fever quinin acts as an antipyretic (aside from its specific action in malaria), partly through this diminution in heat production and partly by depressing the heat-regulating centers. It is said that this influence in diminishing metabolism is useful in certain fevers by preventing an undue loss of pro- tein but it is probably of little value in this way. Quinin has only a slight analgesic action, and this has a limited field of application. TOXICOLOGY The prolonged use of quinin may result in injury to various organs, but the heart, the central nervous system, the gastro-intestinal tract and the kidneys usually suffer most in such cases. QuiNiN n Moderate doses of quinin commonly cause ringing in the ears which lasts for some hours; large doses may cause partial or complete deafness, the effect being brief as a rule, but occasionally permanent. Dizziness, headache, nausea and vomiting with dis- turbances of the circulation and respiration occasion- ally result, and it may cause cardiac failure; dis- turbances of vision are rare. Skin rashes are fairly frequent. The average fatal dose of quinin probably lies between 8 and 15 gm. (120 and 240 grains), much depending on the rate of its absorption. ABSORPTION AND EXCRETION Even the least soluble of the salts of quinin are absorbed fairly readily from the gastro-intestinal tract. In order to secure the more rapid action the more soluble of its salts are sometimes recommended, but there are occasions when an insoluble salt is pre- ferred because of its less pronounced bitterness. The use of the sulphate in the United States affords an example of the force of habit, the hydrochlorate, which is used almost exclusively in England, being much more soluble. Thayer states that the rate of absorption and its total amount vary widely with the solubility of the salt used and the form in which it is administered, absorption being retarded when it is taken with the food. In view of the importance of securing the absorption of quinin at such a rate that the requisite amount will be present in the circulation at the time of segmentation of the parasites, it is unfortunate that our knowledge of the subject is so imperfect.* It is probable that too much importance has been attached to the influence of the degree of solubility of the salts of quinin on their absorption, and too lit- tle attention to the selective capacity of the gastro- intestinal tract for absorbing them. The question is in need of further investigation. The utmost care should be exercised to secure aseptic conditions, when 4. Guinea-pigs were used in a recent study of the absorption of quinin, but this would appear to be an especially unfortunate choice of animal because rodents absorb certain vegetable poisons from the gastro- intestinal tract very slowly, and apparently not at all, in some cases. 78 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM a salt of quinin is injected subcutaneously or intra- muscularly, because of its destructive action on the tissues, which leads to abscess. Quinin usually begins to appear in the urine shortly after its administration, and almost the entire amount may be excreted within two days. A part is excreted into the stomach after its subcutaneous injection. THERAPEUTIC USES The chief therapeutic uses of quinin have been sug- gested in the foregoing discussion, and the subject requires only brief consideration here. Quinin finds its principal field of usefulness in the treatment of malaria, being one of the few directly curative agents in the materia medica. It is a matter of little importance, so far as the action is concerned, which of the salts of quinin is used, provided the one chosen is so administered as to secure absorption at such a rate that the blood will contain the quinin some hours before and during segmentation, or when segmentation would occur if it were not prevented by the drug. Cinchonidin has been used in some cases when an idiosyncrasy, real or fancied, prevented the use of quinin, but the slight antimalarial action and the toxic- ity of cinchonidin render it an unsatisfactory substi- tute for quinin. Quinin is an active antipyretic, and while it may be of some value during protracted fevers, such as typhoid, by reason of its lessening metabolism, and thereby preventing excessive destruction of protein, it is not certain that this advantage will outweigh its disadvantages in such conditions. Its use during labor has been mentioned. While it does not cause spasm of the uterus, it is not always successful in facilitating the expulsion of the fetus! Small doses may be used as a bitter for improving the appetite and digestion; large doses have an oppo- site effect. It is sometimes used at the inception of a cold, but its value in such conditions is problematic. It is also used as an antipyretic and analgesic in influ- enza, but it is probably less effective than phenacetin QUININ 79 and salol. Opinions differ somewhat concerning its value in the treatment of blackwater fever. It would not be profitable to attempt to discuss the innumerable conditions and diseases in which quinin has been used with reputed success; many of these cases merely serve to illustrate the tendency which the body shows to recover regardless of treatment — even when it is distinctly injurious — and it should hardly be necessary to state that such an active agent as quinin should never be used without having a definite action in view. Quinin and urea hydrochlorid has been used as a local anesthetic in the same way as cocain. Quinin is a prophylactic against malaria, and those who are exposed to the bite of the anopheles in malarial regions should take it regularly; but it is of course more sensible to screen houses and destroy mosquitoes than to trust to quinin alone. DOSAGE The widest diversity of opinion exists in regard to the dosage of quinin in the prophylaxis and treatment of malaria. Some authorities advise as much as 2.5 gm. (40 grains) daily during the active treatment, and smaller amounts at stated intervals afterward. A dose of 0.6 gm. (10 grains) of a salt of quinin administered about four hours before the time of an expected paroxysm, and this dose repeated in two hours, will suffice to prevent segmentation and the paroxysm in many cases. When the paroxysm is pre- vented the administration of quinin should be con- tinued for several weeks. Some advise the adminis- tration of doses of 0.3 gm. (5 grains) three times daily for one or two months ; others prefer the admin- istration of somewhat larger doses on those days when the paroxysms would fall had they continued, and none on the other days. It seems more logical, how- ever, to use the drug every day. It is especially unfortunate that these questions of dosage have not been determined conclusively, for the continued administration of quinin in large amounts is certainly capable of causing harm in many cases, but the dan- 80 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM ger of moderate doses for two months is far less than that of an attack of malaria. The prophylactic dose of quinin is probably 0.6 gm. (10 grains) daily, preferably taken in two parts. The tincture of cinchona, or the compound tinc- ture, is generally preferred when the bitter effect is desired ; the dose of either is 4 c.c. ( 1 fluidram) taken just before eating. MATERIA MEDICA Cinchona. — Cinchona, U. S. P. The dried barks of several species of cinchona are official as Cinchona, and Cinchona Rubra; these are required to contain not less than 5 per cent, of the typical cinchona alka- loids. Powdered cinchona was used largely at one time, but it has been almost completely supplanted by quinin. Tinctura Cinchonae. — Tincture of Cinchona, U. S. P. One hundred c.c. of the tincture represents 20 gm. of cinchona in a mixture of alcohol, water and glycerin. Tinctura Cinchonae Composita. — Compound Tinc- ture of Cinchona, U. S. P. This preparation, com- monly called Huxham's tincture, is made from the red cinchona, with bitter orange and serpentaria as aromatics. The menstruum is like that of the simple tincture of cinchona. Quinina. — Quinin, U. S. P. An alkaloid obtained from the bark of various species of cinchona. Quinin is a white flaky or microcrystalline powder, odorless and having a very bitter taste. It is slightly efflores- cent in dry air and only very slightly soluble (1 : 1,750) in water but very soluble (1 : 0.6) in alco- hol. Combined with mild alkalies like sodium bicar- bonate to retard the development of bitter taste in the mouth, quinin alkaloid is perhaps as satisfactory as any of its insoluble salts. Quininae Bisulphas. — Quinin Bisulphate, U. S. P. The acid sulphate of quinin occurs as colorless, trans- parent or as whitish needle-shaped crystals, odorless and having a very bitter taste. Quinin bisulphate effloresces when exposed to air and turns yellow on exposure to light. It is freely soluble ( 1 : 8.5) in water and soluble ( 1 : 18) in alcohol. QUININ 81 Quininae Hydrochloridum. — Quinin Hydrochlorid, U. S. P. The hydrochlorid of quinin occurs as white, silky glistening needles, odorless and having a very bitter taste. It is slightly efflorescent in dry air, and is soluble (1: 18) in water and very soluble (1:0.6) in alcohol. Quininae Sulphas. — Quinin Sulphate, U. S. P. The sulphate of quinin occurs as white glistening crystals or prismatic needles, odorless and having a very bitter taste. It effloresces rapidly on exposure to dry air and is only slightly soluble ( 1 : 720) in water but soluble (1:86) in alcohol. Quininae Tannas. — Quinin Tannate, U. S. P. The tannate of quinin occurs as an amorphous pale lemon- yellow odorless powder, without taste or at most slightly bitter. It is only slightly soluble ( 1 : 800) in water but soluble (1:3) in alcohol. Quinin tannate contains only from 30 to 35 per cent, of anhydrous quinin, is less than one-half the strength of other salts of quinin and must therefore be given in cor- respondingly larger doses. Quininae et Ureae Hydrochloridum. — Quinin and Urea Hydrochlorid, N. N. R. A compound of quinin hydrochlorid and urea hydrochlorid which occurs as white, interlaced prismatic crystals, odorless and hav- ing a very bitter taste. It is freely soluble (1:1) in water, which makes it available for hypodermic use. The comparative value and uses of the salts of quinin enumerated above are suggested by the fol- lowing table showing the relative percentage of anhy- drous quinin in each and also the relative solubility in water and in alcohol. Per Cent, of Anhydrous i One part soluble in^ > Quinin water (parts) alcohol (parts) Quinin 8S.S 1,750. 0.6 Quinin bisulphate... S9.S 8.S 16. Quiniri hydrobromid 76.6 40. 0.7 Quinin hydrochlorid 81 .5 18. 0.6 Quinin salicylate 69.9 77. 11. Quinin sulphate 74.3 720. 86. Quinin tannate 30.35 800. 3. Quinin and urea hydrochlorid 60. 1. ••■• 82 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM Quinin and the several salts of quinin may be administered in the form of pills, capsules, cachets, tablets, troches, solutions and mixtures, but the form in which the article is administered should be adapted to the particular salt of quinin used. The solid forms, like pills and capsules, are, of course, adapted to any of the salts of quinin, while solutions of sufficient strength to be active can be made only by the use of the acid salts. Mixtures, on the other hand, are pre- ferably used for the administration of the more or less insoluble alkaloid and tannate. A syrup of glycyr- rhiza made by mixing one part of fluidextract of glycyrrhiza with three parts of syrup makes a satis- factory vehicle for any of the slightly soluble salts of quinin. A syrup of yerba santa, which was for- merly much used as a vehicle for quinin, is now but seldom employed because it does not compare in elegance or efficiency with the syrup of glycyrrhiza outlined above or a syrup of chocolate, such as is gen- erally used at the soda-water fountain of drug-stores. The commercial form of sweet chocolate is an excel- lent vehicle for quinin, either in the form of the syrup suggested above or as a simple mixture of quinin tan- nate or quinin alkaloid with the chocolate in the form of pastilles or troches. In administering a mixture of quinin it is advisable to direct that the mouth be rinsed with a dilute solu- tion of a weak alkali like sodium bicarbonate, before and after taking the dose of quinin, so as to avoid the bitter taste of a trace of alkaloid which may dis- solve in the mouth. SUBSTITUTES Among the substitutes which have been proposed for the non-proprietary preparations of quinin are: Euquinin, which is quinin ethyl carbonate and is claimed to have the same action as quinin with the advantage of being tasteless owing to its insolubility in water and alkaline medium. It is, howeyer, spar- ingly soluble in water and readily soluble in alcohol and in acid liquids generally, and in solution possesses the characteristic bitter taste of quinin. ACETANILID, ANTIPYRIN AND PHENACETIN 83 Salpquinin is salicyl quinin, the salicylic acid ester of quinin. It is thought to have the advantage of com- bining the properties of quinin and of salicylic acid. It is practically insoluble in water but is soluble in acidu- lated water and moderately soluble in alcohol. Like euquinin, when held in the mouth for an appreciable length of time, it develops a distinct bitter taste and therefore cannot be said to be absolutely tasteless. These complex salts probably have little or no advantage over quinin alkaloid and quinin tannate, which are much cheaper. ACETANILID, ANTIPYRIN AND PHENACETIN GROUP The introduction of the antipyretics and analgesics of this group affords one of the most interesting chap- ters of medical history. The high cost of quinin, which resulted in its adulteration, led to efforts to discover a method of preparing it synthetically, and in addition to the cost of the alkaloid, its bitter taste, and its relative insolubility, which interfered with its use by subcutaneous injection, served as a stimulus in the search for a substitute for it. While these efforts were unsuccessful so far as the immediate aims were concerned, they did lead to the discovery of numerous synthetic compounds, including the antipyretic anal- gesics which have come into use during the past thirty years. Curiously, the best drugs of this group were among the earliest discovered, and the exploitation of the newer members has been largely mercenary. Quinolin was used as the starting-point in the search for synthetic quinin or a substitute, because . it results from the decomposition of quinin, and it retains the antipyretic action of the parent substance, but it is too toxic for therapeutic use. Kairin and thallin were among the first of the synthetic antipyretics; they soon dropped out of use because of their toxicity. Antipyrin was prepared in 1884 by Knorr, who used phenyl-hydrazin as the starting-point, and who supposed that antipyrin con- tained two quinolin rings. It is now known to be phenyl-dimethyl-pyrazolon. 84 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM Anilin was known, as far back as 1861, to have antipyretic actions, but its toxicity precluded its thera- peutic use, and the attempt was therefore made 'to utilize its antipyretic action while reducing its toxic- ity by introducing various radicals into the molecule. Acetanilid, which results from the introduction of an acetic acid radical into the anilin molecule, was one of the earliest of these synthetic anilin derivatives, and it continues to be the cheapest and one of the best. Paramidophenol, which is closely related chemically to anilin and phenol, was found in the urine after the administration of one of the antipyretics, and this led to its use as a starting-point in the preparation of syn- thetic substitutes for the older members of the group. The introduction of an ethyl group into the paramido- phenol forms phenetidin, and the introduction. of an acetic acid radical into this forms acetphenetidin, or phenacetin, as it is commonly called. The antipyretic and analgesic actions of the drugs of the acetanilid and phenacetin type result from cer- tain compounds, such as paramidophenol, which are split off in the body from the parent drug. If they are split off too rapidly the action is too violent, and if they are split too slowly the action is too feeble; hence the therapeutic value of a member of this group depends on a gradual splitting of the drug in the body. Innumerable compounds may be formed by the introduction of other aromatic acid radicals in place of the acetic, or other alkyl groups in place of ethyl, but none of these has proved superior to acetanilid and phenacetin. Some are split very slowly and therefore have very little toxicity, but they are also less active therapeutically, and some are more active therapeutically, but are also more toxic. Fraenkel says that no cheaper and better substi- tute for antipyrin and phenacetin can be prepared from the parent substances, and that it is purposeless to continue to multiply these. While we should con- tinue to search for improved antipyretics and anal- gesics, such improvement can come only with develop- ment along wholly different lines. ACETANILID, ANTIPYRIN AND PHENACETIN 85 The various members of the group have closely similar actions, but they show considerable quanti- tative differences in activity. Their classification as fever narcotics indicates their depressant action on the higher parts of the brain, and in addition to their depression of the heat- regu- lating centers, it is probable that they cause an actual paralysis of certain paths concerned with the percep- tion of pain, because even small doses are usually as effective as larger ones in relieving certain forms of neuralgia. They have a slight tendency to induce sleep, and this tendency becomes more pronounced when one remains quiet after relief from headache or other pain, but the mental faculties may remain alert when one exercises them after the relief of headache. Large doses cause collapse, with disturbance of the respiration and circulation. The heart may become feeble and death may result from cardiac failure, but this is rare, and it never occurs after acetanilid, anti- pyrin or phenacetin, except when overdoses are taken by enfeebled patients, or excessive amounts by those suffering from minor illness. Severe, but not fatal, collapse is not infrequently seen after moderate amounts of these members of the group which are decomposed more rapidly than the three members just mentioned. If such rapidly act- ing members of the group are used, it would be bet- ter to ernploy minimal doses and repeat these more frequently than with the more slowly acting ones, but there seems to be no reason for their continued use. These drugs do depress the heart somewhat, but this action is overrated by manufacturers of nostrums who claim that their preparations lack this cardiac effect because it is overcome by the addition of caffein or other supposedly antagonistic substance. Curiously, caffein and the antipyretic analgesics of this group have a synergistic action on the heart; hence large doses of such compounds are, if anything, more dangerous than the drug which they are intended to displace. The antipyretic analgesics produce cyanosis when large doses are used, or when the smaller doses are 86 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM used continuously, and since they were known to injure the heart to some exent, it was supposed that this injury sufficed to explain the cyanosis. We know that the cyanosis is usually due to the formation of methemoglobin by the products of decomposition of the antipyretics, and the more rapidly they are decom- posed in the body, the greater is the action on the hemoglobin. The milder actions leave the corpuscles intact, but with the more violent action the corpuscles are broken down. This does not take place when the drugs are mixed with blood in a test-tube, because the drugs are not then decomposed. Those antipyretics of this type which are devoid of the action on the blood are also therapeutically use- less, because the paramidophenol, or analogous sub- stance, which causes the formation of the methemo- globin is also responsible for the antipyretic action and only those which are decomposed too slowly to exert a pronounced antipyretic and analgesic action are devoid of the action on the "blood. The antipyretics cause dilatation of the vessels of the skin; this promotes sweating, which is useful in the reduction of temperature ; in case this is excessive, atropin should be administered in small doses. The antipyretics, like narcotics in general, lessen metabolism and therefore the production of heat, but this is of much less importance than their action on the heat-regulating centers, for, as previously stated, it is through their influence on the loss of heat that the temperature is regulated for the greater part. ABSORPTION AND EXCRETION Antipyrin is very soluble in water, while acetanilid and phenacetin are only slightly soluble, but all are absorbed fairly readily from the gastro-intestinal canal, and are nearly always administered by the mouth. The rate of excretion appears to depend on the rate of decomposition to a certain extent, and none of the drug appears in the urine unchanged after the taking of moderate amounts of acetanilid, which is decomposed more rapidly than phenacetin. When the urine of a patient who has taken one of these drugs is exposed to the air, it may assume a ACETANILID, ANTIPYRIN AND PHENACETIN 87 dark color because of the oxidation of certain of the decomposition products. THERAPEUTIC DOSES The antipyretic analgesics are not used so fre- quently as they were formerly for the reduction of body temperature alone, but they are used in much the same conditions for the relief of pain, such as that occurring with influenza; for headache, which accompanies so many types of fever; and to allay nervousness, thereby securing rest and sleep which are essential for the patients' well-being and the want of which is so injurious to the heart and nervous system. They are sometimes used for the reduction of fever, when this is excessively high, but even in such cases the benefit derived is probably due mainly to one or more of the actions just mentioned. They are widely used for the relief of headache arising in the greatest variety of conditions. They sometimes afford prompt relief with small doses, and often fail even when large doses are used. In fact, if a small dose fails to relieve headache or neuralgia a large dose seldom proves efficacious. The wide-spread use of these agents by the laity for the relief of all forms of hea~dache and neuralgia and for pain which often attends menstruation should be discouraged because of the danger of their indis- criminate use, and especially because of the frequency with which overdoses are used in unsuitable cases. The patient who has once obtained relief through the use of a given drug supposes that subsequent fail- ure can be explained only on the basis of his having taken an insufficient amount, with the result that he repeats the dose many times. There is also the danger of the formation of the habit, whenever the drug is used in chronic conditions attended with headache or neuralgia. Antipyrin is applied locally in concentrated solu- tion as a styptic in hemorrhage of the nose. The anti- pyretic analgesics have a more limited field of action than morphin, being of little value in pain due to inflammation, but they deserve the preference over 88 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM opium and morphin in those conditions, such as neuralgia, which they do relieve. They should be used with caution in debilitated patients in whom the danger of collapse is exception- ally . great. Some persons show an Idiosyncrasy toward them and exhibit rashes or exanthemas after even moderate doses. DOSAGE The average dose of acetanilid is 0.2 gm. (3 grains), but it is better to use an initial dose of 0.1 to 0.15 gm. (11/^ to 2 grains) and repeat cautiously when necessary. Antipyrin is given in slightly larger amounts, the average dose being 0.25 gm. (4 grains), and phenacetin is used in somewhat larger doses than antipyrin, the full dose being 0.5 gm. (8 grains), but it is seldom necessary to give more than 0.3 gm. (5 grains) for the relief of neuralgia or headache. The latter dose may be repeated at intervals of three hours until several doses have been taken when nec- essary. All of the antipyretics are more effective in reducing the temperature if given during a natural remission, and the later in the course of the remission, the smaller the dose required for a given effect. It is probable that there is little difference in the danger of the several antipyretics mentioned above in the doses given. There is no question, however, that phenacetin is the least dangerous in equal amounts, but since it is also the least active therapeu- tically, this does not constitute an advantage with the proper regulation of the dosage. Many of the older and some of the later posologic tables give doses of the antipyretic analgesics which can hardly be con- sidered entirely safe. While such doses may be used in certain cases, they are not to be recommended for routine procedure. MATERIA MEDICA Acetanilidum. — Acetanilid, U. S. P. The mon- acetyl derivative of anilin, CeHgNH (CHgCO) is official in several of the foreign pharmacopeias as antifebrinum or antifebrin. It occurs as an odorless crystalline powder having a slightly burning taste. ACETANILID, ANTIPYRIN AND PHENACETIN 89 Acetanilid is only slightly soluble (1: 180) in water but freely soluble (1:2) in alcohol. Acetphenetidinum. — ■Acetphenetidin, U. S. P. Offi- cial in practically all of the foreign pharmacopeias as phenacetinum or phenacetin. Chemically it is known as acetparaphenetidin, QH^ (OCgHj) NHCH3CO. It occurs as white crystalline scales, or a crystalline powder, odorless and tasteless. It is only slightly soluble (1 : 925) in water but soluble (1 : 12) in alco- hol. It differs from acetanilid in containing the ethoxyl group CjHgO. Antipyrina. — Antipyrin, U. S. P. Official in some of the foreign pharmacopeias under its chemical name phenyldimethylpyrazolon C3HN20(CH3)2CeH^. It occurs as a colorless, almost odorless crystalline pow- der or tabular crystals having a slightly bitter taste. It is very soluble (1:1) in water and in alcohol. All of the substances mentioned above are incom- patible with spirit of nitrous ether and with oxidizing or reducing agents generally. Antipyrin being very soluble is more readily affected than the other two substances and all of them are preferably administered alone either in the form of capsules, cachets, pills or tablets. Antipyrin, being soluble, can be administered in the form of solution, care being taken to avoid complex mixtures and particularly preparations of any kind containing tannic acid. Proprietary Preparations and Mixtures The Council on Pharmacy .and Chemistry gave its attention soon after its organization to several of the more widely advertised mixtures which were then claimed to be synthetic preparations. These prepara- tions were found to be simple mixtures of acetanilid, caffein and sodium bicarbonate or other alkalies, and usually contained small amounts of tartaric or citric acid. The mixtures cost about 2 or 3 cents an ounce and were commonly sold for a dollar an ounce at wholesale. Since the enactment of the food and drug law in 1906 the composition of some has been changed, acetphenetidin being used in place of acetanilid. This further emphasizes the fact that manufacturers of nos- 90 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM trums are in business primarily for profit, with little or no consideration of the interests of the consumer or of the physician who is utilized as an advertising medium for the several preparations. No one will deny that mixtures containing coal-tar analgesics relieve pain in many cases. Since they are all sold direct to the public, the danger resulting from self-medication is obvious, because it has been definitely shown that mixtures containing caffein and one of the antipyretics requires a special caution in their use. In addition to these pretended synthetics, which are unworthy of further consideration, there have been introduced innumerable synthetic preparations of the general type of phenacetin or acetanilid with some added advantage, but unfortunately such advantage is invariably offset by disadvantages. For example, when one of these preparations is less toxic it is also invariably less active therapeutically. It is unneces- sary to discuss these substances in detail, for, as we wish to reiterate, there is none which deserves the preference over acetanilid, antipyrin and phenacetin. HYDROCARBON NARCOTICS The terms "soporific," "hypnotic" and "narcotic" are sometimes used without a clear understanding of their meaning. "Soporific" (from the Latin sopor, sleep) and "hypnotic" (from the Greek ^^vos^ sleep) may be considered as having an identical significance ; they are applied to drugs that induce sleep closely simulating natural sleep. The term "narcotic," (from ""^pKi, stupor) is applied to those drugs which in mod- erate doses produce a more profound depression of the higher centers than occurs in natural sleep. The following will serve to distinguish between them : Moderate doses of hydrated chloral induce sleep, during which sudden noises are perceived and their character recognized, while the patient is awakened to a normal condition, showing that the centers con- cerned with the perception of sound are almost as active as normally. Larger doses of hydrated chloral induce narcosis, during which the loudest noises do not awaken the patient nor can evidences of conscious- HYDROCARBON NARCOTICS 91 ness be elicited by any ordinary means, such as shak- ing or pinching, the perception of pain being abolished, of course. The stage of hypnosis passes gradually into that of narcosis, and while there is no sharp distinction between them, we use the terms "soporific" and "hyp- notic" for such drugs or doses as induce the lighter stage of sleep, and "narcotic" for those drugs or doses which abolish the perception of pain and induce profound depression of the higher centers. The hydrocarbon narcotics may be subdivided for convenience of consideration into the following groups: alcohol, chloroform and ether; hydrated chloral and other hypnotics. They have very similar actions in general, differing mainly in the rapidity with which their actions are induced and their dura- tion; hence it will be convenient to discuss the sub- ject of narcosis briefly, even though many of the drugs of this group are never actually used therapeutically for their narcotic effects. Many theories have been advanced to explain the action of narcotics, and while none of these is satis- factory, there is one which has gained acceptance more widely than the others. Hans Meyer and Over- ton advanced theories independently which are similar in many respects, and which are usually spoken of as the theory of Meyer and Overton. They believe that the narcotic activity of different agents is depen- dent on their relative solubility in lipoids (lecithin- albumin compounds) and in water or serum, and that this activity does not within wide limits depend on the solubility in water or serum alone. Meyer determined the relative solubilities of various agents in water and fats, or lipoids, designating this relationship as the "coefficient of distribution." He found that those having a relatively great solubility in lipoids are more actively narcotic than those having a relatively greater solubility in water. He believes that chemically indifferent substances enter the cells of the central nervous system by reason of their solu- bility in the cell envelope, and that their narcotic activity then depends on their possessing molecular 92 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM groups which affect the internal relations of cell com- pounds. The chemically indifferent narcotic compounds exert their actions on all forms of cells which they pene- trate, but not all substances having a relatively high degree of solubility in lipoids are actively narcotic, benzene, for example, being nearly devoid of this action. Baglioni has suggested that anesthesia results from the withdrawal of oxygen from certain compounds in the central nervous system, and it is well known that narcosis results when the inspired air is deprived of oxygen. Other theories do not require mention here. ALCOHOL There are two diametrically opposed theories which are frequently urged to account for the earlier actions of alcohol on the central nervous system. Binz believed that alcohol stimulates the central nervous system, while Schmiedeberg holds that the action is wholly depressant and that such increased function- ing as follows the use of alcohol results from the abolition of inhibition on the centers which normally exercise control over those which then show apparent stimulation. The weight of opinion is in favor of the view that alcohol stimulates certain parts of the nervous sys- tem, the stimulation being brief, usually lasting about half an hour. Jacobi found that the motor areas of the cortex became hyperexcitable and that smaller differences in weight could be appreciated after alco- hol, while even the largest doses did not cause paraly- sis of the motor areas. There, is no clear evidence that alcohol increases the capacity for performing the highest type of mental work, such as clear judgment and the exercise of sound logic require, but the evidence is overwhelming that the capacity for such effort is distinctly lessened, though rapid association of ideas and such feats as rhyming may be facilitated. Such stimulation as alco- hol induces is soon followed by depression. The effects of the stage of stimulation are so well known ALCOHOL 93 that they do not require detailed discussion here. The flushed face, the flashing eye, the ready wit, the good humor are sufficiently familiar to all. Large amounts of alcohol lead to narcosis, which will be discussed when chloroform and ether are considered. The respiration is greatly accelerated during the stage of excitement, just as it is during excitement from other causes, but the therapeutic use of alcohol results in a slightly increased respiration even during sleep. This is frequently attributed to a direct action on the centers in the medulla, but it is not known whether the action is direct or a reflex from the peripheral irritation. At any rate, respiratory depres- sion does not occur unless the dose is large. The vessels of the skin dilate after moderate doses of alcohol, and this dilatation is sometimes accom- panied by a constriction of the splanchnic vessels which is sufficient to increase the blood-pressure slightly; but the changes in blood-pressure are only slight unless large doses have been administered, in which case there is a marked vasodilatation and fall in the pressure. It is not profitable to enter into a discus^ sion here of the seat of this action, because the ques- tion is still unsettled. The vagus center and that concerned with the emesis are probably not affected directly. The heart-rate is not changed after therapeutic doses of alcohol, though the contraction may be slightly stronger, and it has been suggested that this is due to the supplying of energy directly by the alco- hol. This, however, does not seem to be a satisfactory explanation. The behavior of the blood-pressure is inconstant, and it is probably of less importance than is the distribution of the blood. Alcohol acts on the muscles directly and indirectly through the central nervous system. The direct actions are exerted in opposite directions. The imme- diate effect on muscular effort is to diminish the efficiency of the individual contractions, and the remote, to delay the onset of fatigue. Under its influence the muscle contracts less perfectly from the 94 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM start but continues at this slightly lower level for a longer time, with the result that more work is per- formed before it becomes exhausted. It must be understood that this action is available only occa- sionally, for the habitual use of alcohol interferes with muscular efficiency, as it does with nearly all of the functions of the body. The reason for the delay in the onset of fatigue when alcohol is applied to the muscle directly is that the alcohol is oxidized to carbon dioxid and water, which are immediately removed, while the oxidation furnishes muscular energy, and the fatigue products accumulate more slowly than normally. This action is probably negligible when alcohol is taken by the mouth, and the central action is then responsible for the increased capacity for muscular effort. It does this by facilitating the excitation of the motor areas and by lessening the perception of fatigue. Alcohol may therefore prove useful in an emergency, when it becomes necessary to continue physical exertion beyond the time when excessive fatigue would demand rest. The factors involved in increased voluntary muscular effort would not affect the action of the heart, and it is difficult to explain its improving the cardiac action on the basis of any direct action, or of the lessened perception of fatigue; hence we must suppose that any improvement in the condition of the heart which it induces must be sec- ondary to circulatory changes. The association of parental alcoholism and degen- eration or pathologic conditions in the offspring have long been recognized. It is known that epilepsy is more frequent in the offspring of alcoholics than of abstainers; a recent report, moreover, calls attention to the fact that alcoholic intoxication in the father at the time of impregnation may result in an epileptic child even when there is but the single indulgence in alcohol. Alcohol is absorbed rapidly from the gastro- intestinal canal and it also favors the absorption of other substances, probably through its mildly irritant action on the mucous membrane. ALCOHOL 95 Alcohol is eliminated fairly rapidly when small amounts are taken, the habitual user burning it faster than the non-habituated. It has been found that only about 2 per cent, of a dose of 70 gm. (21^ ounces) escaped oxidation when taken during rest, in which extremely small amounts escaped from the lungs. Ten times as much may escape oxidation and be eliminated by the lungs when alcohol is taken during exercise. Gastric digestion is not materially affected by mod- erate amounts of beer and wines of low alcoholic content, and they may even promote digestion; but brandy and whisky, containing about 50 per cent, of alcohol, interrupt digestion when they are taken in sufficient amount, and digestion is not resumed until the concentration of the alcohol is reduced sufficiently through absorption or dilution with the gastric con- tents. Alcohol is antiseptic, absolute alcohol being much less active than that of 70 per cent, strength. This is probably explained by the fact that the stronger alco- hol dehydrates the bacteria, increasing their resistance to its penetration. The continued moderate use of beer and other bev- erages of low alcoholic content commonly results in a gain of weight, due mainly to an increase in fat. Alcohol is also capable of sparing protein in those who have become habituated to its use, but not in those who use it only occasionally, or for a short time. The dilatation of the vessels of the skin causes a sensation of warmth, because the increased blood- supply increases its temperature. This leads to a greater loss of heat than normally, and the body tem- perature may actually fall, even while one feels warmer, because the increased heat loss is not com- pensated for by increased heat formation. For this reason, the practice of taking alcohol before going out in extremely cold weather is dangerous, and severe exposure has often proved fatal under such circum- stances. It is more rational to take alcohol when one returns to a warm room after having suffered from 96 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM exposure to the cold, for then sensation of warmth acts as a stimulant, while th6 warmth of the room prevents further loss of heat. The treatment of chronic alcoholism cannot be dis- cussed here in detail. Attention has recently been called to the often-observed fact that those who are fond of alcohol are not usually fond of sugar, while those who like sugar care little for alcohol ; and it has been suggested that chronic alcoholism results from a disturbance of physicochemical balance, which may be corrected by diminishing the supply of alcohol and increasing that of sugar in the diet. Common experience shows that individuals dififer widely in their response to alcohol. The average fatal dose for a non-habituated adult is probably the equivalent of about 100 to 150 c.c. (3 to 5 fluidounces) when taken in fairly concentrated form, such as brandy or whisky. The more dilute forms, such as wine and beer, are not correspondingly active, because excretion then more nearly keeps pace with absorption. On the other hand, the more concentrated alcoholic beverages are more irritant to the stomach, and cause protective emesis more commonly than the weaker ones. The first stage of alcoholism may be disregarded here, as it does not usually call for therapeutic treat- ment and is of minor toxicologic interest, but severe acute alcoholism, while rarely fatal, is extremely com- mon and often demands treatment. The more common type of acute alcoholism seen in habitues is different in several essentials from that seen in the non-habituated, and will be discussed first. The common drunkard usually falls asleep under the influence of alcohol and will so remain if undis- turbed, but when awakened he is prone to show excite- ment and extreme pugnacity that is difficult to control. The practice prevailing in some of the metropolitan hospitals in dealing with such patients is as follows: The stomach is washed, not so much to remove alco- hol, which has usually been absorbed, as to remove undigested food and relieve nausea and vomiting, and to secure the retention of medicine. A dose of mag- ALCOHOL 97 nesium sulphate (half a pint or more of 10 per cent, solution) is then passed through the tube and allowed to remain in the stomach with the object of causing active purgation. This is followed by the adminis- tration of large doses of paraldehyd — ^three or four teaspoonfuls every half hour until excitement is con- trolled. This may seem contra-indicated in alcoholic intoxication, in view of the similarity of action of the two, but it is said to act extremely well in controlling the delirium of inebriates. Of course it is not used when deep narcosis results from the alcohol, which is rare in these cases. When extremely muscular inebriates cannot be con- trolled sufficiently during the maniacal stage to permit of washing the stomach, a hypodermic injection of apomorphin, 0.008 gm. (% grain), sufifices to cause emesis and quickly reduce the patient to docility. Severe alcoholic intoxication in the non-habituated usually causes more profound depression than in the habituated, and this may succeed the first stage gradu- ally, or may develop suddenly, causing death within a few minutes. During the narcotic stage there is active dilatation of the vessels in the skin, the face becoming scarlet, but soon there is a great fall of blood-pressure, due to the dilatation of the splanchnic vessels, and the skin of the trunk and extremities becomes cool and clammy, the respiration becomes stertorous, the pulse feeble. Emesis may occur at any time before nar- cosis develops, owing to the gastric irritation. When profound narcosis begins emesis stops, but it may recur as the narcosis passes away. The urine and feces are often evacuated involuntarily; with the failure of respiration the skin becomes cyanotic, as in asphyxia from any cause. The odor of alcohol on the breath is characteristic. Chronic inebriates may of course present the stage of profound narcosis when the amount of alcohol taken is excessive, but this is unusual. The patient generally recovers after sleeping a variable length of time, but Kobert states that recovery seldom takes place after coma lasting more than thirteen hours. 98 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM Death occurs rarely from rapid failure of the respira- tory center, or from apoplexy; edema of the lungs may result in death after some days. Cardiac failure or apoplexy may cause sudden death after the patient is apparently on the road to recovery, or this may result after some days from pneumonia or encepha- litis. The latter is of interest in view of the sugges- tion that the headache which commonly follows a drinking bout may be due to pressure of cerebrospinal fluid on the brain due to increased secretion resulting from alcohol. When a patient is seen after taking a dangerous dose of alcohol, the stomach should be emptied by the stomach-tube as promptly as possible, but, as previ- ously suggested, this does not serve to remove much of the alcohol unless it is done immediately after the administration of the alcohol. If a dangerous amount of alcohol has been swallowed, the further treatment must be largely symptomatic — cold applications to the head, and warm applications to other parts of the body to prevent cooling. It has been suggested that venesection might be considered, but that would seem to be a council of desperation. It would seem to be more logical to inject as much as a liter (1 quart) of 2 per cent, solution of sodium sulphate intravenously in desperate cases, in order to dilute the alcohol which contuiues to circulate in the blood, and possibly to hasten elimination, though little benefit is to be expected probably. Caffein is antagonistic to moderate amounts of alco- hol, but its value in excessive depression is prob- lematic. It should be administered intramuscularly (not intravenously) with caution and stopped if it fails to cause prompt, even though slight, improve- ment. Artificial respiration will be required if respira- tory failure threatens. Should the more threatening symptoms subside, the physician will be called on to treat the gastric dis- turbances and the headache which follow, the narcotic stage. These demand the usual gastric sedatives, and caffein and potassium bromid for the headaches. ALCOHOL 99 The following may be found of advantage in such cases : Bismuth subnitrate 10 gm. or 2% drams. Make five powders and give one every three hours until all are taken. The addition of an alkali is preferred by some and may be directed as follows : Bismuth subnitrate 10 gm. or 2% drams. Sodium bicarbonate S gra. or 1% drams. Mix and divide into five powders. Give one three times a day. For the more aggravated case of alcoholic gastritis a moderate dose of cocain may be found advantageous. Cocain hydrochlorid O.OS gm. or 1 grain Bismuth subnitrate 10.00 gm. or 2Va drams Syrup 20.00 c.c. or S fluidrams Water to make 100.00 c.c. or 3 fluidounces Mix and direct that one tablespoonful be given and the dose repeated in two hours if necessary. Caffein may be administered with the bismuth or preferably separately in the form of capsules either as caffein, citrated caffein, or caffein sodiosalicylate, 0.3 gm. (5 grains) in each capsule. Potassium or sodium bromid as a sedative is best administered in the form of simple aqueous solution, 2 gm. or 30 grains in about 20 c.c. of water. The bromids are usually borne best when administered with simple carbonated water. The high tax on ethyl alcohol has led to the abuse of methyl alcohol, which should not be used internally or externally on the body. A great number of fatal cases of poisoning have resulted from its use, and it has even more frequently caused blindness. It is often claimed by the manufacturers of wood alcohol that blindness following its use is due to impurities present, but the purest wood alcohol obtain- able causes it, and this action is explained by the reten- tion of methyl alcohol in the central nervous system and its slow oxidation to formic acid, which acts on the retina, causing degeneration. 100 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM THERAPEUTIC USES Few drugs have been used more extensively than alcohol, and few continue to be the subject of more heated debate. Cabot remarked that there are two camps opposed to each other concerning the actions of alcohol. In the one, those who believe alcohol to be useful in therapeutics are unable to give more than vague impressions that patients improve with its use, or to state wherein the improvement is shown. On the other hand, the opponents of the use of alcohol usually cite old experiments on animals in which enormous amounts were used, or the results obtained with soldiers, typesetters and others who were under- going feats of endurance. Cabot found the action of alcohol to be practically nil with respect to the blood- pressure in 1,105 measurements on forty-one patients suffering with typhoid fever ; nor could he observe any constant effect after therapeutic doses of alcohol with respect to temperature, pulse-rate, respiration rate, appetite, sleep, delirium or renal or cutaneous secre- tion in 2,160 observations on 309 patients in a variety of conditions. Cabot does not deny, however, that alcohol may have well-defined uses as a vasodilator and hypnotic. One reason for the diversity of opinion concerning the therapeutic value of alcohol is that it is often used for its psychic effects, to buoy up the spirits of the patient and engender hopefulness and courage — con- ditions which physicians impart to their patients in such variable degrees by their manner and self-confi- dence. It is obvious that alcohol effects changes in the distribution of the blood. In order to do this it must increase the blood-supply to some regions of the body and diminish that to others, and it is hardly conceiv- able that such changes should not prove beneficial in some cases and harmful in others. The selection of those cases in which the changes will be desirable, while avoiding the use of alcohol in those in which it will prove deleterious, will tax the knowledge, expe- rience and patience of the practitioner. ALCOHOL 101 It is often stated that alcohol improves the circu- lation in shock. One eminent pharmacologist calls attention to the dilatation of the vessels of the skin and explains the improvement sometimes seen after its use when the heart is beating feebly, as due to the lessened resistance to the contraction of the heart which this dilatation affords, thereby perrnitting recu- peration. Another equally eminent authority cites this dilatation of the vessels of the skin as evidence that the splanchnic vessels are simultaneously constricted, according to the usual physiologic rule of compensat- ing action between the peripheral and splanchnic ves- sels, and states that the improvement in the heart results from the increased blood-pressure, which of course increases the resistance against which the heart must contract, but which also affords a better blood- supply to the heart itself. Alcohol may cause increased resistance at one time and decreased resistance at another, and while it is impossible to foresee which will follow in a given case, improvement in the condition of the heart may follow a rise of pressure when this was previously low, or a fall in pressure provided it was not previously too low. When the heart is suffering with the effort to con- tract against high aortic resistance, the effect of the changes in circulation induced by the administration of alcohol will depend on the relative changes in the coronary and in the general circulation. If the blood- supply to the heart is increased in greater proportion than the amount of extra work thrown on the heart by a rise in the blood-pressure, the increased nutri- tion of the heart will cause an improvement in its capacity for meeting the added resistance, and its con- dition will improve; if, on the other hand, the rise of blood-pressure imposes an additional amount of work on the heart out of proportion to the increase in the coronary circulation, then the heart will suffer further injury. Since it is often impossible to fore- see the direction which the change in circulation will take, it is better to use a small dose of alcohol and increase this cautiously if careful study of the circula- tion shows improvement. 102 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM Cardiac failure — ^not simply the actual stoppage of the heart, but the failure to maintain an adequate circulation — is often dependent in part on faulty respiration, and the action of alcohol in improving the respiration may react on the circulation and institute a cycle of improvement. Any improvement in the respiration which alcohol induces is usually little more than incidental, and we have other and better stimu- lants for the respiratory center. It is generally admitted that alcohol is a food, but its value as a food is the subject of much uncertainty. It is not an ideal food, and even under the most favor- able conditions it is utilized at the expense of injury to the organism. It must therefore be decided in any case whether the possible good will probably outweigh the harm. Alcohol in the form of wine affords a pleasant hyp- notic for occasional use, but its well-known tendency to give rise to the habit forbids the routine use of this beverage. Alcohol is often used for bathing the skin in fever, and for hardening the skin to prevent the formation of bedsores. MATERIA MEDICA Alcohol. — Alcohol, U. S. P. In European pharma- copeias this article is usually designated as Spiritus, and varies considerably in strength. The official U. S. P. alcohol is a colorless volatile liquid obtained by the distillation of the fermented mash of grain or other suitable materials which con- tain sugar. It should contain about 94.4 per cent, by volume of absolute alcohol, C2H5OH, and 5.1 per cent, by volume of water. Alcohol has a characteris- tic odor and burning taste and is miscible in all pro- portions with water, ether or chloroform. In pharmacy it is widely used as a solvent, diluent and preservative and many of the extractive prepara- tions, including tinctures and fluidextracts, contain from 30 to 80 per cent, of alcohol. As a diluent or vehicle it is frequently used in the form of: Elixir Aromaticum. — Aromatic Elixir, U. S. P. An aromatic and sweetened elixir containing about 25 per cent, of alcohol by volume. CHLOROFORM AND ETHER 103 The potable forms of alcohol include malt liquors, such as ale, beer and porter, which contain from 3 to 6 per cent, of alcohol. Wine usually contains from 7 to 20 per cent, or more of alcohol, and distilled spirits, such as spiritus frumenti and spiritus vini gallici, con- tain from 40 to 50 per cent, of alcohol. It should be remembered that all these beverages contain, in addi- tion to alcohol, aromatic principles and extractives that may be toxic or physiologically active. GENERAL ANESTHETICS CHLOROFORM AND ETHER GROUP Every one who attempts to administer a general anesthetic at this period should have had a course of training in this special branch of medicine. Inas- much as the general practitioner is called on at times to assume charge of patients who have been anesthe- tized, however, even though he may not have adminis- tered the anesthetic, this discussion will include a con- sideration of the more salient points. In addition, the practitioner would do well to read a fairly comprehen- sive treatise on the subject, such as that of Hewitt. It is remarkable that ether and nitrous oxid were known long before they came into use as general anesthetics. Ether was prepared by Valerius Cordus in 1540 — three hundred years before its use in anes- thesia. Humphrey Davy in 1805 observed that nitrous oxid relieved an aching tooth, and suggested the use of the gas in surgery, but the suggestion went unheeded. Nitrous oxid was first used in dentistry by Horace Wells of New Haven, in 1844. He attempted to give a public demonstration in the Har- vard Medical School, but this proved a fiasco, sub- jecting him to ridicule, and later he killed himself. "Ether parties" were popular about a century ago. Crawford W. Long, a physician of Georgia, observed that he and his companions sustained small hurts with- out feeling the pain while under the influence of ether ; this led him to perform the first surgical operation during ether anesthesia in 1842. Long took little trouble to make the results of his experience widely known, and the first public operation under ^ ether 104 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM was performed by Warren at the Massachusetts Gen- eral Hospital, Oct. 17, 1846. William G. T. Morton, a pupil of Wells, having learned of the action of nitrous oxid, had sought aid in its preparation from a chemist named Jackson, who suggested the use of ether. Morton adopted the suggestion and vainly attempted to keep its identity a secret for personal gain, but he spent the remainder of his life in advocat- ing and popularizing its use. Flourens announced in 1847 that chloroform acts much like ether on the lower animals, and Simpson of Edinburgh used chloroform as a general anesthetic in the same year. Ether and chloroform were both used with little skill at this time, and Snow published the first com- prehensive work on the subject in 1858. Ethyl chlorid anesthesia was known about as early as that of ether, but it attracted little attention for fifty years. A few years ago an effort was made to popularize ethyl chlorid, which was claimed to stand between ether and nitrous oxid in relative safety. This is not the case, and the use of ethyl chlorid is now limited to special cases. Chloroform was the safer anesthetic at first owing to the want of understanding of the actions of ether, and for many years a mixture of alcohol, chloroform and ether was popular. The use of ether has increased steadily, and at present it is employed to a far greater extent than chloroform for general anesthesia. Chlo- roform still has a distinct field of usefulness, how- ever, and with the swing of the pendulum in favor of ether, it seems that certain disadvantages of the latter may be overlooked. The administration of a general anesthetic is always attended with danger, and the physician realizes that he may be called on to defend his choice of anesthetic should it be his misfortune to have a patient succumb during its administration. It always appears easier to defend the choice of that which is sanctioned by common practice than that which is indicated by care- ful study of all the conditions present in any given case, when such conditions happen to indicate the use of the less popular anesthetic; therefore physicians CHLOROFORM AND ETHER lOS tend to fall into the habit of selecting ether on all occasions regardless of whether it is best in a given case or not. While statistics indicate pretty clearly that pro- portionally more deaths occur during the administra- tion of chloroform than of ether, we are in need of a more comprehensive study with statistics of the ulti- mate dangers, including deaths which are indirectly attributable to the anesthetic. The "late chloroform deaths" have now become fairly well known, but many of the deaths from pneumonia which are due to the administration of ether are not reported as ether deaths. Ether is administered for minor surgical operations by professional anesthetists in many thou- sands of cases in which the patient, on regaining con- sciousness after the operation, passes from the anes- thetist's care. If pneumonia develops several days later, the anesthetist may not so much as know that death resulted. The following points are to be considered when choosing an anesthetic: sex and age (these are not usually very important, except where atheromatous arteries are to be expected) ; temperament ; habits (alcoholism, etc.) ; general physique, obesity being unfavorable for chloroform and ether ; respiratory and circulatory systems (difficulties present or anticipated in the respiration increase the risks of anesthesia). Morphinists are tolerant of chloroform and ether, but a dose of morphin administered to a morphinist just before the administration of an anesthetic makes this .smoother. The mere bulk of the anesthetic is of importance on the battle-field, or where a sudden catastrophe demands the transportation of anesthetics for large numbers with insufficient facilities. In such cases nitrous oxid becomes impossible, and chloroform or ethyl chlorid is preferable. The time consumed in administering ether, especially in very hot weather and following battles, is also a great objection, and chloro- form or ethyl chlorid is to be preferred on that account. Probyn- Williams states that ether is the anesthetic of choice for patients between the ages of 6 and 60 years, chloroform being preferred for infants under 3, and a mixture of chloroform and ether for those 106 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM between the ages of 3 and 6. Chloroform is used- for patients over 60, and it is used to induce anesthesia for those between 6 and 10 years, the anesthesia being continued with ether. The actions on the central nervous system of chloro- form, ether and ethyl chlorid resemble those of alco- hol qualitatively in their essentials and need not be described in detail. It is of the first importance that these substances depress the higher parts of the brain and then the cord, while the medullary centers are affected to a much less extent. The stage of excitement is important, but it is so well known that it does not require detailed dis- cussion here; it is important where high blood-pres- sure is to be feared, and in such cases anesthesia is frequently induced with chloroform or nitrous oxid and continued with ether. At present it is custom- ary in many institutions to induce anesthesia with nitrous oxid as a routine measure, and then proceed with ether. With the administration of ether to man there is at first a sensation of suffocation and disturbance of the special senses, which are intensely disagreeable; chloroform is much less so. Excitement comes on after consciousness is disturbed. Sensation is com- monly lost before the loss of motion in the voluntary muscles, and during this stage slight surgical opera- tions, requiring but a minute or two, may be per- formed if muscular relaxation is not necessary, where there is no probability of severe injury which would give rise to injurious reflexes. With increasing depth of narcosis the reflexes are abolished, the winking reflex from touching the cornea being among the last to disappear, but not the very last. During major surgical operations it is usually desirable to maintain that depth of anesthesia in which the corneal reflex is abolished, since this suffices to secure muscular relaxation while avoiding severe reflex injury to the central nervous system which occurs with insufficient depth of anesthesia. On the other hand, if this stage is exceeded materially, the respiratory and vasomotor centers suffer and the respiration stops. With chloroform the heart stops almost immediately CHLOROFORM AND ETHER 107 thereafter ; with ether there is usually a slightly longer interval, during which the opportunity for resuscita- tion is greater than with chloroform. The vasomotor and respiratory centers are not markedly depressed during a moderately prolonged anesthesia with ether, but the breathing is slower than normally, though it should be regular. It is customary to discuss the action of the anes- thetics on the respiratory and vasomotor centers separately, but the respiration and the circulation are so closely interdependent that it is impossible to injure one severely without injuring the other. The respiration may be temporarily inhibited reflexly from the mucous membrane of the nose before the stage of deep anesthesia is reached, just as it may be in health by the inhalation of any irritant gas, but this does not occur during deep anesthesia. Irritation of the mucous membrane of the trachea may also give rise to persistent reflex inhibition of respiration, and this has caused death in some instances. When the respiration ceases early in the administration of anes- thetics the respiratory passages should be examined carefully to insure that they are not the seat of obstruction or irritation from any cause. Of course, careful attention should be given to the air-passages before beginning the anesthesia, for it is obvious that interference with respiration in any way must prove dangerous. Imperfectly aerated blood causes a rise of blood-pressure, increasing the resistance against which the heart must contract, while it affords dimin- ished nutrition to the heart, thus throwing an addi- tional burden on it while it is enfeebled by lack of nutrition; this circulatory disturbance results in fur- ther injury to the respiratory center, establishing a vicious circle. The circulation is subject to so many influences that it is difficult to determine in a given case the mecha- nism by which it may be disturbed. It is well known that ether, when administered properly for a moderate length of time, does not lower the blood-pressure. The actions of anesthetics on the vasomotor cen- ters have been the subject of much study, |Rt there is a want of agreement on the subject, and we cannot deter- 108 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM mine . whether the vasomotor center or the heart is responsible primarily for the fall which follows chloro- form even with the greatest care. It seems probable that the heart and the vasomoter centers are but links in the chain which may be injured at either point. With ether the blood-pressure may remain con- stant for several hours, but with the most careful administration of chloroform the pressure falls pro- gressively, during which the heart evidently suffers. The danger to the heart during the administration of chloroform is admitted by all, but this danger is variously explained. According to a view which has gained some acceptance, the heart becomes hyper- excitable and ventricular fibrillation results, with immediate failure of the circulation. It is maintained that overdosage has nothing to do with this effect, but on the contrary, that excessive caution has led to insufficient administration which favors hyperex- citability with the danger of fibrillation, whereas with the continuous administration of a sufficient amount of chloroform the ventricle is depressed so that hyper- excitability and the resulting fibrillation are impos- sible. The supporters of this view state that with a growing and excessive caution the number of deaths during the early part of chloroform anesthesia shows a marked increase. It is maintained that anything which interferes with a smooth and uniform administration of chloroform increases the danger of ventricular fibrillation and that vagus inhibition is a source of danger only in so far as it interferes with a uniform condition of the circulation. Every one admits the desirability of a smooth anes- thesia, but it is not always attainable even with the greatest care. The heart is subject to direct injury from the anes- thetics in addition to the indirect through circulatory changes, chloroform being far more injurious directly than ether. The action of chloroform is dangerous at three different stages: soon after the inhalation is begun, and it may be before consciousness is lost; during the regular course of anesthesia; and one or several days after the anesthetization. CHLOROFORM AND ETHER 109 According to another view which has found wide acceptance, the source of danger to the heart early in the course of chloroform anesthesia is due to a combi- nation of the direct action on the heart and the indirect through the vagus center as follows: When chloro- form is carried to the heart in somewhat greater con- centration than is desirable it causes the heart to become more susceptible to vagus control, and at the same time the vagus center is rendered hyperexcit- able; at this time the irritation of the mucous mem- brane by the concentrated chloroform vapor sets up a strong reflex inhibition through the vagus center, causing the heart to stop. Vagus stimulation causes only a temporary stoppage of the normal heart, but when it pauses under the condition just cited the dilated chambers are filled with blood containing chloroform vapor in high concentration, and this vapor acting on the heart paralyzes it rapidly. It must be understood that this early danger to the heart may occur before the patient even loses consciousness, for one is prone to think that there is no danger so long as the reflexes are not abolished and the respiration and pulse are good. This danger is avoided by care in seeing that the chloroform is not inhaled in too great concentration and that the patient is not allowed to inhale too much of it when he begins suddenly to breathe deeply, as he may after a pause in the res- piration. The celebrated Hyderabad Commission overlooked this source of danger because they began their experi- ments by anesthetizing their dogs in a box where they were not easily observed. Even though they lost about 6 per cent, of their animals during the induction of anestiiesia they were content to attribute all of these deaths to faulty technic or accident and did not investigate the cause further. In order to prove the real danger of concentrated vapor before consciousness is lost a later investigator succeeded in killing one- fourth of his dogs in this way intentionally. Our discussion is not intended for the guidance of the expert anesthetist, who will rarely have any diffi- culty in avoiding overdosage, but the following experi- ence illustrates the danger when chloroform is 110 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM employed by those who are unskilled in its use : The medical students of a class who had previously used ether exclusively as the anesthetic in laboratory experiments were directed on one occasion to employ chloroform. Its nature was explained, and extreme caution was enjoined. Despite this caution too much chloroform was used with fatal results in nearly every one of the next series of experiments on dogs. Chloroform causes a nearly constant fall in the blood-pressure, and the heart and respiration may fail rapidly at any stage of the operation, especially if the operation involves severe injury to nerve trunks with resulting reflex injury to the centers. Such injuries are more common with light anesthesia than with that stage where the corneal reflex is abolished. The third stage of danger to the heart is attended with degeneration, which is not limited to the heart but involves the liver and other organs. While this degen- eration is often found at necropsy in such cases, the cause of death is not known, for greater degeneration may occur from various other causes without causing death. It has been shown that chloroform and ether may contain various impurities, and it has been maintained that traces of certain of these impurities add to the dangers of anesthesia. It is of course impossible to deny that impure anesthetics might be dangerous, but Hale has shown that pure chloroform is as toxic as that which has stood exposed to light for two years. It has also been shown that ether which contains small amounts of acetaldehyd does not induce post- anesthetic glycosuria in dogs more readily than pure ether. The diet appears to exert a far greater influence on the toxicity of chloroform, and probably of ether, than do mere traces of impurities, and it has been shown that a diet of carbohydrates previous to chloroform anesthesia greatly reduces the tendency of the latter to cause necrosis of the parenchymatous cells of the Uver and kidneys. Ether cannot cause sudden death in a manner analogous to that described, early before conscious- CHLOROFORM AND ETHER 111 ness is lost, but it may cause death during the opera- tion, for ether is also directly injurious to the heart, though much less so than chloroform. The following laboratory experiment serves to illustrate the great difference in the toxicity of ether and chloroform for the heart. Three frogs' hearts are excised and placed one in Ringer's solution, another in Ringer's solution containing 0.25 per cent, of chloroform, and the third in Ringer's solution containing 2 per cent, of ether. The first heart continues to beat for an hour or more. The one subjected to the action of chloroform ceases to beat within a few seconds; if it be transferred at once to pure Ringer's solution it may possibly be made to beat again, but it is usually found to be perma- nently paralyzed. The third heart, which is subjected to the action of ether, will usually continue to beat for a few minutes and if transferred at once to pure Ringer's solution will resume regular beats. This experiment serves to explain why the attempt to resuscitate patients when the respiration ceases after ether is successful more frequently than when the same accident occurs with chloroform. After the respiration ceases with ether the heart is usually cap- able of beating, whereas after the administration of chloroform the heart is usually so severely poisoned at the time the respiration ceases that it soon ceases to beat. Chloroform is said to be about 250 times as actively toxic to the heart as alcohol if compared in molecular proportions. While so much stress is usually placed on the action of chloroform on the heart, Hewitt states that in prac- tice the majority of chloroform deaths occurring dur- ing operations are due to intercurrent conditions which are often not recognized ; these include asphyx- ial states leading to circulatory failure, swelling of the tissues surrounding the air-passages and interfer- ence with the free entrance of air, which may lead to circulatory failure in a susceptible patient. The kidneys participate in the excretion of chloro- form and ether, and frequently suffer injury, espe- cially in the presence of a previous nephritis. Chloro- form is much the more irritant, but so much more ether is required for anesthesia that it causes approxi- mately as much damage to the kidney as chloroform. 112 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM The liver may also suffer degeneration, as previ- ously mentioned, and the existence of hepatitis is a strong contra-indication for chloroform. Ether causes a more copious secretion of saliva and also of mucus in the bronchial passages than does chloroform, and the saliva may be aspirated during sleep and give rise to pneumonia. Atropin adminis- tered previous to the anesthetic prevents this excessive secretion of saliva and mucus. This also suggests the necessity for oral antisepsis prior to anesthesia. It is sometimes stated by surgeons that pneumonia follows ether anesthesia only as the result of care- lessness, or through too great cooling of the body, but this is not correct; pneumonia may follow an extremely brief and carefully conducted etherization. Ether, being quite soluble in the saliva, may be swallowed in sufficient amount to cause irritation of the stomach and give rise to nausea and vomiting. It is for this reason that slight nausea and vomiting are more common after ether than after chloroform, but severe and dangerous vomiting is more common alter chloroform. The cause of this is not known. Ether and chloroform are absorbed readily from the mucous surfaces, the rate of absorption during inhalation being proportional to the partial pressure of the vapor in the alveolar air, since the body tem- perature may be regarded as constant. It is unnecessary to enter into a discussion here of the concentration of the vapor in the air and in the venous and arterial blood at the time of inducing anesthesia and during its maintenance. However important they are for the anesthetist, they belong to the more advanced study of the subject such as one finds in special treatises. Cushny found that about 90 per cent, of the chloro- form administered was excreted in the expired air during anesthesia, that the exhalation of volatile sub- stances from the lungs is exactly analogous to their evaporation from aqueous solutions, and that the amount of a given anesthetic thus eliminated in the expired air depends on its affinity for water to a much greater extent than on its volatility. This explains CHLOROFORM AND ETHER 113 why ether, which is more volatile than chloroform, but also more soluble in water, is retained in the blood more tenaciously. The amount of ether present in the blood at the end of anesthesia is reduced to about one-half in from five to fifteen minutes, and at the end of two hours there is only about one-fortieth as much in the blood. Ether can be detected in the breath, however, for a day or longer after even a brief anesthetization. Chloroform also disappears rapidly at first, and is reduced to one-fortieth the original amount in about seven hours, which is a seeming contradiction to what was said of the more rapid exhalation of ether, but the amount of chloroform present at the start was much less, and a small portion of the chloroform is capable of entering into a relatively stable combina- tion with some constituent of the blood. Buxton states that the administration of oxygen lessens the deleterious effects of chloroform on the different organs. Ether is sometimes used as an active respiratory stimulant in emergencies, 30 or 40 minims being injected intramuscularly. The effects are sometimes striking, but of course the injections cannot be fre- quently repeated, and they are of service only in tiding over an emergency. French surgeons have advised the use of large quantities of ether as an antiseptic in abdominal sur- gery, but it is difficult to see what special advantage it has for this purpose and certainly it is capable of causing serious injury. The volatility of ether constitutes a serious objection to its use in extremely hot climates, for it is difficult to maintain smooth anesthesia with it in very hot weather. Its inflammability is less of an objection now that electric lights are so commonly in use. THERAPEUTIC USES The principal therapeutic uses of the anesthetics are too well known to require discussion, and unfor- tunately, we know far too little of the special indica- tions for one or the other of these in a given case. 114 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM It is recognized of course that certain conditions serve as a contra-indication for one or the other of these, but we are frequently in the dark regarding other conditions which would undoubtedly serve as contra-indications were they known, for the deaths which occur on the operating-table would not occur if these contra-indications were known and the con- ditions recognized in those cases. Ether causes more excitement than chloroform; hence it is contra-indicated where excitement with its attending high blood-pressure is dangerous, but this does not mean that ether cannot be used in such cases after anesthesia has been induced by chloroform or nitrous oxid. Chloroform does undoubtedly serve a most useful purpose in such cases. Chloroform is certainly strongly contra-indicated where the operation is prolonged, because of the progressive injury to the heart. Ether is probably more dangerous where inflammation of the respira- tory passages indicates danger of pneumonia. MATERIA MEDICA Aether. — Ether, U. S. P. A liquid composed of about 96 per cent, by weight of absolute ether or ethyl oxid, (C2Hg)20, and about 4 per cent, of alco- hol containing a little water. Ether occurs as a trans- parent colorless mobile liquid, having a characteristic odor and a burning and sweetish taste. It is soluble in about ten times its volume of water and miscible in all proportions with alcohol, chloroform, petroleum benzin, benzene, fixed and volatile oils. Ether boils at about 55.5 C. and is highly volatile and inflamma- ble. Its vapor when mixed with air and ignited explodes violently. Aethylis Chloridum. — Ethyl Chlorid, U. S. P. A haloid derivative, CjHjCl, prepared by the action of hydrochloric acid gas on absolute ethyl alcohol. It occurs as a colorless, mobile, very volatile liquid, having a characteristic, rather agreeable odor and a sweetish, burning taste. Ethyl chlorid is slightly soluble in water and readily soluble in alcohol. It boils at a temperature of 12.5 to 13 C. and on account HYPNOTICS lis of its extreme volatility should be preserved in her- metically sealed glass tubes and kept in a cool place remote from lights or fire. Because of the difficulty of handling it, it is now rarely used for general anes- thesia. Chloroformum. — Chloroform, U. S. P. A liquid consisting of from 99 to 99.4 per cent, by weight of absolute chloroform, CHClg, and 0.6 to 1 per cent, of alcohol. It occurs as a heavy, clear, colorless mobile liquid of a characteristic odor, and a burning, sweetish taste. It is slightly soluble (1:200) in water but is miscible in all proportions with alcohol, ether and the fixed and volatile oils. Chloroform may deteriorate under the influence of light and air ; hence that intended for anesthesia should be kept tightly stoppered and protected from light. The vapors should not be allowed to come in contact with an open flame because of the irritant action of the gas which is formed. HYPNOTICS We have no theory based on observed facts which is capable of explaining the chemical causes of sleep, but it seems probable that sleep is induced by certain products of metabolism which accumulate during waking. If we could determine just what these sub- stances are and prepare them in a form suitable for therapeutic use we should probably have an ideal hypnotic. The claim is often made that the ideal hypnotic has been found, but such claims invariably prove unfounded, and we find that the new prepara- tion has undesirable, and even dangerous, side actions. Every hypnotic tends to require increasing doses, while the side actions do not diminish correspond- ingly; hence it is better to use different h3rpnotics when it is necessary to continue their use for some time. Small doses of the hypnotics depress the psychic and some other centers in the great brain, while exert- ing little influence on other parts of the central ner- vous system. Larger doses should be avoided in therapeutics because they depress the vasomotor and the respiratory centers. 116 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM Alcohol and opium were formerly our principal hypnotics, but these have been superseded largely by others which may be divided into three main groups as follows: (1) those which depend on halogens for their action; (2) those depending on alkyl groups, and (3) those in which an aldehyd group or ketone group determines the action. Lauder Brunton has stated that the requirements for sleep are: (1) hindrance of blood-flow through the brain (this is not necessarily attended with a diminution of the amount of blood in the cerebral vessels at any given moment) ; (2) depression of the functional activity of the brain (it is a matter of common experience that mental activity prevents sleep). A hypnotic must have a selective action on the brain, and one of the objects sought by investigators is the discovery of compounds having this selective action in the highest degree, with a minimum of action on the medullary centers and the heart. This has led to the introduction of many substances of greater or less value, which have been introduced in most cases with enthusiastic praise of their advantages and a disposition to minimize their disadvantages, and even to deny that they have any side actions worthy of mention. This method of exploitation has fre- quently resulted in the abuse of these newer hypnotics, and many deaths have resulted from overdoses of them, for it must be remembered that there is no such thing as an absolutely safe hypnotic, and that over- doses of most of them are about as dangerous as an overdose of hydrated chloral. HALOGEN DERIVATIVES Aldehyd, or acetaldehyd, CH3.CHO, has some slight hypnotic activity, but it is of no therapeutic value, because the hypnotic stage is preceded by excitement. By the introduction of three atoms of chlorin, form- ing chloral, CClgCHO, however, we obtain a useful hypnotic. Chloral is converted into hydrated chloral by the addition of a molecule of water, and this is the form in which chloral is commonly used. HALOGEN DERIVATIVES 117 Chloral was prepared by Liebig in 1831, and tested on animals in 1860, but it was not used therapeuti- cally until 1869, when it was introduced into the materia medica by Liebreich. He assumed that, because it is decomposed in the presence of alkalies with the formation of chloroform, this reaction occurs in the blood and that the slowly formed chloro- form induces sleep. The blood is practically neutral in reaction, and even though hydrated chloral were decomposed with the formation of chloroform, the amount so formed from a therapeutic dose of chloral would be wholly inadequate to induce sleep during more than a very ■ few minutes, if indeed it would cause sleep at all. Mering showed that hydrated chloral is excreted in the urine as tri-chlor-ethyl alcohol in combination with glycuronic acid. The actions of hydrated chloral resemble those of chloroform qualitatively, at least, quite closely, the chief differences in their behavior being due to differ- ences in their rates of elimination from the body. It will be unnecessary to detail the actions of hydrated chloral on the higher parts of the brain, since this type of action was discussed when alcohol was under consideration. In the absence of pain sleep may be induced by hydrated chloral with doses which exert but little action on the respiratory and vasomotor centers. From this sleep one may be aroused easily by noise, or by any stimulus which would arouse one from ordinary sleep. With larger doses the sleep is deeper, and the vasomotor and respiratory centers suffer depression, constituting, with the direct action on the heart, the principal source of danger with overdoses. The respiration is diminished during sleep from any cause, and with therapeutic doses, of hydrated chloral there is probably no greater depression of respiration than occurs in ordinary sleep; that is, there is probably no direct action on the center by the drug. Toxic doses, however, do depress the center directly, causing a slower rate with some increase in the depth of the individual respirations. Cushny has • shown that the normal response of the respiratory 118 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM center to carbon dioxid is not altered by therapeutic doses of hydrated chloral, while toxic doses prevent the increase in the rate by carbon dioxid but do not affect its action on the depth; hence the deeper res- pirations just mentioned in chloral poisoning. The action of hydrated chloral on the heart and the vasomotor centers precludes its use as a general anes- thetic in man, though it is frequently used for this purpose in laboratory experiments. While the blood- pressure falls greatly with toxic doses, it still responds to stimulation by carbon dioxid, and the asphyxial rise of blood-pressure usually occurs after the cessa- tion of respiration. . The action on the heart is similar to that of chloroform. Hydrated chloral is irritant to the mucous mem- branes of the mouth and gastro-intestinal tract, and when it is administered in too great concentration it causes nausea and vomiting, or if it be administered by the rectum it is expelled. This indicates that the solution of the drug should be well diluted with water or some bland fluid before being administered. It should be remembered that therapeutic doses of hydrated chloral are not analgesic, and that when pain is the cause of sleeplessness a suitable anodyne, such as morphin or antipyrin, is to be preferred. Hydrated chloral is absorbed rapidly from the gastro-intestinal tract, and it may be given by the mouth or rectum, the dose being the same by either mode of administration. It is excreted in the urine in combination with glycuronic acid. The rate of excretion probably varies widely with the dose and the effect which it has on the blood-pressure. A cat may remain under the influence of a just non-fatal dose for as much as three or four days, while another will recover from a dose equally as large in one day, and dogs eliminate hypnotic doses of hydrated chloral in three or four hours. It is probable that the more pro- longed action is attended with a profound fall of blood-pressure which interferes with renal excretion, while the shorter duration occurs where the circulatory disturbance is insufficient to prevent the prompt elimi- nation of the drug. HALOGEN DERIVATIVES 119 The capacity of man for eliminating this drug appears to occupy a place between that of the cat and dog. The repeated use of hydrated chloral tends to induce the habit, and whef-e hypnotics are to be used for some time, occasional recourse should be had to other members of the group, such as veronal or tri- onal, in order to avoid the too frequent use of one drug. Acute poisoning with hydrated chloral is not so common when the drug is used alone, because physi- cians very commonly appreciate its limitations and use it with due caution, but it is a constituent of the proprietary Bromidia, which is commonly used with much less caution, and acute symptoms in such cases are not rare. Absorption is so rapid that it is probable that little or no hydrated chloral remains in the gastro-intestinal tract when toxic S3rmptoms are observed after the oral administration, but the stomach may be emptied when the patient is seen shortly after a poisonous dose has been taken. If the poison has entered the circu- lation, efforts should be directed toward its elimination, and proper s3miptomatic treatment should be instituted. The respiratory and vasomotor centers, especially the former, are usually the seat of danger, and arti- ficial respiration should be instituted when there is any sign of approaching paralysis. Schmiedeberg has recommended the use of coriamyrtin as a physiologic antidote to hydrated chloral, but it is a violent poison and probably has no advantage over the much safer caffein, which stimulates both the respiratory and vasomotor centers. Active diuresis should be induced by the administration of hot drinks and in emergency, intravenous injection of warmed saline, as previously suggested in the treatment of strychnin poisoning, the object in both cases being exactly the same. It is not sufficient to insure the safety of the res- piratory center, for the more prolonged the elimina- tion of the poison the greater is the opportunity for it to exert its toxic action on the heart. Hence the elimination should be hastened as much as possible. 120 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM SULPHONAL AND TRIONAL These two substances are official as sulphon- methanum and sulphon-ethyl-methanum ; chemically they resemble each other closely, differing only in that one of the methyl groups of sulphonal is replaced by an ethyl in trional. This is seen at a glance from the structural formulas: CHs SOsCsHs CHa SO2C2H6 c c CHs SOsv^sMs C2U5 SO2C2XIS Sulphonal Trional Chemical compounds in general which have anes- thetic or hypnotic actions dependent on the presence of ethyl groups are usually less depressant to the heart and the medullary centers than are those which depend on halogens, for their action. Ether or ethyl- oxid has these disadvantages to a much less extent than chloroform, or tri-chlor-methane, and sulphonal and trional possess them to a less extent than hydrated chloral, or tri-chlor-aldehyd. The discovery of the hypnotic actions of sulphonal was accidental. The substance had long been known when Baumann and Kast fed it to dogs during studies in metabolism and were impressed with its hypnotic action. This discovery led to the investigations of closely related products, but none of those discovered since has any great advantage over sulphonal, except that of greater solubility. The actions of sulphonal and trional differ from those of hydrated chloral largely in. their slighter effect on the heart and medullary centers, in their slighter solubility, slighter irritant action and their slower absorption with slower onset of action. They cause depression of the higher centers, inducing sleep in the absence of pain, with little disturbance of the respiration or circulation. Their toxicity is of impor- tance almost exclusively with long-continued use, as very large single doses commonly cause only pro- longed sleep, and slight disturbances. Sulphonal and trional are relatively insoluble, so that they are given as powders or mixtures, and are slowly absorbed, the hypnotic action being usually SULPHONAL AND TRIONAL 121 delayed for an hour in the case of trional and about two hours after sulphonal, which is even less soluble than trional. Occasionally the sleep may be delayed until the following day, or it may occur after the usual interval and drowsiness result on the following day with sleep at the usual hour some twenty-four hours after its administration. The relative harmlessness of large doses of sul- phonal is shown by the effects of a single dose of 100 gm. taken by a student. This was followed by unconsciousness in forty-five minutes. The tempera- ture fell at first but later rose above normal. Sleep lasted five days; this was followed by exanthemas on the sixth day and complete recovery. In another case a dose of 30 gm. caused death from respiratory failure on the third day. Anemia increases the sus- ceptibility to its action, and women are more suscep- tible than men. Such doses as these are never given in therapeutics and can be of importance only in case of accident or suicide. The danger from the continued use of sulphonal is especially insidious, because one may take it in con- stant dosage for long periods without its occasioning any symptoms until these develop quite suddenly in severe form. About 60 per cent, of the cases in which symptoms of severe poisoning occur result fatally despite the most careful treatment. The following illustrates the fact that long-continued immunity is no guarantee that this will continue: A woman suffering from sleeplessness and hallucinations used daily doses of 1 to l.S gm. of sulphonal during three months, after which she became ill, vomiting greenish fluid, the urine was scanty and dark brown from hematoporphyrin ; death was preceded by c6nvulsions. The urine should be examined frequently for hematoporphyrin in every case in which one of these drugs is used habitually. The appearance of hemato- porphyrin in the urine indicates the destruction of the hemoglobin of the blood, and calls for the stoppage of administration and the administration of alkaline water in abundance to hasten the elimination of the poison. The treatment must be continued for several 122 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM weeks after severe symptoms develop. The actions of trional and tetronal are similar to those of sulphonal. The earlier laboratory experiments indicated that tetronal was the most actively hypnotic, trional next, and sulphonal the least, but these results obtained on dogs do not apply to man, and trional has become the more popular, while tetronal has never acquired such popularity as the other two. VERONAL Veronal is related chemically and therapeutically to sulphonal and trional, its formula being; NH-CO CiiHt NH-CO QjHb Chemically, it is diethyl-barbituric acid, or diethyl malonyl urea. Its actions are elicited somewhat more quickly than are those of sulphonal and trional, and it is more active in equal amounts. Soon after its introduction into therapeutics veronal was used in doses of 1 gm. and numerous deaths from it were reported. Experiments on animals indi- cate that veronal is slightly more active than hydrated chloral, equal doses of veronal causing an even greater depression, with fall of blood-pressure. Numerous preparations which resemble sulphonal and veronal somewhat have been introduced as hyp- notics, and while several of these have merit, the reader is referred to New and Nonofficial Remedies for a discussion of them. ALDEHYDS Acetaldehyd causes excitement before inducing sleep, as previously mentioned, but paraldehyd, a polymer of acetaldehyd, is more actively hypnotic without inducing excitement, and has less depressant action on the respiratory center. It is one of the safest of hypnotics, but it has an extremely unpleas- ant penetrating odor which pervades the room of the patient and which persists for more than a day; it has a persistent disagreeable taste. It has very little action on the heart even with large doses. ALDEHYDS 123 Several ketones are of pharmacologic interest, and a few compounds which depend on their ketone groups for their hypnotic action have been introduced into therapeutics; none are important. Acetone is actively hypnotic, and could be utilized therapeutically but for its irritant action on renal epithelium. THERAPEUTIC USES The actions of the hypnotics indicate their legiti- mate therapeutic uses, but caution is necessary regard- ing their use when sleeplessness is due to causes which can be removed. In other words, the hypnotics are in no sense curative, and should never be used when it is possible to induce sleep by removing or preventing that which interferes with it. Pain, worry, excite- ment and digestive disturbances are the common causes of sleeplessness, and these should be relieved or prevented by other means when possible. Pain should always be treated by analgesics rather than by h3rpnotics, of which large doses are required in the presence of pain, whereas small doses of analgesics suffice usually. The use of tea and coffee is a fre- quent cause of insomnia, and these should be stopped before resorting to hypnotics, of course. Hydrated chloral is an antispasmodic, and is some- times used to cause relaxation of the rigid uterine os during labor, and to abolish convulsions in tetanus; for this purpose large doses are required. It is used in combination with potassium bromid when sleep- lessness is due to nervousness. Hydrated chloral is contra-indicated in degenera- tion of the heart, and should be used cautiously in the presence of respiratory and circulatory disturbances. It is often recommended as an antidote to strychnin, but ether seems preferable in every way. Sulphonal, trional and veronal are used as hypnotics in much the same conditions that hydrated chloral is, but minimal hypnotic doses have little action on the circulation and may be used when hydrated chloral is contra-indicated. These drugs should not be given continuously for prolonged periods, even when their use is attended with no visible signs of injury. They 124 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM are also used as antispasmodics in epilepsy, hiccup, chorea and other conditions. Paraldehyd may be used when hydrated chloral is contra-indicated by cardiac disease, or where a prompt action is necessary. It is also antispasmodic. Men- tion has been made of its usefulness in controlling alcoholic mania, and it is especially valuable in con- trolling mania during pneumonia and other diseases in which the heart is threatened with exhaustion and hydrated chloral is contra-indicated. Very large doses may be given in case of need without causing depression of the heart. DOSAGE Hydrated chloral is used in doses of 0.3 to 1.3 gm. (5 to 20 grains), but it is usually much better to employ it in the smaller doses in combination with twice as much potassium bromid where sleeplessness is due to nervous excitement ; such a dose may require repetition in an hour, if sleep does not result. As an antispasmodic much larger doses may be required, but it is better to give the larger dose just mentioned and continue the smaller doses until relief is afforded, or until toxic symptoms indicate that the limit of therapeutic dosage has been approached. The average dose of sulphonal or trional is usually stated as 1 gm. (15 grains), but 0.6 gm. (10 grains) often proves effective. The daily dose should not exceed 2 gm. (30 grains). The older tables gave the dose of veronal as 1 gm. (IS grains), but this is cer- tainly too large for the average, and the dose should be from 0.3 to 1 gm. (5 to 15 grains). The insoluble hypnotics should be given in the form of powders, which may be enclosed in capsules or suspended in hot milk, which is somewhat sedative, but which should be sipped and not drunk rapidly, as it forms an indigestible curd when taken in the latter way, whereas when sipped it is precipitated in flaky curds which are much more readily digested. Hydrated chloral is best taken in a large amount of water or in warmed milk. The dose of veronal sodium is about the same as that of veronal; it is more soluble and acts some- ALDEHYDS 125 what more rapidly. The aqueous solution has a bit- ter alkaline taste that is objected to by some patients. It should be given well diluted. It is sometimes claimed that the greater solubility* of the sodium salt insures its prompt elimination and pre- vents cumulative effects, but experiments on cats fail to substantiate the claim. The average dose of paraldehyd is 2 c.c. (30 min- ims), best administered with cracked ice or in ice- water, on account of its disagreeable taste. It should not be long continued owing to the danger of the for- mation of the habit similar to that with alcohol. Much larger doses are usually required to control alcoholic mania, and from 10 to 15 c.c. (2 to 3 teaspoonfuls) may be given and repeated in half an hour. A word of caution should be uttered here in regard to the use of Bromidia: This preparation is said to represent 15 grains of hydrated chloral, 15 grains of potassium bromid, % grain of extract of cannabis indica and % grain of extract of hyoscyamus in each teaspoonful of the preparation. It is obvious that if this formula is correct a teaspoonful of Bromidia contains four full therapeutic doses of hypnotics and narcotics. The ingredients are incompatible, because extract of Indian cannabis contains a resin not soluble in the menstruum employed. There is no excuse what- ever for combining such a mixture of drugs when a simple hypnotic is required, and if an analgesic is necessary morphin or antipyrin should be used. MATERIA MEDICA Chloralum Hydratum. — Hydrated Chloral, U. S. P. This drug, popularly known as chloral hydrate, CCI3CHO-I-H2O, is the combination of trichloraldehyd or chloral, CCI3.CHO, with one molecule of water. It occurs as colorless, transparent crystals having an aromatic, penetrating odor and a bitter and caustic taste; it is slowly volatilized when exposed to air. It is very soluble in water, alcohol or ether. Hydrated chloral is incompatible with alkalies and alkali car- bonates, which cause the formation of chloroform. A compound of chloral believed to be chloral alco- 126 DEPRESSANTS OF CENTRAL NERVOUS SYSTEM holate sometimes separates out from mixtures con- taining hydrated chloral, an alkali, a bromid and alcohol. Hydrated chloral is best administered in simple aqueous solutions with or without the addition of a bromid. The bitter and caustic taste may be effectually masked by syrup and aromatics. Sulphonmethanum. — Sulphonmethan, U. S. P. Diethylsulphonedimethylmethane, or sulphonal. The product of the oxidation of the mercaptol, obtained by the condensation of acetone with etbylmercaptan, is official in nearly all pharmacopeias and is generally prescribed in this country as sulphonal. It occurs as colorless, inodorous and nearly tasteless crystals or a crystalline powder ; it is slightly soluble ( 1 : 360) in water and soluble ( 1 : 47) in alcohol. It is usually administered in the form of powder, preferably mixed with hot liquids such as weak tea, water or milk. Sulphonethylmethanum. — Sulphonethylmethane, U. S. P. Diethylsulphonemethylethylmethane, or trional, is obtained by the condensation of methylethylketone with etbylmercaptan. It is official in many of the European pharmacopeias and is usually prescribed in this country as trional. It occurs as odorless, colorless, crystalline scales or a crystalline powder having a bitter taste in aqueous solution. It is slightly soluble (1 : 195) in water and freely soluble (1 : 10) in alco- hol. Like sulphonal it is preferably administered in the form of a powder or mixed with hot liquids. Veronalum. — Veronal, N. N. R. This substance is also known as diethyl barbituric acid, diethyl malonyl urea, and malo-urea. It is described chemically as 2,4,6, trioxy-5-diethyl pyramidin, a ureid derived from diethylmalonic acid and urea. Veronal occurs as a white crystalline powder, odorless and having a faintly bitter taste. It is freely soluble (1:8) in alcohol and slightly soluble ( 1 : 500) in water. It may be administered in the form of powder or, like sulphonmethane and sulphonethylmethane, dissolved in hot liquids. Sodii-Diaethyl Barbituras. — Sodium-Diethyl Barbi- turate, U. S. P. This article, also known as medinal and veronal-sodium, is the mono-salt of diethyl- ALDEHYDS 127 barbituric acid or veronal. It occurs as a white crystalline powder, odorless and having a bitter alka- line taste. It is freely soluble (1:5) in water. Because of its solubility in water veronal sodium has been proposed for adininistration by rectal injection or hypodermically. Its use in this way has, however, as yet not been well established. Paraldehydum. — Paraldehyd, U. S. P. Paraldehyd, CgHijOg, is a polymer of acetaldehyd and occurs as a colorless transparent liquid having a strong char- acteristic odor and a burning and cooling taste. It is freely soluble (1:8) in water, and miscible in all pro- portions with alcohol. Paraldehyd is preferably administered with cracked ice or ice-water, but it is frequently objected to because of the odor which per- sists in the breath. CHAPTER III.— LOCAL ANESTHETICS COCAIN Cocain is the only alkaloid of therapeutic impor- tance obtained from coca. There are, however, other bases present in the leaf which probably add materially to its action, but which have not been studied. The use of coca by the natives of Peru was men- tioned by Pizarro in the sixteenth century, and at a very early date remarkable tales were told of the feats of physical endurance which the natives performed while using it. These stories were often considered as mere travelers' tales, but they have been amply verified, and the following interesting account of the endurance of coca-chewers is given by Lloyd of Cornell University : We started across the Paramo, as the lofty summit of the Andes above the timber line is called. On this trip the dozen Indian porters who carried our cargoes all consumed coca unceasingly while on the march. After eating a simple breakfast of ground corn porridge, they would start with their heavy packs, weighing from 75 to 100 pounds, strapped to their backs. All day long they traveled at a rapid gait, over steep mountain spurs and across mucky swamps at an altitude that, to us, without any load whatever, was most exhausting. On these trips the Indians neither rested any- where nor ate at noon, but incessantly sucked their wads of coca throughout the entire day. The first investigation of cocain worth mentioning appears to have been made in 1860, when Woehler isolated cocain. The local anesthetic action of coca when chewed with ashes (as the natives use it) was observed a little later, and was shown to be due to cocain. Nothing came of these observations, how- ever, until Koller, now of New York, introduced cocain into medical practice in 1884. For some years it was very expensive and its use was limited to oph- thalmic practice. Its costliness, its toxicity and other disadvantages have served as a stimulus in the search COCAIN 129 for substitutes, and many synthetic preparations have been introduced, but none of these has attained the popularity of cocain, though some have certain special fields of usefulness. While cocain is used therapeutically almost exclu- sively as an anesthetic, its action on the central nervous system is of importance because of the frequency with which poisoning occurs through its abuse and through accident or overdosage. Cocain stimulates the centers in the same general order in which they are depressed by morphin, but the motor areas, which are not depressed by morphin, are actively stimulated by cocain; this results in circus movements in some animals. The stimulation is fol- lowed by depression of the same areas, but the stimu- lation and depression are not at all uniform, so that one usually observes evidences of mixed stimulation and depression of the various centers during cocain poisoning. Cocain causes a notable rise in the temperature, sup- posedly through its action on the heat-regulating mechanism. The respiratory center in the medulla is stimulated, causing an increased rate, with little change in the depth at first. Later the stimulation gives place to depression, and with large doses the respiration becomes shallow, while the rate may be increased still further. If convulsions result, the respiration is arrested, and, as after strychnin convulsions, may fail to be reinstated, or there may be a gradual respiratory failure, with Cheyne-Stokes respiration and progres- sive slowing and diminished volume until death. The vasomotor centers are stimulated by cocain, causing a great rise in blood-pressure, which may be so extreme as to demand treatment after large doses. It should be noted that this excessive rise in the blood- pressure is quite apart from the local vasoconstrictor actions which follow the local application of the drug, for in the latter case it is present in very much greater concentration than it can be after the absorption of non-fatal doses into the general circulation. 130 LOCAL ANESTHETICS In discussing the peripheral actions of cocain we must distinguish between the local effects of relatively large amounts — that is, where the drug is in relatively high concentration in small areas — and the effects fol- lowing the systemic application. The latter will be discussed first. Cocain stimulates the S3rmpathetic nerve-endings after its systemic application, in which case the amount which comes in contact with the nerve- endings is insufficient to cause paralysis. The degree of the stimulation of the nerve-endings differs widely in different parts of the body. The accelerator nerve of the heart is stimulated prominently, causing an increase in the heart-rate; this tends to augment the rise of blood-pressure caused by stimulation of the vasomotor centers. The S3rmpathetic endings in the pupil are stimulated, causing dilatation of the pupil; this is also observed when the cocain is dropped into the eye. The action of cocain on the sympathetic endings appears to render them more excitable to normal or other stimuli, even when the dose is insufficient to induce any visible effect alone. Thus if an amount of cocain equal to 0.3 mg. (%oo grain) per kilogram of body weight be injected into the veins of a dog it will cause no rise in the blood-pressure, but if a dose of epinephrin that is too small to have any effect on the blood-pressure of a normal dog be injected intra- venously immediately after the administration of the cocain, the blood-pressure rises sharply, because the vasoconstrictor endings are now more excitable than normally. The action of cocain is manifested on the pupil and probably elsewhere in the body in the same way. After the systemic administration of cocain the effects on the sympathetic endings elsewhere in the body are of minor importance, probably because the vasoconstrictor action, which results in a diminished supply of blood to the part, masks the action on the other sympathetic endings. Cocain increases the capacity for muscular work through its lessening the sense of fatigue after its sys- temic application, but since it depresses the nerves with which it comes into contact in sufficient concentration, COCAIN 131 cocain injected directly into the muscle to be tested diminishes its capacity for work. The local application of cocain to mucous mem- brances causes constriction of the vessels, resulting in blanching, presenting a bloodless field for operations and causing stoppage of the secretion of the mucous glands through the interruption of the circulation. This local vasoconstriction is useful in several ways. In addition to presenting a bloodless field, the inter- ruption of the circulation delays the absorption of the cocain into the general circulation, thus intensifying and prolonging the local anesthetic action, and since the intensity of systemic action depends partly on the concentration in which the cocain enters the circula- tion, the slow absorption lessens this action while per- mitting the elimination of a part of the drug. Intense local vasoconstriction may follow the use of concen- trated solutions, and the prolonged local action occa- sionally causes gangrene. This can be avoided by using dilute solutions, but their action is so slow and weak that the same object is attained better by using moderately dilute solutions of cocain with enough epinephrin to cause a sufficient degree of vasoconstric- tion. When cocain is applied to mucous membranes or injected subcutaneously the nerve-endings are para- lyzed, the sensory before the motor. If the solutions are applied to nerve-trunks these are also paralyzed, and here, too, the sensory fibers are paralyzed before the motor. The nerve-endings and trunks are not paralyzed when cocain is taken internally or injected intravenously, because it does not reach those struc- tures in sufficient concentration. An apparent excep- tion to this rule has been demonstrated for the serous surface of the intestine of the dog ; pinching the intes- tine does not cause pain after the subcutaneous injec- tion of a moderate dose of cocain. The difference in the degree of concentration in which the drug reaches the nerve-endings of trunks after systemic and local application is appreciated when one remembers that the amount used for local application to an extremely small part of the body is 132 LOCAL ANESTHETICS equal to that which can be injected safely into the entire body, and which is probably distributed through a large portion of it. When cocain is applied to the tongue it abolishes the sense of taste for bitter substances more readily than those for sweet and sour, the taste for salt being unaffected. Yerba santa affects the sense of taste in the same way. The sense of smell is abolished by the local application of cocain to the nasal mucous mem- brane. Cocain is absorbed rapidly from the gastro-intestinal tract and from the subcutaneous tissues when the local vasoconstriction has passed away, or if the solution injected is too dilute to cause this constriction of the vessels. It is probably destroyed in the body in part, but a part is excreted in the urine unchanged, the elimination being slow after poisonous doses have been taken. Acute fatal poisoning by cocain is comparatively rare, considering its wide-spread use. The fatal dose is probably about 1 gm (15 grains), either by mouth or subcutaneous injection, but a much smaller amount may be fatal when it is injected directly into the spinal canal, because of the facility with which it may ascend to the medulla and paralyze the respiratory center. Death is reported to have followed the injection of 0.02 gm. {y2 grain) in this way in each of two cases. Severe symptoms of poisoning may follow very much less than the average fatal dose. The habitual use of cocain is common, and extreme measures have been adopted in some states, notably New York, in the effort to abolish the illegal traffic in the drug. The sudden withdrawal of cocain from one who has been accustomed to its use by subcutaneous injection causes such severe suffering and dangerous collapse that special provision must be made for the care of the habitues when stringent and effective laws are passed abolishing the sale of the drug except for legitimate therapeutic uses. Those who use it as a snuff are said to withstand the sudden withdrawal without serious consequences. COCAIN 133 The treatment of cocain addiction requires special measures and does not demand discussion here. The treatment of acute cocain poisoning is similar in gen- eral to that of poisoning by other alkaloids — removal from the stomach, if possible, precipitation, elimination and administration of physiologic antagonists; there is no specific remedy for the drug when it has entered the circulation. Excessively high blood-pressure may require relief by means of the nitrates, 3 minims being inhaled from a handkerchief. Hydrated chloral or chloroform may be required to control the excitement and convulsions, but ether is probably preferable, because it is not so dangerously depressant, and its action can be controlled to accord with the different stages of cocain action better than hydrated chloral or chloroform. Artificial respiration should be employed if there is any sign of respiratory failure. Solutions of cocain are decomposed on prolonged boiling with the liberation of benzoic acid and methyl alcohol, but they may be sterilized with insignificant loss by boiling for a short time or by maintaining them at a temperature of 80 C. for an hour on each of two successive days. A solution recently prepared with proper caution with sterile salt solution is practically sterile. The solution decomposes on standing, and only freshly prepared solutions should be used. THERAPEUTIC USES The therapeutic uses of cocain depend almost exclu- sively on its anesthetic and astringent actions when applied to mucous surfaces, to painful ulcers, or when injected subcutaneously, and it is obvious that it is capable of affording relief in a wide range of condi- tions which it is unnecessary to discuss in detail. When applied to mucous surfaces it causes anesthe- sia and intense blanching, due to vasoconstriction; hence it is applied to the conjunctiva, the nose, throat, urethra and other surfaces for the relief of pain, to facilitate examination or to allay congestion. It must be remembered that absorption takes place readily from any of these surfaces after the primary blanch- 134 LOCAL ANESTHETICS ing, and sometimes immediately after the application. Death has followed the injection of a small amount of cocain into the urethra, tihough its injection into the bladder appears to be less dangerous, provided that dilute solutions are used. The application of cocain in dilute solution or pow- der to the nasal mucous membrane relieves the con- gestion and facilitates the passage of instruments, but epinephrin is probably preferable. Cocain may be applied to ulcers when swallowing is painful, as in laryngeal tuberculosis, or it may be injected into the sheath of the larjmgeal nerve, though this is not com- monly advisable. Sometimes cocain is applied to itch- ing piles and to the vulva, but it is better to employ phenol ointment, which does not give rise to a habit in such chronic conditions, for it must be remembered that absorption and systemic effects may follow the use of cocain in any of these conditions. The applica- tion of strong solutions to the gums and to carious teeth is said to be especially dangerous, and at most very small amounts of weak solutions should be used for that purpose. Cocain is sometimes used to facilitate the swallow- ing of the stomach-tube, and to allay nausea of local origin in the stomach, but it is not advised for either of these purposes, because of the difficulty of applying enough of the solution to cause diminished sensation over such large surfaces without using toxic doses. It will be of very little use in allaying nausea of cen- tral origin, though it may diminish the stimulus from the stomach which acts on a hyperexcitable center. Cocain is useful in securing a bloodless field in cut- ting operations on mucous membranes and operations of small area, but it is obviously unsuited for this pur- pose in major operations involving large areas. It is also especially effective in controlling capillary hemor- rhage. It is frequently used as a mydriatic because it induces insensibility to pain. The mydriasis is not so complete as with atropin, but the cocain is said to enhance the action of other mydriatic alkaloids, and a small amount of atropin may be used at the same time if desired. COCAIN 135 Cocain does not cause paralysis of accommodation or the loss of reaction to light. The action is induced mainly through the local stimulant action on the sym- pathetic endings, but in part through the central action when absorption occurs. It is remarkable that atropin and cocain, which are so closely related chemically, should produce mydriasis through opposite kinds of action on different structures. Cocain is sometimes injected intraspinally to pro- duce insensibility to pain in the lower parts of the body, but while those who have become expert in the technic of its use in this way report satisfactory results, it is not suited for general practice because of the grave dangers which it involves. Attention has been called to the fact that shock may result from severe and extensive injuries to nerves during surgical operations under ether or chloroform. Cocain causes complete paralysis of the nerve-trunks if applied to them or to the nerve-endings, and thus prevents the passage of impulses through the nerves. In this way the danger of shock during operation may be lessened, even when it is necessary to combine the local anesthetic action of cocain with a general anes- thetic, such as ether. Wine of coca has been used as a general tonic, but there seems to be no indication for the use of such a preparation. Of course, any wine of coca must contain cocain, otherwise it is not wine of coca. DOSAGE The dose of cocain hydrochlorid for internal admin- istration is said to be 0.03 gm. (i/^ grain). This, how- ever, must be considered rather as a guide to the lim- its of ,safe administration than as any indication of the amount required for systemic effects, for even when taken orally for the relief of pain in gastric ulcer or to allay nausea and vomiting, it is used for its local action, and a systemic effect is undesired. On the contrary, when it is applied locally or taken internally it is desirable to delay absorption so far as possible.' 5. It is possible that the systemic action of cocain might be useful in enhancing the effect of epinephrin in shock, but the technic of its use for this purpose has not been developed. 136 LOCAL ANESTHETICS It stimulates the psychic and other centers, including that of respiration, but we have safer and better drugs for those purposes. The amount of cocain administered at any one time should be limited to 0.06 gm. (1 grain), unless its absorption can be prevented. It is used in solution containing from 1 to 2 per cent, for the relief of pain and in 4 per cent, solution where it is necessary to induce complete anesthesia, as in cutting operations. Anesthesia of the mucous mem- brane and other parts of the eye which are subjected to cutl;ing may be induced within ten minutes; this lasts about fifteen minutes and then disappears, so that the time allowed for operation is brief. It is difficult to produce anesthesia of the nose, throat and larynx, and strong solutions are sometimes employed, but these are not devoid of danger. In laboratory experiments on dogs it was found to be impossible to produce complete anesthesia of the esophagus by applying dilute solutions, and when stronger solutions were used absorption occurred to such an extent that toxic symptoms invariably resulted. One difficulty encountered was due to the presence of an abundant secretion of mucus, which interfered with the direct application of the cocain. This diffi- culty may be overcome in part by the application of atropin in suitable cases. Solutions varying from 0.5 to 4 per cent, are used for subcutaneous injection ; but Schleich suggested the use of solutions of different strength (and containing morphin, without sufficient reason) for the infiltration method. This consists in injecting a relatively large amount — up to 200 c.c. (6 fluidounces) — of a solution of 1 : 10,000 in physiologic saline through a fine needle and permitting it to permeate the tissues about the region to be operated on. Relatively smaller amounts of solutions of 1 : 1,000 may be used in the same way. The pressure of the solution on the nerves assists in the anesthetic action. The solution is injected into — not beneath — the skin at first, and then into the under- lying tissues successively. This method is painful when inflammation exists, and in such cases it is COCAIN 137 preferable to inject the solution around the trunk of the nerve which supplies the region to be incised, thus blocking impulses. It would be preferable to inject the solution directly into the sheath of the nerve-trunk, but it is difficult to do this without first exposing the nerve; hence it is better to inject the solution so that it will lie around the nerve-trunk. Solutions containing from 0.005 to 0.03 gm. (from %2 to l^ grain) injected into the lumbar subdural space produce loss of perception of pain in the parts supplied by the afferent nerves of that region, while the sense of touch and the capacity for voluntary move- ment are retained. With large doses there is a total paralysis of the regions involved soon after the pain sensation is lost. It is essential that the solution be prevented from penetrating along the spinal canal to the medulla, for should even a small amount of cocain reach the medulla death from paralysis of the respiratory cen- ter may result. Aside from the danger of systemic effects with this method, there is also the disadvantage that mus- cular relaxation does not occur. MATERIA MEDICA Cocaina. — Cocain, U. S. P. An alkaloid obtained from several varieties of coca, employed in medicine usually in the form of : Cocainae Hydrochloridum. — Cocain Hydrochlorid, U. S. P. The neutral hydrochlorid of the alkaloid cocain occurs as colorless crystals or a white crystalline pow- der, permanent in air, odorless, having a slightly bit- ter taste, and producing on the tongue a tickling sen- sation followed by numbness of several minutes' dura- tion. Cocain hydrochlorid is very soluble ( 1 : 0.4) in water and freely soluble ( 1 : 2.6) in alcohol. It is incompatible with alkalies, sodium borate and zinc sulphate. It decomposes on standing even in sterile solution. Solutions of cocain hypdrochlorid tend to decompose when boiled, the decomposition giving rise to benzoic 138 LOCAL ANESTHETICS acid, but the loss is insignificant when boiling is not prolonged beyond a few minutes. Solutions prepared with sterile salt solution are practically sterile if care is used. COCAIN SUBSTITUTES The toxicity of cocain, together with minor disad- vantages, such as its instability when boiled or allowed to stand, has served as a constant stimulus in the search for suitable substitutes ; among the more useful of the agents which this search has brought forth are novocain, stovain, alypin, tropacocain, orthoform-new, and others which are described in New and Non- Official Remedies. Novocain is usually said to be from one sixth to one tenth as toxic as cocain, but the toxicity of novocain depends to an extraordinary degree on the way in which it is administered. The injection of a barely non-fatal dose into the vein of a cat causes the respiration and heart-beat to stop immediately, with gradual recovery. Such a dose may be repeated frequently at intervals of about fif- teen minutes, complete recovery apparently taking place in the intervals. Artificial respiration and the injection of epineph- rin saved a certain number of animals after the injec- tion of doses that were 25 per cent, larger than those subsequently required to cause death. A patient is said to have died after the subcutaneous injection of a small amount of novocain, but the details of the case could not be learned. The anesthesia which it induces is more fleeting than that of cocain; this may be overcome by the injection of epinephrin with the novocain. Novocain is not irritant and is gaining in popularity for very short operations, especially among ophthalmologists. Stovain is about equal to cocain in anesthetic activ- ity, but it causes dilatation of the vessels, and where a bloodless field or the astringent action of cocain is required it must be combined with epinephrin. Alypin is closely related to stovain, over which it has no obvious advantage. Solutions of these drugs and of tropacocain may be boiled without causing OTHER LOCAL ANESTHETICS 139 decomposition, but this does not constitute any great advantage over cocain. Orthoform-new resembles cocain in its anesthetic actions, but it is insoluble; hence it is suited mainly for application to painful ulcers ; in fact, it is sometimes used for diagnostic pur- poses in cases of suspected gastric ulcer. When relief is afforded in such cases it is taken as evidence that the pain is due to ulcer. OTHER MEASURES FOR INDUCING LOCAL ANESTHESIA Magnesium sulphate has been used intraspinally for the production of anesthesia, but it is not recom- mended. The injection of pure water under sufficient pres- sure causes anesthesia of the tissues, but it is too pain- ful for general use. Sensory endings in the skin may become depressed as the result of overstimulation, or irritation, by drugs, such as chloroform, which are often used in the form of liniments, and diminished sensation in the region over an abscess before it bursts is probably the result of overstimulation. Protracted immersion of a painful part in warm water lessens its sensibility to pain, and the application of heat results in vasodilatation, which is later fol- lowed by vasoconstriction when the part is exposed to cold. The cells of tissues imbibe water during immer- sion and this lessens the sensitiveness to pain; such protracted immersion is especially useful in allaying itching. Anesthesia can be produced by freezing, either by immersion in a freezing mixture of salt and ice, or, more conveniently, by spraying with a volatile sub- stance, such as ethyl chlorid or rigolene (light gaso- line). With care the freezing with ethyl chlorid spray may be accomplished with little pain, but it is suitable only for small areas and for short operations, such as opening abscesses. Menthol is applied externally for the relief of neu- ralgia and certain forms of headache, the cones or 140 LOCAL ANESTHETICS pencils affording a convenient means of application. It is sometimes inhaled for the relief of rhinitis and sore throat, or it may be dissolved in 100 parts of liquid petrolatum and applied locally. An ointment containing from 1 to 2 per cent, of menthol may be used for the relief of itching. It is sometimes used internally for the relief of gastric pain, but it is not especially effective. The dose is 0.06 gm. (1 grain). Pusey of Chicago introduced solid carbon dioxid into therapeutics in 1907. When liquid carbon dioxid is allowed to escape from a cylinder into a cone it forms a snow that may be collected and formed into pencils that must be handled cautiously. When it is pressed for a few seconds against the skin the latter is frozen, and this is followed by vesication, but not by necrosis. Pencils or crayons of carbon dioxid snow are used for the removal of capillary nevi, warts and moles, and in the treatment of rodent ulcer, lupus vulgaris and in many other conditions. Its employment requires a special technic that does not require further discussion here. Phenol is actively anesthetic, and the ointment of phenol is especially useful for the relief of painful ulcers. The application of an aqueous solution to parts in which the circulation is impaired is attended with serious danger of gangrene, and numerous instances of the loss of fingers and toes from this cause might be cited. The official phenol ointment does not have this disadvantage. Eriodictyon (yerba santa) abolishes the sense of taste for bitter substances ; hence it is used as a syrup to mask the taste of quinin and other bitter substances. CHAPTER IV.— ANTISEPTICS AND DISINFECTANTS Antiseptics have long been used for the preserva- tion of the human body after death and for other pur- poses. Of course the nature of their action was not understood in early times. The modern use of anti- septics and disinfectants in surgery dates from their employment by Lister less than thirty-five years ago. Lister's brilliant results aroused the hope that all pathologic micro-organisms in the human body might be killed, especially those in the blood. Though this hope has not . been fulfilled it has been fostered by manfacturers of proprietary preparations, and there are few branches of the materia medica in which there have been more misunderstanding and deliberate mis- representation. The difficulty of destroying micro-organisms in the body tissues is shown by the results obtained by Bech- hold and Ehrlich in their experiments with a large number of agents, including numerous halogen com- binations with benzene derivatives. Some of these compounds were extraordinarily active against certain organisms in the test-tube, but they were uniformly ineffective in much greater concentration when used in the body. The fact cannot be reiterated too emphatically that test-tube demonstrations of disin- fectants and antiseptics, however brilliant, afford no index of therapeutic value when the agents are used internally against infection in man. The subject of antisepsis and disinfection* concerns the public health and general welfare deeply; there- fore the physician should understand the general prin- 6. There has been so much confusion regarding the use of the terms "antiseptic," "disinfectant" and "deodorant," that it may be permissible to define these terms briefly. A disinfectant is an agent that destroys micro-organisms. An antiseptic prevents the growth of micro-organisms so long as certain conditions are maintained. Deodor- ants absorb or destroy odors': they are not necessarily antiseptic or dis- infectant. 142 ANTISEPTICS AND DISINFECTANTS ciples involved in the use of disinfectants outside of the body, and he should, of course, understand the actions of those antiseptics and disinfectants that he uses internally. It is obvious that all disinfectants will prevent the growth of bacteria, but for some reason the fact is often overlooked that an antiseptic does not prevent the subsequent growth of the mjcro-organisms when the necessary conditions have changed. The importance of this lies in the fact that anti- septics are often recommended for use where disin- fectants' alone are of value. It is obviously useless to employ an antiseptic in washing an infant's nursing- bottle and its fittings, because an antiseptic wash is no better than water for removing bacteria, and unless they are removed or destroyed they will multiply when the bottle is filled with milk, which is an. excellent culture medium. Anything that renders the conditions unsuitable for the growth of bacteria will act as an antiseptic, but a chemical substance, to be actively disinfectant, must penetrate the bacterial cell and act on its protoplasm. Some of the more intensely active antiseptics have been mistaken for disinfectants when tested carelessly, because enough of the antiseptics were transferred to the culture mediums with the bacteria to prevent further growth, leading to the supposition that the bacteria had been killed. The activity of disinfectants is altered by so many different conditions that it is not sufficient to know the aclual or relative degree of activity of a given agent when it is used in a test-tube experiment under the most favorable conditions ; it is necessary to know also the approximate activity under the conditions in which it is to be used. Different organisms manifest wide differences in their resistance to the action of disinfectants, and among the factors which influence the destructive activity of a disinfectant for a given organism are temperature, the presence of organic matter, and the manner of cultivation of the organism. It is obvious that we cannot accurately determine the activity of any disinfectant in a given condition, except by actu- DERIVATIVES OF BENZENE 143 ally testing it under approximately similar conditions ; but the standardization of a disinfectant affords an approximate indication of its value. Of the numerous methods proposed for standardiz- ing disinfectants, the one known as the "Hygienic Laboratory phenol coefificient" ' has been adopted as the basis for purchasing disinfectants by the United States government and is approved by the Council on Pharmacy and Chemistry. Stated briefly, this method consists in comparing the activity of the agent to be tested with that of phenol under conditions which seem best calculated to indicate its usefulness. For convenience of discussion, we shall classify the antiseptics and disinfectants arbitrarily as derivatives of benzene, urinary disinfectants and antiseptics, and general disinfectants and antiseptics. The discussion cannot be either systematic or comprehensive, but it is intended to call the physician's attention to the depend- able resources at his command for internal use, and for such disinfection as the general practitioner may be called on to conduct in emergencies. Many of the derivatives of benzene may be used for general disin- fection, and some of those classified as general disin- fectants may be used internally. DERIVATIVES OF BENZENE Benzene (CgHg) is not actively disinfectant, but phenol, which results from the substitution of an OH for an H of benzene, is sufficiently active to be used as the standard for comparison of disinfectants, though it is far from being the most active even of this group. The toxicity of phenol (carbolic acid) lessens its field of usefulness, but the introduction of certain molecular groups into the phenol molecule lessens its toxicity without diminishing its disinfectant action. Many compounds formed in this way are now used. Phenol combines with protein and precipitates it from solution. When applied to the skin, it forms a white eschar by precipitating albumin, with which it 7. Hygienic Laboratory Bulletin 82, April, 1912, is devoted to a discussion of this method and of the value of a large number of dis- infectants which are advertised widely. 144 ANTISEPTICS AND DISINFECTANTS does not form a stable combination, and from which it may be removed by washing with alcohol or glycerin, in which it is very soluble. The official phenol ointment is not actively disinfec- tant, because the phenol is more soluble in fat than in the bacterial cells and does not penetrate the latter. It is anesthetic, however, because the fat penetrates the skin and permits the phenol to come in contact with the sensory nerves. The high mortality, especially from tetanus, follow- ing infected wounds, in soldiers who were not treated for some time, stimulated the search for a convenient antiseptic dressing for use in emergencies. As a result of preluninary experiments an ointment, consist- ing of 1 part of phenol and 4 parts of lanolin, has been recommended for the purpose. Only those antiseptics that diffuse readily from the ointment base into the tissues should be used in this way. Experiments on animals seem to show that phenol, tricresol and thymol have the necessary dif- fusibility when used in 10 to 20 per cent, strength; but these have not been tested clinically, and while they may be used in emergencies, their use should not be permitted to interfere with other, and better, methods of prophylaxis and treatment. A 25 per cent, solution of phenol in glycerin is recommended for cauterizing wounds, such as those caused by toy pistols, where there is reason to fear infection with tetanus bacillus. The wounds should be cleansed first, of course. Liquefied phenol is sometimes used without dilu- tion for cauterizing wounds when there is reason to fear tetanus infection. It kills the spores in a few minutes, and the pain induced is neither severe nor lasting. Phenol diluted with 20 parts of water is unfit for the purpose because it requires twelve hours or longer to kill tetanus spores. lodin is said to be equally effective against the tetanus spores, but it causes severe and lasting pain. The application of pure phenol or concentrated aqueous solutions to the skin causes pain followed by anesthesia, but the use of dilute solutions is not DERIVATIVES OF BENZENE 14S attended with severe pain. Oily solutions are pref- erable to aqueous when anesthesia is desired, but the aqueous are sometimes applied to infected superficial wounds for their antiseptic action. The water evapo- rates, requiring frequent renewal of the solution, and this may lead to gangrene even when dilute solutions are applied to the extremities in which the circulation is poor, as it is frequently after injuries; it is better, therefore, to add a little glycerin to the solution to retard the evaporation of the water. Concentrated ointments and solutions of phenol should not be used, as a rule, the official 2 per cent, ointment probably being as useful for most purposes as those containing ijiigher percentages of the anesthetic. Fatal doses of phenol depress the central nervous system, causing profound collapse, which is usually preceded by stimulation of the cord, with increased reflexes and possibly with convulsions. Conscious- ness is usually retained until late in the course of poi- soning, and the condition of the patient may be com- pared to that of one suffering from surgical shock. Phenol is absorbed at first fairly rapidly from the alimentary tract, but after the absorption of a large, but not fatal, dose it proceeds more slowly, apparently because of interference with the circulation; hence if the stomach is washed even after severe symptoms of poisoning have developed, a part of the phenol may be removed and the patient's life be saved. When phenol remains in the stomach bland oils are contra-indicated, because they favor its absorption, but they may be used after the stomach has been washed. White of egg should be administered imme- diately if it is at hand, but no time should be lost before washing out the stomach with water. Ten per cent, of alcohol may be added to the water if it does not entail loss of time, but no chemical antidote is comparable in effectiveness to the prompt washing with water in abundance. White of egg may be administered after completing the washing, as it serves the double purpose of combining with any remaining phenol arid protecting the irritated mucous membrane. One should not permit any theoretical considerations 146 ANTISEPTICS AND DISINFECTANTS of the antidotal nature of various chemical substances to interfere with the thorough washing of the stomach with water, and when this has been accomplished (the last washing should have little or no odor of phenol), attention should be paid to methods of restoration, stimulation being required if the patient is in collapse. Concentrated phenol causes corrosion of the esopha- gus and stomach If it is not removed promptly, and a bland oil, such as sweet oil, is useful to allay the pain after the poison has been removed. Sodium sulphate was long supposed to be an effec- tive antidote to phenol, with which it was said to form a sulpho-carbolate. This reaction does not occur in the body, and one should avoid being misled by this popular fallacy. Concentrated phenol "burns" on the skin are treated by washing with alcohol or glycerin, and applying an emollient or ointment. This peculiar white eschar or "burn" is frequently seen on the hands or about the lips of those who have taken phenol by accident or with suicidal intent, and it serves as a guide to the identification of the poison ; in such case the treatment %)f phenol poisoning should be instituted without delay. The odor is character- istic, and it may be detected on the breath in many cases of poisoning. SALICYLIC ACID AND SALICYLATES Salicylic acid differs from phenol by having an H of the latter replaced by the group COOH. Benzoic acid differs from phenol by having the OH of the lat- ter replaced by COOH. Salicylic acid is obtained from oil of sweet birch, or oil of wintergreen, both being composed mainly of methyl salicylate. It is also prepared synthetically from phenol. Benzoic acid is obtained from benzoin and prepared synthetically. The actions of salicylic acid resemble those of phenol in a general way, but it is less depressant to the cen- tral nervous system. Large therapeutic doses induce symptoms resem- bling those caused by quinin, and with still larger doses there may be actual narcosis. The toxic symptoms include dizziness, roaring in the ears, a sense of fulness SALICYLIC ACID AND SALICYLATES 147 in the head perhaps with headache, and sometimes mental dulness. Disturbances of hearing are usually transient but sometimes lasting; they are attributable to circulatory disturbances, as are those of vision, but in the more serious cases there may be injury to the nerve cells in the ear. The respiration becomes rapid with large doses, and respiratory failure ensues in fatal cases. Circulatory disturbances result from the action on the vasomotor centers and partly from the injury to the heart, but the toxic action on the heart is not important except with the largest doses. The vessels of the skin dilate, and sweating is often profuse, the action being similar to that seen with the other drugs of the antipyretic group. The blood pressure falls with the appearance of other symptoms of collapse, when very large doses are administered. Salicylic acid is absorbed and circulates as a salicyl- ate, probably as sodium salicylate, which is only feebly antiseptic, and there is much uncertainty concerning the mechanism of its action in relieving the pains of articular rheumatism. It has been suggested that sali- cylic acid has a specific action on the organisms which cause rheumatism, but there is no clear evidence of this. Relapses are more common in those cases in which salicylates are used than in untreated ones. Salicylic acid and sodium salicylate are irritant to the stomach, and it is customary to administer an excess of alkali with it, preferably sodium bicarbonate, to prevent liberation of the acid by the gastric juice. Many efforts have been made to prepare substitutes for salicylic acid which would be devoid of the action of the latter on the stomach and central nervous sys- tem, while retaining its therapeutic actions. These efforts have been somewhat more successful with regard to obviating the local irritant action on the stomach than with reference to the systemic effects. Several of these substitutes will be discussed later. The relative value of salicylic acid and the syn- thetic substitutes for it constitutes a question apart from that of the relative toxicity of salicylic acid itself prepared synthetically and that obtained from oil of 148 ANTISEPTICS AND DISINFECTANTS wintergreen or oil of sweet birch. There has long been current a mistaken belief that the natural sali- cylic acid is less toxic than the synthetic product. This belief arose from the fact that early reports were to the effect that the synthetic product contained very poisonous impurities; but recently an extended investigation of the subject was undertaken by the Council on Pharmacy and Chemistry, and com- parative results obtained with the natural and syn- thetic products were reported; these reports were reviewed by W. A. Hewlett, who summarized the results obtained by fifteen clinicians in the treat- ment of 139 patients. Hewlett reports that there is no difference between the natural and the synthetic salicylic acid so far as observable results are con- cerned." The natural salicylic acid is many times as expensive as the synthetic. It is commonly stated that salicylates increase the elimination of bile, but this action is probably unim- portant therapeutically. SALOL Among the various compounds which have been introduced with a view to lessening the toxicity of salicylic acid is phenyl salicylate, or salol, as it is com- monly called, consisting of one molecule of salicylic acid united to one of phenol. This is almost insolu- ble in the gastric juice; hence it does not irritate the stomach; but passing into the intestine, it is decomposed with the liberation of its component parts, the salicylic acid combining with sodium salts to form sodium salicylate, this and the phenol being absorbed. Salol lacks the disagreeable taste of sodium salicyl- ate, and it does not irritate the stomach ; but its actions are obviously those of phenol and sodium salicylate, though these actions are slowly developed. Human milk is said to contain a ferment capable of splitting salol, and gastric irritation is reported to have occurred in some cases when salol was admin- istered to breast-fed infants. 8. Hewlett, A. W.: Clinical Effects of "Natural" and "Synthetic" Sodium Salicylate, Jour. Am. Med. Assn., Aug. 2, 1913, p. 319. ATOPHAN AND BENZOATES 149 ACETYL-SALICYLIC ACID Acetyl-salicylic acid (aspirin) is formed by the introduction of the acetyl group into salicylic acid. It is less irritant to the stomach than salicylic acid It is decomposed in the intestine with the formation of acetates and salicylates; hence its systemic actions are those of salicylic acid. ATOPHAN Atophan acts on the kidney, causing some increased secretion of urine but a relatively greater increase in the elimination of uric acid, and some increase in the total nitrogen and ammonia. There is no evidence that it has any influence on the urates deposited in the body or that it increases the formation of uric acid. Through its action, the uric acid of the blood may be diminished one half on a purin-free diet, and when the diet contains purins, the amount of uric acid in the blood may be maintained at a normal level. It is said that uric acid is eliminated so rapidly that it may form deposits in the urinary tubules unless an abundant diuresis is maintained; hence the patient is advised to drink an abundance of water during the time that the atophan continues to act. The action begins promptiy, reaches its maximum within about three hours, and usually is nearly over in nine hours. Atophan relieves the pain of acute gout, and is said to be devoid of disagreeable side actions. It has a slightly bitter taste. Atophan and several closely related compounds are described in New and Nonofficial Remedies. BENZOIC ACID AND BENZOATES Benzoic acid differs from salicylic acid in having no phenolic OH group. It is obtained from benzoin and prepared synthetically. Benzoic acid and the ben- zoates are almost devoid of toxicity for the central nervous system, but they are also much less actively antiseptic and only feebly disinfectant. The wide-spread use of the benzoates as food pre- servatives has led to discussions which at times have ISO ANTISEPTICS AND DISINFECTANTS been more acrid than scientific. We do not know that benzoates are distinctly harmful to healthy adults when taken in moderate amounts even for prolonged periods, but we have no knowledge of their effects on those who are not in good health, lience it is preferable to avoid the constant use of benzoates in foods. If one cannot speak in unqualified condemnation of the use of food preservatives at all times, there can be no question of the undesirability of using them to cover up and hide the renovation of partially decom- posed foods. Food preservatives are sometimes used fraudulently, and for such abuses there can be no extenuation; but Long has recently directed attention to the preju- dice existing against the use of "chemicals" as food preservatives, despite the fact that smoked meats are preserved by very active chemicals, and that potas- sium nitrate has, long been used as a preservative without a hint of its being injurious. He believes that unreasoning prejudice prevents our forming a just estimate of the value of many food preservatives and the benefits that are to be derived from their proper use. Benzoic acid has no important therapeutic uses, so far as its internal administration is concerned. It may be used as a mild antiseptic. CRESOLS The cresols differ from phenol by having a methyl group — CH3 — replacing an H of phenol. The official cresol consists of a mixture of three isomeric cresols. Only one of these is desired for its antiseptic action, but it is expensive to separate them; hence the mix- ture is used where a cheap but efficient disinfectant is desired. Its action resembles that of phenol, but it is less poisonous and about four times as actively germicidal. It has the disadvantage of not mixing readily with water; hence it is commonly employed in a mixture with an equal amount of potassium soap, known as compound solution of cresol. This is useful for dis- CREOSOTE AND GUAIACOL 151 infecting the skin, for lubricating the hands and as a vaginal douche. It is inexpensive and may be used for disinfecting rough furniture and rooms which are not injured by washing with soap and water. Cresol is used as a disinfectant in solutions of 0.25 to 1 per cent. The compound solution is used in 1 to 5 per cent, solutions for washing wounds and as a douche. CREOSOTE Creosote is a mixture of phenols and phenol deriva- tives, including guaiacol and creosol, obtained from beechwood tar. The systemic actions of creosote resemble those of phenol, but it is credited with being useful as an intes- tinal antiseptic, and its beneficial effect in the treat- ment of tuberculosis has been explained as due to this intestinal antisepsis. The odor of creosote in the breath after it had been taken gave rise to the belief that it acts as an antiseptic in the lungs, but it has no destructive action on the tubercle bacilli in the lungs, because they are embedded in the tissues and are therefore inaccessible to the creosote. GUAIACOL Guaiacol is one of the chief constituents of beech- wood creosote, which it resembles closely in its actions. It is somewhat less actively antiseptic and germicidal. It is absorbed from the unbroken skin, and is then capable of reducing the body temperature, but it is prone to cause collapse. It is used much like creosote, over which it has no decided advantages. The carbonate of guaiacol is a crystalline powder, which is inactive until it is decomposed with the lib- eration of guaiacol. It is said that this decomposition takes place only in the presence of putrefactive organ- isms, and that its antiseptic action is developed only where it is needed. Its tastelessness and the decomposition in the pres- ence of putrefactive organisms would seem to give it a decided field of usefulness. 152 ANTISEPTICS AND DISINFECTANTS THYMOL Thymol is a phenol obtained commercially from oil of ajowan and occurring in oil of horsemint, oil of thyme and other volatile oils. It is frequently used as a urinary antiseptic and of late it has come into considerable prominence as a remedy in hookworm disease. Thymol iodid, formerly known as aristol, is an anti- septic powder which was supposed to represent the activities of thymol and of iodin, but it is so stable that it has little of the actions of either. There seems to be no sufficient reason for its continued use as a substitute for iodoform, to which it is inferior in anti- septic action. It is nearly odorless; at least, the odor is not nearly so penetrating as is that of iodoform. It is used as a dusting-powder. This may be taken as representing the type of prepa- rations which have been introduced as substitutes for iodoform, in which it is sought to secure the antiseptic action of the latter without its disagreeable odor. Many of these preparations have been introduced, but they are not antiseptic unless they are decomposable with the liberation of iodin. Most of them have fal- len into disuse, or are employed as dusting-powders, for which purpose they have no advantage over much less' expensive ones. Betanaphthol, also known as naphthol, is a phenol found in coal-tar, but usually manufactured from naphthalene. It is only sparingly soluble in water ( 1 : 950) and is absorbed rather slowly from the ali- mentary tract. When absorbed in sufficient amounts it is capable of inducing toxic effects, including nephritis and destruction of the red blood corpuscles. It is more actively antiseptic than phenol, and has been used as an intestinal antiseptic; for this purpose its slight solubility and absorbability are advantages. H. C. Wood, among others, has called attention to the large volume of fluid which the intestines contain — variously estimated at from 4 to 6 liters — ^and the large amount of antiseptics which would be required to be effective. While the intestinal antiseptics in common use may exert their action in the small intes- THYMOL 133 tine, it seems extremely doubtful whether any of those discussed so far can be administered in sufficient amount to influence the contents of the large intestine to a marked degree. The subject of intestinal antisepsis by means of drugs intended to inhibit the growth of bacteria has received a great deal of attention, but the results hith- erto reported are contradictory and difficult to explain. There can be no doubt that the nature and character of the infection, its location in the intestinal tract, and the condition of the intestinal mucous membrane and its secretions, as well as the food residues in the bowel, must all influence the results of any efforts at intes- tinal antisepsis. It is not certain that absolute asepsis of the intes- tine is desirable, though it is unquestionably desirable to restrain the growth of putrefactive and other patho- logic organisms. The administration of a brisk cathartic at a time when the body has not suffered serious injury from the toxins of the organisms serves to sweep out enor- mous numbers of bacteria mechanically, but unfortu- nately many remain, and if conditions favor their development there will soon be as many as before, for the number which results in one day from the unre- strained development from a single bacterium is incon- ceivably great. It is a matter of common experience that calomel affords greater relief in the condition commonly called "biliousness," than do other drugs of equal purgative activity. This can be understood readily when one remembers the various ways just mentioned in which the development of bacteria may be influenced.^ Others find a brisk saline cathartic more satisfactory in relieving the headaches and depression which are commonly associated with some form of bacterial activity in the intestine. Attempts to modify the bacterial flora have been made by introducing cultures of lactic acid bacilli, the idea being that they will multiply and, splitting sugar. 9. Intestinal Antisepsis is discussed by Norman M, Harris in Jour. Am. Med. Assn., Oct. 12, 1912, p. 1344. 154 ANTISEPTICS AND DISINFECTANTS form lactic acid, which is inimical to putrefactive organisms. This method appears to be attended with some success at times, but the lactic acid bacilli die off rapidly and must be taken constantly for prolonged periods to be of any service. Numerous forms of this culture are described in New and Nonofficial Remedies. THERAPEUTIC USES One part of phenol in five hundred or a thousand parts of water is actively antiseptic for most of the common pathogenic bacteria, and a 1 per cent, solution is actively germicidal for nearly all of the nonsporu- lating forms, destroying them in a few minutes at ordinary temperatures. Anthrax spores, however, are not destroyed by a 5 per cent, solution in twenty-four hours, and tetanus spores are almost as resistant. Phenol is applied to the skin in dilute solution or preferably as an ointment to relieve itching as in piles. It is also useful as an application to small painful ulcers. The statement is often made that the pain of burns is increased by phenol ointment, but such increase of pain is transient and an anesthetic action is then obtained. Phenol cannot be applied to large surfaces because of the danger of absorption. It is often used as an antiseptic in the form of gargles, and mouth-washes, but in such cases it can have little value as an antiseptic. Any benefit derived must be due to the allaying of irritation and the cleans- ing of surfaces, for phenol cannot be kept in contact with the bacteria long enough to have any important influence on their multiplication. It is said to be of some value in vomiting. This is probably explained by its capacity for lessening the irritability of the gastric mucous membrane, by its anesthetic action. In that case it can have little more than momentary value. It has been used to relieve gastric fermentation, but it is not recommended for this purpose. The antiseptic and disinfectant uses of many of the agents which have been discussed require no further consideration. Salicylic acid, the salicylates, including THYMOL 155 salol and aspirin, and the other derivatives of salicylic acid, are used widely for the relief of joint symptoms in articular rheumatism, and for the reduction of fever which attends that condition. Salicylic acid has no influence on the endocarditis that accompanies rheumatism so frequently, however, and, as previously stated, it does not prevent the recurrence of the rheu- matic attacks. The salicylates afiford relief in rheumatism only while medication is continued. They are used for the relief of headache and other neuralgic affections, in chorea, in tonsillitis and in various catarrhal inflam- mations. The salicylates cause some increase in the excretion of uric acid. For this reason, perhaps, they have been used in gout, but they are of little value in that con- dition. There is no evidence that any slight influence which they may have on the secretion of bile is of value in the treatment of constipation. Sodium sali- cylate is said to be useful in certain conditions of the eye, including iritis, keratitis and glaucoma. The caustic action of salicylic acid is utilized for the removal of corns and calluses. Large doses of the salicylates are contra-indicated late in the course of pregnancy because of their tendency to produce abortion. Phenyl salicylate, or salol, is said to have an espe- cial field of usefulness as an antiseptic in diarrhea and enteritis. Its comparative insolubility in the gastric contents has led to its employment for coating pills intended to pass through the stomach and dissolve in the intes- tine, but the amount required to coat one or two large pills constitutes very nearly a full therapeutic dose. DOSAGE Phenol is crystalline at room temperature, and owing to the inconvenience of handling it, the liquefied phenol is usually employed. The dose of the liquefied phenol is 0.05 c.c. (1 minim), corresponding to about 0.04 g™- (% grain) of the crystalline. Salicylic acid is seldom administered as such inter- nally, sodium salicylate being commonly employed, or 156 ANTISEPTICS AND DISINFECTANTS methyl salicylate (oil of sweet birch or oil of winter- green) or aspirin may be used. Methyl salicylate and sodium salicylate are usually given in doses of 1 gm. (15 grains), which may be repeated every hour or every two hours until the maxi- mum permissible amount is given. This is indicated by ringing in the ears, perhaps some dizziness, and occasionally some slight mental disturbance such as confusion. About 6 to 8 gm. (90 to 120 grains) are usually required to induce the symptoms indicative of the limits of tolerance, but if the larger amount fails to induce the usual symptoms, the dose may be given less frequently, or a smaller dose every two hours. After the symptoms appear the administration is usually limited to about three doses per day. For headache and neuralgia much smaller amounts are employed, 1 gm. (15, grains) being usually suffi- cient. Phenyl salicylate, or salol, is given in smaller amounts than is sodium salicylate because of the dan- ger of phenol poisoning from such large doses. For whatever purpose salol is used, the dose should not usually exceed 0.5 gm. (8 grains). Aspirin, or acetylsalicylic acid, is given in somewhat smaller doses than is sodium salicylate in the treatment of rheumatism, the symptoms which indicate the limits of dosage being the same as with sodium salicylate. It is given in doses of 0.3 gm. (5 grains) for the relief of headache. The dose of atophan is 0.5 gm. (7i^ grains). Benzoates might be given in larger doses than the salicylates were there any occasion to administer them internally. Cresol is not often used internally, but the dose is said to be 0.05 c.c. (1 minim). Creosote is given in doses of 0.2 c.c. (3 minims) three times daily, but it should be discontinued when it disturbs the appetite and digestion. Guaiacol is given in doses of 0.1 c.c. (li/^ minims) in an emulsion or dissolved in a bland oil contained in capsules, and if this dose is borne without disturbance MATERIA MEDICA OF ANTISEPTICS 157 it may be increased cautiously to 0.6 c.c. (10 minims). The carbonate of guaiacol may be given more boldly, since it is inactive until it is decomposed, the dose being 1 gm. (15 grains). It is incompatible with alka- line hydroxid. The dose of thymol for ordinary purposes is said to be 0.1 gm. (1^ grains), but in the treatment of hookworm disease, it must be used more boldly. It is especially necessary to prevent its absorption when large doses are used; hence oils and fats should be avoided in the diet. Betanaphthol is used in doses of 0.1 to 0.3 gm. (IV^ to 5 grains). If the intestinal contents measure as much as 4 liters, the larger dose mentioned above would consti- tute a dilution of one part of betanaphthol in about thirteen thousand parts of the contents — ^a dilution in which its antiseptic action is extremely feeble at best. Such a dose probably has little antiseptic action beyond the small intestine. Betanaphthol is sometimes used externally in the form of an ointment. MATERIA MEDICA P/tg«o/.— Phenol, U. S. P. Phenol, or, as it is more popularly known, carbolic acid, is hydroxy-benzene and may be obtained either from coal-tar by fractional distillation and subsequent purification or made synthetically by replacing one hydrogen of benzol by a hydroxy! group as shown in the following formula: H OH c c HC CH HC CH HC CH HC CH Y Y H H Benzol Phenol The official article is required to contain not less than 98 per cent, of phenol (CgHgOH). It occurs as small colorless deliquescent crystals which are lique- fied by the addition of about 8 per cent, of water. The official preparation: 158 ANTISEPTICS AND DISINFECTANTS Phenol Liquefactum. — Liquefied Phenol, U. S. P., contains about 86.4 per cent, of phenol and about 13.6 per cent, by weight of water and remains liquid at ordinary room temperatures. Phenol is soluble ( 1 : 20) in water and miscible in all proportions with alcohol or glycerin. Acidum Salicylicum. — Salicylic Acid, U. S. P. Salicylic acid (HQHgOa) exists, in combination, in various plants but is generally prepared sjmthetically from phenol. It occurs as white needle-shaped crys- tals or as a crystalline, odorless powder possessing a sweetish, subsequently acrid, taste. Salicylic acid is only slightly soluble (1:308) in. water, but freely soluble (1:2) in alcohol or ether. Sodii Salicylas. — Sodium Salicylate, U. S. P. Sodium salicylate occurs as white pearly scales or as an amorphous powder; the commercial product usually has a slight buff or pink tint. It is odorless and has a sweetish taste. It is very soluble ( 1 : 0.8) in water and freely soluble (1:5.5) in alcohol. Sodium salicylate is preferably administered in solu- tion or in gelatin capsules. The widely used com- pressed tablet may act as an irritant, if given on an empty stomach, producing nausea, and occasionally, vomiting. A mixture of sodium salicylate with sodium bicarbonate in the form of an effervescent draught is an acceptable method of administering the salt. The following prescription may be used for a mixture of this kind: gm. It Acidi salicylici 101 3 iiss Sodii bicarbonatis 20 I 3 v Misce et fac chartulas xx. Sig. : Dissolve the contents of one paper in half a glass of water and drink as effervescence is about completed. If an effervescent mixture is not desired, equal parts of sodium salicylate and sodium bicarbonate may be directed to be dispensed in the form of a "shake" mixture with water; care should be taken to have it recently prepared, as the alkali tends to decompose the sodium salicylate on standing. Methylis Salicylas. — Methyl Salicylate, U. S. P. MATERIA MEDICA OF ANTISEPTICS 159 An ester of salicylic acid (CHjQHbOj) which occurs in oil of sweet birch and oil of wintergreen, or which may be produced synthetically, the products from the three sources being identical, and there is no reliable method of differentiating between them. Pure methyl salicylate is a colorless liquid having a characteristic strongly aromatic wintergreen odor and a sweetish, warm, aromatic taste. It is nearly insoluble in water but is miscible in all proportions with alcohol and the fatty oils. For internal use methyl salicylate or either of the natural oils is best directed to be dispensed in cap- sules. It is also readily absorbed from the skin and is frequently applied in the form of a liniment. A type prescription for this kind of application is the follow- ing: c.c. B Methylis salicylatis Linimenti saponis aa 50 { flS xii M. Sig. : Use as a liniment. The soap liniment in the foregoing formula may be replaced by one of the fatty oils like olive oil, or, if an additional counter-irritant is desired, by chloroform liniment. Phenylis Salicylas. — Phenyl Salicylate, U. S. P. — Salol. The Salicylic ester of phenyl (C13H10O3) occurs as a white crystalline powder having a faint aromatic odor and a slight but characteristic taste. It is very slightly soluble (1 : 2,333) in water but freely soluble (1:5) in alcohol. Phenyl salicylate or salol is best administered in the form of powder or recently pre- pared capsules. Salol has such a low melting point that a pill or tablet made of it may fuse into a solid mass without material change in its appearance, but it then dissolves very slowly in the intestinal tract and may traverse it and be voided in the stool. Acetyls alicylic Acid. — Aspirin, N. N. R. — Acetyl- salicylic Acid. The acetyl derivative of salicylic acid, aspirin, occurs as a crystalline odorless powder having a faint acidu- lous taste. It is slightly soluble ( 1 : 300) in water 160 ANTISEPTICS AND DISINFECTANTS and freely soluble (1:5) in alcohol, ether or chloro- form. Because of its slight solubility aspirin is best prescribed in the form of capsules or catchets. Atophan. — Atophan, N. N. R., phenyl-quinolin- carboxylic acid, CoHsN.CeHsCOOH, was first de- scribed by Doebner and Giesecke in 1887, but has been introduced into therapeutics only recently. It occurs as colorless needle-shaped crystals; it is prac- tically insoluble in water, but readily soluble in solu- tions of alkalies and in hot alcohol. Acidum Benzoicum. — Benzoic acid, U. S. P. An organic acid obtained from benzoin by sublima- tion or prepared synthetically, preferably from toluol. It occurs as colorless or almost colorless scales or needles having an agreeable characteristic odor and a pungent acid taste. It is only slightly soluble ( 1 : 400) in water but is freely soluble (1 : 2) in alcohol. It reacts with alkali hydroxids and carbonates to form water-soluble benzoates, the best known of which is : Sodii Benzoas. — Sodium Benzoate, U. S. P. Sodium ■ benzoate occurs as a white, amorphous, odorless powder having a sweetish, astringent taste. It is freely soluble (1:2) in water and soluble (1 : 43) in alcohol. Cresol. — Cresol, U. S. P. A mixture of the three isomeric cresols obtained from coal-tar. Cresol occurs as a straw-colored, refractive liquid, having a phenol-like odor and turn- ing yellowish-brown on exposure to the air. It is solu- ble (1:60) in water and miscible in all proportions with alcohol, petroleum benzin, ether or glycerin. It is also miscible with soap solutions and with solutions of alkali hydroxids, and in this combination repre- sents an economic type of disinfectant. It is at the present time widely employed in the form of: Liquor Cresolis Compositus. — Compound Solution of Cresol, U. S. P. This is a combination of equal parts of cresol and a solution of potassium soap which is miscible in all proportions with distilled, or ordinary soft, water. This compound solution of cresol has about twice the MATERIA MEDICA OF ANTISEPTICS 161 germicidal power of pure cresol, and on account of its saponaceous character may be used for washing walls, floors, and other articles not injured by ordinary soap and water. Creosotum. — Creosote, U. S. P. A mixture of phenols and phenol derivatives, chiefly guaiacol and creosol, obtained during the distillation of wood-tar. Creosote occurs as a colorless or slightly yellowish oily liquid having a penetrating smoky odor and a burning, caustic taste. It is slightly soluble ( 1 : 400) in water and miscible in all proportions with absolute alcohol and the fixed and volatile oils. It is difficult to administer creosote in any form not objected to by the patient, because of its rather disa- greeable odor and taste. A mixture of creosote and a fixed oil like olive oil dispensed in the form of an emulsion or in capsules is perhaps the most acceptable method of administration. Smaller quantities of creo- sote can also be administered in the form of pills, or capsules, by absorbing the cresote in powdered glycyrrhiza. Guaiacol. — Guaiacol, U. S. P. One of the chief constituents of creosote obtained by collecting and purifying the fraction boiling between 200 and 205 C. (392 and 401 F.) ; also prepared syn- thetically. Pure guaiacol at low temperatures occurs as a colorless or nearly colorless crystalline solid which melts at 28.5 C. (83.3 F.). It has an agreeable aromatic odor and a burning, caustic tasts It is solu- ble (1:53) in water and miscible in all proportions with alcohol and the fixed and volatile oils. Guaiacol shares with creosote the difficulty of internal adminis- tration, and like that preparation is best directed to be mixed with a bland fixed oil or an absorbent powder and dispensed in the form of capsules. Guaiacolis Carbonas. — Guaiacol Carbonate, U. S. P. The carbonic ester of guaiacol (CigHi^Og) occurs as a white crystalline powder of neutral reaction, almost odorless and tasteless. It is practically insolu- ble in water, but is soluble ( 1 : 48) in alcohol. It is readily decomposed in the presence of alkalies into 162 ANTISEPTICS AND DISINFECTANTS guaiacol, and is best directed to be administered alone in the form of capsules, cachets or loose powder. Thymol. — Thymol, U. S. P. Thyme camphor, or isopropyl-metacresol, is a crys- talline phenol, obtained commercially from oil of ajowan (produced from an umbelliferous seed grown in India), and found in a number of other volatile oils. Thymol occurs as large colorless crystals having an aromatic thyme-like odor and a pungent, somewhat caustic taste. It is only slightly soluble (1:1,000) in water but very soluble ( 1 : 0.9) in alcohol and readily miscible with fixed and volatile oils. For internal use it is usually directed to be administered in the form of capsules. Thymolis lodidum — Thymol lodid, U. S. P. — Aristol. Dithymol-diiodid (CaoHj^OjIa) should contain approximately 45 per cent, of iodin. It occurs as a bright chocolate-colored or reddish-yellow bulky pow- der having a slightly aromatic taste. It is practically insoluble in water and nearly insoluble in alcohol. Betanaphthol. — Betanaphthol, U. S. P. — Naphthol. Beta-hydroxy-naphthalene (CmHjOH) is a mon- atomic phenol occurring in coal-tar, but usually pre- pared by treating naphthalene with sulphuric acid and subsequently decomposing the naphthalene sulphonic acid thus formed. Betanaphthol occurs as colorless or pale buff-colored crystalline scales or a crystalline powder having a faint phenol-like odor and a sharp pungent but not persistent taste. It is only slightly soluble (1:950) in water but very soluble (1:06) in alcohol. For internal administration it is usually directed to be dispensed in the form of powder or capsules, prefer- ably in combination with bismuth subnitrate or bis- muth subcarbonate. gm. IJ BetanaphthoHs 1 | gr. xv Bismuth subnitratis 10 | 3 iiss Misce et fac chartulas xx Sig. : One powder before meals. HEXAMETHYLENAMIN 163 For use as an antiseptic, protective ointment it may be prescribed as follows: gm. I^ Betanaphtholis 2 1 gr. xxx Petrolati 30 1 Si M. Sig. : Use externally. URINARY ANTISEPTICS AND DISIN- FECTANTS HEXAMETHYLENAMIN Numerous balsams, oleoresins and volatile oils were used formerly as antiseptics for the urinary tract, but these have been almost entirely superseded of late by hexamethylene-tetramin, or, as it is officially known, hexamethylenamin, which is sold under a great many different trade names, including urotropin, formin, aminoform, formamin, cystogen and many others. Hexamethylenamin is not actively antiseptic, but it i? decomposed in acid urine with the liberation of formaldehyd, which is the active agent. Hexamethyl- enamin has no antiseptic action in the tissue fluids or in neutral or alkaline urine. Strongly acid urine liberates the formaldehyd much more effectively than does feebly acid urine; hence it is better to use even small doses of hexametliylenamin while adopting measures to insure marked acidity of the urine than to use large doses of the drug while the urine is alka- line or only feebly acid. The acidity of the urine can be increased by the use of acid sodium phosphate^" (NaHjPOi). Note that this is not the official sodium phosphate U. S. P. VHI, which is disodium phos- phate (Na^HPOJ. Since the disinfectant and antiseptic activity of hexamethylenamin depend on the liberation of for- maldehyd by an acid medium, it is obvious that it can have no material antiseptic value in the spinal fluid during spinal meningitis. Large doses were used for this purpose after it had been observed that hexa- methylenamin is secreted into the spinal fluid. 10. Jordan, Anson; Urinary Antiseptics, Brit. Med. Jour., Sept 13, 1913, p. 648. 164 ANTISEPTICS AND DISINFECTANTS It is obvious that the hexamethylenamin should not be decomposed before it reaches the urine ; hence acids and acid salts, including monosodium phosphate, and acetylsalicylic acid, should not be dispensed in mix- tures with it, even though they are used simultane- ously. Hexamethylenamin is used to prevent the growth of micro-organisms in the urinary tract, and to destroy them when they are present in the urine during infec- tious diseases such as typhoid fever. It is used as an antiseptic in cystitis and as a pro- phylactic in operations on the urinary tract. It is sometimes used to prevent nephritis in scarlet fever, but very large doses cause albuminuria. A solution of f ormaldehyd is a solvent for uric acid, and on this basis hexamethylenamin has been used to dissolve calculi; but it is wholly useless for that purpose. It is one thing to hold a substance in solution or prevent its precipitation when one uses a concentrated solution of formaldehyd, and quite another matter to dissolve calculi in weak solutions such as one may secure in the urine. Hexamethylenamin is sometimes used in infections of the respiratory tract, but formaldehyd can be applied directly in such cases and there is no evidence that hexamethylenamin has any value in such condi- tions. SILVER NITRATE Silver nitrate is a germicide of extraordinary activity against the gonococcus. Solutions of from 1 : 10,000 to 1 : 2,000 have been used for injection into the ure- thra, and solutions of 1 : 5,000 into the bladder, but even dilute solutions are irritant to the urethra, and silver nitrate has been largely replaced in recent years by the less irritant organic silver compounds. Surfaces should be cleansed before applying the solution, the action of which may be stopped at once by applying a solution of sodium chlorid which pre- cipitates the insoluble silver chlorid. This should be borne in mind when solutions are prepared, and only distilled water should be used for the purpose. SILVER NITRATE 165 Silver nitrate has come into wide-spread use for treating the eyes of the new-born to prevent infection, especially where there is reason to fear gonorrheal conjunctivitis. Immediately after the head appears on the perineum the face is wiped clean and a drop pf 2 per cent, solution of silver nitrate is dropped into each eye. It is used in various forms of conjunctivitis but it should not be used indiscriminately, as it is capable of doing much harm when used in unsuitable conditions. Protargol, or silver proteinate, contains 8.3 per cent, of silver combined with albumin. It is used as a non- irritant substitute for silver nitrate in gonorrhea and in diseases of the eye, nose and throat. DOSAGE Hexamethylenamin is frequently administered in doses of 0.3 gm. (5 grains), though many practitioners prefer much larger doses, from 1 to 2 gm. (IS to 30 grains) being administered three or four times a day to patients who do not manifest the unpleasant sec- ondary symptoms that are sometimes caused by it. Silver nitrate is used in solutions varying from 1 : 50 to 1 : 10,000. Protargol is used in solutions up to 20 per cent. The solutions of the latter are best prepared by sprinkling the protargol on the surface of the required amount of water and allowing it to dissolve spontaneously. Copaiba is preferably administered in the form of emulsion or capsules in doses of 1 c.c. (15 minims). Oil of santal is usually given in doses of 0.5 c.c. (8 minims). MATERIA MEDICA Hexamethylenamina. — Hexamethylenamin, U. S. P. This preparation is known and used under a variety " of trade names, and in European pharmacopeias is generally recognized by its chemical title, hexamethy- lenetetramin (CH2)eN4, a product formed by the con- densation of ammonia and formaldehyd with the elimination of water. Hexamethylenamin occurs as colorless, lustrous, odorless crystals having, when in aqueous solution, an 166 ANTISEPTICS AND DISINFECTANTS alkaline reaction on red litmus paper. It is freely soluble (1 : 1.5) in water, and soluble (1 : 10) in alco- hol. Hexamethylenamin is incompatible with acids, acid salts and combination acids like aspirin, which react with it and liberate formaldehyd. It is also incompatible with salts of ammonia, from which it separates ammonia. To avoid possible decomposition it is best administered by itself either in simple solu- tion or in the form of powders, capsules or cachets. Argenti Nitras. — Silver Nitrate, U. S. P. Colorless transparent crystals, becoming gray or grayish-black on exposure to light in the presence of organic matter ; odorless, but having a bitter, caustic and strongly metallic taste. Silver nitrate is very soluble ( 1 : 0.54) in water, and soluble ( 1 : 24) in alcohol. Copaiba. — Copaiba, U. S. P. — Balsam of Copaiba. An oleoresin derived from one or more South American species of Copaiba. It is practically insolu- ble in water and only partially soluble in ' alcohol. Oleum Santali. — Oil of Santal, U. S. P. — Oil of Sandalwood. A volatile oil distilled from the wood of Santalum album. Oil of santal is frequently administered in combination with copaiba and, like that product, is best exhibited in the form of an emulsion or in cap- sules. GENERAL DISINFECTANTS Every one knows that sunlight and heat destroy all bacteria, but the limitations of these agents are not always appreciated. Direct bright sunlight shining immediately on bacteria destroys them rapidly, but when these are protected by even minute masses of dried organic matter, they may escape destruction ; therefore care should be exercised when sunlight is employed as a disinfectant to see that no small masses are present with bacteria in them. Flat surfaces of wood and cloth may be disinfected readily by exposure to direct sunlight. Heat of sufficient intensity destroys all organisms, but small masses of organic matter may protect bac- HALOGEN DISINFECTANTS 167 teria to such an extent that even boiling for a short time will fail to destroy the organisms thus protected. Tetanus spores are not destroyed immediately in boil- ing water, even when they are not protected. Few organisms, even spores, resist steam under pressure for more than a few minutes. Boiling water destroys nearly all organisms within half an hour. Even moderately hot water injures the bacillus of typhoid fever, and it is destroyed almost instantly in boiling water, provided that it is not protected at such times by masses of feces or other matter. Care should be exercised to see that such masses have been dis- solved or disintegrated completely before the disinfec- tion is begun, or, at any rate, before it is completed. HALOGENS AND THEIR COMBINATIONS All of the halogens are actively disinfectant, but fluorin and bromin are too corrosive for general use. Chlorin is commonly used in the form of hypochlorites which yield chlorin. lodin is used in the form of a solution or tincture, or in combination with an organic substance. Tincture of iodin is irritant, but is often applied locally for the disinfection of the skin. It is said that the skin should be thoroughly dried before the iodin is applied. Iodin is very commonly used to paint the skin at the site of a hypodermic injection, or small incision. While there is no question of the disinfectant action of iodin in vitro, there is a good deal of uncertainty concerning the degree of its disinfectant activity after it comes in contact with the tissues with which it com- bines, for it then attacks bacteria less energetically. Iodin is also destructive to larger parasites which infest the skin. Among the combinations of iodin with organic sub- stances are iodoform, iodothymol, or thymol iodid, which has been mentioned. Iodoform is not actively disinfectant, but when applied to moist wounds, it decomposes slowly with the liberation of active iodin, partly free, and partly in unknown combinations. It is sometimes absorbed from open wounds, probably in the form of one of 168 ANTISEPTICS AND DISINFECTANTS these unknown compounds, and gives rise to character- istic symptoms of poisoning. The first symptoms con- sist in disturbances of the central nervous system; these are followed only after several days by excite- ment, restlessness, anesthesia and sometimes by uncon- sciousness. Stimulation may alternate with depres- sion, or there may be pure narcosis. These symptoms do not occur unless iodoform is used over large surfaces or for a considerable period of time. It is not necessary to discuss the actions of iodo- form after internal administration, because there is no occasion to administer it internally. Iodoform is applied in the form of an emulsion or as a dusting powder, especially in the surgical treat- ment of tuberculosis. It may be used as a suppository for the relief of painful hemorrhoids. Chlorid of lime, so-called, which is a mixture con- taining hypochlorites mainly, which readily yield free chlorin, is one of the most commonly used of house- hold disinfectants and bleaching agents. It is corro- sive, attacking metals and destroying fabrics. Chlorin is available in the form of other hypochlo- rites, which may be decomposed to yield free chlorin. FORMALDEHYD Formic aldehyd, or formaldehyd, is a very active antiseptic, but its germicidal powers vary widely with the organism and the conditions under which it is employed. It has been found that tubercle bacilli require forty-five minutes for their destruction in a 5 per cent, solution; with a higher temperature the solution is more active. The gaseous formaldehyd is not to be depended on as a germicide when the tem- perature is lower than 16 C. (60.8 F.). Tightly closed rooms may be disinfected by wetting sheets with 150 c.c. (5 fluidounces) of the official for- maldehyd solution for each thousand cubic feet of space, and allowing this to evaporate. The room is kept closed for twenty-four hours. The formaldehyd may be sprayed through a keyhole into the closed room, but this is inconvenient. Candles are now sold for fumigating rooms with formaldehyd, this being MISCELLANEOUS DISINFECTANTS 169 the most convenient method available. Rooms may be fumigated in the way indicated, but clothing and other fabrics must be hung up so that the gas will come in contact with every portion. The room should be heated if the fumigation is carried out in winter, and the atmosphere should be kept moist by the evapo- ration of water. The gas does not injure fabrics. Formaldehyd has a wide field of usefulness as a dis- infectant, and the solution may be used for fabrics which may be wetted by it without injury. The irri- tant vapor of formaldehyd persists in the atmosphere of a room for some time after the doors- and windows are opened; this disadvantage may be overcome in part by spraying a little ammonia into the atmosphere, or more conveniently, by exposing it freely on plates. MISCELLANEOUS DISINFECTANTS Among the cheaper disinfectants used in cesspools, drains and other large spaces are copperas, or ferrous sulphate, sulphur as brimstone or roll sulphur, which is burned in an iron pot, or other suitable container; and lime, which is used either as milk of lime to dis- solve organic matter and destroy the bacteria, or as a whitewash for application to flat surfaces. Copperas is an excellent deodorant for urinals, a handful of the crystals being thrown into the urinal and allowed to dissolve slowly. Halsey states that sulphurous acid affords the only practical means of destroying the mosquito that car- ries the infection of yellow fever, and that it is com- monly used in living-rooms. Burning sulphur is con- verted into the dioxid, and this into sulphurous acid when it comes in contact with moisture. The fumes of burning sulphur are extremely irritat- ing and poisonous, and they corrode metals and fabrics; hence disinfection by this means is limited to large rooms and spaces where the corrosive action will not cause damage. Polished metal fixtures and many other articles and substances may be protected against sulphurous acid and other corrosive fumes by coating them with paraffin. 170 ANTISEPTICS 'aND DISINFECTANTS The paraffin is melted, and while quite hot it is applied with an ordinary paint-brush. It solidifies instantly, forming a thin coating which may be removed later without difficulty. If preferred, the paraffin may be dissolved in benzin, which evaporates rapidly when the solution is applied to exposed surfaces. Potassium permanganate in solution decomposes all organic matter with which it is brought in contact; it is useful as a deodorant, but not especially as a dis- infectant, since it does not attack bacteria more readily than other organic matter. A solution containing 1 or 2 per cent, of potassium permanganate is useful in the treatment of poisoning with poison ivy (poison oak). The solution is rubbed well into the vesicles to destroy the irritant glucosid on which the action of poison ivy depends. In severe poisoning involving a large part of the hand or fore- arm, the surface may be immersed in the solution kept as hot as the patient can bear it without too great discomfort. The resulting brown discoloration of the skin may be removed by washing with a dilute solution of oxalic acid. Bland oils and salves should not be used, because they tend to spread the irritant substance. If large blisters form, they should be opened, and the escaping fluid collected on gauze or in an absorbent powder such as sodium bicarbonate. Scrubbing small affected areas with a stiff hand brush, using soap and running hot water, will suffice to remove much of the irritant from the ruptured vesicles, after which a paste made of soap, or a pad of gauze moistened with an alkaline solution or a dilute solution of lead subacetate, may be applied to the affected skin. Mercuric chlorid is one of the most powerful disin- fectants which we possess, but its action is greatly interfered with by organic matter. It attacks metals, and hence it cannot be used for the sterilization of surgical instruments. It may be used for sterilizing the water which has been used to bathe a patient suffering from an infectious disease, and to sterilize the urine, or even the feces, provided these are nearly HYDROGEN ' PEROXID 171 liquid and small masses are disintegrated, but it is not so useful for the latter purpose as a strong mixture of lime and water. A solution containing one part of mercuric chlorid to ten thousand parts of water is rapidly fatal to many spores and all non-spore forms of bacteria. The intensity of the action is of course increased with higher temperatures. The extraordinary toxicity of mercuric chlorid is one of the greatest disadvantages in its use. HYDROGEN PEROXID The official solution of hydrogen dioxid has been freely used and widely abused as a germicide and dis- infectant. In the presence of pus or other organic matter it is decomposed with brisk evolution of oxy- gen. This effervescence is of advantage in its vise as a detergent either in connection with open wounds or ulcers, exposed mucous surfaces or as a wash for the mouth and teeth. It is obviously unsuited for injec- tion, into sinuses or subcutaneously, as the gas result- ing from its decomposition tends to destroy tissues and spread infection. Hydrogen peroxid applied to bleed- ing wounds acts as a styptic by coagulating albumin, and has come to be a popular household remedy. Many of the widely advertised antiseptics are wholly useless as disinfectants, and no one should depend on the directions which accompany these for preventing the spread of contagious diseases. The so-called chlorids, such as Piatt's, may have some value as deodorants, but they cannot be used for disinfecting rooms and fabrics. MATERIA MEDICA lodum. — lodin, U. S. P. lodin occurs as heavy bluish-black, friable crystals or masses having a distinctive odor and a sharp and acrid taste. It is quite volatile and is very slightly soluble (1:5,000) in water, but soluble (1:10) in alcohol. It is also soluble in solutions of iodids; it is most frequently applied in the form of: Tinctura lodi. — Tincture of lodin, U. S. P. 172 ANTISEPTICS AND DISINFECTANTS Each 100 c.c. contains 7 gm. iodin and 5 gm. potas- sium iodid dissolved in alcohol. lodoformum. — Iodoform, U. S. P. Iodoform, triiodomethane (CHI3), occurs as a fine lemon-yellow powder or in lustrous crystals having a peculiar very penetrating, persistent odor and an unpleasant slightly sweetish and iodin-like taste. It is readily decomposed by air and light, and should be kept in well-stoppered bottles in a cool and dark place. Calx. — Lime, Calcium Oxid, U. S. P. The official preparation (CaO) is directed to be made by calcining white marble, or the purest variety of native calcium carbonate. For use as a disinfec- tant, however, the ordinary commercial lime, also known as quicklime, will suffice. Calx Chlorinata. — Chlorinated Lime, Chlorinated Calcium Oxid, U. S. P. A compound resulting from the action of chlorin on calcium hydroxid. The official preparation is required to contain not less than 30 per cent, of avail- able chlorin. It is often improperly called chlorid of lime. Chlorinated lime occurs as a white or grayish-white, granular powder, having a chlorin-like odor and a repulsive saline taste. It gradually decom- poses on exposure to air. It should be kept in well- closed vessels in a cool and dry place. As a disinfec- tant it is frequently used in the form of : Liquor Sodae Chlorinatae. — Solution of Chlorinated Soda, U. S. P. — Labarraque's Solution. An aqueous solution of sodium hypochlorite and sodium chlorid, containing at least 2.4 per cent, by weight of available chlorin. It is made by decompos- ing a solution of chlorinated lime with sodium car- bonate and removing the insoluble calcium carbonate formed. A corresponding solution of potash has been used under the popular title "Javelle's solution," but it has no evident advantages over the solution of chlorinated soda. Liquor Formaldehydi. — Solution of Formaldehyd, U. S. P. MATERIA MEDICA OF DISINFECTANTS 173 A solution of formic aldehyd, which is also mar- keted under various trade names and is frequently referred to as "formalin." It should contain not less than 37 per cent, by weight of absolute formaldehyd (HCOH), an oxidation product of methyl alcohol. It occurs as a clear colorless liquid, having a pungent odor and caustic taste. Its vapor acts as an irritant on the mucous membrane. Formaldehyd polymerizes readily with the formation of: Paraformaldehydum. — f araformaldehyd, N. N. R. Solid paraformaldehyd, tri-oxymethylene (CH20)j„ which occurs as a white crystalline or amorphous pow- der or friable mass, odorless at ordinary tempera- ture, but having a pungent odor on heating. It is used chiefly to generate formaldehyd, by heating, for dis- infection or for inhalations. Ferri Sulphas. — Ferrous Sulphate, U. S. P. Sulphate of iron (FeS04), commonly known as copperas, occurs as pale, bluish-green crystals without odor, having a saline styptic taste. It is effervescent in air, and on exposure to moist air the crystals rapidly oxidize and become coated with brownish-yellow basic ferric sulphate. Sulphur. — Sulphur, U. S. P. For use as a disinfectant, the ordinary commercial sublimed sulphur either in the form of powder or masses is used. Potassii Permanganas. — Potassium Permanganate, U. S. P. Potassium permanganate (KMnOi) occurs as slen- der prisms, of a dark purple color, almost opaque by transmitted light and of a blue metallic luster by reflected light, odorless, having a taste at first sweet but afterward disagreeable and astringent. It is solu- ble (1: IS) in water, and decomposes when brought into contact with alcohol, glycerin or other easily oxidizable organic solvents. Hydrargyri Chloridum Corrosivum. — Corrosive Mercuric Chlorid, U. S. P. — Corrosive Sublimate. Mercuric chlorid (HgClj) occurs in the form of heavy colorless crystals or a heavy white powder hav- 174 ANTISEPTICS AND DISINFECTANTS ing an acrid and persistent taste. It is very slowly soluble (1:13) in water and freely soluble (1:3) in alcohol. Ammonium chlorid, sodium chlorid, tartaric acid and citric acid increase its solubility in water. Of the chlorids, the ammonium chlorid is more generally used in this country (probably through mere force of habk), though the sodium chlorid is acknowledged to be more desirable in that it yields a solution that is more permanent. Aqua Hydrogenii Dioxidi. — Solution of Hydrogen Dioxid, U. S. P. — Solution of Hydrogen Peroxid. The official solution of hydrogen peroxid (HjOj) contains approximately 3 per cent., corresponding to 10 volumes of available oxygen. It occurs as a color- less liquid without odor but having a ^lightly acidulous taste and producing a peculiar sensation and thick froth when taken into the mouth. Solution of hydrogen dioxid is frequently used as a constituent of mouth-washes, of which the following is a type : Potassium chlorate 5 parts Water 100 parts Hydrogen peroxid 100 parts Mix, dilute with equal parts of water, and use as a mouth- wash. VOLATILE OILS Spices and related aromatic substances have been used as preservatives from time immemorial, but it is only recently that any experiments have been made to determine the relative antiseptic and disinfectant activity of essential oils and their constituents. Martindale* found that a few of the essential oils compare well with thymol and other phenols in anti- septic activity, though most of them are much weaker. Oil of turpentine has had an especial vogue as an antiseptic in surgery, but most of the volatile oils have come to occupy a subordinate place among the disin- fectants and antiseptics, except for a few special indi- cations, such as that of sandalwood oil in gonorrhea. The following volatile oils (in addition to those mentioned among the urinary antiseptics) are included in "Useful Drugs." 6. Martindale: Perf. Ess. Oil Rec, 1910, i, 266. BORIC ACID 175 Oleum Cinnamomi. — Oil of Cinnamon, U. S. P. — Oil of Cassia. A volatile oil distilled from cassia cinnamon and containing not less than 75 per cent., by volume, of cinnamic aldehyd. It occurs as a yellowish or brown- ish liquid, having the characteristic odor of cinnamon and a sweetish spicy and burning taste. It is only slightly soluble in water, but is soluble in alcohol. Oleum CarophylU. — Oil of Cloves, U. S. P. A volatile oil distilled from cloves and containing not less than 80 per cent., by volume, of eugenol. It occurs as a pale to dark yellow liquid having a strongly aromatic odor of cloves and a pungent spicy taste. It is only slightly soluble in water, but is misci- ble in all proportions with alcohol. Oleum Eucalypti. — Oil of Eucalyptus, U. S. P. A volatile oil distilled from the leaves of eucalyptus and containing not less than SO per cent., by volume, of cineol (eucalyptol). It occurs as a colorless or pale yellow liquid having a somewhat camphoraceous odor and a pungent, spicy, cooling taste. The active ingredient, cineol, is also official as: Eucalyptol. — Eucalyptol, U. S. P. An organic oxid (CmHigO) obtained from the oil of eucalyptus, or other sources. It occurs as a colorless liquid having a characteristic aromatic and distinctly camphoraceous odor and a pungent, spicy, cooling taste. It is practically insoluble in water, but is mis- cible in all proportions with alcohol. Oleum Terebinthinae. — Oil of Turpentine, U. S. P. A volatile oil recently distilled from turpentine. Its physical properties are so well known that they hardly require description. BORIC ACID AND BORAX Boric acid is weakly antiseptic, but hardly at all destructive to the more common bacteria, though it destroys certain molds readily and it is especially use- ful for the destruction of Oidium albicans, the para- site which produces the condition known as thrush. It is soothing when applied to inflamed mucous membranes in the form of solution or dusting-powder, 176 ANTISEPTICS AND DISINFECTANTS but the continued use of even small amounts internally gives rise to gastro-intestinal irritation. Daily doses of as much as 1 gm. (15 grains) increase the combustion of fats and interfere with their utiliza- tion as food, and loss of body weight has been observed after the use of boric acid for a few days. Borax, or sodium borate, is even less actively anti- septic than boric acid; hence such large amounts are required when it is used as a food preservative that they are almost certain to cause some disturbance if taken continuously in the more commonly used foods, such as milk and butter, especially when the elimina- tion — slow at all times — is interfered with as in neph- ritis, leading to accumulation of the poison in the body. Even moderate amounts may induce nephritis, thus setting up a vicious circle of slow elimination and increasing nephritis. Very large doses (such, how- ever, as would not be taken in the form of food pre- servative) cause gastro-enteritis, disturbances of vision, fatty degeneration of various organs and col- lapse. Borax interferes with the coagulation of casein, thereby retarding its digestion ; hence its use as a pre- servative of milk is to be especially condemned. It is sometimes urged in favor of the use of borax as a food preservative that fish and other perishable foods decompose more readily without its use and give rise to poisoning. Even though it does prevent the decomposition of certain foodstuffs, this does not justify its general use, because it is certainly injurious when used too freely. Boric acid is commonly used in from 2 to 4 per cent, solution for washing the bladder in cystitis, as a wash in conjunctivitis and in catarrhal conditions of other mucous membranes. It was formerly used freely for washing the rectum and other organs, and large amounts were frequently left in the organ to act as an antiseptic; but severe, and even fatal, poisoning has resulted from this practice in a number of cases. Boric acid is frequently used in a combination with starch, talcum or other diluent, as a dusting-powder on inflamed surfaces. BORIC ACID 177 Solution of borax is used as a mild antiseptic and astringent eye-wash, and as a gargle and mouth-wash. It may be prescribed somewhat as follows as an eye- wash: gm. or c.c. B Sodii boratis IS gr. viii Aquae camphorae 10 (O fl3 iss Aquae q. s. ad 30 |0 flSi M. A stronger solution may be used as a gargle, or as a wash in pruritus, in which case a small amount of glycerin may be added. Boric acid has been used internally in cystitis, but with the introduction of better urinary antiseptics, such as hexamethylenamin, its use in that way has been discontinued. There are no clear indications for the internal administration of either boric acid or borax. MATERIA MEDICA Acidum Boricum. — Boric Acid, U. S. P. The official substance should contain not less than 99.8 per cent, of H3BO3. It occurs as transparent colorless scales or a white, unctuous, very fine powder. It is odorless, has a faintly bitter taste and is slowly soluble (1 : 18) in water and soluble (1 : 15) in alcohol. Of the preparations of boric acid that are quite widely used, we have : Glyceritum Boroglycerini. — Glycerite of Boro- glycerin, U. S. P. A glycerin solution containing approximately 30 per cent, of boric acid. It is more readily soluble in water than is boric acid itself, and is also used as a local application to inflamed mucous surfaces. Unguentum Acidi Borici. — Ointment of Boric Acid, U. S. P. A 10 per cent, mixture of boric acid with white petrolatum and paraffin used as a protective ointment. Sodii Boras. — Sodium Borate, U. S. P. This preparation, popularly known as borax, is more properly designated sodium tetraborate or sodium pyroborate. It should contain in the unefHoresced con- dition not less than 99 per cent, of NajB^Oj + lOHjO. 178 ANTISEPTICS AND DISINFECTANTS It occurs as colorless, transparent crystals or a white powder, odorless and having a sweetish, alkaline taste. It is soluble (1 : 17) in water and practically insoluble in alcohol, but very soluble (1:1) in glycerin by the aid of heat. Sodium borate is incompatible with min- eral salts, with mucilage of acacia and with the soluble salts of most alkaloids. Carbo Ligni. — Qiarcoal, U. S. P. Charcoal, prepared from soft wood and finely pow- dered, is sometimes applied to fetid ulcers as a deodo- rant. It acts by absorbing putrefactive gases and con- densing them on its surfaces. Since charcoal is extremely porous, the surfaces available for condens- ing the gases are more extensive than would at first appear. It has been used internally with the object of absorbing gases resulting from fermentation, but it is almost devoid of absorbing power when it has become saturated with liquid. It is sometimes administered in capsules or cachets in order to determine the length of time required for it to pass through the alimentary canal. It is not absorbed, and its appearance in the blackened feces is easily detected. DISINFECTANTS USED IN SKIN DISEASES The substances considered under this heading do not constitute a well-defined therapeutic or pharmaco- logic group, but they are conveniently considered together. Balsam of Peru^^ consists of a mixture of oils and resins with somewhat more than 50 per cent, of cinnamein (benzyl ester of cinnamic acid) and about 10 per cent, of free cinnamic acid. Balsam of Peru is absorbed to some extent after its external application, and severe temporary albuminuria frequently follows its free application in the treat- ment of scabies. In the absence of albuminuria, the 11. It is obviously impossible to discuss the drugs of this group with their therapeutic applications comprehensively, for the treatment of skin diseases constitutes a separate branch of medicine. 12. The term '^balsam" has been applied to various substances that are used externally, but the pharmacopeia limits the term to oleoresins that contain aromatic acids, such as benzoic and cinnamic. DISINFECTANTS IN SKIN DISEASES 179 urine may contain resin after the use of one of these oleoresins, such as copaiba and balsam of Peru, and this resin may be precipitated by the addition of acid, giving rise to the mistaken diagnosis of albuminuria. The precipitated resin may be dissolved in an excess of alcohol. Tar contains numerous antiseptic substances, includ- ing phenol and the cresols, but the less toxic members of the group (creosol and guaiacol) are more abun- dant than phenol, and tar is therefore actively dis- infectant without being so toxic as phenol. It is absorbed slowly through the skin, which it irritates only slightly. Resorcinol, or dioxy-benzol, differs chemically from phenol in that it has two OH groups instead of one. Its systemic actions resemble those of phenol, but it is somwhat less caustic and toxic than the latter. Chrysarobin is closely related to chrysaphanic acid, a constituent of several of the purgative drugs of the anthracene group. Chrysarobin is too actively irritant to be used internally. When swallowed, it causes nausea, vomiting and diarrhea. It is absorbed slowly from the skin, and is excreted through the kidneys, which it irritates, causing albuminuria in some cases. A part of the chrysarobin is oxidized to chrysophanic acid during its passage through the body. It is actively irritant to the skin, causing itching and redness and sometimes pustulation. Chrysarobin stains the skin, nails and clothing, and this constitutes a serious objection to its use. The stains may be removed by washing with a weak solu- tion of sodium hydroxid or a solution of chlorinated soda or chlorinated lime. When sulphur is applied to the skin, it is converted in part into hydrogen sulphid, which is irritant. It is especially destructive to the parasite that infests the skin and causes itch. Th*e internal use of sulphur is mentioned in connection with its use as an evacuant. Sodium sulphite and thiosulphate are antiseptic and are commonly used externally in the treatment of parasitic skin diseases. Either of these salts may be used in a 10 per cent solution as a local application in 180 ANTISEPTICS AND DISINFECTANTS scabies and favus, and as a mouth wash in aphthous stomatitis, mucous patches and ulcers of the tonsils. The thiosulphate is sometimes used for ringworm. They are sometimes used internally, but there is no clear indication for their use in that way. The thiosulphate is used for the removal of stains on the skin caused by iodin and silver nitrate. It is also widely used in photography. THERAPEUTIC USES Balsam of Peru has been used subcutaneously in pulmonary tuberculosis with a view to its causing inflammation with cicatrization in the diseased areas. It has not proved satisfactory, but sodium cinnamate is still used intravenously for this purpose occasion- ally. Balsam of Peru seems to be of some value in the treatment of lupus, scabies and other parasitic skin diseases. It may be painted over the skin on retiring and washed off the next morning, or it may be used in the form of an ointment containing 1 part each of balsam of Peru, green soap, sulphur and chalk, and 25 parts of petrolatum. Syrup of tar is often used in cough mixtures. A solution or ointment containing from 2 to 4 per cent, of tar may be used in the acute inflammation of pruritus, the strength of the application being ' increased grad- ually if necessary. Tar is sometimes applied without dilution in the chronic forms. The official ointment may be used without dilution in ringworm and in psoriasis, the weaker applications in eczema. Resorcinol, or resorcin, is rarely used internally because of its toxicity, but it has been used in doses 0.3 gm. (5 grains) to stop gastric fermentation. It is sometimes used in 10 per cent, solution against dandruff, and a solution or ointment may be used for pruritus. Chrysarobin is used chiefly in the treatment of psoriasis, but it should not be applied to the face and head, because it irritates the mouth, eyes and nose. It is commonly used in the form of an ointment con- taining from 2 to 20 per cent, of the drug, but the weaker is said to act as well as the stronger without DISINFECTANTS IN SKIN DISEASES 181 causing dermatitis in many cases. It has been sug- gested that it acts by withdrawing oxygen from the skin. Sulphur is commonly used in the form of an oint- ment as a parasiticide in the treatment of scabies (itch). As this troublesome parasite burrows under the skin, it is necessary to use an ointment that is soft enough to be rubbed well into the skin or is slightly alkaline so as to soften or modify the outer horny layers of the skin. The following may be used as a type formula for the latter form of ointment: Sublimed sulphur 20 parts Precipitated calcium carbonate 15 parts Soft soap 35 parts Lard 35 parts An ointment formerly much used in England in the treatment of scabies is made as follows: Precipitated sulphur 2 parts Potassium carbonate 1 part Lard 8 parts Mix and make into an ointment. The official diluted mercurial ointment (33 per cent.) is very commonly used for the destruction of body lice. It is interesting to note that the louse that trans- mits typhus fever remains attached to the inner surface of the clothing and riot to the human body. Ointment of ammoniated mercury is used in the treatment of psoriasis. MATERIA MEDICA Balsamum Peruviatmm. — Balsam of Peru, U. S. P., occurs as a dark brown liquid having an agreeable odor and a bitter, acrid taste. It is freely soluble (1 : 1 ) in alcohol and in chloroform, but only partially soluble in ether and in petroleum benzin. Water dis- solves out traces of the contained cinnamic acid. Fix Liquida. — Tar, U. S. P. This substance, also known as wood tar or Stockholm tar, is obtained by the destructive distillation of pine wood. It occurs as a viscid, blackish-brown, semiliquid, having an empyreumatic odor and a sharp, terebinthinate taste. Tar is miscible with alcohol and the fixed and volatile 182 ANTISEPTICS AND DISINFECTANTS oils, and should not be confounded with coal tar, a by-product in the destructive distillation of bituminous coal. Unguentum Picis Liquidae. — Tar Ointment, U. S. P. A mixture of tar (SO), yellow wax (15) and lard (35). Resorcinol. — Resorcinol, U. S. P. A dihydric phenol that occurs as white or nearly white, needle-shaped crystals, having a faint, characteristic odor and a sweetish followed by a bitter taste. It is very soluble (1 : 0.5) in both water and alcohol. Chrysarobinum. — Chrysarobin, U. S. P. A mix- ture of substances extracted from Goa powder. It occurs as a pale orange-yellow crystalline powder, practically odorless and tasteless, but irritating to the mucous membrane. It is very slightly soluble (1 : 1,812) in water, and rather more soluble (1 : 308) in alcohol. It is freely soluble in dilute or in concen- trated solutions of the alkaline hydroxids. Unguentum Chrysarobini. — Chrysarobin Ointment, U. S. P., represents a solution of about 5 per cent, of chrysarobin in benzoinated lard. Sulphur in its several forms will be discussed in connection with its use as an evacuant, but the only preparation of direct value in the treatment of skin diseases is: Unguentum Sulphuris. — Sulphur ointment, U. S. P. A mixture of washed sulphur (15) with benzoinated lard (85). Some practitioners prefer to use the pre- cipitated sulphur, which is somewhat more finely divided and therefore more active. Mercurial ointment is official in two forms : Unguentum Hydrargyri. — Mercurial Ointment, U. S. P. ■ A mixture of mercury (50) with prepared suet and benzoinated lard (to make 100). Unguentum Hydrargyri Dilutum. — Blue Ointment, U. S. P. A mixture of mercurial ointment (67) with petrolatum (33). Hydrargyrum Ammoniatum. — Ammoniated Mer- cury, U. S. P., popularly known as white precipitate, represents about 80 per cent, of metallic mercury in DISINFECTANTS IN SKIN DISEASES 183 the form of the insoluble mercuric-ammonium chlorid. It is generally used in the form of: Unguentum Hydrargyri Ammoniati. — Ointment of Ammoniated Mercury, U. S. P. — A mixture of ammo- niated mercury with white petrolatum and hydrous wool fat. Sodii Sulphis. — Sodium Sulphite, U. S. P., Na^SOs, THjO. It occurs as colorless, transparent crystals. It is freely soluble (1:2) in water, but practically insoluble in alcohol. Mineral adds decompose it with the liberation of the irritant gas, sulphur dioxid. Sodii Thiosulphas. — Sodium Thiosulphate, U. S. P. (Sodium Hyposulphite, U. S. P. 1890). NajS^Os, SHjO. It occurs as colorless transparent crystals that are very soluble in water (1:0.5), but practically insoluble in alcohol. It is incompatible with acids, iodin and chlorin. CHAPTER v.— DRUGS WHICH STIMU- LATE SYMPATHETIC ENDINGS EPINEPHRIN Oliver and Schaefer investigated the actions of extract of the suprarenal gland previous to the isola- tion of an active principle by Abel in 1897. This active principle has been prepared by many workers, by whom it has been given different names, including "epi- nephrin," "suprarenalin," "supracapsulin," "adrenin" and "adrenalin," the last being the commercial name by which it is commonly known. The synthetic prepa- ration has likewise received a number of names, including "homorenon" and "1-suprarenin synthetic." The epinephrin obtained from the gland is levoro- tary, but the artificial is either levorotary or dextro- rotary, or it may consist of a mixture of these two. Levorotary epinephrin is of uniform activity, so long as it has not undergone decomposition, to which it is prone, whether it is derived from the gland or pre- pared artificially. The market supply of artificial epinephrin is levorotary. Dextrorotary epinephrin is only about one-fifteenth as active as the levorotary, according to Cushny. Mix- tures of the two forms are of variable activity. Epinephrin stimulates the sympathetic myoneural junctions in muscles. Elliott has stated it as a law that the action of epinephrin on these connections between any given nerve and its muscle proves that the inner- vation is of the sympathetic system — in other words, that epinephrin acts only on the endings of the sym- pathetic. It is also true that it acts on all of these, with possibly one exception, and we shall see that the innervation of the sweat-glands in the skin, which is always attributed to the sympathetic, behaves toward many drugs, including atropin and pilocarpin, as though it belonged to the parasympathetic system. Epinephrin does not act on them. EPINEPHRIN 185 This conception of the actions of epinephrin sim- plifies its pharmacologic study, for the actions of epinephrin on any structure of the body are simply those of stimulation of the sympathetic. When this stimulation results in inhibition, as it does in the non-pregnant uterus of some animals, then epinephrin also causes inhibition ; but if stimulation of the nerve causes motor effects, as it usually does in the pregnant uterus, then epinephrin also causes motor effects. A given dose of epinephrin, however, varies widely in the intensity of its action in different organs, and these differences must be understood in order that epinephrin may be used therapeutically. When it is injected intravenously no pronounced action is observed on the higher parts of the central nervous system, and the effects on the medullary cen- ters are mainly secondary to the rise of blood-pressure. For example, the heart is accelerated at once after an intravenous injection, because of the stimulation of the sympathetic myoneural junctions, or endings, as we shall call them for convenience, in the heart; fol- lowing this the vagus center is stimulated by the higher blood-pressure, and the heart is slowed. The action on the respiratory center is somewhat peculiar, result- ing in an interruption of respiration, followed by a period during which the rate and the depth are increased, interruption and augmentation alternating. The most prominent effect which follows the intra- venous injection of epinephrin is the sudden high rise of blood-pressure, which is comparable to that seen after the intravenous injection of convulsive doses of strychnin. This is due to the increased heart-rate and strength of beat and to the constrictor action on the vessels. In practice this sudden rise of pressure is avoided by injecting very dilute solutions slowly. The heart soon becomes much slower and the blood-pres- sure falls below normal and then returns to its original level. The cause of the extreme brevity of the action of epinephrin on the vessels has been the subject of much debate. Apparently the action lasts only so long as the drug is actually in course of penetration into the endings, and when equilibrium is reached between 186 DRUGS STIMULATING SYMPATHETIC ENDINGS the concentration of the drug in the blood and that in the nerve-endings the action ceases. It has been shown that the musculature of the vessel walls does not become fatigued so readily, for the high blood-pressure can be maintained almost indefinitely by the slow, con- tinuous injection, and the destruction of the drug in the blood is not sufficiently rapid to account for the fleeting nature of the action. Epinephrin does not affect the vessels of all areas equally, some being much less under the control of the sympathetic than others, and the cerebral, pulmonary and coronary arteries react so slightly that it has been denied frequently that the drug has any influence over them. The larger trunks of the pulmonary artery do, however, show marked constriction, the primary branches less and the smaller twigs little or none. The coronary arteries often behave in a manner opposite to that of the vessels of other large areas. It has been found that exceedingly small amounts of epinephrin — much less than those required to increase the general blood-pressure — cause constriction of the coronaries; with moderate amounts, such as cause a rise in the general blood-pressure, the coronaries show at most a fleeting constriction and a rapidly following dilatation. The necessity for the difference in the behavior of the coronary arteries and those of the general arterial system is readily apparent. When the general blood- pressure rises, the heart must perform more work, which would be impossible if its supply of blood were diminished essentially, for it has been shown conclu- sively that the functional capacity of the heart and its blood-supply are very closely related. If the rise of blood-pressure following the injection of epinephrin were attended with constriction of the coronaries of stifficient degree to interfere seriously with its supply- ing blood to the heart, the latter would be exhausted rapidly. This discussion bears on the action of other drugs which affect the heart and the general circula- tion, and it may be accepted as a rule that no drug which increases the work of the heart can interfere seriously with its blood-supply if the condition of the EPINEPHRIN 187 heart improves under its use. Mention of this will be made when digitalis is under discussion. Epinephrin stimulates the vasodilators as well as the vasocon- strictors, in the general circulation, but the action on the latter usually predominates, at least for a time. When the vasoconstrictor nerves are paralyzed by apocodein or ergotoxin, the administration of epi- nephrin results in stimulation of the dilators from the beginning, and the primary action of epinephrin then causes a fall of blood-pressure. This secondary dilatation which follows the con- strictor effect of epinephrin may become annoying at times. If epinephrin is heated to a temperature of 120 C. (248 F.), the constrictor action is lost while the dilator is maintained, and a similar change may apparently take place when the solution has been kept open for a time. One of us (Hatcher) has seen a specimen of which even small doses caused a rapid fall in the blood-pressure without any preliminary rise. The specimen had been kept on hand, but unopened, for some weeks. Epinephrin causes constriction of the vessels of the mucous membrane to which the solution is applied, resulting in relief in various inflammatory conditions, but the frequent application with alternate constriction and dilatation may ultimately give rise to hypertrophy of the mucous membrane, with a chronic inflammatory condition. Secondary hemorrhage may follow the use of epinephrin in surgical operations when the vascular dilatation succeeds the constriction, and a fall of blood- pressure may succeed its use in shock of minor importance. Such hemorrhage frequently occurs from four to six hours after the use of epinephrin in opera- tions on the turbinate bone, and the patient should be kept under the supervision of a surgeon after such operations. The pupil behaves differently to epinephrin in different animals; in man epinephrin has little effect under normal conditions, but in exophthalmic goiter the sympathetic nerve to the eye shares with other sympathetic nerves an increased susceptibility to stimulation; epinephrin then causes dilatation of the 188 DRUGS STIMULATING SYMPATHETIC ENDINGS pupil. Hence this reaction may become of some diag- nostic importance in cases of suspected Graves' dis- ease. It is possible that the reason for the increased effect of epinephrin in exophthalmic goiter is that the blood then contains more than the normal amount of epinephrin, and that the sympathetic is kept under more active control by it. A similar mydriatic action occurs with epinephrin in pancreatic diabetes. The application of epinephrin to the eye causes con- striction of the vessels of the conjunctiva and increases the mydriatic action of cocain. We have already seen that cocain increases the constrictor action of epi- nephrin. The uterus behaves differently toward stimulation of the sympathetic in different animals, and in some it responds with contraction in the later stages of preg- nancy, but not in the virgin. The human uterus dur- ing pregnancy responds with contraction to sympa- thetic stimulation; consequently it responds to epi- nephrin with contraction, and so actively that even the subcutaneous injection of epinephrin, which does not affect the blood-pressure to an important degree, causes uterine contractions. This is of therapeutic importance, in that it permits of the use of epinephrin after delivery of the placenta in securing firm con- traction of the uterus without increasing the blood- pressure. Increase of blood-pressure is undesirable, since the object is to prevent post-partum hemorrhage. Epinephrin acts on the heart in various ways. It accelerates the rate and increases the energy by stimu- lating the sympathetic. This and the vasoconstriction induced cause an increase of blood-pressure which acts on the vagus center, producing a secondary slowing of the rate. When the vasoconstriction ceases, as it does in two or three minutes after the injection is com- pleted, the blood-pressure falls, and the heart is again accelerated by the stimulation of the sympathetic, or it may be that the increased rate is due to the lowered blood-pressure, since the heart normally responds to lowered blood-pressure by increase in rate. EPINEPHRIN 189 So remarkable is the action of epinephrin on the heart that the latter may sometimes be restored to normal rhythm after having been stopped by ether. On the other hand, the rapid intravenous injection of a large dose is capable of causing a normal heart to stop promptly. Intravenous injections of epinephrin must be made with extreme caution. It will be recalled that other drugs are also very much more active by intravenous injection than by other modes of adminis- tration, and while this method is essential in some cases, it must be looked on as suitable only for emergencies. The action of epinephrin on the intestine is that of stimulation of the sympathetic, but the action is too brief to admit of its therapeutic application. Epinephrin is one of the few alkaloids in the materia medica which are not absorbed from the gastro-intes- tinal canal with such rapidity as to induce any appre- ciable effect. When injected subcutaneously it causes an unimportant rise in blood-pressure, but, as pre- viously stated, enough of it is absorbed to cause tonic contraction of the uterus when it is administered after the delivery of the placenta. Intramuscular injections are followed by a greater rise of blood-pressure than are subcutaneous injections, but not nearly so great as that following the intravenous injection. The intense constriction of the vessels in the immediate region of the injection retards the absorption. Epinephrin is absorbed from the mucous mem- brane of the nose, throat, mouth, urethra, vagina and rectum. Epinephrin is destroyed almost immediately in alka- line solution, and it was suggested that the brief action after intravenous injection might be explained by its destruction in the alkaline blood. The blood, how- ever, is now known to be practically neutral in reac- tion, ■ and epinephrin mixed with blood and allowed to stand twenty-four hours is not totally destroyed, but if oxygen be passed through the blood after the addition of epinephrin, the latter is destroyed rapidly. Epinephrin is also destroyed in the other tissues. 190 DRUGS STIMULATING SYMPATHETIC ENDINGS Many biologic tests have been proposed for estimat- ing the amount of epinephrin in specimens taken from the circulating blood, but most of the reactions which have been proposed are given by other substances; hence they have only a negative value. That is, when the. blood fails to respond to these tests, epinephrin may be considered as absent; at least, no more than traces can be present. A recently proposed test of extreme delicacy, which is said to respond only to epinephrin among the substances which one might expect to find in the blood, consists in the perfusion of the vessels of an isolated limb of the frog with the blood to be tested, which is added to Ringer's solu- tion in such dilution that it just causes constriction. One part of epinephrin in 800,000,000 of the perfused fluid can be detected in this way. Solutions of epinephrin decompose on exposure to light and air, becoming pinkish and later brown in color. THERAPEUTIC USES The principal therapeutic indications of epinephrin have been indicated, for nearly all of these depend on its constrictor action. The circulatory effects may be utilized when a rise of blood-pressure is desired ; where it is necessary to maintain an increased blood-pressure for some time, resort may be had to slow intravenous injection of a very dilute solution (1:100,000), but there are many difficulties in the way of maintaining the injection for prolonged periods. It should be noted that the administration of epinephrin may result in an increase in a hemorrhage, quite as well as in a decrease. Nature lessens hemorrhage by a fall of blood-pressure not by a rise — the latter occurring in hemorrhage only when the circulation in the nervous centers becomes insufficient to sustain life. Epinephrin finds its greatest field of usefulness in local applications for constricting the vessels of mucous membranes, and in bleeding areas. It is added to solu- tions of cocain and other local anesthetics to delay absorption and thus prolong and intensify the anes- thetic action. EPINEPHRIN 191 Applications of epinephrin to the nasal mucous mem- brane during an attack of hay fever or acute catarrh cause immediate shrinking of the inflamed tissues, affording prompt relief. The action is brief, but if the patient remains quiet in a warm room the relief is much more lasting. As previously stated, dilatation commonly follows the constriction after application to the nasal mucous membrane, and if the drug be repeated too frequently for prolonged periods, chronic inflammation results. Epinephrin is used in bronchial asthma, but as the cause of this condition is unknown, the mode of action of epinephrin is not understood. It is sometimes injected subcutaneously — not intra- venously — after the delivery of the placenta to induce firm contraction of the uterus, preventing hemorrhage. Epinephrin has been suggested as an antidote to strychnin, but it increases the action of that alkaloid on the cord and cannot be considered as in any way antidotal, though strychnin is said to be antagonistic to the depressant action of epinephrin. The action of the latter is usually so rapid after fatal doses that little time is available for treatment. Suprarenal gland is recommended for the treatment of Addison's disease (tuberculous disease of the supra- renal gland), but it is admitted that the results are usually unsatisfactory. HEMORRHAGE When hemorrhage results from injury to a vessel which can be tied, the latter treatment is obviously indicated; but when it occurs in an inaccessible region, or results from injury to large areas where capillaries are involved, resort to drugs is often neces- sary. The most diverse methods have been employed in attempting to stop hemorrhage from inaccessible vessels; but since bleeding has a strong tendency to cease spontaneously owing to the formation of a clot when the pressure falls sufficiently, it is difficult to define the role of drugs, and when success attends their use, they are too frequently credited with the result when they have actually done harm, or had no appreciable effect. 192 DRUGS STIMULATING SYMPATHETIC ENDINGS The results of experiments with drugs in hemor- rhage are contradictory, and it is impossible to state just what value many of these have under different conditions. Epinephrin stops capillary hemorrhage, but when the constriction has passed, dilation and increased oozing may occur. A laboratory experiment serves to illus- trate the natural control of hemorrhage and the effects of the injection of epinephrin during bleeding. If the dog's chest be opened under ether anesthesia, and a sec- tion of the chest be removed, there is at first a copious hemorrhage from numerous arteries which are cut across; but with the exposure of the thoracic cavity, there is a sudden fall of blood pressure and the hemorrhage ceases almost completely; if epinephrin, or other vasoconstrictor be injected into a vein, the blood begins to spurt from numerous arteries. This continues until the constriction passes, or until the loss of blood causes a great fall in the pressure. There is a superficial similarity between the action of heat and that of epinephrin. When a bleeding finger is dipped in water, the bleeding increases tempo- rarily, because the vessels in the finger dilate while the general blood pressure is unaffected, of course; when the finger is removed from the hot water, con- striction soon takes place and the retardation of the flow favors the formation of a clot. It has been said that certain vasoconstrictors lessen hemorrhage by favoring the formation of a clot, after temporarily increasing the bleeding, in the manner described above. Whether such a drug will do harm or good in a given case depends on factors which cannot always be determined. If the loss of blood has been so great as to have reduced that in the body to the point at which further loss will be fatal, it is obvious that the sudden rise of pressure and the consequent loss of blood may prove fatal promptly; but when the fall of pressure does not suffice to stop the flow or perinit of the formation of an effective clot, it may be better to suffer the slight additional loss if clotting will ensue. It can only be said that our knowledge on this point is wholly unsatisfactory, and interference will often EPINEPHRIN 193 prove disastrous, at a time when one must feel the urgent need of action. Tannin, ferric salts, including the solution of ferric subsulphate or Monsell's solution, alum and dilute acids, such as vinegar, are among the best of the astringents for local application to stop bleeding by favoring the formation of a clot. Since the fall in blood pressure is the natural means of favoring clotting, it may be advisable to administer a vasodilator early in severe hemorrhage before the pressure has fallen dangerously low; amyl nitrite, sodium nitrate or nitroglycerin may be used in an emergency. It would be preferable to lessen the circulation by slowing the heart, if this could be accomplished with- out causing an increased force of the individual beat, for the stronger impulse tends to dislodge clots, and the mechanism controlling the circulation usually results in stronger beats to compensate for any slowing. Gelatin has been used to some extent in solution for hypodermic injection to promote the formation of a clot in aneurysm and to arrest hemorrhage. It is sometimes contaminated with the spores of tetanus which are not killed by boiling for a few minutes, and many cases of tetanus have been reported from its injection. DOSAGE The dose of epinephrin will obviously depend much on the purpose for which it is employed. It is applied to the nasal mucous membrane in the form of a spray of the 1 : 1,000 solution for hay fever, catarrh, or to reduce the swelling of the turbinated body. From 0.2 to 0.3 c.c. (3 to 5 drops) of a 1 : 1,000 solution may be added to a solution of cocain for subcutaneous injection to delay absorption and prolong local anes- thesia. Much larger doses are sometimes injected sub- cutaneously in order to secure bloodless fields of opera- tion. No harm follows unless the dose is excessively large, because of the slow absorption, but when the dose exceeds 0.5 mg. (K25 grain), care must be taken to see that the hypodermic needle does not enter a vein. 194 DRUGS STIMULATING SYMPATHETIC ENDINGS When epinephrin is injected intravenously to increase the blood-pressure in shock, a solution of 1 : 10,000, or even a weaker one, should be used, and this should be injected very slowly, 1 c.c. (15 minims) in five or ten minutes being sufficient to maintain slight rise in the pressure. For capillary hemorrhage a solu- tion of 1 : 1,000 is used. It is said that little improve- ment is to be expected in most cases of bleeding from gastric ulcer, because of the dilution to which the epinephrin is subjected in the fluid in the stomach. Epinephrin may be used in far larger doses by the mouth than intravenously, and if it fails to stop the bleeding it will probably do no harm. From 5 to 10 c.c. (from 1 to 2 teaspoonfuls) of a solution 1 : 10,000 may be used. For the relief of bronchial asthma 0.6 to 1.0 c.c. (10 to 15 minims) of a solution of 1:1,000 subcu- taneously is recommended, or sprayed into the nose at the beginning of the attack, or 1 mg. (%o grain) may be used in the form of a tablet which is allowed to dissolve in the mouth. When the heart stops suddenly during the adminis- tration of ether or chloroform, it is essential that the beat be restored immediately, for the chambers of the heart are then filled with blood containing the anes- thetic, and especially when this occurs with chloroform, the heart is rapidly paralyzed and rendered incapable of contracting again. If epinephrin is injected intra- venously in such cases it must traverse the right heart and the pulmonary circulation before it can act on the left ventricle, involving 'the loss of valuable time. If the injection is made intravenously the heart should be massaged through the chest wall at the same time. Delay is avoided by injecting the solution of epi- nephrin, 1 c.c. (IS minims) of 1: 10,000, directly into the heart by means of a fine hypodermic needle. MATERIA MEDICA Epinephrina. — Epinephrin, N. N. R. This substance, commonly referred to and used as adrenalin, is described as l,2-dihydroxy-4^ methyl- amino ethyl-4^-ol, benzene. It is the blood-pressure- raising principle of the suprarenal gland, also pro- EPINEPHRIN 195 duced synthetically. Among the names, other than those already mentioned, that have been applied to epinephrin or epinephrin-like substances are "adneph- rin," "adrenal," "adrenamine," "atrabilin," "chela- frin," "epirenan," "haemostasin," "hemisine," "ischae- min," "paranephrin," "renaglandin," "renastyptin," "renoform," "supranefran," "suprarenin," "supra- renadin," "1-suprarenalin," "suprarenaden" and "suprenalin." The several mixtures of epinephrin with cocain, eucain and other substances have also been given special names, so that the nomenclature of this article and its simple mixtures would probably total at least one hundred titles. Epinephrin, as such, occurs in commerce as a finely crystalline white or yellowish white powder, odorless, having a slight bitter taste. The free base is prac- tically insoluble in water and the product is usually dispensed in the form of an aqueous, usually acid, solution, 1 : 1,000, of one of it salts. Epinephrin is oxidized readily with the development of a red color ; and such red, pink or turbid solutions should not be used. Epinephrin is frequently used in the nose in the form of a spray. For this purpose the commercial 1 :1,000 solution may be diluted with 4 parts of water or physiologic solution of sodium chlorid, and if nec- essary a sufficient amount of cocain hydrochlorid added as in the following formula: C.c. or Gm. 5 Solution of epinephrin, 1 :1,000 61 flS iss Cocain hydrochlorid 6 Distilled water or physiologic solution of sodium chlorid to make 30 flS i Epinephrin is sometimes prescribed with an alkali, such as sodium bicarbonate, or with sodium benzoate. The first is evidently incompatible, and the second is hardly less objectionable, for the trace of hydrochloric acid usually present in solutions of epinephrin reacts with the benzoate, liberating benzoic acid, which has little preservative action so far as the epinephrin is concerned. 196 DRUGS STIMULATING SYMPATHETIC ENDINGS For use in suppositories epinephrin hydrochlorid is preferable to epinephrin itself because of the greater solubility and consequent activity of the salt. Supposi- tories of epinephrin may be prescribed by directing that each suppository contain approximately 0.001 gm. iVes grain) of epinephrin hydrochlorid and a suffi- cent amount of oil of theobroma to make 1 gm. PITUITARY The pituitary body, or hypophysis, consists of two portions, a large anterior lobe, and the posterior, or infundibular, portion. The anterior lobe is glandular in character; it is essential to life; at least, its total removal has usually been followed by the death of the animal, while its partial removal, or injury by disease, results in retarded growth or infantilism in the young, and in obesity and other disturbances of nutrition, the evidence suggesting that it has an internal secretion. Acromegaly and gigantism have been frequently found to be associated with tumor or hypertrophy of the pituitary, and it is believed that the abnormality is related to the change in the anterior portion. The therapeutic administration of the anterior lobe has given favorable results in the later stages of acromegaly and in the condition known as dystrophia adiposo-genitalis, though it is, of course, contraindi- cated in the early stages of acromegaly. The intravenous administration of extracts of the anterior lobe cause no marked physiologic actions on the circulation or respiration, but Gushing and Goetsch have observed some interesting effects on the repro- ductive organs following the use of the anterior lobe, and histologic changes in it have been observed in hibernating animals. Despite the fact that this portion of the pituitary body is essential to life, extracts of it appear to be of little, or no, therapeutic importance at present, and the following discussion applies only to the posterior lobe and its preparations. The posterior, or infundibular, portion (and with this may be included what is called the pars inter- media) consists mainly of neuroglia cells and fibers. PITUITARY 197 It yields to boiling water and other solvents various principles on which its pharmacologic and therapeutic actions depend, but none of these principles is avail- able in pure form. This has resulted in confusion regarding the actions of the extracts of the pituitary. The intravenous or subcutaneous injection of extract of the pituitary body cause stimulation of plain mus- cle, especially that of the blood vessels and uterus. This stimulation of the musculature of the vessels causes a moderate, but somewhat prolonged, rise of blood pressure. This rise is seldom as great as that which may be obtained by suitable amounts of epineph- rin, and while some observers report that it may per- sist for as much as half an hour, this is seldom seen after the injection of commercial preparations into dogs, and the blood pressure usually falls below the previous level within five minutes. Subsequent injections cause diminishing rises if suit- able intervals of time are permitted to elapse, but eventually a condition is reached where the injection causes only a fall in pressure. The rate of the heart beat is slowed, partly due to the direct action on the heart itself, but the contraction is apparently not favorably influenced through this direct action. The renal vessels dilate while the splanchic vessels constrict, and this effect has been invoked to explain the well-known diuretic action of pituitary, but there is no reason to doubt that it also acts directly on the renal cells causing an increased secretion, both actions probably being concerned in the diuresis. The actions of pituitary on the uterus are important, but unfortunately there is a want of exact agreement among investigators on this point, especially among clinical observers. There is no question concerning the capacity of pituitary to stimulate the musculature of the uterus to increased contraction, and it has been shown that the effect is much greater during pregnancy than during the non-pregnant state, but the question of the degree to which it causes tonic contraction of that organ is naturally of the first importance. 198 DRUGS STIMULATING SYMPATHETIC ENDINGS The intestinal musculature is also stimulated by pituitary, but, for obvious reasons, this action is of much less importance than that on the uterus. It is used for its uterine effects when a comparatively few active contractions serve to expel the contents, or later, to cause tonic contractions to prevent hemorrhage, but a few extra peristaltic intestinal movements would be of no great value in chronic constipation and tonic contraction of the intestine is, of course, undesired. We are in especial need of more comprehensive knowledge of the pharmacologic actions of pituitary, especially since the manufacturers of the numerous preparations are most optimistic regarding the thera- peutic value of their preparations in a great variety of conditions, in some of which they are certainly use- less, if not positively dangerous. An increased secretion of cerebrospinal fluid, and a temporary increase in the secretion of milk have been observed. The secretion of milk soon falls below the normal, however, and the mammary action appears to be of no therapeutic importance.^ Various methods have been proposed for standardiz- ing the pituitary preparations, but the most satisfactory consists in comparing the activity with that of pure beta-iminazolylethylamin on the isolated uterus of the virgin guinea-pig. A dilution of 1 part of pituitary extract of good quality in 10,000 is equal in activity to 1 part of pure beta-iminazolylethylamin in a dilu- tion of 20,000,000. Unfortunately, the various commercial preparations of pituitary vary widely in their activity, and it should be remembered that tests based on the capacity for increasing the blood pressure or the secretion of urine afford no index of the activity on the uterus. Since the therapeutic value of pituitary depends on its uter- ine action, physicians should demand preparations that have been standardized by comparison with beta-imin- azolylethylamin in the manner mentioned. 1. Ntimeraus other effects have been reported as following the injection of pituitary, but many of the results reported lack agreement and they do not call for discussion here. A review of tnttch of the literature may be found in Hygienic Laboratory Bulletin No. 100, November, 1914. PITUITARY 199 THERAPEUTIC USES It would be a waste of time to attempt to enumerate all of the conditions in which pituitary has been rec- ommended; rather is it our duty to call attention to some of the therapeutic claims made by manufacturers that have no rational basis, in the present state of our knowledge. For example, one preparation has been recommended "in every individual stage of labor," but careful observers are in agreement that it should not be used before the os has dilated or become dilata- ble. It has been extolled in paralytic distention of the intestine, but it is not dependable in that condition. It probably has little, or no, value in shock. Quigley (Jour. Am. Med. Assn., 1915, 64, 1122) states that the ideal conditions for the use of pituitary (note that he does not say that pituitary is ideal for the condition) is uterine inertia occurring during the sec- ond stage of labor, that is, when the os is fully dilated or dilatable, with a presenting part that is engaged or that can be made to engage, and in the absence of any obstruction on the part of the passage or the passenger. He states that its action in post-partum hemorrhage is more prompt than that of ergot but not so lasting. Quigley afld others lay especial stress on the exis- tence of any obstruction, such as contracted pelvis or an occiput posterior stationary at the brim, as a contraindication for the use of pituitary. Rupture of the uterus has followed the use of pitui- tary in several cases where obstructions to rapid deliv- ery existed. DOSAGE As much as 4 c.c. (60 minims) of pituitary extract was used by some of the observers in the earlier stages of pituitary therapy, but there is no apparent reason for the employment of such doses; when a moderate amount proves ineffectual in causing increased uterine contractions it may be repeated once, but if this has no effect it indicates that the drug is unsuitable for that case. Ip the absence of uniformity of activity in the com- mercial preparations of pituitary, and since there is no official preparation of it, no exact dose can be given. 200 DRUGS STIMULATING SYMPATHETIC ENDINGS but 0.5 c.c. (8 minims) is the average dose of an extract of which a dilution of 1 : 10,000 is equal in uterine activity to a dilution of beta-iminazolylethamin of 1 : 20,000,000. Solutions of pituitary extract undergo decomposi- tion on exposure to the air and only sealed ampules containing one or two doses should be used. MATERIA MEDICA There are many preparations of pituitary. Pitui- tary Liquid, Armour, and Solution Pituitary Extract, Mulford, supplied in 1 c.c. ampules, are described in New and Nonofficial Remedies. Desiccated Pituitary Substance {Anterior Lobe), N. N. R., occurs as a light grayish yellow powder hav- ing a slight, peculiar odor. This is the preparation that has been used in the later stages of acromegaly and in certain cases of obesity. It is given in doses of from 0.05 to 0.20 gm. (1 to 4 grains) in powder or in cap- sules. Desiccated Pituitary Substance {Posterior Lobe), N. N. R., like the preceding, is a light grayish yellow powder with a slight, peculiar odor and is partly solu- ble in water. It may be given by mouth in doses of from 0.5 to 0.20 gm. (1 to 4 grains), but this method of administration is said to be less effective than the parenteral introduction of aqueous extracts which may be made extemporaneously by extracting the soluble portions of (0.5 gm.) the ground substance with (10 C.C.) distilled water by boiling for ten minutes or more, allowing to cool and using the supernatant clear liquid. It should be remembered of course that the preparation used should be active and of standard quaUty and that proper precautions be used in making the solution to prevent bacterial contamination. ERGOT Various grains are invaded by a fungus known as ergot; that growing on rye and replacing its grain is the official ergot. In damp seasons this fungus may constitute as much as 10 per cent, of the flour made from the rye, and the bread made from such flour is ERGOT 201 poisonous, giving rise to a condition known as ergot- ism. The symptoms are of two general types, in one of which convulsions are the predominant feature, and in the other gangrene. These types are not sharply sepa- rated, and both are usually seen in epidemics of ergotism. Such epidemics are now uncommon, but they still occur occasionally. Premature delivery and abortion were frequently observed during epidemics of ergotism, and this prob- ably led to the use of ergot in obstetrics. Ergotism, however, does not always prevent the normal progress of labor. The marked differences observed in the general types of poisoning suggest strongly that ergot differs widely in its constituents at different times, and this has been shown to be the case. Ergot has proved an unsatisfactory drug at best for the clinician, while its chemistry has presented many difficulties for the inves- tigator. It has been claimed on many occasions that the active principle of ergot had been discovered, but expe- rience has shown invariably that the supposed active principle represented at most a part of the activities of the drug, and often an insignificant part. This much is certain, that ergot contains a number of active principles, some of them present in minute quantities, but having extraordinary activity, and there are at least four constitutents which deserve mention. These are ergotoxin and ergotinin, two alkaloids which are closely related, and two principles commonly con- sidered as putrefactive principles, because they are present in putrefying meat; these are tyramin, or hydroxy-phenyl-ethyl amin and histamin, or beta- iminazolyl-ethyl-amin. Ergotoxin, an extremely active alkaloid, is the hydrate of ergotinin, which is inactive, but Which is probably changed into ergotoxin under conditions which are not very well understood. Ergotinin has been known since 1875; ergotoxin, only recently dis- covered in pure form, constitutes the active portion of various substances which have been isolated in greater 202 DRUGS STIMULATING SYMPATHETIC ENDINGS or less degree of purity by various investigators and given diiferent names. Ergotoxin stimulates those sympathetic endings which have motor functions, and in large doses para- lyzes them ; the endings of those fibers which are con- cerned with inhibition are not affected by ergotoxin. Here again we have an example of a drug acting on whole groups of nerve-endings which have similar functions; this results in constriction of the blood- vessels, with rise of blood-pressure, and in contraction of those smooth muscles which contract in response to stimulation of the sympathetic. It will be seen that ergotoxin resembles the action of epinephrin so far as the latter acts on the motor nerve endings, or myo- neural junctions of the sympathetic, while it differs from epinephrin in that the latter also stimulates the myoneural junctions of the sympathetic which are con- cerned in inhibition, while ergotoxin does not. As stated previously, in the discussion on epinephrin, the pregnant human uterus responds to sympathetic stimulation by contraction. It also responds to ergo- toxin by contraction, and this serves to explain why ergot sometimes causes abortion, and also why acci- dents occur so frequently when ergot is used to empty the pregnant uterus, since overstimulation of the sym- pathetic results in tonic contraction instead of the peristaltic waves which are present in normal child- birth. This tonic contraction, being desired after delivery of the placenta, also indicates the use of ergot at that stage of labor. The uterus is more susceptible to the action of ergo- toxin and epinephrin at the time of labor than during the non-pregnant state ; hence ergotoxin, like epineph- rin, then causes active uterine contraction with doses which have little effect on the general blood-pressure. Tonic contraction is the normal physiologic condition of the uterus after delivery of the placenta, and it is only natural that stimulation of the sympathetic has a more pronounced action at this stage than at a time when tonic contraction would be an abnormal condi- tion, for it is a fairly general rule that drugs influence ERGOT 203 structures more actively in the direction of their nor- mal functions than in opposition to them. Ergotoxin also acts on other smooth muscle which is innervated by the sympathetic, but these actions do not require discussion here. Ergotinin, being inactive, does not require further discussion except to state that it may be converted into ergotoxin by hydration. Tyramin, or hydroxy-phenyl-ethyl-amin, resembles epinephrin in its chemical constitution and its pharma- cologic action. It is formed from tyrosin during putre- faction, from which circumstance it received the name "tyramin." It causes active contraction of the preg- nant uterus, and probably constitutes the chief con- stituent of aqueous preparations of ergot, ergotoxin being in soluble in water. Histamin may be derived from histidin; it is said to be present in ergot in amounts too small to influence the uterine action of the latter to any marked extent. It is so extraordinarily active on the uterus, however, that it is difficult to believe that it is without impor- tance,, though it may escape isolation in amounts that can be utilized profitably. It can be prepared syn- thetically, and may be obtained commercially, should further investigation indicate it has special value. It is said to cause a perceptible contraction of the uterus when that organ is perfused with a solution containing one part of the histamin in 200,000,000 parts of Ringer's solution. It causes constriction of some vessels, but dilatation of others, the effect of its intravenous injection being a fall of blood-pressure. In addition to the four constituents which have been discussed, ergot also contains saponin, which may be of some importance when preparations of ergot are injected intravenously, but which is of little or none when these are used orally. In addition, there are present minute amounts of various substances which have not been isolated in pure form. It seems probable that all of the pharmaceutical preparations of ergot, both aqueous and alcoholic, which have decided therapeutic activity, contain either 204 DRUGS STIMULATING SYMPATHETIC ENDINGS tyramin or ergotoxin, or both, and while the older nomenclature is confusing and should not be employed in prescribing, the following tabulation will show the relationship between some of these preparations and the active principles known to exist in ergot, as given by Barger and Dale: Ecbolm and ergotin (Wenzell) mixtures of alkaloids, containing cholin (Meulenhoif). Sphacelinic acid (Kobert) : inactive resin with adherent alkaloid. Cornutin (Kobert): an alkaloidal resin, probably containing some ergotoxin, and also some other active substance which may be a decom- position product of ergotoxin. Cornutin (Keller): impure mixture of ergoUnin with ergotoxin. Chrysotoxin (Jacobi): inactive yellow coloring-matter with a small proportion of adherent alkaloid. Secalintoxin (Jacobi) : mixtu<*e of ergotoxin and ergotinin. Sphaeclotoxin (Jacobi) : impure ergotoxin. Hydroergotinin (Kraft) : recent synonym for ergotoxin. The foregoing tabulation may serve to suggest the unwisdom of prescribing every new preparation which appears with the claim that it represents the parent drug in a new and improved form. Among the numerous proprietary preparations which have been brought forward in recent years as substitutes for ergot is clavin, which was widely advertised for a time, and which has been shown to be a mixture of leucin and aspartic acid, and to be devoid of pharma- cologic or therapeutic action. Unfortunately there is no agreement as to the exact pharmacologic action desired when ergot is used thera- peutically in many conditions other than childbirth, hence it is impossible to determine which of the sev- eral active principles should be used in its place in those cases. Ergot exerts a marked efifect on the central nervous system, the convulsions being due to this action, but this has not been studied sufficiently to make its con- sideration profitable. The depression which toxic doses induce in the cock is due apparently to the action on the cerebrum; the ataxia to action on the cerebellum; the central emetic action and the clonic type of convulsions suggest that the medulla is the seat of these actions. The vagus center in the medulla is ulso stimulated, and the emesis which sometimes results appears to be ERGOT 205 due to central action, for vomiting movements promptly follow the intravenous injection of ergot in eviscerated dogs ; but much larger doses can be admin- istered by the mouth without causing gastric dis- turbance. The most striking effect of the injection of ergot in the cock is the gangrene of the comb and wattles which it induces. Ergot gangrene in man commonly affects the extremities. Many explanations have been offered to account for the phenomenon; but it can be said with certainty only that ergot exerts some peculiar action resulting in active contraction of the vessels (probably due to the ergotoxin and the t^ramin in part) and that this is attended with stasis and hyaline thrombosis, with the resulting gangrene. Certain ani- mals are much more susceptible to the gangrene action than others, the chicken, the pig and man being among those which are readily affected. When fluidextract of ergot is injected directly into the veins it causes a slight and temporary fall of blood-pressure, followed by a brief rise, and then return to normal. The fall in pressure is due appar- ently to saponin and does not occur after the oral administration of ergot, because saponins are not absorbed rapidly, if at all, from the gastro-intestinal tract. Small doses of ergot cause rhythmic contractions of the pregnant uterus, while large doses cause tonic contractions. Unfortunately, it is impossible to stimu- late the rhythmic contractions by ergot without risk of inducing the tonic also; hence the danger of using ergot before the uterus has been emptied. Ergot varies quantitatively, as well as qualitatively, in its actions, deterioration being quite rapid accord- ing to the general belief, but we have no biologic test which will indicate the therapeutic activity quantita- tively; hence it is impossible to say how rapid the deterioration really is. One investigator estimated that ergot was but one-eighth as active after one year as at the time of being collected, and the pharma- copeia directs that it shall not be kept for more than one year. The liquid preparations of ergot deteriorate 206 DRUGS STIMULATING SYMPATHETIC ENDINGS also, but their rate of deterioration appears to be far more variable than is that of the crude drug. Prepa- rations made with diluted alcohol and kept without exposure to the air keep fairly well. The want of a chemical test for the activity of ergot has led to the introduction of various biologic methods of standardization ; the most generally useful of these is probably that which consists in determining the amount of ergot required to cause gangrene of the cock's comb. The action on the uterus of the virgin guinea-pig would appear to have the advantage of test- ing the therapeutic activity on the organ for which the ergot is used therapeutically, but this test yields no more satisfactory results than does that on the cock's comb. One or more of the principles which induce gangrene appear to deteriorate more rapidly than those which act on the uterus, and the test is therefore more suit- able for fresh specimens than for old ones. Acute poisoning with ergot is rare, if one does not include the untoward action on the uterus, but occa- sionally overdoses give rise to gastro-intestinal dis- turbances, convulsions and later to gangrene. There is no specific antidotal treatment for ergot poisoning, and one can only combat the symptoms as they arise. THERAPEUTIC USES Few drugs have been used in a greater variety of conditions than ergot, often where opposite eflfects are required; for example, in shock to increase blood- pressure, and in hemorrhage, where an increase in blood-pressure is contra-indicated. It was formerly used extensively to hasten the expulsion of the fetus in normal labor, but one can never be certain of securing the increased rhythmic contractions and avoiding the tonic which prove so dangerous. Ergot should be used in labor only after the uterus has been emptied, to prevent or control post-partum hemorrhages. If used before the fetus or the placenta is expelled, only the smallest thera- peutic dose should be employed, and this should not be repeated even if no effect is perceptible. This use, however, is strongly contra-indicated. ERGOT 207 Ergot is used for excessive menstrual flow, and because it is useful in this condition it has been assumed that it would be equally useful in uterine hemorrhage from other causes, including that due to tumors, but there is no reason to expect favorable results in such cases. There seems to be no sufficient reason for the con- tinued use of ergot in any chronic condition, as it is liable to cause poisoning. While ergot is capable of increasing the blood- pressure to a certain extent, it is inferior to epinephrin in this respect, and it is not sufficiently dependable for use in shock. The other purposes for which ergot has been rec- ommended do not appear to merit discussion. DOSAGE Ergot is commonly administered in the form of the fluidextract, which may be given by the mouth or injected intramuscularly — not subcutaneously, because of the pain which the last-named method involves. The action after oral administration is usually delayed for about twenty minutes; hence the intramuscular injection is preferable when post-partum hemorrhage is to be feared. Not exceeding 2 c.c. (30 minims) of an active fluidextract of ergot should be administered before the expulsion of the fetus, but, as previously stated, even this is not recommended. This dose given after delivery of the placenta may be repeated if necessary after fifteen minutes. The dose required will depend largely on the activity of the specimen at hand, but it is better to have a reliable specimen always at hand for emergencies. MATERIA MEDICA JSrsfofo.— Ergot, U. S. P. In Continental pharmacopeias this drug is generally known as "secale cornutum." It is officially described as the dried sclerotium of Claviceps purpurea, replac- ing the grain of rye. The drug as it occurs in com- merce is derived chiefly from Spain and Russia, though other countries, notably Germany, Austria and Sweden occasionally furnish supplies of good ergot. Spanish 208 DRUGS STIMULATING SYMPATHETIC ENDINGS ergot is larger than the Russian variety, but is said to contain less ergotinin, which may be converted into the active ergotoxin. Ergot deteriorates rapidly when kept in open vessels and in a damp atmosphere. This is particularly true of the powdered drug. The Brussels Conference Pro- tocol and foreign pharmacopeias generally direct that ergot should not be more than one year old, and should be preserved entire. The powder when called for on prescriptions should be prepared at the time that it is wanted. This drug is still frequently administered in the form of powder in doses of 1 to 2 gm. (15 to 30 grains) in the form either of capsules or cachets. It is more frequently administered in the form of: Fluidextractum Ergotae. — Fluidextract of Ergot, U. S. P. This preparation is a hydro-alcoholic, slightly acid liquid, having a reddish-brown color and a character- istic rather unpleasant odor. It is readily miscible with water, but precipitates slightly when mixed with an equal volume of strong alcohol. Considerable difficulty has been experienced in securing reliable and reasonably permanent fluidextracts or other prepa- rations of ergot. Recent observations appear to indi- cate that samples of the fluidextract preserved in small vials or hermetically sealed tubes keep better than similar preparations exposed to the air, and the product at the present time is frequently dispensed in sealed vials or tubes containing from one to four doses. Efforts to prepare purified extracts of ergot for hypodermic use or to isolate the active principles in water-soluble form have met with some success, and several preparations of this type now available are described in New and Nonofficial Remedies. HYDRASTIS This drug, its chief alkaloid, hydrastin, and hydras- tinin, which is derived from hydrastin artificially, are often classified with the morphin group, but they act on the central nervous system much like strychnin. On the other hand, they are often used therapeutically HYDRASTIS 209 for their effects on the uterus : hence it is convenient to consider them here. Hydrastis contains berberin and another unimpor- tant alkaloid, canadin, in addition to hydrastin. The berberin probably has no especial value, but it is some- times used for the effects of its bitter taste. Hydrastin stimulates the central nervous system, overdoses causing hyperexcitability of the cord. Very large doses may cause strychnin-like convulsions. Moderate doses cause a rise of blood-pressure, prob- ably through constriction of the arterioles ; the mech- anism of this is in some doubt, and its therapeutic importance has been greatly exaggerated. Toxic doses cause depression of the respiratory center and a fall of blood-pressure, with cardiac depression. Hydrastis and hydrastin induce uterine contractions which may be peristaltic in character or they become tetanic : hence they are used to prevent excessive men- strual flow or uterine bleeding from other causes except post-partum hemorrhages, in which they are said to be much less effective than ergot. They are sometimes used in subinvolution of the uterus. It is possible that their tendency to cause a rise of blood- pressure may interfere with their therapeutic useful- ness in arresting uterine hemorrhage. They are commonly credited with some special tonic action on mucous membranes, and have been widely used, largely in the form of proprietary preparations, as applications to the nose, throat, urethra and vagina in chronic catarrhal conditions. Hydrastinin acts locally and centrally to induce vasoconstriction, and at the same time it is said not to depress the heart ; hence the general blood-pressure rises when it is injected. It is said to be better than hydrastin for checking uterine hemorrhage from vari- ous causes. It is sometimes used in solution for local application to various mucous surfaces to check hemor- rhage. Its action on the uterus is much like that of hydrastin. There is no very clear indication for the therapeutic employment of hydrastis and its alkaloids. Hydras- tinin would seem to have the advantage over hydras- 210 DRUGS STIMULATING SYMPATHETIC ENDINGS tis and hydrastin in nearly every case except those in which hydrastis is used for its bitter taste. Hydrastis and its alkaloids afford an illustration of the way in which drugs of little therapeutic^ value attain wide popularity in the treatment of a variety of conditions. These agents have a great diversity of actions on the central nervous system, on the heart and vascular system and on mucous membranes. The proprietary preparations containing them have been lauded in many clinical conditions regardless of the fact that we have better drugs for nearly all of these conditions. DOSAGE The average dose of the fluidextract of hydrastis is 2 C.C. (30 minims) ; smaller doses may be used for the bitter effect ; the dose of hydrastin or hydrastin hydro- chlorid is 0.01 gm. (% grain) ; that of hydrastinin is 0.03 gm. (Ingrain). MATERIA MEDICA Hydrastis. — Hydrastis, U. S. P. The dried rhizome and roots of Hydrastis canaden- sis, yielding by the process given in the U. S. P. not less than 2.5 per cent, of hydrastin. Hydrastis also contains about 3 per cent, of berberin and a minute quantity of canadin. The drug is used principally in the form of: Fluidextractum Hydrastis. — Fluidextract of Hydrastis, U. S. P. A solution of the soluble constituents of hydrastis in a mixture of glycerin, alcohol and water. One hun- dred c.c. should contain 2 gm. of hydrastin in addition to the other alkaloids of hydrastis. Of the alkaloids occurring in hydrastis, only one is at all widely used. This is official as: Hydrastina. — Hydrastin, U. S. P. Because this alkaloid is almost insoluble in water, it is preferably used in the form of hydrastin hydro- chlorid. It is hygroscopic and must therefore be kept in well-closed glass bottles. EMMENAGOGUES 211 Hydrastininae Hydrochloridum. — Hydrastinin Hydrochloric!, U. S. P. An artificial alkaloid derived from hydrastin or made synthetically. It occurs as white or faintly yel- lowish crystals having an intensely bitter taste. It is very soluble (1:1) in water and freely soluble (1:3) in alcohol. EMMENAGOGTTES The drugs intended to stimulate the menstrual flow were formerly treated at some length in text-books of therapeutics under the heading given above, but all of the emmenagogues have other actions on which their therapeutic use depends and they do not form a well-defined pharmacologic or therapeutic group. Menstruation is attended with uterine congestion and is disturbed or prevented by numerous causes which interfere with the uterine circulation or with the general health. Hence emmenagogues may be classified as (1) measures intended to improve the general health; (2) measures or agents which pro- mote uterine congestion. Iron, strychnin and cod liver oil are frequently classified as emmenagogues which act by improving the general health, but it is obvious that this class must be nearly coextensive with the materia medica. Among the measures intended to promote the uter- ine circulation are hot baths and irritants of the colon and of the genito-urinary tract. Hot baths do not require detailed discussion in this place; the mechanism by which irritants of the colon, such as aloes and other evacuants of the anthracene group, cause uterine congestion will be discussed later ; various volatile oils and other irritants which are excreted by the kidneys serve as irritants to the genito- urinary tract and induce uterine congestion, but their use is now limited almost entirely to users of patent medicine and mixtures intended to induce abortion. These mixtures are usually fraudulent and the doses recommended seldom contain active constituents in dangerous amounts. Indirectly, the sale and use of such nostrums has resulted in many fatalities due to 212 DRUGS STIMULATING SYMPATHETIC ENDINGS the ingestion of dangerously large doses of volatile oils or of drugs containg them. It is obvious from the foregoing discussion that the emmenagogues do not call for detailed discussion under this heading. Valerian and viburnum may be discussed in this place. Valerian is now believed to be useful in attacks of nervousness and hysteria by a psychic stimulation resulting from its disagreeable odor. Viburnum prunifolium was formerly credited with the power to avert threatened abortion and to exert a favorable influence on menorrhagia. Reports sus- taining these views have appeared in the literature, but the experience of most physicians fails to justify a belief in the qualities claimed for this drug. Vibur- num contains small amounts of a volatile oil with a disagreeable odor and may act like valerian reflexly through the sense of smell.^' It is probable that viburnum prunifolium continues to maintain a certain degree of popularity because of extravagant claims made in advertisements in reputable medical journals by the manufacturers of various pro- prietary preparations such as Hayden's Viburnum Compound and Dioviburnia. The advertising creates a certain demand for these preparations and the con- tinued demand for them serves as a stimulus to pharm- aceutic manufacturers to market more or less similar compounds for those who do not care to use the pro- prietary preparations, a sort of vicious circle of exploitation and demajid being thus established. 13. The literature of these two drugs affords an example of the unsat- isfactory conditions that obtain with reference to many articles in the materia medica as the result of the blind following of those who blindly copy others equally blind. Many text-books state or imply that the actions of valerian and viburnum are practically alike, but they also state that they are used therapeutically for unlike conditions. Thus valerian is copimonly used for the relief of hysteria, while viburnum is often employed as a uterine sedative in painful and excessive menstrua- tion and kindred conditions, but no explanation is offered for this dif- ference in their application.. One is almost forced to the conclusion that very little discrimination has been shown in the use of these drugs, and while accumulated clinical experience would seem to show that valerian has at least a limited field of usefulness, there is no apparent reason to retain viburnum in the materia medica in the absence of evi- dence that it has therapeutic value, and it would seem wiser to sub- stitute valerianic acid for either of them in a given case. As a matter of fact, the whole subject requires investigation. EMMENAGOGUES 213 It seems probable that the ammoniated tincture of valerian will serve any purpose that the more expen- sive proprietaries may. DOSAGE Valerian is commonly administered in the form of the ammoniated tincture, in doses of 2 c.c. (30 min- ims), and viburnum is used in the form of the fluid- extract in like amounts. Valeriana. — Valerian, U. S. P. The dried rhizome and roots of Valeriana officinalis. Tincture Valeriana Ammoniata. — Ammoniated Tincture of Valerian, U. S. P. One hundred c.c. represent the soluble constituents of 20 gm. of valerian in aromatic spirit of ammonia. CHAPTER VI.— DRUGS WHICH ACT MAINLY ON THE HEART THE DIGITALIS GROUP The digitalis group is one of the best defined in the materia medica because the cardiac actions of all its members are quite similar qualitatively, though they show wide quantitative differences and nearly all of the drugs of the group are used for their cardiac actions almost exclusively. The characteristic action of these drugs on the heart is called the digitalis action, and all drugs exertjng this action are called digitalis bodies, regardless of the source from which they are derived. A drug is said to possess the digitalis action if it causes the frog's heart to come to a standstill with the ventricle in systole and the auricles in diastole, following a characteristic behavior. This usually includes a period of slowing of the heart-rate ; a period of increased rate, and a period during which there are typical irregularities in the rate and force of con- traction. The beat of the auricles and that of the ventricle usually show complete dissociation shortly before they stop. This digitalis action on the heart is interesting, for it exhibits all of the direct actions for which the drug is used therapeutically, except that on the vagus center. Fatal doses of digitalis cause the intact mammalian heart to stop in diastole because it is incapable of beating after the coronary circulation is interrupted, but when the mammalian heart is perfused with a solution of a digitalis body it also stops with the ventricles in systole. This systolic standstill is an expression of the increased tonicity of the heart which is the foundation of the therapeutic use of the drug in a large proportion of cases. Our knowledge of the drugs of this group has been extended greatly within the past few years with the DIGITALIS GROUP 215 result that their therapeutic uses and limitations have been determined far better than those of most drugs. Digitalis, however, cannot be used successfully with- out an understanding of its pharmacologic actions, and there are few drugs concerning which there have been a greater number of erroneous conceptions. With the advance in our knowledge of the drug it has become necessary to revise much of the teaching that was current but a decade ago; therefore the pharmacologic and therapeutic actions of the digitalis bodies will be discussed in somewhat greater detail than those of many other important drugs.^* The digitalis bodies have no important direct actions on the higher parts of the brain, though they have a slight tendency to induce somnolence when large doses have been administered. They stimulate the vomiting center in the medulla, and nausea and vomiting are commonly observed when the therapeutic dose is exceeded slightly with any member of the group, and it is difficult or impos- sible to elicit the full therapeutic effect of some of them without causing nausea. These symptoms afford a guide to the limitations of therapeutic doses, and these and other signs will enable the physician to elicit the full therapeutic effects on the heart while avoiding the dangerous side actions in the majority of cases. Digitalis bodies stimulate the vagus center and the vagus endings in the heart, but the latter effect is probably of minor importance. The vagus stimula- tion does not always suffice to cause pronounced slowing of the heart-rate, but there is a group of cases in which it occurs almost invariably. These will be discussed later. Excessive doses cause an increase in the rate, with various forms of irregularity. The rate of the heart-beat is controlled normally by impulses which arise in a small mass of tissue, 14. It may be remarked in passing that advances in our knowledge of digitalis have gone hand in hand with equal advances in our knowledge of the cardiac conditions for which the drug is useful, and physicians who are not familiar with the recent progress in the diagnosis and treatment of cardiac disease will find a little volume entitled "Clinical Disorders of the Heart," by Thomas Lewis, extremely valuable. The subject is discussed in a simple and easy manner which one can under- stand without being a specialist in cardiac diseases. 216 DRUGS ACTING ON THE HEART known as the sino-auricular node, or the pace-maker of the heart, which is situated in the region about the mouths of the great veins which empty into the auricle. The impulses or stimuli for contraction which arise in the pace-maker pass down to the auricles, causing them to contract, and the impulses are then trans- mitted through the minute bundle of muscle fibers known as the auriculoventricular bundle to the ven- tricles, causing them to contract. Digitalis depresses the conductivity of the auriculo- ventricular bundle, delaying or preventing the passage of impulses through it and causing what is known as heart-block. With moderate doses impulses are delayed, and a few of them may be prevented from passing; the block is then said to be partial. In such cases the interval between the beat of the auricles and that of the ventricles is increasingly prolonged with successive beats until one of the ventricular beats drops out, the auricles then beating three or four times to two or three beats of the ventricles. In such cases the ventricles may appear to be beating with almost perfect regularity, but careful observation will show a slight irregularity at least, and a difference between the number of the auricular and the ven- tricular beats. With larger doses of digitalis there may be a com- plete block, so that impulses do not pass from the auricles to the ventricles, and the latter then take up an independent rhythm, usually much slower than that of the auricles. Partial or complete heart-block may result from disease, or a small dose of digitalis may convert a partial into a complete block. This action of digitalis is exerted through the vagus, and it is interfered with by atropin. Heart-block is beneficial in cases of auricular fibrillation, in which condition it relieves the ventricle of innumerable stimuli which cause it to beat irregu- larly and usually very rapidly, but it must be under- stood that digitalis has no perceptible influence on the fibrillating auricle, which continues to fibrillate independently of the improved circulation. DIGITALIS GROUP 217 Auricular fibrillation is a condition which has only recently come to be recognized as of common occur- rence in man, the condition being formerly diagnosed as myocarditis. The fibrillating auricle does not con- tract as a whole, but a fine tremor constantly involves the surface of the auricle, and instead of the rhyth- mic impulses which normally pass from the auricle to the ventricle, numerous impulses arise without any sort of order in the fibrillating auricle, and passing to the ventricle cause it to beat with extreme irregu- larity of rate and force, and usually very rapidly. A heart which beats with abnormal rapidity does not contract adequately during systole, and the blood is dammed back into the veins, with the well-known evil consequences. Digitalis causes the ventricle to beat more slowly, to dilate more completely in diastole, and to contract more forcibly and completely in systole, hence to empty itself more perfectly, discharging a larger amount of blood at each beat. It is easily understood that these changes result in a better circulation unless the slowing has been too great, and this improved circulation is the object of digitalis medication regard- less of the symptoms of which the patient complains. There are few conditions in which digitalis is so dependable as in auricular fibrillation occurring in patients under 40 years of age.^° IS. It may not be amiss to refer briefly to the means of diagnosing this condition, which is said to occur in 60 per cent, of the patients -who enter the general hospitals with evident signs of cardiac insufficiency. It occurs rarely in those under 17 years of age, and not often before the fortieth year without a history of rheumatism or chorea. With advancing years it becomes more frequent in the absence of such a history. The most characteristic symptom is an absolute irregularity of the rate and force of the ventricular beat, that is, not even regularly recurring groups of beats can be made out. When a patient more than 15 years of age has a ventricular rate above 120 beats per minute at the apex and an absolutely irregular heart, one may strongly suspect auricular fibrillation. The occurrence of such symptoms in one who presents a history of rheumatism or chorea points even more strongly to that condition, and when to these are added other symptoms of cardiac insufficiency the diagnosis can be made almost with certainty. If the rate is slow but absolutely irregular the diagnosis may be aided by letting the patient take gentle exercise which causes the ventricle to beat more rapidly; the irregularity increases if the auricles are flbrillat- ing, but decreases if it arises from other causes. Many beats can be heard at the apex which cannot be felt at the wrist, and the number of these is an index of the insufficiency of the heart. Auricular flbrillation usually persists from the time of its appearance until the death of the patient, but it is only temporary in about 10 per cent, of the cases. 218 DRUGS ACTING ON THE HEART If the heart is slowed to an excessive degree the volume expelled in a unit of time may be less than before the digitalis was given, but with moderate slowing which usually results, the improvement in the circulation is pronounced. It is impossible to state in exact terms what constitutes excessive slowing, but a reduction of 50 per cent, in the rate may be bene- ficial when the rate has been extremely rapid. During cardiac dilatation, acute or chronic, the heart dilates excessively during diastole and contracts very imperfectly during systole, and much of its energy is then lost through the regurgitation of the blood through the incompetent valves. In such cases digitalis does not cause increased dilatation during diastole, but its capacity for increasing the tonicity of the heart becomes more prominent, and its effects are more pronounced in increasing the systole, whereby the amount of blood expelled at each beat is greatly increased. It is said by some to be much more effective in acute than in chronic dilatation, but others report good results in both conditions. Since the heart rests only during diastole, the slow- ing of the rate, which is largely due to prolonged diastole, permits of a greater opportunity for rest. The blood is squeezed out of the tissues of the heart during systole, and when this is rendered more com- plete, a larger volume of fresh blood will flow through the capillaries and the heart will be nourished more efficiently. The opportunity thus afforded for the improved nutrition of the heart probably explains in part the increased force of contraction after digitalis, this being supplemented by the better general circu- lation in which that of the coronaries participates. The complete recovery of the heart requires some time and the full effect of digitalis may be induced, slowly, even though its maximum direct action may be elicited promptly. The mechanism of this increased nutrition should be borne in mind, for it will serve to explain why a rise of blood-pressure is seldom injurious to the heart even when the heart was previously overtaxed, for with the improvement in its nutrition the slight additional energy required to force the blood out DIGITALIS GROUP 219 against the increased pressure will be more than com- pensated for by its increased capacity for contraction. The effect of the digitalis bodies on blood-pressure has been the subject of a great deal of discussion. One difficulty which the investigation of this subject presents is that pharmacologists are unable to secure animals which suffer from cardiac diseases similar to those in which digitalis is used therapeutically, and we have seen that it tends to restore the heart-beat toward normal; hence the pharmacologic experiments have given conflicting results. It is commonly stated that digitalis causes an increase in the blood-pressure, but it is true that it may produce the desired therapeutic effects while the blood-pressure rises or falls, dependent on whether it was previously too low or too high. When the heart fails to supply enough blood to the central nervous system a greater or less degree of asphyxia with cyanosis results, and this causes con- striction of the blood-vessels so that the increased blood-pressure may maintain a sufficient circulation in the central nervous system which must be supplied if life is to be maintained at all. Since the blood- supply elsewhere is insufficient, it is obvious that cer- tain organs must suffer injury, one of these being the heart itself. When the heart begins to beat more efficiently the asphyxia is relieved, and the high blood- pressure may return to normal while the patient's condition improves. When the vasomotor control of the pressure is impaired I while the heart supplies an insufficient amount of blood, the blood-pressure is low, and such a condition must result in injury to some of the organs, especially the heart. When the heart-beat is improved in such cases by digitalis, the blood-pressure rises. There is an extensive literature dealing with the constrictor action of the digitalis bodies on the vessels, especially concerning the capacity of certain members of the group to constrict the coronaries. This vas- cular action of the digitalis bodies is not very impor- 220 DRUGS ACTING ON THE HEART tant, but it has given rise to so much misunderstand- ing that it deserves a word of explanation. All digitalis bodies act directly on the blood-vessels with which they are brought in contact in sufficient concentration, causing constriction; hence, when organs are perfused with blood or Ringer's solution containing any digitalis body in sufficient amount, the vessels are constricted, digitoxin being very active, while some other members of the group, notably strophanthin, are much less so relatively to their cardiac activity. It has been supposed that when these digitalis bodies are administered to patients they cause a similar vascular change, but this supposition is based on two erroneous conceptions. The first is that when digitalis is given in therapeutic doses, it enters the circulation in concentration comparable to that used in perfusion experiments, and the second is that the vasoconstrictor action persists for some time. Digitalis has been shown to leave the blood-stream within a few minutes after its intravenous injection — and it acts on the vessels only while it is present in the circulating blood; in the next place it is never present in the blood of patients in the concentration in which it is used in perfusion experiments. From this one may say with a reasonable degree of assur- ance that the digitalis bodies exert no direct vascular action of any importance, and that when they exert any such action it is only through the general improve- ment in the circulation. The diuresis which follows the use of the digitalis bodies is sometimes explained as being due to the constriction of the vessels of the liver and certain other areas, and dilatation of the vessels of the kid- ney. The renal vessels are normal in cardiac dis- ease; if digitalis acted on them then it would affect them in the same way in health, but digitalis does not act as a diuretic in healthy men. Further, if it were capable of causing dilatation of the renal vessels some increase in the secretion of urine would be seen even in those cases in which digitalis failed to improve the condition of the heart; but, as a matter of fact. DIGITALIS GROUP 221 diuresis does not occur when the drug fails to improve the heart-beat and the circulation. There is no evidence whatever that digitalis has any direct action on the kidneys. The diuresis which it induces in patients suffering from dropsy due to the insufficient action of the heart is explained as follows : When the heart fails to pump the blood from the veins into the arteries as rapidly as the veins supply it, certain organs begin to suffer, as previously stated, and water begins to pass from the circulat- ing blood into the tissues in abnormal amounts; in other words, the patient becomes edematous. When digitalis causes an improvement in the action of the heart and in its capacity for removing the blood from the veins into the arteries, the water which previ- ously tended to pass out into the tissues now begins to pass back into the veins, causing hydremia, and hydremia always causes diuresis if the kidneys are capable of secreting urine abundantly. If the kidneys have suffered irreparably from the deficient circulation they may be incapable of secret- ing an additional amount of urine even though digi- talis may cause some improvement in the heart-beat.^* The tardy appearance of the therapeutic effects of digitalis has long constituted one of the serious objec- tions to its use. It has been taught that the delay is due to the slow action of digitalis after it comes in contact with the heart, but this is an erroneous view. Any delay in inducing the therapeutic actions of any of the members of the group in suitable cases must be attributed to the failure to secure the prompt absorption of an effective dose. The intravenous injection of a very large dose of any member of the group causes death by cardiac action within a few minutes, and sometimes within a few seconds, espe- cially when digitoxin is used in excessive amounts, 16. Hydremia, however caused, as by the rapid absorption of water from the gastro-intestinal tract, causes a similar diuresis. The physician may convince himself of this by the simple experiment of drinking several glasses of hot water while avoiding active perspiration, and observing the amount of urine secreted. The experiment should be begun when the stomach is nearly empty. 222 DRUGS ACTING ON THE HEART though digitoxin was formerly supposed to be the slowest to act of -any of the digitalis bodies in com- mon use. The ultimate effects of digitalis action on the heart must be distinguished from the direct action itself. Digitalis is absorbed within the course of a few hours fairly completely, a small part being probably destroyed in the gastric juice ; strophanthus, or stro- phanthin, is absorbed very irregularly after the oral administration. Five times as much strophanthus as would be required by intravenous injection to cause death may be given by the mouth to a cat or dog without causing any perceptible symptoms as a rule, but occasionally rapid absorption and death will occur from such doses. A patient received six doses of strophanthus by the mouth in twenty-four hours without showing any effect that could be detected by the most careful observation with frequent pulse- tracings, but the seventh dose of the same amount as the previous ones was followed promptly by alarming symptoms of toxic action which continued for several days before improvement began. These experiences both in the laboratory and in the hospital show that strophanthus and strophanthin are wholly unsuited for oral administration. Digitalis and its galenical preparations and digitoxin are the most absorbable of the digitalis bodies known. CUMULATION, SO CALLED When any digitalis body is given in repeated doses, toxic S3rmptoms may appear rather suddenly, and these have been commonly attributed to cumulative action, so called, which has been looked on as a more or less mysterious property of the drugs which exhibit it. This so-called j:umulation is nothing but the accumulated effects of several doses. The fol- lowing will illustrate the action: A cat received 75 per cent, of the fatal dose of digitalis intravenously at one dose; a week later it received 50 per cent, of a normally fatal dose (or two-thirds as much as it had received a week previously), and succumbed promptly, the reason being that at least 50 per cent, of a fatal dose remained in the heart, or that the action DIGITALIS GROUP 223 of that much remained in effect, and when 50 per cent, of the usually fatal dose was given its effects were added to those already present and the heart was brought to a standstill. A similar summation of effect results when several therapeutic doses are administered to man, and a given symptom appears when the added effects suffice to produce the symptom. Laboratory experiments show that the effects of a single very large dose of digitalis or digitoxin may persist in part for two weeks or more, and clinical tests have shown that the effects of full therapeutic doses of digitalis may not completely disappear for ten days or more. The effects of strophanthin dis- appear much more rapidly, usually within from thirty-six to forty-eight hours. Little is known concerning the fate of the digitalis bodies in the human body, but the persistence of the action on the heart and central nervous system sug- gests that some of them at least are destroyed or eliminated slowly. It is important to note, however, that they leave the blood-stream of all animals hitherto examined within a few minutes after intravenous injection, and they also appear to act on the blood- vessels only while they are present in the blood- stream. STANDARDIZATION We have no satisfactory means of standardizing the digitalis bodies; there is no chemical test for deter- mining the amounts of the various pure principles present, and none of the biologic tests is free from objection. The forthcoming Pharmacopeia will probably direct the standardization of digitalis bodies by means of the frog test, which consists in determining the amount required to cause the frog's heart to stop with the ventricle in systole in one hour. This test has the disadvantage of not affording a comparison of the therapeutic activities of such different members of the group as strophanthus and digitalis ; for example, the amount of digitalis required to kill a frog of given weight by this method will have far greater tfiera- 224 DRUGS ACTING ON THE HEART peutic activity than the strophanthus required to kill a frog of the same size. Guinea-pigs are preferred by some for standard- izing these drugs, and the determination of the fatal dose by intravenous injection in cats has been sug- gested as affording a fairly satisfactory means of comparing the therapeutic activity of all digitalis bodies. STABILITY It has been generally taught that digitalis leaves and all of the galenical preparations of digitalis deterior- ate rapidly despite any amount of care in preserving them. This appears to be one of the numerous errors in vogue regarding this drug, for digitalis leaves cer- tainly retain their activity for many years with little loss, and the tincture also keeps extremely -wsH if made with 70 per cent, alcohol. The infusion some- times deteriorates rapidly, despite the addition of a small amount of alcohol, and it should not be kept for more than a week in warm weather. Recent experiments have shown that an infusion of digitalis made without alcohol, filtered and bottled while hot, can be kept unopened in a warm room for several weeks with little loss of activity. The belief in the instability of digitalis and its official prepara- tions has been fostered by those who exploit proprie- tary preparations of the drug with claims of greater activity and uniformity of action. The loss of activity in digitalis preparations, such as the tincture, appears to proceed slowly for a cer- tain length of time, and then to cease; it is probably due to the instability of some principle which is pres- ent only in small amount. This is not a serious objection, since one can use a little more of a tincture which has become weaker; and it is quite possible that the unstable body is responsible for a greater pro- portion of the side actions which all digitalis bodies exert, than of the therapeutic effects. Unfortunately, no one appears to have investigated the subject. Among the curious misconceptions in vogue con- cerning digitalis is the belief that the tincture and the infusion have different therapeutic properties. The tincture represents the leaf fully, and so does the DIGITALIS GROUP 225 infusion when it is made properly — which, however, is not always the case. As a matter of fact, the use of the infusion of digitalis should be abandoned, since the tincture serves every purpose that the infusion does, and has the advantage of being more nearly uniform in activity, more stable, less expensive and requiring a smaller bulk for each dose. THERAPEUTIC USES There are few drugs which have more sharply defined uses than the digitalis bodies. They are indi- cated in all cases in which the tonicity of the heart is impaired, and while loss of tonicity is either the cause or the result of a large proportion of the symp- toms observed in cardiac disease of long standing, there are stages of cardiac disease in which digitalis does harm. It probably finds its greatest field of usefulness in those cases of cardiac insufficiency which are induced by auricular fibrillation, and in acute dilatation, though it may cause improvement in chronic dilatation also. It is not necessary to discuss the various symptoms which result directly and indirectly from impairment of the circulation, for serious impairment of the heart is usually attended with symptoms which direct atten- tion to the heart at the time that digitalis is needed, and whatever the symptom which the patient com- plains of, whether it be difficulty in breathing, swell- ing of the legs or an unpleasant feeling in the region of the heart, the use of digitalis is based ultimately on its capacity for improving the heart's tonicity directly and indirectly through its causing heart-block and slowing with improved nutrition and added rest with recuperation of the heart. Digitalis is sometimes used in the treatment of tachycardias which are not attended with auricular fibrillation, but it is seldom of benefit in paroxysmal tachycardia, especially in those cases in which the impulses arise in the ventricle, and when used in that condition its action must be watched carefully, and its administration discontinued when full therapeutic doses fail to cause improvement. 226 DRUGS ACTING ON THE HEART Heart-block has been mentioned as one of the eifects of digitalis, and it might be supposed that this condition, when present, constitutes a contra-indica- tion to the use of digitalis; but it is neither an indi- cation nor a contra-indication for the drug. If a want of tonicity attends heart-block, digitalis may be used, even though it may convert a partial into a complete block. Acute dilatation with its threat of impending death sometimes affords an opportunity for results that are positively brilliant, for occasionally such a patient will show marked improvement within a few minutes after the intramuscular or intravenous injection of stro- phanthin, and he may be restored to comparative com- fort within a few hours. Auricular flutter is a condition attended with an extremely rapid beat of the auricles and usually of the ventricles; digitalis converts this condition into one of auricular fibrillation, and at the same time heart-block is induced with the result that the ven- tricle is made to beat more slowly, in the manner already described. In some cases the ventricle is made to beat regularly and more slowly without heart-block apparently. Digitalis bodies are contra-indicated in sinus arrhyth- mias, which are characterized by an irregularity of the whole heart, due to some abnormal condition in the sinus region. It will be observed that nothing has been said in regard to the various valvular lesions as indications or contra-indications for the use of digitalis. This is because a valvular lesion alone is neither an indica- tion nor a contra-indication for the drug. Various valvular lesions are found complicating other cardiac conditions, but so long as the heart maintains an ade- quate circulation it does not require digitalis what- ever the lesion, and when it begins to fail owing to a want of tonicity it demands digitalis no matter what valvular lesion may exist, even aortic regurgitation being no bar to its use when loss of tonicity prevents it from maintaining an adequate circulation. The most diverse views are held regarding the use of digitalis in pneumonia, diphtheria and other infec- DIGITALIS GROUP 227 tious diseases. There can be no question that the tonicity of the heart is frequently impaired in such conditions, but it is obvious that digitalis has no direct action on the toxins which cause the injury to the heart. There is no reason to anticipate such excellent results from its use in these conditions as in auricular fibrillation, in which it removes the immediate cause of injury to the ventricle, and in acute dilatation, in which it inaugurates a cycle of improvement. DOSAGE Examination of various posologic tables inclines one to think that this question is in a confused state because of the great differences in the amounts of digitalis bodies advised by various authorities. The reason for these differences is not far to seek. Digi- talis is given for a definite action, and it is given until that action is induced, or until the appearance of toxic symptoms indicates that the limits of safe dosage have been approached. Patients vary rather widely in the amounts required to produce a given effect, dependent somewhat on the way the drug is given. The single dose of digitalis leaf is given as 0.065 gm. (1 grain), while that of the tincture is 1 c.c. (15 minims), which represents 0.1 gm. (1.5 grains) of the leaf. This inconsistency probably arises from a mistaken idea that the tincture does not represent the full activities of the leaf. The dose of the infusion is given as 8 c.c. (2 fluidrams), which corresponds closely with the dose of the tincture, but there is more ground for the belief that the infusion does not always represent the leaf fully. It seems certain that we must sooner or later revise our methods of administering digitalis and its prepara- tions.* An adult who has not had any previous medi- cation will usually require a total of about 1 to 2 gm. (15 to 30 grains) of digitalis of good average quality, or the equivalent of the tincture — from 10 to 20 c.c. (from 2.5 to 5 fluidrams) — ^to produce the full therapeutic effects. Nevertheless we do not advocate such single doses as 10 c.c. (2.5 fluidrams) of the tincture. * See EuKleston, Arch. Int. Med.. July. 1915. 228 DRUGS ACTING ON THE HEART No one should administer any dose of digitalis with- out observing the effects carefully, and stopping the administration or diminishing the dose when the therapeutic effects are induced, or when toxic symp- toms indicate that the limits of therapeutic dosage are being approached. The following effects are to be especially noted as indicative of digitalis action, and as signs for diminishing the dose or discontinuing it altogether. Slowing is fairly common, but it is not an invariable result, and disaster has resulted from persisting in the administration of digitalis because the rate failed to show the influence expected of the drug, for the rate may become more rapid with other toxic symp- toms without preliminary slowing. When the auricles are fibrillating, the rate at the apex and that of the wrist-pulse should be deter- mined; the difference, known as the "pulse deficit," indicates the number of beats which are too feeble to be felt at the wrist, and in general denotes the rela- tive efficiency of the heart. With improvement in the force of the heart-beat a larger proportion of the apex-beats can be felt at the wrist, so that the pulse deficit decreases, and the wrist-pulse may actually increase in rate, while the apex-beats diminish as the heart's condition improves with digitalis action. When all beats are felt at the wrist the maximum digitalis action is approached or reached. One should never make the mistake of counting the wrist-pulse alone in such cases. Partial or complete heart-block is a fairly com- mon symptom of digitalis action; coupled rhythm, or bigeminal pulse, during digitalis medication calls for its immediate discontinuance. The substitution of a regular rhythm for an irregular one also indicates therapeutic action. While these signs of digitalis action are commonly attended with improvement in the patient's condition, some of them, the coupled beat, for example, may be observed even while the patient grows worse. The clinical symptoms alone cannot be depended on to show the limits of dosage. DIGITALIS GROUP 229 The following clinical signs of improvement are valuable as showing that enough digitalis has been given, or that the dosage may be reduced: improve- ment in breathing (a patient who has been forced to sit up and who breathes with difficulty begins to breathe more easily and is able to sleep while lying down, while the cyanosis diminishes) ; marked increase in the amount of urine secreted while the intake of water is limited, and a simultaneous dis- appearance of edema; the diminution or disappear- ance of epigastric pain, and especially of tenderness and pain along the margin of the liver ; the disappear- ance of nausea and vomiting. The latter symptom calls for a word of discussion because it is frequently misunderstood. Venous congestion due to cardiac insufficiency is commonly attended with gastric disturbances, includ- ing indigestion, nausea and vomiting, and since one comes under treatment as his symptoms grow worse, it often happens that nausea and vomiting begin or are accentuated very soon after beginning digitalis medication, and they are then commonly attributed to the local action of the digitalis. It must be empha- sized that digitalis has no such local action on the stomach in doses which are used therapeutically. If the administration is continued the nausea and vomit- ing will frequently stop with the appearance of other signs of improvement. One must therefore not take nausea and vomiting as a sign of the full digitalis action in the absence of the other signs mentioned above when it occurs early in the administration. The following applies only to patients who have not had medication with any digitalis body during the previous two weeks: One who suffers from cardiac insufficiency attended with auricular fibrillation may take 5 c.c. (1^4: fluidrams) of a standard tincture of digitalis by the mouth «t the first dose, and 1 c.c. (15 minims) every four hours thereafter until some signs of digitalis action are obtained. The patient must be watched carefully and the medication be discontinued at once when the therapeutic effects appear. This will serve 230 DRUGS ACTING ON THE HEART to induce the therapeutic efifects in suitable cases within from twelve to twenty-four hours. Strophanthin is suited only for deep intramuscular or intravenous injection, but it is especially useful where immediate action is essential, as in acute cardiac dila- tation. The single and daily intravenous or intramus- cular dose is from 0.5 to 1 mg. (%20 to %o grain), preferably in 4,000 parts of normal salt solution, as concentrated solutions may cause considerable pain. Crystalline ouabain (so-called crystalline strophan- thin) acts like strophanthin, over which it has the advantage of greater purity and uniformity of action. The intramuscular or intravenous dose of crystalline ouabain is 0.5 mg. (/420 grain) ; otherwise it is used like strophanthin. Both are now sold in ampules containing sterile solutions. Neither strophanthin nor crystalline ouabain should be injected subcutaneously because such injections give rise to severe pain. We believe that strophanthus and the tincture are unsuited for oral administration, for the reasons already given. The tincture may be given intramus- cularly when strophanthin is not available, but the intramuscular dose of the tincture must be carefully regulated, for a single dose of 2 minims has caused death in a patient who had previously taken digitalis. It must be borne in mind that all digitalis bodies are strictly synergistic, so that half a dose of each of any two digitalis bodies constitutes a full dose. The single or daily intramuscular dose of tincture of strophanthus is about 0.1 gm. (1^^ minims), which should be well diluted with normal salt solution. This dose should not be repeated within twenty-four hours. Even this dose would be dangerous immediately after other digitalis medication. The dose of true digitalin has never been deter- mined, but it is too expensive for general therapeutic use; digitalein is not obtainable in pure form; conse- quently its activity is too variable to justify its thera- peutic use. Digitoxin is somewhat less variable in activity, but the physical difficulties in the way of its use interfere with its intravenous and intramuscular DIGITALIS GROUP 231 injection ; it can be dissolved in alcohol or made into pills or tablets and used by the mouth. The dose is about 1 mg. (%5 grain), and 0.5 mg. (%25 grain) may be given thereafter at intervals of four hours, provided the patient is watched carefully for the signs of digitalis action, and the administration discontinued when these are observed. It is an extremely danger- ous drug in the hands of those who are not skilled in the treatment of cardiac disease. The action of digi- toxin is very persistent. MATERIA MEDICA Digitalis. — Digitalis, U. S. P. The dried leaves of Digitalis purpurea, collected from plants of the second year's growth at the commencement of flowering. European pharmacopeias generally direct that digi- talis leaves be thoroughly dried and carefully pre- served from moisture and light. The powdered leaf represents the drug fully and is frequently administered in the form of pills, gelatin capsules or cachets. The chemistry of digitalis is still imperfectly known. A number of so-called active principles have been isolated and several are now available in a commercial way. These include: true digitalin, digitalein and digitoxin. The products marketed as digitalin vary widely in composition and are sometimes differenti- ated by the designations "true," "German" and "French." The German digitalin is the preparation usually found on the market and is ordinarily dis- pensed when digitalin is prescribed. This preparation is a mixture of several glucosids, and its composition varies according to the method by which it is pre- pared. The more widely used and more reliable of the commercially available digitalis principles are described in N. N. R. Physicians who use these preparations should assure themselves of their nature and identity. Digitalis is used principally in the form of: Tinctura Digitalis. — ^Tincture of Digitalis, U. S. P. One hundred c.c. of the tincture represent 10 gm. of digitalis in diluted alcohol. 232 DRUGS ACTING ON THE HEART Infusum Digitalis. — Infusion of Digitalis, U. S. P. One hundred c.c. of the infusion represent 1.5 gm. of digitalis, with 10 per cent, of alcohol added as a pre- servative. Infusion of digitalis prepared recently from powdered leaves (not the bruised), but other- wise according to the pharmacopeial directions, rep- resents the full activities of the leaf. Strophanthus. — Strophanthus, U. S. P. The ripe seed of Strophanthus Kombe, deprived of its long awn. The seed of different species of strophanthus have long been used in Africa for the preparation of arrow poisons, but the drug and specimens of the prepared poison were first brought to Europe about 1860, and the seed used for the preparation of stro- phanthin about 1865. The testimony concerning the therapeutic value of strophanthus has been conflicting, owing to the fact that it has been administered orally in nearly all cases, and its absorption is so variable. There is no question of the value of strophanthin when it is administered intravenously or intramuscularly in suitable cases. Tinctura Strophanthi. — Tincture of Strophanthus, U. S. P. One hundred c.c. of this preparation rep- resent 10 gm. of strophanthus in approximately 65 per cent, alcohol. Strophanthinum. — Strophanthin, U. S. P. A glu- cosid or mixture of glucosids obtained from stro- phanthus. Strophanthin occurs as a white, or faintly yellowish, powder having an intensely bitter taste. Because of its toxicity great caution should be used in tasting it. It is very soluble in water and in diluted alcohol but less soluble in absolute alcohol. Some of the unofficial varieties of strophanthus, notably Strophanthus gratus, contain glucosids that are more active than is the glucosid from the official variety of the drug. Gratus strophanthin, or, as it is sometimes called, crystallized strophanthin, is iden- tical with ouabain, a glucosid obtained from Acocan- thera ouabaio. While its pharmacologic action is con- sidered to be qualitatively identical with that of the official strophanthin, it is more active and should therefore not be confused with the official drug. An PROPRIETARY PREPARATIONS OF DIGITALIS 233 effort is being made to popularize the use of the name "ouabain" in literature in place of the various titles or synonyms that have been proposed, and physicians generally should lend their aid to this effort. The possible mistaking of "g-strophanthin," or of crystal- lized strophanthin for the official strophanthin might readily prove serious. PROPRIETARY PREPARATIONS The well-known disadvantages of all the digitalis bodies, especially their variability and their tendency to cause nausea and vomiting, have led to the intro- duction of numerous proprietary preparations, nearly all of which have been exploited with extravagant praise. Digalen is claimed to be a solution of amorphous digitoxin, but no such substance as amorphous digi- toxin is known to science, and several investigators have submitted evidence that digalen is either a solu- tion of impure digitalein or of another substance with actions similar to it.* It is sometimes claimed that the defatted tincture of digitalis is less actively emetic than the official tinc- ture. The therapeutic dose of the official tincture of digitalis contains about 6 mg. (%o grain) or less of the fat — not enough to account for the emetic action ; hence if a defatted tincture is less actively emetic than the official. It must be because it is a weaker preparation, containing less of the active principles of digitalis. Digipuratum is an extract of digitalis from which inert matter has been removed and sugar of milk added to make it of the same degree of activity as the leaf. It was formerly claimed to be less actively emetic than the official leaf, but the claim is not sub- stantiated by the results of pharmacologic experi- ments. It is many times more costly than the official leaf. Digipoten is much like digipuratum. Cumulation, so called, or persistence of action, is an inherent property of every digitalis body. Every * See Report of the Council on Pharmacy and Chemistry, Jour. Am, Med. Assn., Sept. 5, 1914, p. 881. 234 DRUGS ACTING ON THE HEART digitalis body causes nausea and vomiting in over- doses, and no proprietary substitute has as yet been offered which is less nauseant in proportion to its therapeutic activity than digitalis. In some cases persistence of action is a decided advantage in that, when once the action on the heart is induced, it obviates the necessity of further medi- cation while the heart continues to improve. The physician who uses digitalis leaf or tincture of good quality — and there is no difficulty in getting these of good quality — can have the satisfaction of knowing that with these he can accomplish all that can be accomplished with any digitalis preparation whether it be official or proprietary, except in those infrequent cases in which intramuscular or intrave- nous injections are required to avoid loss of time, and in such cases the official strophanthin or cystalline ouabain may be used. CAFFEIN AND CAMPHOR The pharmacologic actions of caffein and camphor have been discussed and attention has been called to the fact that we have no satisfactory explanation to offer for their use in cardiac disease. Caffein may increase the tonicity of the heart, but it is practically impossible to regulate the dosage so that the action will be limited to that which is desired. It seems probable that any value which it may have in improving the circulation is due to its stimulation of the vagus, whereby the pulse-rate is slowed, and to its stimulation of the vasomotor centers, causing a rise of blood-pressure with the consequent improved nutrition of the heart. It does not cause heart-block, which plays such an important role in the effects of digitalis in auricular fibrillation, but it may be of value in certain cases of acute cardiac dilatation, by reason of its action on the musculature. The diuretic action of caffein results in the removal of a larger proportion of water than of salts from the circulation, and this facilitates the reabsorption of fluid from edematous tissues; hence caffein is useful PROPRIETARY PREPARATIONS OF DIGITALIS 235 as an auxiliary to the digitalis bodies in dropsical con- ditions ; but it should be used with" caution, for caifein and the digitalis bodies have synergistic actions on the heart. Camphor stimulates the medullary centers, and it is possible that its beneficial action in cardiac disease is due to the stimulation of the vagus and the vaso- motor centers. While we are unable to state the exact dose of camphor which is suitable for use in these conditions, it is probable that much larger doses than those com- monly advised will be needed, probably not less than 0.5 to 1.0 gm. (8 to 15 grains). We would again call attention to the inadvisability of using caffein intravenously, even in urgent cases of cardiac disease, and to the advisability of injecting small doses very slowly, if it is so used. CHAPTER VII.— CIRCULATORY DE- PRESSANTS, DIURETICS AND DIAPHORETICS CIRCULATORY DEPRESSANTS It is well known that, though the blood-pressure undergoes frequent minor changes, it is under the con- trol of a coordinated mechanism which tends to main- tain a close approximation to a certain level from day to d^ during health. Even after the administration of drugs which affect the distribution of the blood, any considerable change in blood-pressure is usually only fleeting. When the vessels of the splanchnic region are constricted, those of the periphery usually undergo a compensating dilatation; if the constriction of the splanchnic vessels is sufficient to cause a rise of blood- pressure, the heart is commonly slowed, so that the pressure in the large arteries tends strongly to remain constant. The blood-pressure may be lowered by diminishing the amount of blood in the circulation ; by dilating the vessels, or by diminishing the activity of the heart by decreasing either its force or its rate. Venesection, or bleeding, was formerly employed widely, but this has fortunately fallen largely into dis- use.* Drastic cathartics were also used at one time somewhat more freely than at present; diaphoretics and diuretics remove liquid too slowly to be satisfac- tory in those emergencies in which vasodilators are commonly used. The blood tends strongly to maintain a uniform concentration, and when much fluid is removed by diuretics or diaphoretics this is largely replaced in the circulating blood by fluid drawn from the tissues. * It is possible that the future development of the process of "vividiflfusion" recently described by Abel and his associates may lead to a modified form of bleeding in therapeutics. THE NITRITES 237 There is an even greater tendency on the part of the vasomotor mechanism to compensate for changes induced in the vessels of different areas, and the vaso- dilators often exert only an inconspicuous and brief influence on the general blood-pressure. The rate of the heart-beat is influenced by many factors which tend to regulate it according to the demands of the circulation. Consequently, the heart often responds to the systemic actions of drugs in a manner directly opposite to that which would result from the action on the heart alone. VASODILATORS: THE NITRITES Therapeutic doses of many drugs cause dilatation of the vessels of certain areas, and many cause general vasodilatation when toxic doses are given. Attention has been called to the dilator action of the antipyretics on the vessels of the skin whereby they promote sweating and the elimination of heat. They are not used to lower the general blood-pressure, how- ever, even though this does result from their collapse action. Alcohol also causes dilatation of the peripheral ves- sels even with small doses, and it was used formerly to lower blood-pressure. Toxic doses of hydrated chloral cause a marked vascular dilatation, and it is commonly stated or implied that therapeutic doses also lower the blood-pressure. Any such action, however, is commonly incidental to its narcotic effect and not due to its vasodilator action, which is unimportant except with toxic doses. Guthrie is credited with having been the first to observe the effects of the nitrites in causing flushing of the face. Lauder Brunton is chiefly responsible for their introduction into therapeutics about 1867, after he had observed the effects of amyl nitrite on a patient who suffered from anginal attacks. Tracings of the pulse taken by him after the admin- istration of amyl nitrite during one of these attacks do not show any essential difference from tracings of the normal pulse, the amyl nitrite having overcome the vasoconstriction which accompanied the attacks. 238 CIRCULATORY DEPRESSANTS The actions of the several nitrites, including amyl nitrite, glyceryl nitrate or nitroglycerin, which acts as a nitrite, and sodium nitrite, are qualitatively quite similar, though they differ somewhat in duration. The nitrites have little direct action on the higher parts of the brain, except for the dilatation of the cerebral arteries. This is attended with a sense of fulness in the head and diziness, with some disturbance of the special senses, and often with headache. The effects on the medullary centers are direct and indirect, but it is not easy to determine which of these is the more important in some cases. The vasomotor centers are certainly depressed after the administration of small doses of the nitrites, but this depression is probably not alone responsible for the vasodilatation which results, especially after large doses. The vessels of the face and neck — the so-called blush area — are affected first, and the vessels of the skin of the upper part of the body in general appear to dilate before the splanchnics, but these also participate in the effects of therapeutic doses. There has been a good deal of discussion concerning the seat of the dilator action of the nitrites, and some authors attribute the effect almost entirely to the action on the musculature in the vessel walls, while others consider this wholly secondary and attribute the effect mainly to the depression of the vasomotor centers. The question is of more than purely theoretic importance, because it is frequently stated that the nitrites have an especial action on the coronaries. It seems probable that they have no specific action on the coronaries, but that the benefit which they confer in conditions attended with high blood-pressure is due mainly to the relief of an overburdened heart by diminishing the resistance. Attention has already been called to the physiologic necessity for the coronaries to respond to increased cardiac action with dilatation when other arteries are constricted, from which it is evident that they do not behave toward all agents in the same way that other arteries do. It is uncertain whether the nitrites have any impor- tant direct action on the other medullary centers, THE NITRITES 239 though the functions controlled by these centers show active changes. It is sometimes stated that the vagus is depressed, leading to an increase in the heart-rate. The heart, however, responds normally to lowered blood-pressure by an increase in the rate of the beat." and it is not probable that vagus depression is due largely to the direct action of the nitrites. At any rate, it is important to remember that the heart is not injured by therapeutic doses of the nitrites, since these are used in precisely those conditions in which the heart suffers from overexertion. After the administration of amyl nitrite the respira- tory center behaves as it does during fall of blood- pressure from other causes, that is, it responds to the stimulation of carbon dioxid (or lack of oxygen), and increased respiration results. There is no reason to suppose that the nitrites stimulate the center directly. The text-books state that enormous doses of the nitrites result in the formation of methemoglobin. This does not occur, however, with doses such as are used therapeutically ; it is of no interest to the clinician, except in possible cases of poisoning. Other smooth muscle beside that of the arterioles is depressed by the nitrites, and spasm of the bronchial muscles is said to be relieved by the fumes from the burning of potassium nitrate mixtures, which contain nitrites. Hirschfelder has recently observed that the nitrites relieve intense intestinal peristalsis induced experi- mentally by the administration of lead and he main- tains that since colic is associated with peristalsis and spasm the relief afforded by the nitrites in lead colic, tabetic crises and angina abdominis is due to their inhibition of intestinal movement rather than to any vasodilator effect. The nitrites cause venous dilatation, and this prob- ably contributes somewhat to the fall of blood-pres- sure, by providing reservoirs for the blood. 17. The tone of the vagus depends to a great extent on tlie blood- pressure in the medulla, and when this falls, the lowered vagus tone permits of acceleration through the action of the accelerator center. The delicacy of this regulating mechanism in the dog is such that it is extremely difficult at times to cause a notable fall in the blood- pressure by administering amyl nitrite to that animal, the heart becom- ing much faster with a slight fall. The rabbit lacks this delicate control and amyl nitrite causes a prompt fall of the blood-pressure. 240 CIRCULATORY DEPRESSANTS The nitrites are oxidized in the body and appear in the urine chiefly as nitrates. In addition to the effects of nitrites which have been discussed, other secondary effects will be observed at times,^* but these are inconstant, and are to be explained by the differences in the distribution of the blood which are seen at different times. If the renal vessels are dilated to a disprolportionately greater extent than those of the general circulation, there may be an increased secretion of urine, but diuresis in such cases is not to be attributed to any direct action of the nitrites on the kidneys. ACONITE The actions of aconite are those of its principal alka- loid, aconitin, but tincture of aconite is used much more frequently than the alkaloid, because of the diffi- culty of obtaining aconitin of constant activity, and because of the inconvenience involved in the use of a drug of such extraordinary potency. The actions of aconitin on the central nervous sys- tem are difficult of analysis, but these consist of stimu- lation and subsequent depression. The heat-regulating center (if we may refer to the coordinating mechanism as a center) seems to be influ- enced by aconitin in the same way in which it is by the antipyretics, and aconite has a distinctly antipyretic action. The vagus center is stimulated, and Cushny states that aconitin affords one of the best means of obtain- ing pure slowing of the heart. Fatal doses affect the heart partly through the vagus, and it is stated that larger doses of aconitin are survived if atropin be given than without it. 18. The question has been raised frequently whether the small amounts of nitrites present in flour bleached by the several processes in common use are injurious to health and whether flour bleached in this way is less digestible than unbleached. There is no evidence that minute amounts of nitrites are injurious, and it cannot be said that the flour so bleached is less digestible than the unbleached, but on the other hand, we are unable to say that small amounts of the nitrites continued over long periods are without deleterious influence on the health, and there still remains the larger subject on which there can be no discussion, that bleaching is often employed for fraudulent pur- poses. ACONITE 241 Aconitin stimulates the respiratory center, but this shows a strong tendency to become depressed, and death from aconitin frequently results from paralysis of the respiratory center. So great is the tendency of aconitin to cause depression that it cannot be used therapeutically as a respiratory stimulant. Vomiting often occurs late in the state of poisoning, this being due to stimulation of the vomiting center (unpublished experiments). The direct action on the vasomotor centers does not appear to be constant, and there may be either reflex stimulation or depression, but there seems to be some evidence that vasodilatation is the more common effect of aconitin action. The effect of aconitin on the heart is due to vagus and accelerator stimulation and to the direct action on the heart itself. There is apparently a brief period during which the heart beats more energetically because of accelerator stimulation, but this is unim- portant, and with the slowing from vagus stimulation there is no corresponding increase in the strength of the contractions, so that less blood is expelled from the heart in a unit of time, and in consequence the blood-pressure falls. With severe poisoning from aconitin the heart becomes very irregular; in fact, various forms of irregularity are seen in the exposed heart of an animal poisoned with it, the heart finally stopping in diastole. It is more than possible that aconitin causes a fall of blood-pressure through its combined actions on the cardiac muscle, the vagus center and the vasomotor centers. Aconitin causes tingling when applied to the tongue or to the skin in such a way that it penetrates to the sensory nerves, and when large doses have been taken this tingling is manifested in the same way as after local application. It is one of the most typical symp- toms of aconite poisoning, and usually serves to call the patient's attention to something being amiss in such cases. Aconite was formerly administered therapeutically to the point of commencing tingling in the fingers. The sensory stimulation is followed by anesthesia, but this 242 CIRCULATORY DEPRESSANTS action is much less pronounced with aconitin than with cocain, or even than with atropin, to both of which aconitin is closely related chemically. Aconitin is absorbed rapidly from the alimentary canal, and, to some extent, from the unbroken skin when applied in the form of an oleate or liniment. Poisoning by aconite is not rare, but less frequent perhaps than formerly, when the drug was widely used for a great variety of complaints. Absorption takes place so rapidly that there is usually little time for treatment after a fatal dose has been swallowed. Tingling and irritation of the mouth and throat are observed soon after the poison has been taken. This is due to the local action, and soon after the poison is absorbed the tingling is felt in the finger- tips, and later over a large part of the body. Nausea, vomiting and diarrhea may occur. The respiration suffers severely as well as the circulation, and death probably results from a combination of the actions on the heart and the respiration. Of course, any poison remaining unabsorbed should be removed from the stomach by washing; atropin is said to be antidotal, but it is probably of limited value in most cases, and artificial respiration would be pre- ferable to the atropin action on the respiratory center. A single dose of 1 mg. (%o grain) of atropin may be given, and repeated once if it causes improvement in the respiration or if it fails to abolish the vagus influ- ence on the heart. The patient Is kept as quiet as possible, and heat is applied to the body. Tincture of aconite probably undergoes deteriora- tion when kept long, and dogs sometimes withstand enormous doses even when these are injected intra- venously. It is probable that the fatal dose of pure aconitin for a man is only a few milligrams. THERAPEUTIC USES The nitrites are used, as already indicated, for reducing blood-pressure. Amyl nitrite finds its espe- cial field of usefulness in giving relief in attacks of angina pectoris, in which it is often supposed to USE OF NITRITES AND ACONITE 243 abolish spasm of the coronary arteries. It seems much more probable that amyl nitrite relieves this distressing and even terrifying condition by abolishing the exces- sive resistance against which the heart contracts. It may be used to relieve any pain which is due to arterial spasm, to prevent or relieve epileptic convul- sions, in bronchial asthma, and in lead colic. Amyl nitrite is sometimes used to stop hemorrhage when this results from the rupture of a vessel in the lungs, brain or elsewhere through very high blood- pressure, but it is apt to do harm if the hemorrhage has progressed to a point where the general arterial pressure is already low. Owing to the brevity of its action it is unsuited to those conditions in which a prolonged effect is necessary. Nitroglycerin is used much like amyl nitrite, but its action is not induced instantaneously as that of amyl nitrite is, and it is therefore employed where a slower and somewhat more lasting action is desired, as in the high blood-pressure of arteriosclerosis and of neph- ritis, as well as between the attacks of angina pectoris. It is sometimes used with digitalis with a view to overcoming the reputed vasoconstrictor action of the latter. It has been brought out in the discussion of digitalis actions that this direct vasoconstrictor action is negligible, and that digitalis may actually cause a fall of blood-pressure when this was previously abnor- mally high. It is probable that nitroglycerin is seldom of any benefit in influencing the action of digitalis. Sodium nitrite is used for exactly the same purposes as nitroglycerin, and it probably has no advantages over the latter. Er3rthrol tetranitrate (for description see New and Nonofficial Remedies) is used for the same purposes as nitroglycerin, over which it has the advantage of exerting a more prolonged action. It is very expen- sive, and is said to be even more prone than nitro- glycerin to cause severe headache. The vasodilator actions of alcohol have been referred to; spirit of nitrous ether has a feeble vaso- 244 CIRCULATORY DEPRESSANTS dilator action, and is used to promote diuresis and diaphoresis. In some cases the splanchnic vessels appear to be incapable of dilating in response to the action of the nitrites, and in such cases the slight fall in the blood- pressure, and probably some direct depression in the vagus center, result in such an increase in the heart- rate that the fall is converted into a temporary rise of pressure. Aconite is used occasionally as an antipyretic and diaphoretic in fever patients of sthenic type, or early in other febrile conditions — not late during protracted fevers, such as typhoid. It may be used cautiously when it is desired to reduce the blood-pressure, if the heart is in good condition. There is little scientific basis for its continued internal use in therapeutics. It is used externally in the form of liniments and ointments for the relief of neuralgias. Absorption may occur from the unbroken skin, and it should be used only with caution. It should not be applied to mucous membranes, from which it is absorbed promptly. Veratrum viride is sometimes used for the reduction of the extremely high blood-pressure often seen in eclampsia. While good results have been reported in some cases, the action of the drug is not sufficiently understood to justify its use in general practice, and there is little reason to doubt that it sometimes pre- cipitates a catastrophe in this dangerous condition. Veratrum viride is not recognized in "Useful Drugs," nor is it recommended here. It probably owes any popularity which it has to its former exploitation as a proprietary preparation under the name of "Nor- wood's Tincture." DOSAGE Amyl nitrite is commonly used in the form of glass capsules, or "pearls" containing from 0.2 to 0.3 c.c. (3 to 5 minims). These are carried about by the patient, and at the approach of an attack one of the "pearls" is broken in the handkerchief and the con- DOSAGE OF NITRITES AND ACONITE 24S tents inhaled. It is said that amyl nitrite causes less headache when inhaled through the mouth than when inhaled through the nose. Amyl nitrite is sometimes sold in sealed glass con- tainers holding about 25 gm. (1 fluidounce).^® These tubes should never be grasped in the bare hand. Before being opened they should be cooled, and wrapped in several folds of a towel loosely ; the oper- ator, when filing the neck, should point the tube away from his face. Nitroglycerin being explosive, is commonly used in the form of the spirit or in tablets. The average dose of spirit of nitroglycerin is 0.05 c.c. (1 minim), which is to be repeated several times daily when it is desired to maintain the effect. It gradually loses its capacity for lowering the blood-pressure, owing to the develop- ment of habituation, and the intensity of the headache which it frequently causes is a great disadvantage in its use. Spirit of nitrous ether, popularly used as a diuretic, has, to a limited extent, the vasodilator action of other nitrites, but is now seldom used. The average dose is 2 c.c. (30 minims). The dose of sodium nitrite is about 0.05 gm. (1 grain) repeated several times daily. It is always administered in solution, but it is prone to undergo oxidation with the formation of the nitrate; hence only enough of the solution should be prepared to last a short time. Aconite is almost invariably administered in the form of the tincture, of which the dose is 0.2 c.c. (3 minims) repeated every hour until the desired effect is produced, or until its uselessness for that case is demonstrated. Smaller doses may be given with corre- spondingly greater frequency. 19. The following experience may be of interest: The neck of one of these tubes was filed with the intention of opening it, when it exploded violently; a second tube was cooled in a freezing mixture of salt and ice, and the neck then filed; there was a severe explosion; several tubes were then opened after wrapping them in towels, but in every case explosions of extreme violence resulted. The makers are well-known chemists, but they have been unable to explain the extreme violence with which these tubes exploded. 246 CIRCULATORY DEPRESSANTS MATERIA MEDICA Amylis Niiris. — Amyl Nitrite, U. S. P. A volatile and inflammable liquid consisting chiefly of isoamyl nitrite. It should be kept in hermetically sealed glass bulbs, or "pearls," or in dark amber- colored glass-stoppered vials in a cool and dark place. Amyl nitrite occurs as a clear yellowish liquid, of a peculiar ethereal, fruity odor, and a pungent aro- matic taste. It is never given internally by mouth, but is administered by inhalation. Spiritus Glycerylis Nitratis. — Spirit of Glyceryl Trinitrate, U. S. P. — Spirit of Nitroglycerin. — Spirit of Glonoin. An alcoholic solution containing 1 per cent, by weight of glyceryl trinitrate. It should be carefully preserved and stored in a cool place remote from light or fire. Spirit of glyceryl trinitrate occurs as a clear, colorless liquid having the odor and taste of alcohol. It does not mix clear with water but is miscible in all proportions with alcohol. It is best administered alone in water. Spiritus Mtheris Nitrosi. — Spirit of Nitrous Ether, U. S. P.— Sweet Spirit of Niter. An alcoholic solution of ethyl nitrite containing not less than 4 per cent, of the pure ether. Spirit of nitrous ether occurs as a pale yellowish or faintly greenish-yellowish liquid having a fragrant, ethereal and pungent odor free from acridity, and a sharp burning taste. When freshly prepared, it is neutral to litmus paper and is miscible with alcohol or water. The preparation deteriorates rapidly. Sodii Nitris. — Sodium Nitrite, U. S. P. The official sodium nitrite is required to contain not less than 90 per cent, of NaNOj and is directed to be kept in well-stoppered bottles. It occurs as white or nearly white opaque fused masses or colorless crystals, odorless and having a mild saline taste. It is freely soluble (1 : 1.1) in water, but only slightly soluble in alcohol. COLCHICUM 247 Aconitum. — Aconite, U. S. P. The tuberous root of Aconitum napellus L., used preferably in the form of : Tinctura Aconiti. — Tincture of Aconite, U. S. P. One hundred c.c. represent 10 gm. of the drug in approximately 65 per cent, of alcohol. This preparation is occasionally used as a local application either alone or in mixtures with from 4 to 9 parts of soap liniment. COLCHICUM * The actions of colchicum are due to its alkaloids,! colchicin and colchicein. These are of some toxico- logic importance, but what is known of their actions does not serve as a rational basis for the therapeutic use of colchicum, which is employed empirically in the treatment of gout and rheumatism. When colchicum (or colchicin) is taken by the mouth or injected subcutaneously, no effect is observed for from three to six hours, however large the dose. This peculiarity has been explained on the theory that colchicin itself is not toxic, but that it must undergo oxidation to form the poisonous oxydicolchicin. Another suggested explanation of the delay in the onset of symptoms is that the poison is absorbed slowly by the central nervous system, the delayed action of tetanus toxin being cited by way of analogy. Colchicum and colchicin are actively irritant to sub- cutaneous tissues and to certain mucous membranes. They cause gastro-intestinal irritation with nausea, vomiting and diarrhea. The stools resemble ordinary watery evacuations at first, but later they may become bloody. In addition to the irritant action on the intestine, colchicin is said to act like pilocarpin and physo- stigmin on smooth muscle, increasing intestinal peri- stalsis and the contraction of the bronchial, and other, musculature, but it does not affect the heart directly. Nephritis is sometimes induced, but the effects on the kidney are inconstant, probably dependent on the * This drug bears little relation to the others of this group, but it is considered here for convenience. t Colchicin and colchicein are classified as alkaloids, though they also have acid properties. 248 CIRCULATORY DEPRESSANTS degree to which elimination takes place by way of the intestine. The circulation is not affected to an important degree early in the course of poisoning, but Dixon and Maiden state that death results in colchicin poison- ing through paralysis of the vasomotor centers. Others maintain that death results from paralysis of the respiratory center. Falck collected statistics of fifty-five cases of poison- ing by colchicum, and it is said to occur in Germany through the careless gathering of the herb. The stomach and intestine should be emptied after a poisonous dose of colchicum has been swallowed if it is discovered in time, that is, before the symp- toms develop. Wood states that tannin is the only possible antidote, but that it is not dependable. If the drug has been absorbed, the treatment must be symptomatic, since the early vomiting and diarrhea will serve to remove any that may have escaped absorption. It is commonly stated that as little as 3 mg. (Vso grain) has proved fatal to a patient suffering with gout and nephritis. A case of poisoning has been reported in which a robust man took a nostrum containing colchicin in the hope of averting an anticipated attack of gout. It is said that a total of 34 mg. (% grain) of colchicin was taken in a period of nineteen days. Paralysis then began in the hand, and within twelve days involved the entire trunk and the limbs. The symp- toms were followed by rapid improvement. THERAPEUTIC USES Colchicum is used mainly to avert attacks of gout or to abate their severity. It relieves the pain and swelling in the joints, and seems to shorten the dura- tion of the attacks. Von Noorden believes that it is useful in gouty seizures, but that it is useless in the intervals between attacks as well as in chronic and atypical gout. It seems to have some analgesic action in rheuma- tism, but it is not used so commonly in that affection as in gout. COLCHICUM 249 It does not appear to have any important or con- stant influence on the elimination of uric acid, but the testimony on this subject is somewhat conflicting. DOSAGE The pharmacopeia states that the average dose of colchicum seed is 0.2 gm. (3 grains), and that that of colchicin is 0.5 mg. (Yiso grain) ; but the seed is required to contain 0.55 per cent, of colchicin, and hence the dose stated for the seed contains more than 1 mg. (%5 grain) of colchicin. It would seem to be unwise to give more than 3 mg. (%o grain) of colchicin daily, whether one uses the seed, the tincture of the seed or the alkaloid itself, and the administration should be interrupted or the dosage diminished if diarrhea is induced. The average dose of the tincture is 2 c.c. (30 min- ims), which contain 1 mg. (%5 grain) of colchicin. MATERIA MEDICA Colchici Semen. — Colchicum Seed, U. S. P., is gen- erally used in medicine in the form of : Tinctura Colchici Seminis. — Tincture of Colchicum Seed, U. S. P. A hydroalcoholic preparation repre- senting 10 w/v per cent, of colchicum seed and con- taining approximately 0.05 per cent, of colchicin. DIURETICS The secretion of urine may be influenced by drugs in many different ways; hence the diuretics do not constitute a well-defined group, and in fact, few of them are used as diuretics exclusively. Some of the diuretics have been discussed among other groups, and others will be discussed elsewhere. Sollmann^" classifies the diuretics as follows: 1. Those acting through changes in the general cir- culation. 2. Those acting purely by local irritant stimulation of the kidney cells. 20. Sollmann: Pharmacology, Philadelphia, W. B. Saunders Company, 1906, Ed. 2, p. 546. 250 DIURETICS 3. Those acting by non-irritant stimulation of the kidney cells. 4. Those acting mainly by salt action. Under normal conditions the rate at which the urine is secreted varies with the volume of blood which passes through the kidneys in a unit of time, but there is a minimum blood pressure (about 40 mm. of mer- cury), below which the kidneys do not function. On the other hand, intense constriction of the renal arter- ies causes a diminution of the secretion even though the general blood pressure may remain high. The actions of the digitalis bodies have been dis- cussed and it is necessary to call attention here only to the fact that they cause diuresis by improving the circulation. There is no evidence that they act on the kidneys directly, and in fact they do not cause diuresis in healthy man, since they do not improve the normal circulation. VASODILATORS While our knowledge of the actions of the vaso- motor nerves in controlling the circulation is consid- erable, we do not know much about the changes which drugs cause in the renal circulation under different conditions, unless they induce diuresis, which may be accepted as evidence that the circulation has been improved. But improvement usually means only a closer approximation to normal conditions, since either vasodilatation or vasoconstriction may interfere with the secretion. We may conclude then that the vasodilators will facilitate the secretion of urine when they abolish an excessive constriction of the renal arteries without causing too great a fall in the general blood pressure, but we are unable to state in what cases this beneficial effect will follow their use. The nitrites and other vasodilators have been employed in many cases in which they could hardly be of benefit, for example, they have been recommended frequently to overcome the vasoconstrictor action of the digitalis bodies, but, as we have already pointed out, the direct vasocon- strictor action of therapeutic doses of the digitalis bodies is wholly negligible, and when an improvement IRRITANT DIURETICS 2S1 in vascular tone follows their use it is due to the gen- eral improvement in the circulation, and does not call for vasodilators. It is hardly probable that the vasodilators can often have any important action in promoting diuresis, but the indications for their use in any case may be deduced from the discussion of their actions. The drugs of the caffein group influence the general circulation but their most pronounced diuretic action is exerted on the kidney directly. IRRITANTS The second class of drugs — those which act through their local irritant action on the renal cells — embraces the volatile oils, which have been mentioned under urinary disinfectants, and certain glucosidal bodies, such as scoparin, and some others which are not used therapeutically for their diuretic action. Thftjiiost important drug usually classed among the 'irritant diuretics is calomel. There is no question that large doses of calomel are capable of causing renal irritation, hence caution is urged when it is employed in nephritis, and some authorities state that it should not be used when there is the least suspicion of nephritis. That view would appear to be extreme, however. An entirely different theory has been advanced recently to account for the diuretic action of calomel. It causes increased peristalsis in the small intestine resulting in a lessened absorption, and consequently in the emptying of a larger amount of fluid into the colon than normally. It is explained that calomel does not affect the large intestine markedly, and the excess of fluid in the colon undergoes rapid absorption. In the meantime the composition of the blood has been restored to the normal through the withdrawal of fluid from the tissues to compensate for that excreted into the small intestine, and this rapid absorption of fluid from the large intestine induces hydremia and consequent diuresis. It is urged that the copious diu- resis which accompanies the absorption of small amounts of calomel prevents the latter from exerting its irritant action on the renal cells. 252 DIURETICS It is a matter of common experience that calomel diuresis is attended with greater improvement in the condition of dropsical patients, than is seen when it causes the removal of water by purgation. There is no apparent advantage in securing the absorption of water from the colon only in order that it may be excreted by the kidneys, hence we must sup- pose that the advantage is due to a milder action whereby the sudden removal of a large amount of fluid from the circulation is avoided. The combination of opium and calomel causes diu- resis more certainly than does calomel alone, and this is explained on the basis that the delayed peristalsis permits of a greater absorption of calomel, or accord- ing to the view of calomel action just discussed, it permits of a greater absorption of water from the large intestine. Several investigators have found that a given amount of water administered by the mouth causes a greater diuresis than an equal amount injected intra- venously or subcutaneously. It has been suggested that some substance which is actively diuretic, is absorbed with the water from the intestine, and that it is the absence of this hypothetic substance in the cir- culation which accounts for the slighter diuresis when the water is injected intravenously. It is probable that the diuretic action of calomel may stand in relation to this observation. CAFFEIN GROUP The drugs of the caflEein group are the only ones of importance which induce diuresis through their non- irritant stimulation of the renal cells. We have called attention to their influence on the heart, and on the vasomotor system, and it remains to discuss their specific action on the renal cells. It is generally held that they act on the tubules, stimulating them to increased secretion, but there is another theory of their action which is diametrically opposed to this view, according to which caffein inhibits the capacity of the tubules for reabsorbing water, with a consequent increase in the amount eliminated. METHODS OF CAUSING DIURESIS 253 Whichever theory is correct, the essential fact for the clinician is that caffein and theobromin act on the kidneys and do not cause irritation, hence they may be used in the presence of chronic nephritis. While this statement applies to theobromin, it does not seem to be true of theobromin and sodium salicylate. It is sometimes maintained that these agents cause a specific dilation of the renal vessels, but the vessels of every organ dilate when it begins to function more actively, and it is impossible to say whether the renal dilation is the cause or effect of renal activity. OTHER MEANS OF CAUSING DIURESIS The rate of secretion of urine varies with the vis- cosity of the blood, and anything which causes water to pass into the circulation tends to promote the secre- tion of urine. This may be accomplished by causing water to be absorbed from the body tissues or from the alimentary tract. The absorption of tissue fluids into the circulation may be accelerated during health by the intravenous injection of a saline solution which has a higher con- centration than the blood. The renal cells offer little resistance to the passage of sodium sulphate, and when a 2 per cent, solution is injected intravenously, tissue fluid passes into the circulation and active diu- resis is induced. This is one of the most active diure- tics at our command, and may be depended on to hasten the elimination of those poisons which are excreted by the kidneys. Obviously, this method is only suited for emergencies. Venous stasis favors the passage of water from the blood into the tissues, and conversely, the relief of venous stasis is commonly followed by the return of the water from the tissues into the circulation, with the resulting hydremia and diuresis. Even a comparatively small initial change of this sort may institute diuresis with the ultimate elimina- tion of enormous quantities of water with progressive improvement in the circulation and relief of the stasis ; hence any drug which causes improvement in the gen- eral circulation in dropsical conditions will act as a diuretic if the kidneys are capable of functioning. 254 DIURETICS Owing to the slight absorbability of sodium sulphate by the intestinal epithelium it does not usually pass from the intestinal tract into the circulation with suffi- cient rapidity to cause active diuresis, but the acetate and citrate of potassium are absorbed promptly and are commonly used as diuretics. They are also com- monly used when it is desired to render the urine alkaline. Potassium acetate is absorbed more readily than the citrate, and is therefore a more active diuretic; large doses of the citrate act as a laxative, and may then fail to produce diuresis, and may even diminish it temporarily, since the removal of water by the bowel will increase the viscosity of the blood. THERAPEUTIC USES The urine serves to remove toxic substances from the body, whether these be waste products formed during health, the results of disease, or poisons intro- duced in the form of drugs, though not all toxic sub- stances are removed in this way. From this the chief uses of the diuretics in normal circulatory conditions are obvious. When the circulation is impaired and water accumulates in the tissues, it causes distress, and its removal becomes imperative. This may be accomplished in part by sweating and purgation, but diuresis affords the most satisfactory method of dis- posing of the accumulations when the kidneys are capable of functioning normally. It is not feasible to consider all of the therapeutic indications for diuretics, and only a few of them will be discussed here. We do not know enough about the toxic substances (toxins) which are formed during disease and the best method of securing their elimination to enable us to state just what measures should be employed, and therefore we do not know to what extent the use of active diuretics will prove beneficial in many cases. We know that certain vegetable poisons at least are excreted practically unchanged in the urine, while others are decomposed to a greater or less extent before they are eliminated, and still others are removed from the circulation by the liver, and exert USE OF DIURETICS 2SS practically no effect on the kidneys, and their elimina- tion is practically unafJected by diuresis. Our knowledge of the fate of many of the vegetable poisons is fragmentary, and we are often unable to state whether they are eliminated by the kidneys, or by the liver, or are destroyed in the organism. Even in those cases in which we know that a poison is eliminated by the kidneys, we are seldom able to state whether it is excreted through the glomeruli or through the activity of the tubular epithelium, hence we do not know which of the diuretic drugs is to be preferred in a given case. Fortunately, diuresis, how- ever induced, appears to favor the elimination of many of those poisons which are excreted through the kid- neys, and the necessity of choosing one diuretic rather than another does not appear to be pressing, and in cases of acute poisoning by a drug such as strychnin, which is excreted mainly by the kidney, and when the necessity of securing its rapid elimination is urgent, one's efforts should be directed toward inducing copious diuresis by the most effective means at hand. When poisons which are capable of inducing nephritis have entered the circulation, it seems prob- able that we should secure the largest possible flow of blood through the kidney vessels, as well as the most copious diuresis ; hence caffein and theobromin, which are said to cause a specific dilation of the renal ves- sels, probably deserve consideration in addition to other diuretic measures. It is surprising hqjv little attention has been paid to the possibilities of extreme diuresis and flushing of the kidneys to the maximum in cases of poisoning with mercuric salts, which have become all too common of late, but it is not to be understood that this subject has been wholly neglected, and diuresis does play an important role in the treatment in such cases. We do not believe that the possibilities of the treatment have been appreciated, however, just as the possibilities of the elimination of strychnin during intense diuresis have been overlooked, even though every text-book mentions diuretics as a part of the routine treatment in such cases. 256 DIURETICS The choice of diuretics in a given case is often empiric though there are certain conditions which demand a definite method of procedure. When there is an accumulation of water in the tis- sue (dropsy) due to the faulty action of the heart and its failure to maintain an adequate circulation, the digitalis bodies are of the first importance, and their action may be supplemented advantageously by that of caff ein. The different drugs of the digitalis group con- tain irritant principles and it is barely possible that some of these may induce diuresis after the manner of the second class mentioned above, that is, those acting purely by their irritant action on the renal cells, but the evidence against this has been cited. The irritant digitalis principles are probably excreted almost entirely through the liver, and when they are excreted through the kidneys this appears to take place so slowly that they are never in sufficient concentra- tion to cause severe irritation. At any rate the digitalis bodies do not cause serious renal irritation and they are used in the presence of nephritis. The action of the digitalis bodies may be supple- mented by diuretics which cause dilation of the renal vessels (caffein), or by those which cause hydremia (calomel, potassium acetate). Just as digitalis bodies are indicated when the car- diac action is impaired, so they are contra-indicated when the heart beat is normal, and in such cases dependence should be placed in drugs which diminish the viscosity of the blood, or tMfcse which act on the kidneys directly when diuresis is desired. There is seldom any special indication for the use of the volatile oils as diuretics alone, but they are sometimes used in small doses which produce only a mild stimulation of the kidney cells. The injection of physiologic salt solution commonly causes a marked diuresis, but the kidney may become resistant to the passage of sodium chlorid as the result of continued administration or under pathologic condi- tions, in which case the administration of salt le^ds to a -diminution of urinary secretion. It then becomes DOSAGE OF DIURETICS 257 necessary to reduce the ingestion of salt to a minimum. Attention has been called recently to the slow intra- venous injection of hypertonic solution of glucose when sodium chlorid is contra-indicated. Venous engorgement involving the abdominal veins which results from cardiac insufficiency, interferes with the renal circulation by retarding the outflow, and, as is very well known, anything that interferes with the free outflow from the renal veins interferes with the secretion of urine. Hence anything which relieves the venous stasis promotes the secretion of urine. Active cathartics which remove a large amount of water may suffice to relieve the interference with the renal circulation. In like manner dropsical accumula- tions may interfere mechanically with the venous return and thereby lessen the secretion of urine, and in an analogous manner the purgative sometimes affords relief by removing the water which presses on the veins. Clinicians often experience great difficulty in removing accumulations of fluid in patients who suffer with renal insufficiency. The retention of urea in nephritis is so well known as to require no further comment. Saline diuretics and drugs of the caffein group are said to be best for use during chronic nephritis. DOSAGE The dosage of the^ftigitalis bodies has been discussed in the article dealing with cardiac drugs. The dosage of cafFein and theobromin for inducing diuresis is commonly limited by its actions on the heart and central nervous system, especially in the case of caffein by its tendency to produce wakefulness, and in the case of theobromin by its action on the heart. The diuretic dose of caffein is usually given as 0.3 gm. (5 grains) but the drug is commonly given up to the limitations imposed by its side actions. It may be repeated about three times a day. Theobromin is given in about the same amounts, but owing to the 258 DIURETICS more rapid action it may be repeated about four times a day."^ Much larger doses of theobromin and sodium sali- cylate have been used, and Taylor has recently stated that 5 gm. (80 grains) is a normal daily dose, in patients suffering with myocardial disease. Smaller doses were found unsatisfactory. The volatile oils are seldom administered alone for their diuretic action, but they are sometimes used in the form of infusions, or other preparations of drugs which contain them. The dose of potassium acetate is about 2 gm. (30 grains). It is commonly used when it is desired to increase the urine and render it alkaline, and the dose may be repeated every two or three hours until the desired object is attained. It is converted into the carbonate, in which form it is excreted largely. Calomel is given in doses of from 0.1 to 0.2 gm. (from 11^ to 3 grains) several times daily when it is desired to cause diuresis. Since such doses cause diarrhea in most cases, it is often advised that opium be administered with it in sufficient amounts to prevent active purgation. This interferes with the evacuation of large amounts of water, and does cause diuresis in the manner described, but it is probably better to use smaller doses of calomel, and avoid the necessity of using opium. In many cases the removal of even a small amount of water by purgation will suffice to inaugurate an increased secreti^ of urine, and with a mild action one avoids the depression which is such an objectionable feature of violent calomel purgation. 21. It seems probable that theobromin may be administered conveni- ently in the form of cocoa in sufficient amounts in many cases. It is often objected that this requires the administration of too much water, but every patient must have some fluid every day, and since cocoa should be made with milk only — not with water — there is no apparent reason why the cocoa should not be administered with the milk which forms an important part of the diet as a rule in such cases. The better class of powdered cocoas contain about 1 per cent, of theobromin, hence 10 Rm. of powdered cocoa, sufficient for one cup, would contain 0.1 gm. (1}^ grains) of theobromin. If desired, the theobromin administered in this way may be supplemented by theobromin or the theobromin and sodium acetate or salicylate. An advantage in the use of cocoa in this way is the reduction of the amount of sodium salicylate or acetate which it presents, and the lessened gastric disturbance. MATERIA MEDICA OF DIURETICS 259 Small doses of calomel often cause purging with little more discomfort than accompanies a normal move- ment. The severe depression which accompanies calo- mel purgation is probably due in a large measure to the determination of an excessive amount of blood to the splanchnic region as the result of active intestinal secretion. Moderate doses are not accompanied by this excessive activity of the intestinal glands and the resulting depression. It seems probable that the combined use of digitalis, calomel and caffein or theobromin would be better than calomel with opium, except when the opium is needed for its other actions. MATERIA MEDICA * Potassii Acetas. — Potassium Acetate, U. S. P. It should contain not less than 98 per cent, of pure potas- sium acetate (KC2H3O2). It occurs as a white pow- der or in crystalline masses, odorless and having a saline taste. Potassium acetate is deliquescent on exposure to air. It is very soluble ( 1 : 0.4) in water and freely soluble (1:2) in alcohol. It is best admin- istered in the form of simple aqueous solution. The saline taste may be disguised with syrup. Potassii Citras. — Potassium Citrate, U. S. P. It should contain not less than 99 per cent, of pure potas- sium citrate (KjCeHgO^.HjjO). It occurs as trans- parent crystals or a white granular powder, odorless and having a cooling, saline taste; deliquescent on exposure to air. It is very soluble (1:0.5) in water but only slightly soluble in alcohol. It is best admin- istered in the form of a simple solution with water or as an effervescent draught. Potassii Citras Effervescens. — Effervescent Potas- sium Citrate, U. S. P. A mixture of potassium citrate 20 per cent, with sodium bicarbonate, tartaric acid and citric acid. This product must be kept in well- stoppered bottles. It may be administered in doses of 4 gm. (60 grains.) * The materia medica of other diuretics will be found under other groups to which they also belong. 260 DIAPHORETICS DIAPHORETICS One of the functions of the sweat glands is to pro- vide moisture, which by its evaporation cools the body, the secretion of sweat being increased when the-pro- duction of heat by the body is increased. This secretion is controlled largely by the heat regulating centers, and when the blood flowing through the carotids is warmed it causes an increased secre- tion, as does the warming of the surface of the body also. The activity of the sweat glands is influenced less by the blood supply than is that of most of the glands of the body, and profuse sweating may occur when the skin is pale, and, on the other hand, there may be little secretion when the skin is flushed and hot in fever. However, heat increases the excitability of the nerve endings in the sweat glands arid an abundant supply of blood often promotes the secretion. The composition of the sweat and the daily amount secreted varies widely 'under normal conditions, and still more widely under pathologic conditions. The amount of sweat secreted in twenty-four hours by a healthy man with light exercise probably does not often fall below 500 c.c. (1 pint), but with hard work during hot weather the secretion may become more than ten times as active, and under pathologic condi- tions, as during sudden collapse, the amount secreted in a few minutes may equal the amount which is secreted in an entire day under ordinary conditions. The sweat contains small amounts of salts, of which sodium chlorid constitutes much the larger part, and usually only insignificant amounts of organic mat- ter, but when the activity of the glands is greatly increased, during severe muscular exercise or by hot vapor baths, the amount of organic matter is increased notably, and when the kidneys become incapable of secreting urea as fast as it is formed, so that it accu- mulates in the blood, a considerable amount is found in the sweat, and it is commonly stated that crystals of urea sometimes may be found on the skin under those conditions. PILOCARPIN 261 It seems probable that one of the functions of the sweat glands is to provide a means of eliminating water from the blood without a corresponding loss of -its salts, but when the loss of water from the blood is made up by absorption either from the gastro- intestinal tract or from the tissues, the loss of salts may be important, and the blood may then have a lower concentration than before active sweating was induced. From this it would seem that the sweat glands supplement the action of the kidneys to an important degree at times. Sweating also serves to remove large numbers of bacteria from the deeper layers of the skin, and it is probable that with the profuse sweating of exercise that this action is not without importance. The methods of inducing active sweating without the use of drugs do not call for discussion in this place; the actions of the analgesic antipyretics and various vasodilators have been discussed elsewhere. PILOCARPIN Pilocarpin stimulates all parasympathetic nerve end- ings and the sympathetic nerve endings in the sweat glands, which, as previously stated, behave toward several drugs like the parasympathetic. The sweating begins in about fifteen minutes and lasts about two hours. The stimulation of the chorda causes profuse salivation, while the secretion of the bronchial glands may embarrass respiration, and pilo- carpin is therefore contra-indicated in patients in whom there is a predisposition to edema of the lungs. Pilocarpin stimulates the vagus endings, causing moderate slowing of the heart rate, but the action dif- fers essentially from that of digitalis, for the stimula- tion resulting from small doses tends to pass into depression so that the heart rate increases, and when large doses have been administered the stiniulation is brief and the depression almost as great as that result- ing from atropin. Hence it is impossible to induce an important degree of slowing of the heart by doses of pilocarpin. The toxic actions of pilocarpin on the central ner- vous system are exerted mainly on the medulla. 262 DIAPHORETICS Eggleston (personal communication) found that the intravenous injection in the dog of doses cor- responding to 45 mg. (% grain) for a man caused vomiting through the action on the center, and that the emetic action of very much larger doses could be prevented by the injection of atropin in amounts equal to less than one one-hundredth of that of the pilocarpin used. Nausea and vomiting are commonly accompanied by a flow of tears, saliva and sweat; in the case of pilocarpin, the effect is augmented by the stimulation of the nerve ends in the glands. Diarrhea is also a s)rmptom of poisoning with pilo- carpin, the action being partly peripheral and prob- ably partly central, since many drugs that stimulate the vomiting center in the medulla also cause diarrhea through their central action. The respiration is increased at first, and later there is depression of the respiratory and vasomotor cen- ters ; but when death results, it is probably secondary to the pulmonary edema, even in those cases in which the heart actually stops before the respiration. The action of physostigmin resembles that of pilo- carpin qualitatively, but it is so much more depressant than pilocarpin to the central nervous system in doses producing an equal diaphoretic effect that it is never used for that purpose. THERAPEUTIC USES Sweating serves to increase the concentration of the blood, thus promoting the absorption of dropsical effusions if the amount of water ingested is restricted sufficiently. Profuse sweating serves to remove a certain amount of various substances which are usually excreted by the kidneys, and while the amount of nitrogenous mat- ter normally excreted in the sweat during rest is insig- nificant, a much larger amount is excreted during pro- fuse sweating. The amount of urea eliminated during even profuse sweating would seem to be too small to account for the improvement which results from sweat baths in nephritis and uremic poisoning, hence one cannot say DIAPHORETICS • 263 to what the improvement is attributable. It is possible that the removal of chlorids from the blood may relieve the kidney, for, as previously stated, sodium chlorid is actually injurious to the kidneys under cer- tain circumstances. It is popularly supposed that other toxic substances are excreted in this way, but our knowledge of this subject is very imperfect. A popular treatment of "colds" consists in the use of large quantities of hot lemonade while the body is kept warm to induce sweating. A hot mustard foot bath is commonly taken at the same time, and this treatment frequently results in the disappearance of the symptoms, probably because the alteration in the distribution of the blood which is induced relieves the local congestion. The same objects are often accomplished by the use of the compound powder of ipecac and opium and the mustard foot bath, or by a hot bath taken just before retiring in a warm room ; this induces active sweating which continues for some hours, if the patient is kept warmly covered. Chronic rheumatism and gonorrheal arthritis are often treated by placing the affected limb in a hot-air chamber for half an hour, while maintaining a tem- perature of from 70 to 90 C. (150 to 180 F.). A limb, or even the whole body except the head, may be subjected to a high temperature for a short time if care is taken to provide for a sufficient circulation of air to insure the evaporation of water as fast as it is eliminated in the sweat. Heating a limb or the body causes the body temperature' to rise — sometimes as much as several degrees — and cold water or an ice bag should be applied to the head to prevent the effects on the brain which would ensue. Solution of ammonium acetate and spirit of nitrous ether are commonly used as diaphoretics during fevers, but their action is feeble, and we have many better means of inducing sweating. Pilocarpin is used as a diaphoretic in certain dis- eases of the skin, and it is generally credited with the property of stimulating the growth of the hair, but 264 DIAPHORETICS failure is far more common than success when it is used in baldness. Doses just short of that required to induce sweating are sometimes used to relieve itching in generalized acute eczema, urticaria and other conditions. Its use as a miotic has been discussed. Pilocarpus owes its therapeutic effects to the pilo- carpin which it contains, but it would seem that there is never any occasion to use the crude drug rather than pilocarpin. DOSAGE The diaphoretic dose of the compound powder of ipecac and opium is 0.6 gm. ( 10 grains) ;''the dose of the hydrochlorid or nitrate of pilocarpin is from 0.001 to 0.01 gm. (%o toys grain). Doses of S mg. (%2 grain) of pijocarpin hydro- chlorid administered three times a day are said to cause moderate sweating without inducing salivation or bronchial secretion that is so often complained of by patients. This dose may be utilized in chronic renal disease, in which pilocarpin is said to be a most useful drug. MATERIA MEDICA The compound powder of ipecac and opium has been mentioned under the morphin group; spirit of nitrous ether under the circulatory depressants. Liquor Ammoniae Acetatis. — Solution of Ammo- nium Acetate, U. S. P. This preparation, formerly known as spirit of Mindererus, should be freshly pre- pared ; it is a clear, colorless liquid, free from empy- reuma, having a saline taste and an acid reaction. The solution should contain about 7 per cent, of ammonium acetate with small amounts of acetic and carbonic acid. Pilocarpus. — Pilocarpus, U. S. P. Jaborandi. The dried leaflets of Pilocarpus Jaborandi and of P. micro- phyllus. This drug is occasionally used in the form of an infusion or as the official fluidextract, the latter in doses of about 2 c.c. (30 minims). The action of the drug is essentially that of the chief alkaloid, pilocar- pin, and as the drug and preparations of it may vary DIAPHORETICS 265 in activity, the alkaloid is usually preferred. This is official as: Pilocarpinae Hydrochloridum. — Pilocarpin Hydro- chlorid, U. S. P. This salt occurs as colorless, odor- less crystals, having a faintly bitter taste. It is deli- quescent in moist air and very soluble (1:0.3) in water and freely soluble (1:2.3) in alcohol. Pilocarpinae Nitras. — Pilocarpin Nitrate, U. S. P. This salt occurs as colorless crystals or a white crys- talline powder, having a faintly bitter taste. It is permanent in air and is freely soluble (1:4) in water and soluble ( 1 : 60) in alcohol. This preparation is somewhat less soluble than the hydrochlorid and apart from being permanent in air, has no evident advan- tages over the more widely used salt of the alkaloid. Both the hydrochlorid and the nitrate may be admin- istered in the form of solution, though they are fre- quently given in the form of pills or compressed tablets. CHAPTER VIIL— EVACUANTS Drugs that are used to cause evacuation of the bow- els are variously classified; according to their origin and chemical nature ; according to the intensity of their action, and according to their general mode of action. The term laxative is applied to those which cause a nearly normal movement of the bowel, attended with little or no pain; if the action is much more vigorous and several movements are induced, ihe term purga- tive or cathartic is employed ; and when a large amount of fluid is evacuated with the feces the action is termed drastic, or hydragogue. For prattical purposes it will be convenient to dis- cuss the evacuants with reference to the part of the intestine on which they exert their main action, for a drug may be laxative or drastic, dependent on the dose employed and other conditions, and evacuants must be chosen with strict regard to their mode of action and the seat of this action. The processes of digestion are so closely related to the intestinal movements that a brief discussion of the physiology of the gastro-intestinal tract is indispensa- ble for a clear presentation of the subject of evacuants. The stomach is an automatic organ, containing within its walls the plexuses of Meissner and Auer- bach, on which its automaticity probably depends; at any rate the surviving excised stomach is capable of maintaining regular movements, and the processes of secretion of gastric juice may take place after the connection with the central nervous system has been severed, but the stomach is influenced both as to move- ments and secretions, by two sets of nerves from the central nervous system, the parasympathetic (vagus), the functions of which are here mainly motor, and the sympathetic (splanchnic) which is mainly inhibitory. The control of these two nerves is so coordinated that when one of them is stimulated the other is usually depressed. EVACUANTS 267 The functions of the stomach are to secrete the gastric juice and to maintain movements which serve to mix the food with this juice and to drive the digested food into the intestine. The length of time during which food remains in the stomach varies with the nature of the food, and it may be influenced greatly by drugs. Proteins are digested more slowly than carbohydrates, and fats pass still more slowly into the intestine, and if they be taken before proteins and carbohydrates they delay their passage through the pylorus. The sphincter of the pylorus relaxes periodically to allow the fluid portions of the stomach contents to pass into the intestine. An alkaline reaction in the duodenum promotes, an acid reaction delays, this relaxation, but when water or a dilute solution of a salt is taken during digestion, it passes along the lesser cur- vature of the stomach, and reaching the pylorus with- out mixing with the rest of the stomach contents, passes rapidly into the intestine. This is of some practical importance with reference to the action of certain of the purgatives. Strong stimulation of the vagus, such as toxic doses of morphin induce, cause spasmodic contraction of the pylorus and the passage of the stomach contents may be delayed indefinitely. Stimulation of the splanchnic causes cessation of the movements of the normal stom- ach and relaxation of the pylorus, but such stimulation of the splanchnic cannot overcome strong vagus stimu- lation. In such cases depression of the vagus is more effective, hence atropin is used to lessen excessive movements of the stomach in gastric ulcer. This also serves to explain why large doses of morphin are contra-indicated in that condition, but small doses, sufficient to lessen pain, may be used, for the gastric effects of vagus stimulation are not usually elicited from less than 10 mg. (% grain), while half that amount exerts a marked analgesic action. Atropin is not so effective in quieting the move- ments of the stomach when these are due to diminished tone of the splanchnic, for then the automatic mecha- nism alone suffices to increase the activity of the move- ments and depression of the vagus is then of little 268 EVACUANTS value. Unfortunately, we have no drug which is of much use in increasing the tone of the sympathetic, unless it be ergot. The mechanism controlling the activities of the intestines is much like that of the stomach. Peristal- tic movements in the intestine consist of waves of contraction preceded by relaxation of the musculature of the wall; these are automatic, but they are influ- enced by parasympathetic (vagus) and sympathetic (splanchnic) nerves. The function of the parasympathetic nerve to the intestine is mainly motor and that of the sympathetic is mainly inhibitory, as in the stomach, but it seems probable that there are some inhibitory fibers in the vagus, and some motor fibers in the sympathetic. The vagus is distributed to the intestine as far down as the descending part of the colon, where its place as a parasympathetic motor nerve is taken by the erigens, on which atropin and some other drugs act in the same way that they do on the vagus, but less effec- tively. The nerves which supply the colon and rectum also supply the uterus, which explains in part the effect of certain purgatives on that organ. Stimulation of the parasympathetic (vagus or eri- gens) nerve to the intestine causes active peristalsis, and strong stimulation of certain centers in the medulla is followed by diarrhea. The intestinal move- ments are also subject to psychic influence, but the mechanism of this is not understood. It is possible that the intestinal peristalsis which accompanies cer- tain emotions may be due in part to an increase of car- bon dioxid in the blood, this increase being due to respiratory depression, for carbon dioxid and hydrogen sulphid are normal stimuli to the intestine, causing peristalsis.^^ The movements of the large intestine differ con- siderably from those of the small. The contents of the 22. Certain emotions, such as fear, exert two types of action in different individuals; in one type the effects are referable to stimula- tion of the sympathetic, and include high blood pressure and inhibition of the gastro-intestinal movements; in the other their effects are referable in part to stimulation of the parasympathetic nerves, and include low blood pressure and active movements of the gastro-intes- tinal tract. EVACUANTS 269 colon are forced along to the descending part because of overfilling from the ileum, and such movements as occur in the ascending and transverse portions are in the reverse direction, serving to keep the contents thor- oughly mixed and promoting absorption. In the descending colon the contents are driven very slowly toward the rectum by means of peristaltic movements much like those in the small intestine. It is uncertain whether the rectum normally contains fecal matter except just before defecation, but there is no reason to doubt that its distention by feces causes a desire to go to stool. The retention of feces in the rectum may lead to dilatation, and the development of a form of chronic constipation. Anything which increases the bulk of the intestinal contents will promote intestinal peristalsis, for this dis- tention of the intestine seems to be one of the chief stimuli to the automatic mechanism. The fluid contents of the intestine may be increased by augmented gastric or intestinal secretion, or by diminished absorption from the intestine into the circulation. Estimates of the total amount of fluid secreted by the different digestive organs vary considerably, but it may be accepted that from 3 to 5 liters (from 6 to 10 pints) of fluid are secreted daily by the salivary, gastric and intestinal glands and the pancreas and liver together, and that nearly all of this, together with the liquefied food, enters the small intestine, and a large part of it reaches the colon. From this it is evident why so much fluid may be removed from the body by even a mild, but rapidly acting, evacuant. The composition of the blood can be altered rapidly in this way, and especially by those cathartics which stimulate the intestinal glands to increased secretion. With the changes in the com- position of the blood thus induced are associated corre- sponding changes in the secretions and excretions throughout the body, for most of the glands are influ- enced profoundly by the composition of the blood, as well as by changes in the amount with which they are supplied. The passage of fluid through the small intestine requires from eight to twenty hours, as a rule (oijly a 270 EVACUANTS few minutes in some conditions of hyperexcitability of the intestine), and the passage through the large intes- tine requires a shorter period, during which active absorption of fluid takes place, leaving the fecal mass composed mainly of bacteria, undigested food particles, such as the lignin of vegetables, detritus of the intes- tine, and various principles in small amount, together with Enough moisture to make it plastic. If the intestinal movements are unduly sluggish, opportunity is afforded for the absorption of too large a proportion of fluid, the feces become hard, dry and difficult to propel by the normal peristaltic movements, and it becomes necessary to soften such masses before they can be evacuated. There are various physiologic ways of preventing this sluggishness of the intestinal movements, and it is obvious that such means should be tried before resort- ing to the use of drugs. The taking of an adequate amount of cold (not iced) water between meals affords the simplest means of hastening peristalsis in the small intestine, and thus indirectly, in the large, for, as pre- viously stated, when water is taken during digestion it passes rapidly into the intestine, and probably even more rapidly if taken when the stomach is empty. Some stress is placed on the taking of this cold water between meals, rather than with them, for secre- tion of the digestive fluids depends to some degree on the amount of fluid in the circulation and tissues. If a normal amount of the digestive secretions is avail- able it supplies the fluid which is requisite for normal peristalsis, and it is only when this has been absorbed, at least in large part, that the additional water taken between meals is required to maintain the bulk of intes- tinal fluid which is required for active peristalsis. Some stress is also placed on the use of cold water rather than hot fluids, such as tea and coffee, for hot fluids promote rapid absorption from the small intestine and even less fluid will then reach the colon. It seems probable that the constipating effect which tea and coffee often exert is due in part to the fact that the rapid absorption of iluid from the small intestine indyces active diuresis, which is further augmented by EVACUANTS 271 the action of the caflfein which they contain, and that this diuresis increases the viscosity of the blood, which in turn diminishes the gastric and intestinal secretions, the increased absorption from the intestine, and the diminished secretion into it cooperating to deprive the intestine of its normal stimulus to peristalsis. A glass of cold water taken on rising is often suffi- cient to cause prompt evacuation of the bowels. Laxatives increase the peristalsis slightly and the feces are evacuated without becoming dehydrated in the colon. Many persons habitually eat too little, and it is a matter of common observation that one who suffers from mild chronic constipation associated with a spare diet will often have a normal stool soon after taking a large meal. Of course, overating is not advocated. It is often urged that a part of the food should not be too readily digestible, and while it is true that indigesti- ble food does promote peristalsis, it does not appear to be necessary, provided that the diet is abundant. A good appetite, which insures the taking of a fairly large amount of food, and good digestion, which insures the secretion of an adequate amount of fluid in the gastro-intestinal tract, are far more effective in securing active peristalsis than a small amount of indi- gestible food would be, for undigested food constitutes only an insignificant part of the normal intestinal con- tents, and furthermore, soft indigestible matter always invites the activity of pathogenic micro-organisms. An ideal cathartic should pass through the stomach without disturbing it and exert its action on the intes- tine without causing pain or inflammation, and these conditions must be approximated in order that a drug may be of any use as an evacuant of the intestine. We are in need of an evacuant which is suitable for subcutaneous injection, and which will then produce purgation without giving rise to excessive irritation at the point of injection, or irritating the kidneys. None of the agents which we use as cathartics is well adapted for therapeutic use by subcutaneous injection, some being local irritants, others having undesired side actions. 272 EVACUANTS Evacuants may be classified conveniently for study as follows: (1) those acting mainly on the small intes- tine; (2) those acting mainly on the large intestine; (3) those acting on the small and large intestines including alkaloidal evacuants ; (4) those acting on the rectum; (5) miscellaneous measures for inducing pur- gation. 1. EVACUANTS ACTING MAINLY ON THE SMALL INTESTINE OILS Neutral fats and saponifiable oils like butter and ^olive oil pass practically unchanged through the stom- ach, but are saponified more or less completely in the small intestine, and the resulting soaps may be suffi- ciently irritating to the intestinal mucous membrane to cause increased peristalsis and with an excess of the fat or oil act as a mild laxative. Castor oil, which consists largely of ricinolein, yields a soap that is much more irritating and prompt in its action. The direct influence of the irritation is usually limited wholly or mainly to the small intestine, because these soaps are absorbed into the circulation without reaching the colon. The increased peristalsis in the small intestine rapidly drives a large amount of fluid into the colon, distending it and causing an evacuation before the stools become fully formed, or at least while they are still soft, because a suffici^t interval of time is not aflforded for as much fluid to be absorbed as usual. Castor oil acts mildly even in fairly large doses, because the ricinoleic acid is liberated slowly, and the more active the peristalsis the less is the time allowed for the further liberation of the acid, hence, to a cer- tain extent, its action is self-limiting. Croton oil contains some free crotonoleic acid, which is irritant to the body tissues, hence it irritates the throat and stomach unless measures are taken to pre- vent it, and it may give rise to nausea and vomiting. It is decomposed in the small intestine, with the for- mation of crotonoleates. These are far more actively OILS 273 irritating than the ricinoleates, and croton oil causes more violent peristalsis than castor oil, but it may induce intestinal inflammation without purgation. THERAPEUTIC USES Castor oil is used frequently for children, being a dependable laxative or purgative which may be admin- istered without fear of causing intestinal inflammation or disturbing the stomach seriously, but it is not suited for continued use in chronic constipation because of its gradually lessening effect. It is also applied to the skin and to the eye as a demulcent. Croton oil finds its special field of usefulness in mania and coma, when a prompt evacuation of the boAvels is desired. Its irritant action in the stomach, and the possibility of its causing severe intestinal inflammation limit its use as an evacuant to those cases in which the adminis- tration of a rapidly acting drug in small amount is nec- essary. DOSAGE The dose of castor oil is 15 c.c. (4 fluidrams). The taste is disagreeable, and children manifest an espe- cial repugnance for it, so that it is best administered in such a way that the taste is masked. Because of its disagreeable taste castor oil is given preferably with pungent, freely frothing beverages, or enclosed in soft gelatin capsules holding about 1 tea- spoonful. It may also be administered in the form of a mixture or emulsion and this latter type of adminis-' tration is becoming popular. The following may be used as a type formula : gm. or c.c. Benzosulphinid (saccharin) 0|0S 1 grain Oil of Cloves 0|2 3 drops Oil of Cinnamon 0|3 5 drops Alcohol 410 ' 1 fl. dram Castor oil, a sufficient quantity I 3 fl. ounces to make lOO] In making this mixture, the benzosulphinid, oil of cloves and oil of cinnamon should be dissolved in the alcohol and this in turn added to the castor oil. 274 EVACUANTS The dose of croton oil is 0.05 c.c. (1 minim). It may be administered in drop doses placed well back on the tongue, in the form of a pill made with bread- crumb or other absorbent, or diluted with a bland oil and given in a ge^tin capsule, or simply dropped on a small lump of sugar, which should be swallowed quickly. MATERIA MEDICA Oleum Ricini. — Castor Oil, U. S. P. — ^A neutral fatty oil obtained from the seeds of Ricinus communis and having the property of being miscible with alcohol in practically all proportions. When well washed, castor oil is colorless or slightly yellow with practically no odor, but because of its viscosity and slightly acrid taste is not readily swallowed. Oleum Tiglii. — Croton Oil, U. S. P. — This is a fatty oil expressed from the seeds of Croton Tiglium; it varies in color from pale yellow to brown. Like castor oil it is soluble in alcohol, the degree of solubility increasing with age and the nature of the resulting decomposition. Croton oil is frequently adulterated and a pure oil is probably not now obtainable. RESIN ANHYDRIDS There are many vegetable drugs which contain glu- cosidal acids, or anhydrids, which induce purgation in much the same way that castor oil and croton oil do. The drugs of this group, as a rule, are only slightly irritant to the stomach, but they become much more actively irritant in the presence of bile and when they reach the intestine cause increased peristalsis. The action of small doses is limited to the small intestine mainly but large doses often cause gastric irritation, with nausea and vomiting, and in addition to the effect on the small intestine some of the drug passes into the colon, causing pain, tenesmus and watery evacuations. Very large doses may cause bloody stools, collapse and even death. Moderate doses of these drugs cause little or no pain, but active peristalsis in the small intestine is accompanied by sounds and sensations due to the move- ments of fluid and gas. RESIN ANHYDRIDS 27S THERAPEUTIC USES All the members of this group except podophyllum and its resin are used to secure prompt evacuation of the bowels, and all of them are capable of causing pro- fuse watery stools. Their actions are quite similar, differing only in minor details, hence it is often a mat- ter of no great importance which of the drugs of the group is used in a given case. They are used for the removal of fluid in dropsical conditions, especially as a preliminary to the use of digitalis and other drugs which promote diuresis. They were formerly used much more for this purpose than at present, and many physicians have abandoned their use in this way because of the dangerous depression which they sometimes cause in those suffering from cardiac diseases, and in asthenic and anemic patients. These drugs, in doses sufficient to cause watery stools, remove fermenting and putrefying material, as well as bacteria, from the intestinal tract, and repeated catharsis may render the bowel almost sterile for a time perhaps, but large doses of such irritants may injure the natural protective powers of the intestine against bacteria and permit the latter to grow more rapidly than before. Colocynth extract, resin of jalap or elaterin may be used for the removal of poisons which have passed through the stomach into the intestine, especially when the poison has been taken in a slowly absorbable form (belladonna berries). The action of podophyllum is usually elicited too slowly for this purpose. The severe irritant action of these agents contra- indicates their use in the presence' of severe inflamma- tion of the intestine, and large doses are contraindi- cated in menstruation and in pregnancy, but small doses have practically no effect on the uterus, and may be used without fear of inducing miscarriage or abortion^ The resin anhydrids are sometimes used for the removal of hard dry masses of feces which have been allowed to accumulate in the colon, because of the large amount of water which they drive into that organ. It is more rational to administer a suitable enema when such masses are to be softened, because they do not 276 EVACUANTS take up liquid rapidly, and even violent peristalsis may be insufficient to force them through the anus if they are formed into large masses. Different members of this group have been recom- mended for the treatment of chronic constipation, and while they are useful at times, it should be remembered that constipation is a symptom of some other condi- tion. It is better to determine the nature of the cause and direct one's efforts toward relieving it than to use the same method of treatment in every case because of the presence of a single symptom. It is impossible to enumerate here any considerable number of the causes of chronic constipation, but it is probable that its ultimate cause may be found in any one of a large number of habits, or minor derangements of various organs. It has been explained that the diuretic action of tea and coffee may augment chronic constipation by increasing the viscosity of the blood; excessive sweat- ing may do this also. The habitual taking of an insuf- ficient amount of water between meals is a common cause, and at least six glasses of cold water should be taken during the day in addition to any liquid that may be taken at meals. An even larger allowance should be taken if one drinks much tea and coffee, provided that this causes diuresis ; or if one sweats a great deal. One is apt to suppose that any loss of water from the body in the urine and sweat is quickly made up throflgh the amount taken for the relief of thirst thus induced, and while this is ultimately true, the amount of water in the circulation and tissues varies quite considerably from hour to hour. An insufficient, or 'poorly regulated diet, is probably the commonest cause of chronic constipation, even the value of open air exercise being due largely to the increased appetite, as well as to the improved circula- tion and consequent secretion of digestive juices. The trouble usually lies in the sluggishness of the large intestine, whether this be due to an atonic condi- tion of its musculature, or to the lack of bulk in the contents received from the ileum, but the choice of the remedy may be governed by the necessity of avoiding irritation in that part of the intestine which is the seat RESIN ANHYDRIDS 277 of inflammation ; for example, one would not use_ an irritant to the colon in the presence of appendicitis, even after the symptoms have begun to abate. It is conceivable that muscular atony may be the cause of disturbance in one case, while another presenting much the same clinical picture may be due to some distur- bance in Auerbach's plexus. DOSAGE Colocynth is not used in substance; the extract is laxative in doses of about, 0.03 gm. (V^ grain) and drastic in somewhat larger doses, but nearly all evacu- ants vary widely in their action on different individuals, and with the same individual at different times. One reason for this is that there are all degrees of inertia of the bowel to be overcome, and just as constipation is due to so many different causes, the dose of any given drug to correct it will vary. It is true, however, that any individual who suffers from chronic constipa- tion, or even from occasional attacks, will usually require approximately the same dose to relieve it at different times. Hence the doses given for the purga- tives are approximate only, and the drastic dose for one will be merely laxative for another. In the absence of experience as to the dose required for a given patient it is well to give a small dose at first and repeat it in from four to six hours if necessary, except in the cas'e of podophyllum. Drastic doses are not recommended. The compound extract of colocynth contains extract of colocynth, aloes, scammony and soap, and belongs to the group which acts on the small and large intestines. It is given in doses of 0.5 gm. (7^/^ grains). It is much used in the form of the official compound cathartic pill,^^ which is recommended only for its effectiveness. The dose of elaterin is 0.005 gm. (%o grain). Jalap is seldom used in substance alone, but the dose is stated as 1 gm. (15 grains). The compound powder of jalap, containing potassium bitartrate, acts as a saline, as well as a resin anhydrid. _23. This preparation is a survival of the "sliotgun" type of mix- tures; there is a rational basis, perhaps, for the employment of two evacuants having different seats of action, but _ there is no apparent advantage in using together two substances having such similarity of action as colocynth and scammony. 278 EVACUANTS Podophyllum is seldom given in substance ; the laxa- tive dose of the resin of podophyllum is about 0.005 gm. (%o grain), the purgative dose is about 0.015 gm. (Yi grain). Drugs belonging to the group of resin anhydrids are preferably administered in the form of pills or massed and enclosed in gelatin capsules. MATERIA MEDICA Colocynthis. — Colocynth, U. S. P. — The pulp of the peeled fruit of Citrullus Colocynthis, popularly known as bitter apple, has been used medicinally from the earliest times. It is now used chiefly for making : Extractum Colocynthidis. — ^Extract of Colocynth, U. S. P. — Made by exhausting colocynth pulp with diluted alcohol and evaporating the solvent. Extractum Colocynthidis Compositum. — Compound extract of Colocynth, U. S. P. — ^A complex mixture of extract of colocynth (16), purified aloes (50), carda- mom (16), resin of scammony (14), and soap (14). Elaterinum. — ^Elaterin, U. S. P. — Commercial ela- terin is a more or less variable mixture of principles obtained from elaterium, a substance known to the Greeks and Romans and made now, as then, by sedi- mentation from the juice of Ecballium Elaterium, popularly known as the "squirting cucumber." Ela- terium has been dispensed by mistake for elaterin, and this substitution, and the variable composition of the more active official product are probably responsible for the steadily decreasing popularity of the crude drug. Jalapa. — Jalap, U. S. P. — The dried tuberous root of Exogonium purga yielding not less than 7 per cent, of total resin is frequently used in the form of pow- der, more particularly as: Pulvis Jalapae Compositus. — Compound powder of Jalap, U. S. P. — A mixture of approximately 1 part of powdered jalap and 2 parts of potassium bitartrate. Podophyllum.— Poio^hyWnm, U. S. P.— The dried rhizome of Podophyllum peltatum, mandrake or May apple, one of the comparatively few widely used drugs ANTHRACENE DERIVATIVES 279 of North American origin, is seldom if ever used in any form except: Resini PodophylU. — Resin of Podophyllum, U. S. P. — This preparation, popularly called podophyllin, occurs as a gray or greenish-yellow amorphous powder and is directed to be made by precipitating a somewhat con- centrated alcoholic extract with a mixture of hydro- chloric acid and water. 2. EVACUANTS ACTING MAINLY ON THE LARGE INTESTINE ANTHRACENE DERIVATIVES The drugs of this group depend for their evacu- ant action on one or more substances which may be considered as derived from anthracene (C14H10) or from a derivative of it called anthraquinone (Q^HsOa), which differs from anthracene by having two CO groups uniting two benzene rings, whereas in anthracene the rings are united by two CH groups. Hydroxyanthroquinone has an OH replacing an H of anthraquinone, and several hydroxyanthroquinones are present in different drugs of this group. Among the most common are di-hydroxy-anthroquinone, or emo- din, and tri-hydroxy-anthroquinone, or chrysophanic acid. Emodin is present in all the crude drugs of this group, it and other closely related bodies being formed by the decomposition of glucosidal bodies which are present in larger amount in the crude drugs. These hydroxyanthroquinones pass through the stomach and small intestine causing no irritation and exert their specific action on the colon. They cause purgation after the lapse of about sixteen to twenty hours following their administration in most cases. Small doses cause normal evacuations attended with little or no colic; larger doses cause soft, or watery stools, which may be preceded by severe colicky pains. This irritant action on the colon contraindicates their use in menstruation and in pregnancy, because they induce reflex irritation in the uterus, increasing the 280 EVACUANTS menstrual flow when menstruation is in progress, or tending to cause expulsion of the fetus during preg- nancy. It is possible that they also act directly on the nerves supplying the uterus. The action which contra- indicates their use during menstruation indicates their employment as emmenagogues when it is desired to institute the flow. Aloes contains about 10 per cent, of aloin which belongs to the hydroxyanthroquinone group. Aloin is inactive itself but is changed into an irritant amor- phous substance in the colon, and on this decomposition product the purgative action depends. The formation of this decomposition product is facilitated by the pres- ence of alkalies and iron, hence aloes and aloin are fre- quently administered with soap and iron. Aloes is especially prone to cause uterine contrac- tions, probably because the aloin is absorbed in part and acts directly on the uterus, hence purgative doses of aloes are especially contraindicated in pregnancy, but it is the most frequently used of the group for its emmenagogue action. Aloin, after its subcutaneous injection, is excreted into the large intestine causing purgation, but the injection is painful. Fresh cascara sagrada contains emodin and also a ferment having an emetic action, but this ferment is gradually destroyed when the drug is stored. It also contains a bitter principle which may be utilized as a tonic but the taste is so disagreeable that many prefer to use a preparation in which the taste is masked, or one from which the bitter has been removed in part. Rhubarb contains chrysophanic acid and emodin. The chrysophanic acid is quite irritant, but it is absorbed without reaching the colon, hence it does not participate in the typical rhubarb action. The irritant action of chrysophanic acid is utilized therapeutically as an application to the skin in the form of chrysarobin ointment, chrysarobin being a compound of chryso- phanic acid. Rhubarb also contains tannin ; hence it is astringent in small doses, laxative in large, and the astringency tends to assert itself after the laxative effect has been induced. It sometimes causes nausea PHENOLPHTHALEIN 281 and headache. The aromatics present in the aromatic syrup enhance the astringent effect. Senna contains emodin, and a bitter resin which is not soluble in diluted alcohol, and which is there- fore not present in the fluidextract (or in the syrup which is made from the latter). PHENOLPHTHALEIN The action of phenolphthalein is much like that of the other hydroxyanthroquinones over which it appears to possess no very decided advantage; it is capable of giving rise to poisoning when overdoses are used. It is a constituent of many proprietary purgatives. THERAPEUTIC USES The evacuants of this group are widely used in small doses as laxatives in the treatment of chronic constipa- tion. Aloes, or aloin and cascara sagrada being espe- cially valuable for this purpose. Cascara often exerts a tonic action on the intestine, permitting of a gradual diminution and stopping of the dose as the intestine regains its normal function. The irritant action of the drugs of this group is so slight that they may be used in small doses for long periods without giving rise to inflammation, and the colon does not appear to habituate itself to their action, so that the same dose may continue to be effective for years. It is true, however, that with increasing obsti- nacy of the constipation larger doses are often called for in time, but this is rather from an augmentation of the condition which gave rise to constipation, and not from habituation to the drugs of this group. Cathartic doses of aloin and aloes are not especially to be recommended, cascara sagrada or senna being preferred in such cases. One of the most effective of the common cathartic mixtures is the old time com- pound infusion of senna (senna, 6; manna, 12; mag- nesium sulphate, 12; fennel, 2; water to make 100), which acts on the large intestine and in addition pro- motes peristalsis in the small intestine by preventing absorption of fluid. Rhubarb is used in the earlier stages of diarrhea to remove irritating substances and then to check intes- 282 EVACUANTS tinal movements; the aromatic syrup is especially adapted for children. DOSAGE The laxative dose of aloes is from 0.03 to 0.05 gm. {y2 to 1 grain), the purgative dose (which is not rec- ommended) is from 0.1 5 to 0.3 gm. (2 to 5 grains). As an emmenagogue the larger dose is employed. Aloin, or the extract of aloes, is commonly used with extract of belladonna or atropin in the treatment of chronic constipation, but the continued use of atropin even in small doses is not certainly free from objec- tions, and there seems less reason for its use with small doses of these drugs than with the larger ones used for active purgation. The official compound laxative pill, which is practically identical with certain proprietary preparations, contains 0.8 mg. (%o S'-^^^) o^ extract of belladonna, representing about %o ™&- (%5o grain) of atropin. This dose of atropin is probably without material effect on the intestine when a single dose is taken, but the possibility of its disturbing the digestion when long continued is worthy of consideration. The compound laxative pill also contains strychnin and ipe- cac. The aloin alone in the form of a pill will often act quite as well as the more complex mixture. To avoid gastric irritation aloes and aloin are pref- erably administered in the form of pills or, like the drugs belonging to the group of resin anhydrids, massed and enclosed in gelatin capsules. For making the necessary mass it has long been a practice to use soap or one of the gum resins like myrrh or asafetida which have the additional advantage of being some- what aromatic. Typical combinations for pills of aloes are included in the several pharmacopeias, the only objection to them being that they are set formulas instead of being adapted to the case in hand. They serve, however, to illustrate the combinations that have been used. Aloes may be prescribed somewhat as follows : Aloes ??• ?ri Soap 1.3 20 Mix and make into 10 pills. DOSAGE OF EVACUANTS 283 Aloes 1.3 20 Myrrh 0.6 10 Powdered Glycyrrhiza O.o 10 Syrup a sufficient quantity. Mix and make into 10 pills. Aloes 1.0 15 Asafetida 1-0 15 Soap 1.0 15 Mix and make into 10 pills. The dose of extract of aloes is only slightly smaller than that of the aloes itself, and there are no sufficient reasons for the use of this preparation. The laxative dose of aloin is from 8 to 20 mg. (% to % grain). Phenolphthalein is given in doses of 0.05 to 0.5 gm. ( 1 to 8 grains) in capsules of cachets. Larger does are not to be recommended in case the smaller are not effec- tive. Cascara sagrada is rarely given in substance; the fluidextract and the aromatic fluidextract may be given in doses of 0.6 to 2 c.c. (10 to 30 minims), the smaller dose is for repetition several times daily, the larger dose is given after dinner or at bedtime, pref- erably so that the action may be induced the next morning. The dose of the extract of cascara sagrada is from 0.1 to 0.5 gm. (2 to 8 grains) . One should aim to use the smallest dose which is effective, and reduce this from time to time. Rhubarb is sometimes used in the form of the pow- der, or one may obtain the drug in the form of "cubes" or "fingers" which are carried conveniently when it is desired to take several doses during the day. The laxative dose of rhubarb is about 1 gm. (15 grains) or more; with smaller doses — 0.1 to 0.3 gm. (l^^ to 5 grains) the bitter and astringent actions only are obtained. The dose of the extract of rhubarb is about one-fourth that of the crude drug. The dose of the aromatic tincture is about 2 c.c. (30 minims) and that . of the aromatic syrup about 8 c.c. (2 fluidrams). The cathartic dose of senna is about 4 gm. (60 grains) in the form of powder or infusion. The dose of the compound powder of glycyrrhiza (in reality a prepara- tion of senna) is 4 gm. (60 grains). The fluidextract is given in doses of 2 c.c. (30 minims) and the syrup in doses of 4 c.c. (1 fluidram). This dose of the syrup is only half as active as the dose given of the fluidextract. 284 EVACUANTS MATERIA MEDICA Aloe. — Aloes, U. S. P. — The inspissated juice of the leaves of Aloe vera and of other species of Aloe has long been used as medicine and is still one of the more popular and widely recognized drugs. The better grades occur in commerce in two forms: the "liv- ery" or "hepatic" containing crystals of aloin dis- tributed throughout a brown more or less opaque mass and the "vitreous" or "lucid" form which is glossy and shows no distinct crystals even under the microscope, due to fusion of the mass by heat. These forms of the drug are due to the method of preparing it and in no way indicate the source or origin. The West Indian (Curasao and Barbadoes), South Afri- can (Cape and Uganda) and East African (Socotrine and Zanzibar) varieties of aloes occur most frequently in commerce and although the two aloins found in them (barbaloin and isobarbaloin) differ somewhat in chemical constitution, they are practically uniform in their action. Extractum Aloes. — Extract of Aloes, U. S. P. — This is made by exhausting the drug with boiling water and evaporating the resulting liquid to dryness on a water bath. Because of the large amount of water-soluble material in aloes this preparation has little or no advan- tage over the drug itself. Aloinum. — -Aloin, U. S. P. — A microcrystalline pow- der obtained from aloes varying in composition and properties according to the source from which it is obtained. The aloin used in this country is chiefly barbaloin derived from the West Indian variety of the drug. Rhamnus Purshiana. — Cascara Sagrada, U. S. P. — The dried bark of Rhamnus Purshiana, a shrub or small tree growing in Northern California, Oregon, and Washington, is probably the most widely used of all North American drugs. Little is as yet known of the constituents of cascara beyond the fact that the fresh bark is bitter, nauseating and comparatively inac- tive and that these characteristics are modified on keep- ing. It is for this reason that the pharmacopeia directs that the bark should be collected at least one year MATERIA MEDICA OF EVACUANTS 285 before being used. The more widely used preparations are: Fluidextractum Rhamni Purshianae. — Fluidextract of Cascara Sagrada, U. S. P. — Each c.c. of this prepa- ration represents 1 gm. of the bark extracted with approximately 40 per cent, alcohol. Fluidextractum Rhamni Purshianae Aromaticum. — Aromatic fluidextract of Cascara Sagrada, U. S. P. — Each c.c. of this preparation represents 1 gm. of cas- cara sagrada, the bitter principle of which has been modified by magnesium oxid and the preparation is aromatized with glycyrrhiza and compound spirit of orange. Rheum. — Rhubarb, U. S. P. — The dried rhizome of Rheum officinale collected principally in China and Thibet where the drug has been used for many cen- turies. Rhubarb contains two dififerent groups of glu- cosids, rheotano-glucosids and rheoanthra-glucosids. The drug is used in the form of powder or pieces of the rhizome are directed to be chewed and swallowed. The more widely used preparations are : Erxtractum Rhei. — Extract of Rhubarb, U. S. P. — Made by exhausting rhubarb with a mixture of alcohol (8) and water (2), and evaporating the resulting liquid. Tinctura Rhei Aromatica. — Aromatic Tincture of Rhubarb, U. S. P. — Made by exhausting rhubarb (20) , Saigon cinnamon (4), cloves (4), and myristica (2) with a mixture of glycerin (10) alcohol (40), and water (40) to make the required (100) amount. Syrupus Rhei Aromaticus. — Aromatic Syrup of Rhubarb, U. S. P. — A mixture of aromatic tincture of rhubarb (IS), and a trace of potassium bicarbonate (0.1) with syrup (85). Senna. — Senna, U.S. P. — The dried leaflets of Cassia acutifolia (Alexandria Senna) or of Cassia angustifolia (Indian or Tinnevelly Senna) . This drug is frequently administered in the form of an infusion ; also in powder form as : Pulvis Glycyrrhizae Compositus. — Compound Pow- der of Glycyrrhiza, U. S. P. — A mixture of powdered 286 EVACUANTS senna (18), powdered glycyrrhiza (23.6), washed sul- phur (8), oil of fennel (0.4) and sugar (50). The more widely used fluid preparations of senna are: Fluidextr actum Sennae. — Fluidextract of Senna, U. S. P. — Each C.C. of this preparation represents 1 gm. of the drug extracted with diluted alcohol. Syrupus Sennae. — Syrup of Senna, U. S. P. — A mixture of fluidextract of senna (25), oil of coriander (0.5), and syrup (to make 100). Phenolphthaleinum. — Phenolphthalein, N. N. R. — A product of the interaction of phenol and phthalic anhy- drid which has long been in use as an indicator in chemical analysis. Phenolphthalein occurs as a white or grayish white crystalline powder that is soluble (1 :12) in alcohol but nearly insoluble in water. Acid solutions are colorless ; alkaline solutions are bright red. SULPHUR It is well known that sulphur acts as a laxative, but the exact mechanism of this action is not known with certainty. It was formerly believed that when sulphur was taken by the mouth it passed the stom- ach unchanged and that it was partly converted into sulphids in the intestine, these being finally absorbed into the circulation. This view was supported by the fact that the diges- tion of sulphur w;ath intestinal mucous membrane results in the formation of hydrogen sulphid. It now seems more probable that when sulphur is administered to man, it is partly converted into sul- phurous acid by the mucous membrane of the intes- tine, and that the acid causes irritation with hyperemia and increased peristalsis. When large doses of sulphur are taken, only a small proportion undergoes this change as a rule, and it is possible that the rest forms an insoluble mass which increases peristalsis slightly as any insoluble matter does. Rarely serious symptoms of poisoning have fol- lowed the administration of large doses of sulphur, presumably due to the absorption of hydrogen sulphid, but this must be a rare accident indeed. THE MERCURIALS 287 That traces of hydrogen sulphid are formed in accordance with the older idea is extremely probable despite the evidence against it elicited by recent inves- tigators, since the gas is eliminated by the lungs of those who have taken sulphur, and the elimination in this way is said to constitute one of the objections to its use. DOSAGE Sulphur, because of its insolubility and practical inertness, may be administered in liberal doses ; 4 gm. (60 grains) being frequently given. It is still used in medicine in the form of the compound powder of glycyrrhiza referred to under senna. MATERIA MEDICA Sulphur is not volatile at ordinary temperatures, is insoluble in water or alcohol, but is soluble in fats and in ether. It is official in the Pharmacopeia in three forms : Sulphur Latum. — Washed Sulphur, U. S. P. Sulphur Praecipitatum. — Precipitated Sulphur, U. S. P. Sulphur Sublimatum. — Sublimed Sulphur, U. S. P. — In any of the foregoing forms it should contain from 99 to 99.5 per cent, of pure sulphur. 3. EVACUANTS ACTING ON THE SMALL AND THE LARGE INTESTINES THE MERCURIALS The insoluble purgative mercurials, including calomel (mild mercurous chlorid), mass of mercury, (blue mass), and mercury with chalk (gray powder), have little action on the stomach unless their passage through it is delayed ; their action on the intestine is mildly irri- tant, increasing peristalsis directly, and possibly increasing the secretion of the intestinal glands, thereby promoting peristalsis indirectly and causing soft stools with little or no pain, or with larger doses causing watery stools with some colic. 288 EVACUANTS Only a small part of the dose of a mercurial is absorbed when evacuation is induced promptly, but when there is interference with the movement of the intestinal contents the mercurials are absorbed. If there is great interference with the passage of the intes- tinal contents after a large dose of calomel, or other mercurial salt, diuresis is induced. This interference is sometimes secured by administering opium or mor- phin with small doses of calomel, but if it occurs after large doses toxic symptoms may result. Other steps should be taken to induce purgation should one of the mercurials fail to act, except when they are taken for their diuretic action. The mercurials were long supposed to increase the secretion of bile, but this error arose from the fact that they protect the bile from decomposition by the intes- tinal flora, and prevent its absorption by hastening its passage through the intestines, so that it appears in the stools if the dose be large enough to cause liquid evacu- ations. The green color of the stools in such cases is sometimes attributed to bile, but it is probably due to the formation of a sulphid of mercury. There is much uncertainty concerning the reputed antiseptic action of calomel in the intestine. It does not destroy the bacteria in all probability, or greatly inhibit their growth during their stay in the intestine, but great numbers are removed during the purgation. It is a matter of common experience, however, that the condition commonly called "biliousness" (which does not require further description) is often relieved far more effectually even by a merely laxative dose of calomel, than by other evacuants which act as promptly as calomel. On the other hand, many persons find that headaches which are attributed to the products of intestinal putrefaction resulting from bacterial activity, are relieved quite as well by a quickly acting saline purge as by calomel. This does not disprove the claim that calomel has an especial action in the condition mentioned, for obviously, an active cathartic which sweeps out the intestinal contents with a large amount of water in a very short time must remove undigested and putrefying food and enormous numbers of bac- THE MERCURIALS 289 teria, and thus give relief, but stress is laid on the fact that a mildly acting dose of calomel or other mer- curial, which causes only a soft, not liquid stool, gives decided relief from certain forms of headaches which are not relieved by vegetable laxatives. Calomel often fails to relieve the diarrhea of infants which is caused by bacterial activity, but this does not prove that calomel is not bactericidal. The hypersecre- tion of mucus in such conditions affords excellent opportunities for the multiplication of bacteria after the calomel has passed through the intestine, and it is not feasible to keep the entire intestinal canal supplied with the drug, since so much would have to be used that systemic poisoning would ensue. Calomel is more useful in preventing the develop- ment of the severe symptoms when taken in time, than in curing them after full development. Mercury with chalk is less irritating than calomel; the chalk is said to interfere with peristalsis sometimes. Calomel has little action on the uterus, and moderate doses are therefore not contraindicated in pregnancy. The action of blue mass is much like that of mercury and chalk. THERAPEUTICS The therapeutic indications for the use of the mercu- rial purgatives is sufficiently indicated in the discussion of their actions. Calomel, blue mass or mercury with chalk may be used when there is need for a mild laxa- tive, or in somewhat larger doses when a cathartic is required. Headache due to intestinal putrefaction, the condition called "biliousness," putrefactive diarrhea, and in fact any condition attended with intestinal putre- faction, may serve as an indication for one of the mercurial purgatives unless there is a specific contra- indication for their use. DOSAGE Calomel was used formerly in enormous doses for a variety of conditions and salivation was a common result, but with a more rational and more limited use of the drug this condition is now rare. 290 EVACUANTS As a result of the reaction following the use of such large doses of calomel physicians went almost to an opposite extreme, and minute, but frequently repeated doses came into favor. If one desires to use such small doses from 3 to 5 mg. (%o to %o grain) may be given every fifteen minutes until ten doses are taken. This method of administration sometimes induces nau- sea without any apparent advantage in the action, but it is possible that it secures a more prolonged, or more frequently repeated, antiseptic action in the intestine. A dose of from 30 to 60 mg. (% to 1 grain) will often act as a laxative after from eight to twelve hours, but it is preferable to give a saline laxative about four to six hours after administering the calomel unless purgation has taken place. Doses of from 0.15 to 0.30 gm. (2y2 to 5 grains) of calomel induce severe purga- tion with copious watery stools attended with severe griping and a considerable degree of nausea, but such doses have little advantage over smaller doses followed by a saline purgative which causes an equally active purgation with much less discomfort. From 8 to 15 (% to 14 grain) of calomel given to a child at the beginning of an attack of diarrhea, and followed by doses of 5 mg. (i^o grain) twice a day for several days, will often avert more serious symptoms. It is probable that doses of calomel larger than 0.12 gm. (2 grains) are never required for an adult; should this fail to cause purgation dependence should be placed on other evacuants, particularly the salines. Sodium bicarbonate is commonly added to calomel under the mistaken idea that it is necessary to admin- ister an alkali with the mercurous salt to prevent its conversion into a mercuric salt by the gastric juice. The amount of sodium bicarbonate usually employed is wholly inadequate to neutralize more than a small part of the gastric juice in the stomach, and no such change takes place when calomel is subjected to the action of the gastric juice without neutralization. Mass of mercury or mercury with chalk may be given in doses of 0.25 gm. (4 grains). SALINE EVACUANTS 291 MATERIA MEDICA Hydrargyri Chloridum Mite. — Mild Mercurous Chlorid, U. S. P. — Calomel occurs as a heavy, white, impalpable powder that is odorless, tasteless and per- manent in air. It is practically insoluble in water, alcohol or ether but undergoes slow changes when exposed to light or when brought in contact with alka- lies, acids or decomposable salts. The official sub- stance should contain not less than 99.5 per cent, of mercurous chlorid, HgCl, and should be free from mercuric chlorid and other soluble impurities. Massa Hydrargyri. — Mass of Mercury, U. S. P. — Popularly known as "blue mass," this preparation is a mixture of mercury (33) with powdered glycyrrhiza (10), powdered althea (15), glycerin (9), and honey of rose (to make 100). It occurs as a homogeneous, bluish mass which may be readily formed into pills. Hydrargyrum Cum Creta. — Mercury with Chalk, U. S. P. — This preparation, popularly known as__gray powder, occurs as a light gray, rather damp, gowder made by thoroughly mixing mercuty (38), clarified honey, (10), and prepared chalk (57) with enough water to moisten the mass, and then shaking until the globules of mercury are no longer visible under a low power lens. The mixture is subsequently dried and powdered. SALINE EVACUANTS Wlien a concentrated solution of one of the slightly diffusable salts is taken into the stomach it becomes diluted with the gastric secretion, or, if the stomach was previously empty, it withdraws fluid from the cells of the stomach, causing irritation, with nausea and vomiting at times. The rate at which this dilution in the stomach occurs in the absence of a sufficient amount of fluid pre- viously present, will depend to a considerable degree on the relative amount of fluid in the blood and tissues. If they contain an abundance of water, secretion will be active as a rule, and when the solution of the salt has become fairly dilute it will pass into the intestine, but if the blood and tissues contain relatively little 292 EVACUANTS water gastric secretion is slow and nausea and vomit- ing may result. This is best illustrated by the protocols of two laboratory experiments (hitherto unpublished). Two dogs, A. and B., received an equal amount of sodium sulphate. Dog A. received the salt in concentrated solution after having been deprived of water for twenty-four hours, and vomited within about five minutes ; he even refused water owing to nausea, but when enough water was passed through a tube into his stomach to dilute the salt somewhat, he drank water almost immediately. Dog B. was given the same amount of salt in dilute solution after having had the usual allowance of water; he showed no signs of nausea, and ate food at once (showing absence of nausea). When a solution of salt has passed into the intes- tine it retains its water of solution until its concentra- tion has been so reduced as to be approximately equal to that of the blood, the distention of the intestine by the fluid causing peristalsis, the action being exerted in the small and large intestine. The salts of this group are not absolutely non- absorbable, and when peristalsis is prevented by any means the solutions may be absorbed into the circula- tion completely. If the absorption takes place, as it always does to some slight extent, the salt is excreted by the kidney, and it may induce diuresis if the absorption has been sufficiently rapid, for the renal epithelium, in marked contrast to that of the intestine, is readily permeable to inost of these salts. Occasionally, large doses of magnesium sulphate have been absorbed in pathologic conditions of the bowel more rapidly than they could be eliminated by the kidney, and have given rise to symptoms of poi- soning, and in a few instances death has followed, but this accident is not to be feared except when obstruc- tion of the intestine exists, and, of course, no purga- tive should be given in such conditions. When magnesium sulphate (Epsom salt) is absorbed rapidly, or is injected intravenously, in sufficient amounts, it depresses the nervous system and induces complete narcosis with muscular relaxation. The depressant action following the subcutaneous injec- tion is now being utilized in the treatment of the . chronic form of tetanus with reported success. The SALINE EVACUANTS 293 absorption from the intestine is probably too slow in any case to induce serious poisoning unless the kidneys are diseased or marked depression of the central ner- vous system previously exists. The other purgative salts are devoid of toxic actions after absorption. Mag- nesium citrate should be open to the same objection as the sulphate, but no cases of poisoning have been reported after its use, so far as we are aware. The precise mechanism of the purgation induced by these salts is not understood fully, but there is no reason to doubt that their action results largely from their capacity for retaining water and thus distending the bowel. This also explains why concentrated solu- tions require so much longer time than dilute before causing purgation, and twenty hours may elapse before their effect is induced, whereas dilute solutions are commonly effective within three hours. The purgative salts have a disagreeably bitter taste, and not infrequently concentrated solutions are taken in order to lessen the time required to drink them; when they are taken in this way a glass of water should be taken immediately to dilute them in the stomach, unless the removal of an excess of water from the tis- sues is the object in view, in which case concentrated solutions are usually employed. In such cases, gastric irritation may be avoided by taking small amounts of the solution at short intervals. It is probable that moderately dilute solutions would be more serviceable in such cases than the concentrated ones commonly used. The amount of fluid which can be removed by purgation is very much greater than that required for the moderate dilution of the salt, and the absence of gastric disturbance and the much more rapid effect of the dilute solutions suggest that they might be employed even in dropsical conditions. Magnesium sulphate is partly converted into car- bonate in the intestine, and the liberated sulphuric acid combines with the alkalies which are absorbed and excreted in the urine ; thus depriving the body of them. This becomes a matter of importance when the salt is administered continuously for some time, and it is customary in .such cases to administer sodium bicar- bonate to make up the deficiency. This loss of alkali 294 EVACUANTS does not occur with the use of sodium sulphate or the other purgative salts. The administration of the sulphates (Epsom salt or sodium sulphate) is followed by the formation of some hydrogen sulphid in the small intestine, and this may give rise to discomfort, with rumbling. The insoluble magnesium carbonate and the oxid, or calcined magnesia, are partly converted in the stomach into the soluble chlorid, and in the small intestine partly into the soluble bicarbonate. Should they fail to undergo the change they do not cause purgation, and an accumulation of the insoluble carbonate may occur after large doses and cause intestinal obstruction. Magnesium oxid has an advantage over the car- bonate in that it does not yield carbon dioxid gas when neutralized in the stomach. The oxid and carbonate have the advantage over the soluble salts of this group, of being tasteless, and requiring a less bulky dose. Potassium citrate and bitartrate are absorbed some- what more rapidly than the other purgative salts, so that small doses induce diuresis without purgation, while large doses cause both, but at best they are only mild laxatives, rarely giving rise to watery stools, but they are active diuretics. Sodium chlorid or the ordinary table salt in proper dilution is also useful as a laxative and may at times advantageously replace other objectionably bitter salines. Various acid fruits are mildly laxative, partly because of the citric and malic acids which form citrates and malates in the intestine, and partly because of their cellulose, pectin and sugars which are in part indigestible and absorb liquid, thus increasing the bulk of the intestinal contents in much the same way that the purgative salts do. THERAPEUTIC USES The uses of the saline laxatives are indicated largely in the discussion of their actions. They are useful when for any reason a rapid evacuation of the bowels is indicated, as in poisoning by slowly absorbable sub- stances which cannot be removed from the stomach; SALINE EVACUANTS 295 to remove bacteria and fermenting masses of food ; to remove dropsical effusions, and in simple constipation. They have an especial usefulness in that they do not cause irritation when used in dilute solutions. This would be an appropriate place to' discuss the use of purgative mineral waters were it not for the fact that there is no obvious advantage in their use. There can be little doubt that the extraordinary repu- tation enjoyed by many of these waters depends on the success attained in the treatment of patients at the springs, where special attention is given to all the habits of. life, and where only the most pleasant condi- tions obtain. There is no satisfactory evidence that the ordinary purgative mineral waters have any impor- tant action not possessed by a simple solution of the same salts made artificially, and, in f_act, many of the mineral purgative waters are more or less artificial, since some are mixtures of waters from different springs while others consist of evaporated spring water, and during the process of evaporation changes occur in the salts present. Much has been made of the fact that the waters of many mineral springs are radio-active, but radio- therapy is almost wholly in the experimental stage. One especial advantage which natural mineral waters have over the solutions of purgative salts as they are too often taken is that they are very dilute, and the patient is thus required to take a fairly large amount of water with them. This advantage can be secured so easily, however, by attention to the proper dilution of purgative salts that it is not sufficient to justify the expense of the natural waters. Magnesium sulphate is largely used in obesity because the magnesium ion combines in part in the intestine with fatty acids which are thus prevented from being absorbed. The tasteless magnesium oxid and carbonate are often used as laxatives in children, especially when it is desired to neutralize the hyper- acidity of the stomach. The normal sodium phosphate is alkaline in reaction and when it is desired to increase the acidity of the urine the acid phosphate, NaHjPO^, is to be preferred. 296 EVACUANTS or the official di-sodium phosphate may be used adding about three times as much dilute phosphoric acid to it. A concentrated solution of magnesium sulphate is used as a local application in inflammatory conditions. DOSAGE The amount of the several salines required to accom- plish a given purpose depends largely on accompanying factors, such as the degree of dilution and the suscep- tibility of the individual, which vary considerably. Epsom salt or magnesium sulphate, the effervescent preparation of this substance and sodium sulphate, or Glauber's salt, are usually given in doses of 16 gm. (240 grains) or more, dissolved in from one-half to a full tumbler of cold water. Potassium and sodium tartrate, or Rochelle salt, is given in doses of 8 gm. (120 grains). Sodium chlorid, or ordinary "table salt," and sodium phosphate are given in doses of approximately 4 gm. (60 grains), well diluted with water. The effervescent preparation of sodium phos- phate is usually given in double the dose of the simple salt or about 8 gm. (120 grains). Magnesium sulphate has been used frequently in controlling muscular rigidity in tetanus. One observer reports that he begins with tentative doses of not over 5 c.c. (75 minims), increasing until slight general anesthesia is induced. He reports that as much as 20 c.c. (5 drams) of a 10 or 15 per cent, solution may be injected subcutaneously three or four times daily. He reports that he never saw respiratory failure, but a solution of calcium chlorid is kept at hand. Should the respiration show signs of failure, 5 c.c. (75 min- ims) of a 5 per cent, solution are injected intra- venously. Magnesium oxid — ^heavy or light — is given in doses of 2 gm. (30 grains) and the carbonate in somewhat larger amounts, 3 gm. (or 45 grains). Because of the fact that these two substances are insoluble in water they must be administered in the form of mixtures with water or in the case of the heavy magnesium oxid the dry powder can be placed on the tongue and washed down with cold water. SALINE EVACUANTS t^l The solution of magnesium citrate is usually dis- pensed in bottles sufficient for one dose which is drunk as an effervescing draught. Potassium bitartrate, one of the more agreeable of the salines because of its acid taste, is given in doses of 2 gm. (30 grains) mixed with water. Potassium citrate may be given in about the same dose 2 gm. (30 grains) and the effervescent preparation in double this dose--4 gm. (60 grains). The administration of the salines is somewhat sim- plified in that their action is enhanced by the presence of water and that, whether water-soluble or not, they are preferably given with copious draughts of water. MATERIA MEDICA Magnesii Sulphas. — Magnesium Sulphate, U. S. P. — The official "Epsom salt" contains not less than 97.7 per cent, of pure MgSO^ -f 7H2O. It occurs as small, colorless and odorless crystals that have a cooling, saline and bitter taste. It is freely soluble (1:1) in water but practically insoluble in alcohol. Magnesii Sulphas Effervescens. — Effervescent Mag- nesium Sulphate, U. S. P. — A mixture representing magnesium sulphate (50 per cent, crystals) with sodium bicarbonate (40), tartaric acid (21), and citric acid ( 14) . It occurs as irregular granules that should be kept in well-stoppered bottles. Sodii Sulphas. — Sodium Sulphate, U. S. P. — This salt, popularly called Glauber's salt, should contain 99 per cent, of NajSO^ -|- 10 HgO, or about 44 per cent, of absolute NajSO^. This salt occurs in large or small colorless crystals that are odorless and have a bitter, saline taste. It is freely soluble (1:3) in water, but is practically insoluble in alcohol. Sodii Chloridum. — Sodium Chlorid, U. S. P. — The official salt contains not less than 99 per cent. NaCl. It hardly requires description. Sodii Phosphas. — Sodium Phosphate, U. S. P. — Di-sodium-ortho-phosphate should contain not less than 99 per cent, of NaaHPO^ -f 12 H^O, or about 40 per cent, of absolute NaHPO^. It may occur in large or small colorless crystals that should be odorless 298 EVACUANTS and have a cooling, saline taste. It is freely soluble (1 :5.5) in water but practically insoluble in alcohol. Sodii Phosphas Effervescens. — Effervescent Sodium Phosphate, U. S. P. — A mixture of exsiccated sodium phosphate (20), sodium bicarbonate (48), tartaric acid (25), and citric acid (16). This mixture occurs in the form of irregular granules that should- be kept in well- stoppered bottles. Sodii Bfphosphas. — Sodium Acid Phosphate, N. N. R. — Sodium biphosphate or sodium acid phos- phate should contain not less than 82 per cent, of anhydrous sodium dihydrogen phosphate. It occurs as transparent crystals or a white crystalline powder having a saline, somewhat acid taste. It is very solu- ble in water, but insoluble in alcohol. It is best administered in sweetened water like lemonade. It should not be prescribed in solution with hexamethyl- enamine. Magnesii Oxidum. — Magnesium Oxid, U. S. P. — This preparation, which is frequently referred to as "calcined magnesia," occurs in the shops in two forms, the heavy and the light magnesium oxid. In either form it should contain after ignition not less than 96 per cent, of MgO. It occurs either as a bulky, or a dense, fine white powder that is without odor, but has an earthy, not saline, taste. Both forms are almost insoluble in water and quite insoluble in alcohol. The light magnesium oxid unites with water to form a gelatinous hydroxid, differing in this respect from the denser, heavy magnesium oxid. The now widely used magma magnesia or milk of magnesia is a magnesium hydroxid made by precipitating a solution of magne- sium sulphate with sodium hydroxid and washing the resulting magma with distilled water to free it of the sulphates. Magnesii Carbonas. — Magnesium Carbonate, U. S. P. — The official magnesium carbonate is a mix- ture containing carbonate, hydroxid and water that should yield on ignition, approximately 40 per cent, of SALINE EVACUANTS 299 MgO. It occurs in white, friable masses or as a bulky white powder without odor and having a slightly earthy taste. Magnesium carbonate is practically insoluble in water and in alcohol but is soluble with effervescence in dilute acids. In pharmacy it is used chiefly to make : Liquor Magnesii Citratis. — Solution of Magnesium Citrate, U. S. P. — A solution containing about 10 per cent, of a mixture of neutral and of acid magnesium citrates with potassium citrate and free carbon dioxid. The solution should be freshly prepared when wanted. Potassii Citras, Potassium Citrate, U. S. P., and Potassii Citras Effervescens, Effervescent Potassium Citrate, U. S. P., have been described under the diu- retics. Potassii Bitartras. — Potassium Bitartrate, U. S. P. — This product, popularly known as cream of tartar, con- tains not less than 99 per cent, of KHC4H^08. It occurs in the shops as a white gritty powder, odorless and having a pleasant, acidulous taste. It is only slightly soluble ( 1 : 200) in water and nearly insoluble in alcohol. Potassium bitartrate is one of the ingre- dients of the compound jalap powder referred to pre- viously. Potassii et Sodii Tartras. — Potassium and Sodium Tartrate, U. S. P. — Popularly known as Rochelle salt, it contains not less than 99 per cent, of KNaC^HiOg -I- 4H2O. It occurs as la^ge colorless crystals or as a white powder odorless and having a cooling saline taste. Rochelle salt is freely soluble (1 :1.2) in water but practically insoluble in alcohol. Potassium and sodium tartrate is the main ingredient of : Pulvis Effervescens Compositus. — Compound Effer- vescing Powder, U. S. P. — This is among the oldest of the effervescing saline draughts ; it is popularly desig- nated "Seidlitz powder" and is directed to be dispensed in two papers. The blue paper contains a mixture of sodium bicarbonate (2.5 gm.) and sodium and potas- sium tartrate (7.7 gm.) ; the white paper contains tar- taric acid (2.1 gm.). ' 300 EVACUANTS ALKALOIDAL EVACTJANTS PHYSOSTIGMIN It is apparent from the discussion of the physiology of the gastro-intestinal movements that any drug which stimulates the parasympathetic nerves (vagus and erigens) will cause intestinal peristalsis, or contraction of the muscles of the intestinal walls. We have a number of agents which stimulate the endings of these nerves, or which increase their excita- bility to the normal stimuli which reach them through the blood, but these drugs have other actions which usually overshadow their actions on the intestine and prevent their use as evacuants. Pilocarpin and physostigmin stimulate the vagus and erigens, and induce active movements, not only in the intestine but also in the stomach and uterus. Physo- stigmin probably acts directly on the smooth muscle of the intestine rendering it hyperexcitable to normal stimuli, and thereby promoting peristalsis. Large doses cause tonic ring-like contractions of the intestine and interfere with the passage of the contents. Large doses of physostigmin cause violent uterine contractions which may be tonic in character. There seems to be Httle reason for the use of any of the pharmaceutic preparations of physostigma, since they contain eseridin and calabarin in variable amounts in addition to physostigmin. Eseridin resembles phy- sostigmin in its physiologic actions, but it is weaker, and calabarin has a strychnin-like action. Physostigmin sulphate is hygroscopic and the solu- tion decomposes rapidly with the formation of a ruby- red substance known as red resin. The salicylate is soluble in about 150 parts of water. It is somewhat more stable than the sulphate in solution but it also undergoes the same decomposition. THERAPEUTIC USES The actions of physostigmin on the intestine are usually overshadowed by its effects on the central ner- vous system, and it is far from satisfactory as an evacuant, its use as such appearing to depend rather on ALKALOIDAL EVACUANTS 301 a forlorn hope in the search for a dependable purgative after abdominal operations. The use in man has been encouraged perhaps by the observation that it is a very much more valuable purgative for the herbivora. The indication for which physostigmin is used as a purgative is atony of the intestine. It should not be used in the presence of inflammation of the intestine or when there is mechanical obstruction. The local and systemic actions of physostigmin are counteracted by atropin in doses of 1 mg. (%o S^^^^)> which may be repeated once or twice if necessary. DOSAGE Physostigmin salicylate is used as an evacuant in doses of 1 mg. (%o grain) and doses of even 2 mg. (%o grain) are sometimes given, but Sollmann states that such doses are somewhat dangerous, this being especially true in the presence of depression of the cen- tral nervous system. ATROPIN; STRYCHNIN Atropin and strychnin are never used alone as evacu- ants, but both of them are added to other substances which induce purgation, and atropin is used to relieve spasm of the intestine which interferes with the pas- sage of the intestinal contents. Small doses of atropin are said to stimulate Auer- bach's plexus, while large doses depress it, and all doses which have any effect depress the parasympa- thetic (vagus and erigens) endings in the intestine. This is of benefit when overstimulation causes tonic contraction instead of normal peristaltic waves. There is a possible disadvantage in the long-continued use of even very small doses of atropin which is gen- erally overlooked or disregarded, but which is worth considering. Atropin depresses the vagus endings in all of the organs which it supplies, and even small doses tend to abolish those parts of the gastric, pan- creatic and biliary secretions which are under nervous control. It is certain that the minute amount of atro- piii (Mo ™S- — %50 gr'iin) commonly used with aloin in laxative pills has no very pronounced action on these secretions when a single dose is taken, but, on the other 302 EVACUANTS hand, we have no knowledge of the effects of its long- continued use, and in the absence of definite advantages it would be better to omit it when laxative pills are to be taken for prolonged periods. Strychnin is used in doses of 1 mg. (%o gf'iiii), which are correspondingly larger than those of atropin, and it seems to be useful through its stimulation of Auerbach's plexus. Extremely small doses of nicotin stimulate, large doses paralyze, the ganglia of the enteric system, and it is a matter of common observation that smoking often promotes peristalsis. Nicotin is not used thera- peutically, however, for this purpose. 4. EVACUANTS ACTING ON THE RECTUM Irritation of the rectum reflexly induces peristalsis in the colon and leads to evacuation of the feces. This rectal irritation may be induced in various ways, the simplest method being a form of local irritation by means of a suppository of soap or glycerin, the injec- tion of a small amount of glycerin or distention by the injection of cold water, or warm water to which soap, glycerin, or other mild irritant, has been added. If constipation is the result of sluggishness of the movements of the colon, the moderate distention of the rectum by cold water alone will usually suffice to cause a normal evacuation. When the feces have become hard and dry through absorption of an undue amount of their fluid, the normal peristaltic movements are insufficient to drive the intestinal contents along, espe- cially if these have become aggregated into large masses, and the addition of soap to the warm water which is injected slowly, and in sufficient amount so that it penetrates into the colon, aids in softening the masses so that they become at once more plastic and more slippery, and then the peristalsis which is induced by distention of the rectum will suffice to evacuate them. It is probable that a tube cannot be passed through the rectum high into the colon, but if the fluid be injected slowly and with very slight pressure — not more than that exerted by holding the reservoir a foot EVACUANTS ACTING ON RECTUM 303 above the recumbent patient — it will pass gradually into the colon, and may even find its way into the ileum. Daily stools do not invariably prevent the accumu- lation of such dry, hard masses of fecal matter, for the colon is so voluminous that soft feces may be forced past such masses which gradually increase in size until they finally obstruct the entrance into the rectum, and cannot be evacuated until they are softened or otherwise broken up. A warm 5 per cent, solution of sodium sulphate is preferable to water alone for such an enema, because the salt delays the absorption of the water, and permits it to act on the fecal masses for a longer time than it would otherwise. Glycerin is irritant through its capacity for with- drawing water from the tissues. When introduced into the rectum it sets up peristalsis almost at once by reflex action on the colon. It may be injected in pure form, or added to water or used in the form of a sup- pository. Soap may be added to warm water to increase its irritant action on the rectum, or to soften fecal masses as just mentioned, or it may be used in the form of a cone, cut from a piece of castile soap and inserted about 2 inches. Molasses, oil of turpentine and various other irri- tants are used as additions to warm water enemas, but they do not require detailed discussion. DOSAGE Glycerin as such is injected into the rectum in doses of from 4 to 15 c.c. (1 to 4 fluidrams) or used in the form of a glycerin suppository. When used in the form of an enema it is usually added in quantities of from 15 to 30 c.c. (4 to 8 fluidrams) to from 500 to 1,000 c.c. (a pint to a quart) of warm, but not hot, water, to be injected slowly at one time. Soap enemas are made by dissolving not exceeding 5 per cent, by weight of either hard or soft soap in from 500 to 1,000 c.c. (a pint to a quart) of lukewarm water. Cold water, while often efficient, is not so uni- 304 EVACUANTS formly satisfactory as water at, or slightly above, the body temperature when fecal masses are to be soft- ened. MATERIA MEDICA Glycerinum. — Glycerin, U. S. P. — This substance, more properly designated glycerol, is obtained by the decomposition of fats or fatty oils and should contain not less than 95 per cent, of the triatomic alcohol, glycerol. It occurs as a clear, colorless liquid of a thick syrupy consistence, odorless, sweet to the taste and producing a sense of warmth in the mouth, due probably to its great afifinity for water. It is miscible in all proportions with water and with alcohol. Suppositoria Glycerini. — Suppositories of Glycerin, U. S. P. — ^Each suppository contains approximately 3 gm. (45 grains) of glycerin combined wiht stearic acid soap. Sapo. — Soap, U. S. P. — The official soap is directed to be prepared from sodium hydroxid and olive oil and corresponds to what is known in commerce as "pure Castile soap." For use as a suppository a piece of soap is formed into suitable shape and size to weigh approximately 4 gm. (60 grains) . Sapo Mollis. — Soft Soap, U. S. P. — A soap pre- pared from potassium hydroxid and linseed oil because it is more readily soluble in warm water is frequently used in place of olive oil and sodium hydroxid or hard soap in the making of enemas. MISCELLANEOUS EVACUANTS It has been stated frequently that many cases of intestinal stasis or chronic constipation are due to an overdigestion of the food as compared with nor- mal conditions, and that the absence of bulk and nec- essary moisture retard or otherwise prevent peristalsis. An effort has been made to overcome these, largely mechanical, factors by the administration of substances which are not in any way affected in the stomach or intestines but which will increase the bulk of the feces, prevent undue absorption of moisture and thus facili- MISCELLANEOUS EVACUANTS 305 tate peristalsis. It has long been recognized that certain foods, such as fruits and whole wheat bread, containing a comparatively large percentage of indiges- tible material, will assist materially in establishing regular habits. Much the same effect can be obtained by the admin- istration of agar-agar, which has long been used in bacteriologic work as a solidifying material for culture mediums. It is a gelatin-like substance extracted in the East Indies from various seaweeds and has the property of absorbing and retaining water. It prevents the dehydration of feces in the large intes- tine by holding water tenaciously and thereby serves to increase the bulk of the feces. Liquid petrolatum or liquid paraffin has long been used to accomplish much the same purpose, though originally it appears to have been given largely with the idea of lubricating the feces. When adminis- tered before meals it is mixed with the intestinal material, protecting it to some extent from digestion and preventing the absorption of the contained water. Lane advised that the heavy Russian mineral oil, or liquid petrolatum, be used to promote the evacua- tion of the bowels ; but Bastedo, who investigated the subject for the Therapeutic Research Committee of the Council, reports that there is no important differ- ence between the actions of the Heavy Russian, and the heavy and light American mineral oils. The lightest of the American specimens that he investigated had a specific gravity of 0.857 at 22 C, and was markedly fluorescent. All specimens used caused nausea at times, and this was independent of whether the entire dose — from % to 3 ounces (15 to 60 c.c.) was given at once or in three parts. The oil sometimes shows a tendency to ooze from the anus between the times of going to stool. It must be understood that Bastedo's report did not take into consideration many of the very light American mineral oils, such as are commonly used for spraying. 306 EVACUANTS DOSAGE Agar-agar is given in doses of from 5 to 15 gm. (75 to 240 grains) of the coarsely comminuted sub- stance and may be taken either in water or mixed with food. Liquid petrolatum should be a colorless and taste- less product, and may be prescribed as "Petrola- tum Liquidum Leve" or "Grave," in quantities of from 15 to 30 c.c. (4 to 8 fluidrams) half an hour or an hour before meals, or in larger doses, from 30 to 60 c.c. (1 to 2 fluidounces) on retiring. It is odor- less and tasteless and can be taken alone, or, if pre- ferred, a small amount of oil of peppermint may be added to give a distinctive flavor. CHOLAGOGUES Cholagogues are agents which stimulate the liver cells, causing an increased secretion of bile. The greater part of the bile which is secreted normally disappears during its passage, along the intestine, but various drugs which increase intestinal peristalsis, or which interfere with the decomposition of the bile by bacteria, cause it to appear in the feces in increased amounts, and such drugs were formerly termed chola- gogues, though most of them have no action on the liver cells. Later investigations have shown that very few drugs except the salicylates and bile itself have any true cholagogue action. Bile is partly an excretion, containing such waste products as cholesterin and lecithin, but cholagogues are employed only with reference to the influence of bile in promoting the splitting and absorption of fats in the intestine, or as an adjuvant to the action of cer- tain evacuants, such as aloes. Bile also indirectly pro- motes the digestion of proteins in the intestine, since unabsorbed fats envelop proteins and interfere with the action of digestive enzymes on them. The secretion of bile varies with the amount of blood which circulates through the liver, and it seems probable that a hormone present in the blood stimulates the liver cells to secrete bile. The introduction of hydrochloric acid into the duodenum causes an CHOLAGOGUES 307 increased biliary secretion, and it seems probable that this is due to the secretin which is formed from pro- secretin by the acid. Ox bile, or salts of the bile acids and salicylic acid are the only drugs which are commonly used as cholo- gogues, and their action is feeble at best. The appearance of fat in undue amounts in the feces suggests the use of cholagogues, but there are seldom any clear indications for their use in adults, except perhaps as an addition to evacuants. Cholagogues are contraindicated in the presence of jaundice due to obstruction of the bile ducts. DOSAGE The dose of the purified ox bile is 0.5 gm. (7% grains), but much larger amounts may be used. It is best administered in the form of pills, or preferably in gelatin capsules which have been treated with for- maldehyd to render them less soluble in the stomach. MATERIA MEDICA Pel Bovis. — Oxgall, U. S. P. — The fresh bile of Bos taurus, used in medicine principally as : Pel Bovis Purificatum. — Purified Oxgall, U. S. P. — A yellowish-green soft solid, or, more frequently, a yellowish or greenish-yellow powder, having a peculiar odor and a bitter taste. It is prepared by concentrating oxgall and purifying with alcohol. Purified oxgall is very soluble in water or alcohol but is practically insoluble in ether. CHAPTER IX.— EMETICS, ANTI- EMETICS AND EXPECTORANTS EMETICS The first stage of the actions of emetics begins with nausea, salivation, increased bronchial secretion, usually sweating, and often a flow of tears. Great muscular weakness attends this stage and the act of vomiting is usually preceded by increased respiration which then becomes irregular and ceases during the vomiting. Usually the saliva drools from the mouth of animals just before emesis occurs. Vomiting is accomplished by the coordination of a series of actions which include the following: The pylorus is closed, preventing the passage of the con- tents of the stomach into the intestine ; there are anti- peristaltic movements of the antrum of the stomach, which move the contents into the fundus; the cardia relaxes while the abdominal muscles contract, com- pressing the stomach and forcing its contents out through the esophagus and the mouth, and sometimes through the nose. The muscles of respiration are fixed, preventing the aspiration of the vomitus. The reflexes which control the several active move- ments and inhibitions of the vomiting act are coordi- nated through a center in the medulla which lies near that of respiration and which is evidently associated with it physiologically. This center is spoken of as the vomiting center, and stimulation of it either directly or reflexly leads to nausea and vomiting. Occasionally the process is arrested before vomiting actually occurs, and the stage of nausea and general muscular depression may then persist for some time. The fact that vomiting depends on the coordina- tion of reflexes through the central nervous system explains why emesis cannot be induced during narco- sis. This must be remembered when it becomes nec- essary to empty the stomach of a patient who is under the influence of a narcotic such as morphin. EMETICS 309 There are two types of emetics : those which irritate the sensory nerve ends in the gastric mucous membrane in a specific manner, whereby vomiting is reflexly induced, and those which act directly on the center without coming in contact with the gastric mucous membrane. Nearly all drugs which violently irritate the mucous membrane of the stomach cause vomiting unless they also induce narcosis or collapse before the emetic action can be developed, and this coordination of the several actions requires some little time, usually from two to ten minutes. Sensory irritation in the stomach does not always cause emesis, and certain drugs induce nausea and vomiting without causing painful stimuli. The fact that irritants so commonly cause vomiting has given rise to an unfortunate misconception, and it is frequently argued that a given substance must irri- , tate the stomach directly and induce nausea and vom- iting if it is irritant when applied to the mucous mem- branes of other areas, such as that of the nose or con- junctiva. It is true that a substance may be intensely irritant to the nasal mucous membrane and yet be virtually without action on the stomach. This is pre- cisely what one should expect, for one of the functions of the nasal mucous membrane is to protect the air passages against the entrance of foreign bodies, and it accomplishes this by causing sneezing due to irrita- tion of the nasal mucous membrane, hence the latter possesses a high degree of irritability, but the stomach is frequently subjected to the action of a great variety of irritant vegetable substances, and it has acquired a high degree of tolerance to many of them because its function is to retain ingested material. Many drugs — ^perhaps a much larger number than is generally supposed — act directly on the vomiting cen- ter. When emesis is the object sought, it may be of less importance to determine the seat of the action than it is in those cases in which it is a side action. We do not know the mechanism of the emetic action of ipecac in full,^° but this does not interfere with our 25. Recent experiments indicate that the action is at least partly central. 310 EMETICS AND ANTI-EMETICS employment of it, whereas it is of the first importance to know whether this efiEect can be avoided by proper methods of administration when it constitutes a side action of a drug which is used for its systemic effects. If such an action is central it can be avoided only by proper regulation of the dosage, and not merely by the choice of the channel by which it is administered. It is understood that these remarks apply to the usual conditions observed in the more common dis- eases, and not to those in which the stomach is extraordinarily irritable, for even the sight of food or the odor of a drug may cause emesis in such excep- tional conditions, and a drug which would have no effect under ordinary circumstances might then cause nausea and vomiting. A few drugs which irritate the stomach directly are also capable of stimulating the vomiting center when they enter the circulation in sufficient concentration, this being probably true of' sodium salicylate, even when it is administered in dilute solution. Nausea of various grades and emesis are encoun- tered so frequently as side actions that it may be worth while to point out the cause in some of the cases in which it is commonly encountered : Nearly all readily soluble salts either dry or in concentrated solution (from 5 to 20 per cent.), cause irritation of the stom- ach; this can be avoided by using dilute solutions. Hydrated chloral is also very irritant to the stomach, and should be administered in dilute solution, and preferably in a bland fluid. The digitalis bodies without exception, drugs of the picrotoxin group, including wild parsnips, which are frequently eaten by mistake for parsnips, tobacco or nicotin, lobelia, morphin (occasionally pilocarpin) and ergot stimulate the vomiting center directly when over- doses are administered by any channel. Emetics were used formerly more frequently than they are at present, the stomach tube being employed now in the majority of cases in which it is desired to empty the stomach after poisons have been swallowed, and even after their subcutaneous injection if they are excreted into the stomach, as morphin is. The stom- IPECAC 311 ach tube may be used to remove fermenting masses of food, but tenacious curds, undigested meat, and vege- tables, not masticated properly, may obstruct the tube, in which case emetics are preferable. The removal of poisons from the stomach requires the use of rapidly acting emetics when the stomach tube is not available. Emetics are also used to remove foreign bodies from the esophagus and from the upper respiratory passages, and to relieve spasm of the larynx and bronchi in asthma, in nondiphtheritic croup and analogous conditions. It is frequently stated that emesis may facilitate the passages of gallstones through the bile duct, and it is possible that their action is explainable at least in part by their causing muscular relaxation of the duct. The nauseant stage of the action of the emetics will be discussed when the expectorants are considered. It is often stated that emetics are contraindicated after corrosive substances have been swallowed, because of the danger of rupturing the walls of the stomach when they have been weakened by the corro- sives, but this danger must be remote in the great majority of cases which the general practitioner is called on to treat. The mechanism of emesis which has been described does not depend on the contraction of the musculature of the stomach alone for expelling the contents, and the contractions of the abdominal muscles serve to compress the walls of the stomach against the contents, but this does not subject them to any severe tension which alone can cause their rup- ture. Certainly the removal or neutralization of caus- tics demands action, even though it involves risk. EMETICS ACTING DIRECTLY ON THE STOMACH IPECAC Ipecac contains two alkaloids which contribute to its actions, one of which is of relatively little impor- tance. These are cephaelin, to which the emetic action is due for the greater part; emetin, which was so named when it was supposed to be the only active con- stituent present ; and psychotrin, which is unimportant. 312 EMETICS AND ANTI-EMETICS The different alkaloids of ipecac have not been studied in great detail, and we are not able to deter- mine in every case to which we may attribute a given action of the crude drug. Emetin is known to be less actively emetic than cephaelin, but commercial specimens of emetin cer- tainly cause emesis whether they are administered intravenously or by the mouth. Emetin is said to appear in the stomach after its subcutaneous injection, and since it acts slowly after the latter method of administration, we may infer that its action is partly local, but it also stimulates the center directly after its absorption. The alkaloid is also irritant to the skin and to the mucous membranes of the nose and other regions, and when large doses of ipecac are given by the mouth, a portion passes into the intestine and may cause diarrhea. Emetin possesses a specific action on the ameba of dysentery, and it alone appears to be responsible for the therapeutic effects of ipecac in that disease. It is also actively destructive to the endameba that is said to cause pyorrhea dentalis and pyorrhea alveolaris. It is said to cause irritation of the intestinal mucous membrane when present in sufficient amount, causing inflammation with paralysis of the capillaries, much as colchicin and arsenic do, the symptoms resembling those caused by arsenic. Ipecac causes prolonged nausea which is useful when it is employed as an expectorant, but a disadvan- age when it is used as an emetic. Moderate doses do not cause such severe depression as antimony. ZINC SULPHATE AND COPPER SULPHATE These two salts act on the mucous membrane of the stomach and cause vomiting after a fleeting nauseant stage, and as nearly the whole of the dissolved salt is removed when vomiting occurs, the side actions are brief and of little importance in most cases. When emesis is delayed or when it fails to occur, after the administration of copper sulphate, the latter passes into the intestine and causes diarrhea, but it is TARTRATES 313 absorbed very slowly and almost never gives rise to symptoms of poisoning. Copper sulphate affords one of the best means at our command of combating phosphorus poisoning when that poison is still present in the stomach in solid form. Solutions of copper sulphate deposit an impervious coating of copper on the surface of the phosphorus almost instantly when brought in contact with it, and the rapid emetic action of the antidote serves to remove the phosphorus. The deposition of copper occurs with extreme rapidity even when dilute solutions are used, hence large amounts of dilute solu- tions are preferable to small amounts of concentrated solutions. Zinc sulphate causes emesis in the same way that copper sulphate does, and it is equally harmless. The nauseant stage induced by copper and zinc sulphate is too fleeting to permit of their use as expectorants. Copper sulphate is used for giving a green color to preserved vegetables, and while there is no proof that enough copper can be taken in this way to cause injury, the practice is properly prohibited in the absence of proof that even such small amounts are altogether harmless. It is said that fruits dried in zinc- lined trays contain notable amounts of the metal, but there is no evidence of harmfulness on that account. The nauseant stage induced by copper and zinc sul- phate is too fleeting to permit use as expectorants. ANTIMONY AND POTASSITTM TARTRATE j\ntimony and potassium tartrate, or tartar emetic, acts locally on the gastric mucous membrane to induce nausea and vomiting, but tartar emetic is more actively poisonous when it enters the circulation than are the sulphates of copper and zinc, its systemic effects resembling those of arsenic, but fortunately, the poi- sonous actions of antimony are seldom observed after its therapeutic use as it is seldom employed except in small doses as a nauseant. When large doses are taken and vomiting fails to remove the greater part of such a dose, tartar emetic passes into the intestine and causes severe diarrhea 314 EMETICS AND ANTI-EMETICS with corrosion of the mucous membranes and absorp- tion into the circulation. In addition to the usual effects which accompany nausea and vomiting, tartar emetic poisoning is attended with copious watery stools, fall of blood pressure, and slow and labored respiration and depression of the central nervous sys- tem, ending in collapse and death in .rare instances. Some depression of the central nervous system is present even with emetic doses, hence it is not well suited for use in debilitated patients. As little as 0.15 gm. (2 grains) of tartar emetic has caused death when vomiting failed to occur after its administration. When vomiting is delayed for an hour or more after the admimstratioji of the usual emetic dose, tannin, lime-water or magnesia should be given to precipitate the antimony and the stomach should be washed, after which active purgation should be induced. Tartar emetic ointment is irritant, resulting in pus- tulation, after its application to the skin, the exact mechanism being unknown, though it has been sug- gested that the double salt is decomposed with the lib- eration of acid, to which the pustulation is due. Anti- mony destroys trypanosomes even in dilute solutions. Nauseant doses of antimony are not dangerous. OTHER LOCALLY ACTING EMETICS Warm water, slight irritation of the pharynx, as by tickling with a feather, alum, common salt, alkalies (including ammonium carbonate) mustard and numer- ous other means are employed in domestic practice to induce vomiting through their reflex actions, but these hardly require detailed discussion here. EMETICS ACTING DIRECTLY ON THE VOMITING CENTER APOMORPHIN Apomorphin is the only drug commonly used as an emetic that induces vomiting by its direct action on the medullary center. When small amounts of apomorphin are injected subcutaneously, nausea and vomiting are induced APOMORPHIN 315 within a few minutes, these effects being due to the direct action on the vomiting center in the medulla. Less is required by intramuscular injection, and much less intravenously, to induce the action on the center, but the effects of intravenous administration to dogs are somewhat peculiar in that a definite amount is required — neither more nor less in many cases. If less than the emetic dose is given no perceptible effects are observed; if too much is given depression occurs without emesis, as a rule, and the animal remains refractory for some time. All doses above the mini- mum effective administered in any other way cause emesis. Much larger doses are required by the mouth than by other channels, and a longer interval ensues before emesis is induced. In experiments on dogs effective intravenous doses cause emesis within five minutes usually, the emesis is not repeated, and after ten minutes the repetition of the same dose will again produc.e the same effect as the first. This may be repeated many times with little difference in the effects of the subsequent doses. Small doses of apomorphin depress the higher cen- ters somewhat as morphin does in animals, depression following very promptly any excitation ; but in man the depression of the higher parts of the brain is much less conspicuous, the muscular weakness and other symptoms noted being for the most part secondary to the nauseant action. Cushny states that apomorphin has not caused death in man, though it does occasion- ally cause collapse. When small doses are administered the nausea is brief and vomiting occurs but once or twice, but if large doses are used vomiting may be repeated fre- quently for some time, or there may be prolonged nau- sea and great muscular weakness without actual eme- sis, with a slight degree of somnolence. THERAPEUTIC USES The therapeutic uses of the emetics have been sug- gested already in the discussion of this subject, but it remains to point out special indications for the choice of the emetic. 316 EMETICS AND ANTI-EMETICS When it is merely desired to empty the stomach of indigestible or fermenting food, the simplest emetic is to be preferred, and warm water, mechanical irritation of the pharynx, warm solution of salt, warm mustard water, or other domestic measures suffice. When prompt results are imperative, as in poisoning, the use of the stomach tube is indicated, but if this is not available a promptly acting and dependable emetic such as apomorphin is required, and the emesis may be made more certain by resorting to accessory means, such as irritation of the pharynx with the finger or a feather, or the use of one of the domestic emetics, such as water with warm salt or mustard, should the apomorphin prove ineffective in a few minutes. When simple emesis is desired for the purpose of removing indigestible food, copper sulphate or zinc sulphate may be used, and accessory measures may be employed at the same time. Syrup of ipecac is still used to induce vomiting in children in nondiphtheritic croup, when it is desired to secure relaxation of the laryngeal muscles. The use of emetics to facilitate the passage of gall- stones through the duct would seem to depend, partly at least, on the muscular relaxation which accompanies nausea, and vomiting, and as this muscular relaxation is greater with apomorphin than with the other eme- tics in general use, probably because of a specific muscular action of the drug, it probably deserves the preference for this purpose, just as it is utilized in overcoming the motor excitement in acute alcohol- ism, which, being abolished, is followed by quiet or sleep. Apomorphin is also used as a hypnotic in small doses. Ipecac has been used for many years in the treat- ment of amebic dysentery, its actions having been variously attributed to its tannin and to its alkaloids. There is no reason to doubt that ipecac owes its value in this condition to its emetin, and since the doses of this alkaloid which are effective in amebic dysentery are not necessarily emetic, the alkaloid has come to replace ipecac largely for this purpose. It may be given orally, intramuscularly or subcutaneously. Hal- USE OF EMETICS 317 sey recommends the use of pills of ipecac coated with salol, in order that they may pass the stomach undis- solved and act on the amebas in the intestine. He calls attention to the fact that the large doses which are required may cause dysenteric symptoms which may be mistaken for the continuance of the disease. Such large doses are frequently combined with opium to prevent the diarrhea, and to permit the more prolonged action of the alkaloid emetin on the amebas. The use of ipecac, and especially of emetin hydro- chlorid, has been recommended in the treatment of pyorrhea dentalis and pyorrhea alveolaris, which has recently been shown to be extremely common among adults. While emetin is capable of destroying the endameba concerned, reinfection is almost certain to occur unless precautions are taken to prevent it. Bass and Johns urge that all persons who are now free of the disease should use fluidextract of ipecac as a prophylactic mouth wash. One drop is to be used on the wet tooth brush after cleansing the teeth, and a little of the solution drawn in between the teeth, after which the mouth should not be washed. The disadvantage of such procedures is that life becomes too burdensome if measures are adopted against every one of the innumerable diseases that threaten us. DOSAGE The average emetic dose of ipecac is stated to be about 1 gm. (15 grains) ; the expectorant dose is from one-tenth to one-twentieth the emetic. It is used in minute doses — about 0.005 gm. (%2 grain) as a gas- tric sedative. The initial dose for amebic dysentery is 2 gm. (30 grains) and as this amount will usually cause emesis unless steps are taken to prevent it, it should be pre- ceded by a dose of morphin or opium, or it may be directed to be enclosed in gelatin capsules previously treated with formaldehyd, or made into pills coated thinly with salol. Unless care is taken in coating the pills an overdose of salol will be administered. It is 318 EMETICS AND ANTI-EMETICS obviously better to use emetin for amebic dysentery; it should be given in doses of 0.03 gm. (i/^ grain). Copper sulphate and zinc sulphate are given in doses of 1 gm. (15 grains) as emetics. They are not used internally for other purposes. The emetic dose of apomorphin is 0.005 gm. (%2 grain), injected subcutaneously at intervals of ten minutes until effective, but when used to evacuate poi- son a somewhat larger dose of apomorphin may be given at once, unless severe depression exists, and emergencies may demand the use of a dose of 0.01 g^. (% grain). It is not recommended as an expectorant, but it is sometimes used for that purpose in doses of 0.002 gm. (1/30 grain). The hypnotic dose is about 0.002 gm. (%o grain) and this or somewhat larger doses may be used sub- cutaneously in the case of vigorous and violent sub- jects of alcoholism. Purves Stewart states that the hypodermic adminis- tration of 10 mg. (%o grain) of apomorphin hydro- chlorate will cut short an outbreak of dipsomaniacal drinking (the congenital desire, alternating with the lack of it, or aversion) by bringing on nausea without vomiting, followed by deep sleep lasting from three to eight hours. The hypnotic action is maintained by the administration of doses of from 1 to 2 mg. (34o to Yso grain) every three hours, if necessary, until three doses have been given. Nauseant doses of apomorphin suffice, if used dur- ing the preliminary stages when there is restlessness. It is stated that 0.004 gm. (%g grain) has caused the death of a patient enfeebled by bronchitis, but this must be considered an extraordinary case, and remarkably few deaths have been attributed to it. Apomorphin is practically never given by the stomach to induce emesis, because of the large dose required and the delay in the action. Antimonials are rarely used for producing emesis at present, but are frequently employed as nauseant expectorants. The emetic dose of antimony and potas- sium tartrate (or tartar emetic) is 0.03 gm. (i^ grain) but this use is not recommended ; the expectorant dose MATERIA MEDICA OF EMETICS 319 is 0.001 gm. (%o grain) which may be repeated every hour, or so often as may be necessary to maintain a slight degree of nausea and its accompanying increased secretion, provided the dose is not pushed to the point of causing severe depression. It is obvious that robust patients can stand repeated doses better than those who are already debilitated. MATERIA MEDICA Ipecacuanha. — Ipecac, U. S. P., is described as the dried root of Cephdelis Ipecacuanha, commercially known as Rio, Brazilian, or Para ipecac, or Cephaelis acuminata, commercially known as Cartagena ipecac. The former variety of this drug is the one that is gen- erally used in European countries and the plant is being cultivated to some extent in Brazil and also in the Straits settlements. The cultivated variety is usu- ally larger than the wild drug of Brazilian origin though in other respects samples of variable origin resemble each other closely. The Cartagena variety comes from Colombia and differs somewhat in appear- ance from the Rio ipecac and also varies in the nature of its constituents. The drug is described in the United States Pharmacopeia as containing not less than 1.75 per cent, of ipecac alkaloids: a variable mix- ture of emetin, cephaelin and psychotrin, which in the drug itself are probably combined with ipecacuanhic acid. Rio ipecac contains about 1.25 per cent, of emetin. Ipecac is preferably administered in the form of pills, capsules or cachets. The more widely used preparations of the drug are : Pluidextractum Ipecacuanhae. — Fluidextract of Ipecac, U. S. P. — One hundred c.c. of this preparation represent 100 gm. of ipecac in approximately 75 per cent, alcohol. Syrupus Ipecacuanhae. — Syrup of Ipecac, U. S. P. — One hundred c.c. of this preparation represent 7 c.c. of fluidextract of ipecac in syrup. It is approximately seven times the strength of the international standard syrup of ipecac. 320 EMETICS AND ANTI-EMETICS Emetinae Hydrochloridum. — Emetin Hydrochloric!, N. N. R., occurs as a white crystalline powder solu- ble in water and in alcohol. It is frequently used in the form of injections and is preferably dispensed in ampules containing from 0.02 to 0.03 gm. (% to % grain) of emetin hydrochlorid. Zinci Sulphas. — Zinc Sulphate, U. S. P. — This sub- stance is popularly known as white vitriol. It should contain not less than 99.5 per cent, of pure zinc sul- phate, ZnSO -|- 7H2O. It occurs as colorless, trans- parent crystals or a crystalHne powder without odor and having an astringent caustic taste. It is efflores- cent in air and should be kept in well-stoppered bot- tles. Zinc sulphate is very soluble (1 :0.53) in water, but practically insoluble in alcohol. When used as an emetic it should be dissolved in about 50 parts of water. Cupri Sulphas. — Copper Sulphate, U. S. P., is popu- larly known as blue vitriol. It should contain not less than 99.5 per cent, of pure copper sulphate, CuSO^ + 5H2O. It usually occurs in large, deep blue crystals, odorless but having a nauseating metallic taste. Copper sulphate is freely soluble ( 1 : 2.2) in water but only slightly soluble ( 1 : 400) in alcohol. Like zinc sul- phate, it should be dissolved in about 50 parts of water before being administered as an emetic. Antimonii et Potassii Tartras. — Antimony and Potassium Tartrate, U. S. P., is more frequently referred to as tartar emetic. It should contain not less than 99.5 per cent of the salt, 2K (SbO) C^H^Oo + HjO. It occurs as colorless, transparent crystals or as a white granular powder, odorless and having a sweet afterwards disagreeable metallic taste. It is soluble (1 : 15.5) in water but practically insoluble in alcohol. As an emetic it is preferably administered in the form of a solution like the official wine of anti- mony which contains 0.4 w/v per cent, of antimony and potassium tartrate. Apomorphina Hydrochloridum. — Apomorphin Hydrochlorid, U. S. P., is the hydrochlorid of an arti- ficial alkaloid described in connection with morphin. It is soluble ( 1 : 40) in water and in alcohol and as ANTI-EMETICS 321 an emetic is usually administered by subcutaneous injection. Solutions decompose readily hence only freshly prepared solutions of crystalline apomorphin hydrochlorid should be used. ANTI-EMETICS— GASTRIC SEDATIVES This heterogeneous group, if it can be called a group, of drugs will be discussed briefly. The physi- ology of emesis which has been discussed in the pre- ceding pages suggests the nature of those agents which may be used to lessen nausea and vomiting, for it is obvious that if emesis results from irritation of the gastric mucous membrane and from stimulation of the vomiting center in the medulla, emollients, demul- cents, and other protective agents will lessen the local gastric irritation, and if relief is urgently demanded depression of the central nervous system may be resorted to, though this is seldom necessary, except as a temporary measure, for example, when it becomes necessary to prevent vomiting while administering a drug by the stomach. Unfortunately, we have no drug which depresses the vomiting center without causing an undesired depression of other nervous centers. Occasionally vomiting results from reflexes arising elsewhere than in the stomach and other measures than those just mentioned must be employed, for it is well known that -foul odors and pther purely psychic influ- ences may cause nausea and vomiting. Psychic influ- ences may contribute to gastric disturbances, or may prolong them even when they are not alone sufficient to induce actual emesis, and attention should be paid to such influences. Heat.and atmospheric humidity interfere with diges- tion and contribute markedly to nausea and vomiting when there may be another exciting cause. Vomiting occurring after ether anesthesia usually ceases spontaneously after the mucus which has been swallowed is expelled but emesis Occurs frequently when food is taken some hours after chloroform anesthesia. Hot water — not tepid — should be sipped, or a glassful may be drunk if small amounts do not give relief. 322 EMETICS AND ANTI-EMETICS Cracked ice is sometimes more serviceable than hot water. Thirst following chloroform anesthesia may be relieved by drinking hot water, when it is taken easily, but as this causes diuresis, which may or may not be indicated, and since the taking of rather large quantities of water tends to tax the stomach unduly, rectal injections of warm water may be used to avoid gastric irritation, warm water being retained better than cold. Infants regurgitate milk without indications of gas- tric disturbance, when more than sufficient is taken, but when vomiting with distress occurs, due to gastric disturbances, it may indicate the need of substituting barley water for the regular food for a day or two. When vomiting is secondary to diphtheria it is said to indicate cardiac weakness demanding urgent relief for the heart. Vomiting occurs in nephritis and disturbances of other organs in which the stomach is not irritated directly, and if the emesis is severe and persistent it may call for sedatives for the vomiting center, in which case morphin may be injected subcutaneously. Cyclic vomiting has been described as accompany- ing a variety of symptoms, and is probably not depen- dent on a single cause. Its treatment cannot be dis- cussed here as the symptoms are too various and these call for separate treatment. The vomiting of pregnancy often taxes the resources of the obstetrician, and occasionally it cannot be relieved by any means short of terminating the preg- nancy. It would be profitless to enumerate all of the drugs which have been suggested for the relief of this symptom, for such a list would be little less than a catalogue of the materia medica. Hygienic and die- tary measures appear to be the main dependence in such cases. Psychic influences play an important role in this condition. Cerium oxalate gained a certain degree of popularity in the relief of vomiting from this and other causes, but there is no evidence that it has any therapeutic value. Nausea and vomiting which result from indigestion require rest for the stomach, which should be emptied HYDROCYANIC ACID 323 by washing with a weak alkali if the vomiting does not suffice to remove mucus. A weak solution of sodium bicarbonate may serve the double purpose of dissolving the mucus and causing its removal by vom- iting, when there is ineffectual retching. When there is gastric catarrh, requiring protectives, bismuth subnitrate or subcarbonate may be used ; these are preferably administered in the form of powders or mixtures and are not advantageously given in com- pressed tablets or even in the form of capsules. Acidity may be neutralized by lime-water, magnesia, or by a solution of sodium bicarbonate. Depressants of the vomiting center include hydrated chloral, morphin and opium, atropin and cocain, and in fact, probably all hypnotics and general anesthetics. HYDROCYANIC ACID Hydrocyanic acid may be discussed here, since it is sometimes used to allay nausea; but it is not rec- ommended for that (or any therapeutic use). Its toxicology is of some interest because of the frequency with which it is employed for self-destruction. Hydrocyanic acid stimulates and later depresses or paralyzes the respiratory center; moderate doses stimulate the vagus center (the endings slightly), caus- ing a slower heart beat. The vessels are constricted and the blood pressure may rise despite the slower heart rate. The symptoms of poisoning resemble those seen in carbon monoxid poisoning. The latter unites with hemoglobin to form a stable compound that prevents the carrying of oxygen by the corpuscles to the tis- sues, but hydrocyanic acid acts on the tissues and pre- vents their utilizing the oxygen that is brought to them. Hydrocyanic acid is usually absorbed rapidly from the mouth or gastro-intestinal tract, and symptoms of poisoning may occur within a few seconds after it has been swallowed. Fatal doses usually cause death within half an hour, and this may occur within five minutes if a very large dose has been taken. The symptoms of poisoning with hydrocyanic acid include vertigo, headache, palpitation, dyspnea, con- 324 EMETICS AND ANTI-EMETICS vulsions and stoppage of respiration. The heart con- tinues to beat for a time after the respiration ceases. The characteristic odor of hydrocyanic acid may be detected at necropsy if any remains in the gastro- intestinal tract. It is often said that the blood presents a venous appearance after death from this poison, but if death results quickly after a large dose has been taken, the blood may be bright red. If a patient is seen while a poisonous dose of hydro- cyanic acid (or a cyanid) remains in the alimentary tract, the stomach should be emptied as promptly as possible, after which a rapidly acting evaucuant (30 gm., 1 ounce of magnesium sulphate in a large tumblerful of water) should be administered. Hydrogen peroxid, potassium permanganate and sodium thiosulphate (hyposulphite) are said to be use- ful antidotes to hydrocyanic acid. Since hydrogen peroxid is commonly found in the household, it may be added to the water used in washing the stomach if its use involves no delay. Sodium thiosulphate (4 gm., 60 grains) may be added to the evacuant used after the stomach has been emptied, with a view to forming an innocuous compound with any of the poison that may have passed into the duodenum. SoUmann advises the subcutaneous injection of 100 c.c. (3 fluidounces) or more of a 3 per cent, solu- tion of the thiosulphate, or the intravenous injection of normal saline with 1 per cent, of sodium thiosulphate. Unfortunately, this antidote will seldom be available in time. Artificial respiration is indicated if symptoms of severe poisoning develop. The fatal dose of undiluted hydrocyanic acid is supposed to be about 0.06 c.c. (1 minim), correspond- ing to 3 c.c. (50 minims) of the official dilute acid, but the activity of the latter varies widely owing to the readiness with which it decomposes. MATERIA MEDICA Acidum Hydrocyanicum Dilutum. — Diluted Hydro- cyanic Acid., U. S. P., contains 2 per cent, by weight of absolute hydrocyanic acid (HCN). It should be kept in small bottles in a cool place protected from the light. EXPECTORANTS The respiratory passages are lined with ciliated epithelium, and normally the secretions of the mucous glands are moved toward the mouth (or anterior nares) by the movement of the cilia, but when the secretions in the smaller air passages become excessive during inflammation, or when they become thick and tenacious, the cilia are incapable of effecting their removal, and coughing is induced. If the secretions become excessively viscid even coughing may be incap- able of effecting their removal and it becomes neces- sary to liquefy them by increasing the secretion of mucus or by means of alkalies. As previously stated, all nauseants increase the secre- tion of mucus, hence in practice we choose an agent which has a persistent nauseant action, with a mini- mum depressant effect on the central nervous system. Antimony and potassium tartrate is absorbed very slowly from the gastro-intestinal tract, hence small doses suffice to induce prolonged nausea of slight degree, and it is commonly used in the form of a solu- tion or the wine of antimony in the early stages of laryngitis and bronchitis when the secretion is usually scanty and the cough troublesome. The choice of expectorants is often largely^ empir- ical; we do not know whether any of them stimulate the cilia to increased activity or not, and it has been suggested that some of them may act on the smooth muscles of the alveoli and terminal bronchioles in the lungs, increasing their peristaltic movements and forc- ing mucus accumulations into the bronchi, as the alveoli and the terminal bronchioles are not provided with cilia. Many salts, including sodium chlorid, ammonium chlorid, and potassium iodid, increase the secretory activity of the mucous glands, effecting the liquefac- tion of the mucus through the alkalies when these are contained in the secretions, and by diluting these with the increased fluids secreted. It seems probable that the especial usefulness of ammonium chlorid as an expectorant may depend 326 EXPECTORANTS partly on the formation of very small amounts of ammonium carbonate in the bronchial mucous mem- brane, which is especially effective in liquefying tena- cious mucus. A cough which is merely sufficient to remove the secretions from the air passages does not call for treat- ment, but when there is considerable irritation with frequent coughing while the secretion is scanty, seda- tives, such as codein, are indicated. In some cases it is desirable to increase the secretion by means of a nauseant while diminishing the irritation with a seda- tive to the point that the cough will just suffice for the removal of the secretion. Patients frequently demand relief from cough when free secretion contraindicates interference.'^* Excessive bronchial secretion may be lessened in various ways; atropin depresses the vagus endings in the glands; various volatile oils including the oils of turpentine, of cubebs, and of copaiba are sometimes used, but terpin hydrate has almost completely sup- planted the volatile oils for this purpose. Balsam of Peru, benzoin, creosote and other irritants are also used in this way. Syrup of tolu and syrup of wild cherry are little more than vehicles, the hydrocyanic acid in the latter being present in the merest traces and without thera- peutic effect. Hydrocyanic acid was formerly used much more frequently in cough mixtures than it is now. The compound syrup of white pine of the National Formulary contains chloroform and morphin in addi- tion to extracts of white pine, wild cherry, sanguinaria and other substances — a typical "shot-gun" mixture of nauseants, depressants of the respiratory center and stimulants of the bronchial mucous membrane. 26. The following incident illustrates the unfortunate results of inter- ference in such cases. A patient suffering from a cough with free secretion received a mixture containing morphin, and expressed his satisfaction at the prompt relief afforded. Later he felt greatly dis- couraged because (as he supposed) he had "caught fresh cold/' which he attributed to his low resistance. In fact, the morphin suppressed the cough while the secretion continued, becoming purulent, and the necessary cough returned when the effects of the morphin had passed away. DOSAGE OF EXPECTORANTS 327 Sore throat is best treated with gargles, sprays, or demulcents in the form of lozenges. A dilute solution of hydrogen peroxid is useful for cleansing the throat, or a hot 5 per cent, solution of potassium chlorate may be used as a gargle ; to this may be added a few drops of solution of ferric chlorid. Small ulcers or areas of inflammation in the throat may be swabbed with cot- ton dipped in a mixture composed of one part of solu- tion of ferric chlorid to ten parts of glycerin. The official lozenges of ammonium chlorid are use- ful in treating sore throat but it is not easy to explain the effect of the ammonium chlorid in that case. Loz- enges of elm bark allay slight irritation of the throat. There are few conditions in which self-medication and its unfortunate consequences are more common than in coughs and "colds," and there is a striking simi- larity between the composition of nostrums advertised to physicians in numerous medical journals and that of the patent medicines, so-called, which are advertised directly to the public. It is obvious that it matters little, so far as the consequences are concerned, whether the patient doses himself with Ayer's cherry pectoral or Jayne's expectorant, or has compound syrup of cocillana or glyco-heroin (Smith) prescribed for him by a physician. DOSAGE The nauseant dose of several of the emetics has been given. The dose of ammonium chlorid is commonly stated as from 0.3 to 1 gm. (5 to IS grains) but it is much more frequently used in doses of 0.15 to 0.2 gm. (2 to 3 grains). The troches of ammonium chlorid each containing 0.1 gm. (1^ grains) with extract of glycyrrhiza, tragacanth and sugar, flavored with tolu, afford a convenient form of treatment iot sore throat; It may be prescribed for cough (laryn- gitis or bronchitis) somewhat as follows : gm. or c.c. Ammonii chloridi 51 5 i Syrupi acidi citrici SO fl S iss Aquae q. s. ad 100| fl g iii M. Sig. : One teaspoonful every two or three hours. Ammonium chlorid has a disagreeable taste which is disguised somewhat by the acidity of the mixture. 328 EXPECTORANTS Ammonitim carbonate is given in doses of 0.25 gm. (4 grains). Physicians sometimes overlook the acid character of syrup of squill and prescribe it with the strongly alkaline ammonium carbonate. A nauseant and sedative may be prescribed together somewhat as follows : gm. or c.c. 15 gr. viii 10 SSi flSiii Codeinae sulphatis i Syrupi ipecacuanhae 30 I A^uae q. s. ad 100 M. Sig. : One teaspoonful every two or three hours. One should avoid the use of too much of the seda- tive in such cases, as this will lead to the total suppres- sion of the cough. Terpin hydrate is given in doses of 0.12 gm. (2 grains) in powder, capsules or dissolved in elixir. Many of the patent medicines, so-called, which are sold directly to the public, as well as those which are advertised directly to physicians, contain saponin derived from sanguinaria or other source, and a seda- tive such as heroin or morphin. No ready-made mix- ture is suitable for any considerable number of patients, because the doses of nauseants and sedatives should be adjusted carefully to the needs of each patient. MATERIA MEDICA Ammonii Chloridum. — Ammonium Chlorid, U. S. P., usually occurs as an odorless, white crys- talline powder having a cooling saline taste. It is freely soluble (1:2) in water and soluble (1:50 in alcohol. Ammonium chlorid is incompatible with alka- line hydroxids and carbonates which liberate ammonia. In mixtures with the soluble salts of silver and of lead, the insoluble chlorids of these metals are formed. Ammonii Carbonas. — Ammonium Carbonate, U. S. P. — ^The official ammonium carbonate consists of a mixture of acid ammonium carbonate and ammonium carbamate. It occurs as white hard masses, having a strong odor of ammonia and a sharp, saline taste. On exposure to air the salt loses both ammonia and carbon dioxid. It is slowly but freely soluble in water, the ammonium carbamate being thereby con- verted into normal ammonium carbonate. Alcohol dissolves the carbamate and leaves the acid carbonate. MATERIA MEDICA OF EXPECTORANTS 329 Ammonium carbonate like other alkali carbonates is incompatible with acids and the soluble salts of most metals, and alkaloids. Among the preparations con- taining ammonium carbonate, the only one that is now at all widely used is : Sfiritus Ammonii Aromaticus. — Aromatic Spirit of Ammonia, U. S. P., a solution of ammonium car- bonate with some free ammonia and aromatic oils in a mixture of water and alcohol. The actions and uses are the same as those of ammonium carbonate, the average dose being about 2 c.c. (30 minims). Balsamum Tolutanum. — Balsam of Tolu, U. S. P., is a balsam obtained from Toluifera Balsamum. Syrupus Tolutanus. — Syrup of Tolu, U. S. P., is a saturated solution of the aromatic principles of balsam of Tolu in syrup. Prunus Virginiana. — Wild Cherry, U. S. P., is the bark of Prunus serotina. It yields a small amount of hydrocyanic acid when moistened. Syrupus Pruni Virginianae. — Syrup of Wild Cherry, U. S. P., is a syrup representing an aqueous extract of 15 w/v per cent, of wild cherry bark. Terpini Hydras. — Terpin Hydrate, U. S. P., is the hydrate of the diatomic alcohol terpin. It occurs in colorless crystals, nearly inodorous, having a slightly aromatic but somewhat bitter taste. It is only slightly soluble in water ( 1 : 200) but much more soluble in alcohol ( 1 : 10) , so that it may be administered in the form of an elixir, but this requires a rather large dose of alcohol. CHAPTER X. — ARSENIC, ANTIMONY AND PHOSPHORUS ARSENIC Toxic doses of the strongly ionizable inorganic com- pounds of arsenic cause gastro-enteritis with vomiting, diarrhea and abdominal pain, these symptoms being commonly delayed for half an hour or more. The first symptom frequently is a feeling of constriction in the throat with difficulty in swallowing. The evacuations are normal in appearance at first but later become watery and contain shreds of desquamated intestinal epithelium closely resembling the "rice-water" stools of Asiatic cholera. The fluid, unlike that of simple diarrhea induced by saline cathartics, consists of the serum of the blood, or it may also contain some blood, and this loss of serum results in a train of symptoms closely resembling those of actual hemorrhage. There is weakness, dizziness, headache, cold sweat and col- lapse. The features are pale and shrunken, the pulse weak, the respiration deep, later depressed. The symp- toms are intensified until coma and death occur. Con- vulsions may occur (asphyxial) or they may be absent. The urine is commonly diminished or totally sup- pressed, because of the increased viscosity of the blood and the lowered blood pressure. Death may result from either circulatory or respiratory failure, that is, either the heart or the respiration may fail first, but when both are affected so profoundly each reacts upon the other, so that one cannot say that either alone is the cause of death. The gastro-intestinal symptoms have been attrib- uted to the local irritant action of arsenic, but they are now considered as the effects following absorption, and are explained in the following way: Arsenic causes paralysis of the walls of the capillaries, and later those of the arterioles, especially of the splanchnic region, rendering them more permeable than normally, so that ARSENIC 331 there is a copious effusion of serum or even of blood, into the tissues. After the administration of very large doses of arsenic to animals one may observe extrava- sations of blood beneath large areas of the peritoneum. The escape of serous fluid raises blisters beneath the gastro-intestinal mucous membrane, and this is soon desquamated with the escape of large amounts of serum into the stomach and intestine, causing the "rice-water" diarrhea. The diarrhea and its attendant pain and loss of water cause a great fall in the blood pressure, and this is later augmented by the direct action of the arsenic on the heart, should the patient survive long enough for this action to take place. Such serious disturbances of the circulation are always attended with corresponding depression of the central nervous system; especially is this true when the circulatory changes are induced suddenly. One has only to recall the frequency of dizziness due to interference with the cerebral circulation when one rises suddenly from a sitting or recumbent position, to appreciate that the great loss of serum in arsenic poisoning and the resulting circulatory disturbance must cause a variety of secondary effects. If vomiting occurs early the symptoms may be of almost any degree of severity, because much, or com- paratively little, of the arsenic may be evacuated thereby, dependent partly on the amount which has passed into the duodenum, or the poisoning may take on an extremely chronic character, even from a single dose. There should be little difficulty in diagnosing chronic arsenic poisoning following the typical symptoms of acute poisoning, or where it is known that a large dose of arsenic has been taken, but the symptoms resulting from the repeated administration of very small amounts are often obscure and require patience for their recognition. The symptoms of acute and chronic arsenic poison- ing are discussed in greater or less detail in almost all text-books of pharmacology and materia medica, and every physician should familiarize himself with these 332 ARSENIC symptoms because of the frequency with which this type of poisoning occurs. It will suffice for our purposes at present to enumer- ate some of the symptoms of the chronic type, merely to show the necessity for more careful study than it commonly receives. The symptoms are sometimes divided into three stages; in the first there is lassi- tude, loss of appetite, and there may be nausea and vomiting. This stage might lead one to suspect the presence of typhoid fever. The intestinal symptoms may be present, or they may be absent. In the second stage there may be symptoms resembling those of a "cold" owing to the irritation of the mucous mem- branes of the larynx and nose and of the conjunctiva. Various affections of the skin are described as occur- ring in this stage, including a typical discoloration or blackening. In the third stage there are disturbances of sensation and motion in the hands and feet, and peripheral neuri- tis, together with numerous other manifestations which require careful consideration. The symptoms are not sharply marked off in the stages mentioned, but many of those commonly described as belonging to the sec- ond or third may appear earlier than this classification would indicate. When vague symptoms lead one to suspect even the possibility of chronic arsenic poisoning the urine should be examined for traces of the metal. Of course one would not expect to obtain evidences of the poison by the grosser tests, but, on the other hand, the most delicate tests enable one to detect the faintest traces of arsenic in the urine. Such traces have com- paratively little significance unless this evidence is supported by others of great weight, because traces of arsenic may be derived from foods containing it, either as a natural or as an added ingredient. Chronic arsenic poisoning is attended with degenera- tive changes in the walls of the capillaries and later in the intestinal epithelium, and in various organs, includ- ing the heart, liver and kidneys. ' Icterus results from the changes in the liver, and effusions occur in various tissues, that into the eyelids ARSENIC 333 being usually early and fairly characteristic. The damage to the heart may f aiUto attract attention in the presence of other symptoms, such as nephritis, to which the attention may be mainly directed if the true cause of the trouble is not suspected. The toxicology of arsenic is interesting from various standpoints. It played an important role in the crimes of professional poisoners in earlier times, and it is still employed occasionally for purposes of murder and suicide. It lends itself, unfortunately, to the poisoning of one member of a household by another when small doses can be administered frequently, because, owing to its tastelessness and lack of odor, it does not arouse suspicion and is all too easily obtained in the form of rat poison. All arsenic preparations which might be used in this way should be colored distinctively by the addition of lamp-black or indigo which cannot be mixed with most foods without attracting attention. Fortunately, the metal can be detected in the vomitus, urine and feces, and in the cadaver long after death, so that it is probable that few adults die of acute arsenic poisoning without the fact becoming known. The treatment of acute arsenic poisoning requires further investigation. It was accepted for many years as an established fact that as soon as possible after a poisonous dose of arsenic had been swallowed the patient should receive a large dose of moist ferric hydroxid, or preferably, the hydroxid with magnesia, which can be prepared more conveniently and quickly, when the materials are at hand. Serious doubt has been thrown on the value of this procedure during the past few years, and the stomach should be washed out as promptly as possible whether the iron antidote be employed or not. Active catharsis should be induced with magnesium sulphate solution in order to remove any of the poison that has passed into the duodenum. Since prompt purgation is neces- sary in such cases, a large dose of the dilute solution of magnesiurn sulphate should be administered — preferably a pint of solution containing about an ounce of the salt. Naturally, purgatives are contraindicated after the intestinal symptoms have developed. 334 ARSENIC The elimination of arsenic depends somewhat on the way in which it is administered. When a toxic dose has been taken by the mouth the larger part may be evacuated with the vomitus, or with the washings of the stomach, and a large part of the remainder may be evacuated in the feces, especially if prompt purgation is induced. After absorption into the circulation arsenic may, be found in almost all the body tissues. Elimination goes on very slowly indeed, so that months may elapse before it ceases to appear in the secretions, and some of it appears to be retained almost indefi- nitely. A larger portion of the poison is said to be eliminated by the intestine after its oral administration, and a smaller part in the urine, but after the subcutaneous injection the kidneys eliminate more than the gastro- intestinal tract. Diuretics should be administered after the subcutaneous injection of a poisonous dose if the patient is seen early, but caffein and theobromin will have little or no effect after the appearance of the "rice-water" stools because of circulatory disturbances previously mentioned; hence it would seem probable that the intravenous injection of a 2 per cent, solution of sodium sulphate, as mentioned in connection with strychnin poisoning, might be of benefit, but we are unaware of any experiments bearing on the subject. The extraordinarily slow elimination of arsenic and its consequent tendency to accumulate in the body and to produce chronic poisoning are of especial interest in connection with the uses of arsenic in fabrics, and food preservatives. A manufacturer of a food product used anilin to color it, the finished food as eaten containing about one part of arsenic in 20,000 million parts of food. He was probably unaware of the presence of arsenic in the anilin, and it would require about 1,000 tons of the food to furnish an amount of arsenic equal to a toxic dose for a man; nevertheless it was maintained that the practice was unlawful, though it could hardly be held that enough arsenic could be taken in that way to produce any perceptible effect in a life time, especially, as arsenic is frequently taken over long periods for its ARSENIC 335 medicinal effect. Quite a different case was that of a manufacturer whose candy was found to contain six parts of arsenic per million. One pound of the candy contained as much as an average dose of arsenic for an adult, and its continued use in large amounts might very well cause symptoms. In seeming contradiction to the preceding statement is the well-known fact that the administration of small and increasing doses of arsenic by the mouth leads to a higher degree of tolerance, apparently through an acquired resistance to absorption from the gastro- intestinal tract, for such tolerant animals are not more resistant than others to arsenic administered subcu- taneously. Remarkable stories of toleratice are com- monly told of the arsenic eaters of Tyrol. As little as 0.1 gm. (l^/^ grains) of arsenic has proved fatal, but very much larger oral doses have been survived, and if vomiting occurs within less than half an hour after a fairly large dose has been swal- lowed the chances of recovery are fairly good, but of course one cannot depend on this alone, and other treatment should be instituted, as previously stated. There is an unfortunately widespread belief among the laity that larger doses of arsenic may be safer than smaller, but toxic, ones. This is doubtless based on the fact that large doses do occasionally induce emesis in time to save life, while smaller doses may prove fatal. In view of what has been said of the widespread use of arsenic in the arts, in medicine and in foods, with the consequent frequency with which at least small amounts may be taken without the knowledge of the patient, and the extreme slowness with which elimination takes place, it is obvious that the detec- tion of traces of arsenic in the excreta or in a cada- ver does not prove that observed symptoms or death resulted from arsenic in a given case, and one will understand the necessity of a careful study of the actions of arsenic before expressing opinions that may be of far-reaching importance. The administration of small amounts of arsenic to young animals may cause them to grow more rapidly 336 ARSENIC than other members of the same litter that receive the same food without the arsenic. Several observers found that the bones of the animals that received arsenic were longer and thicker than those of the con- trols ; that their fur was glossier, and other evidences of rapid development were also observed, but these effects are not always obtained and other investigators came to different conclusions with regard to the effects of arsenic on metabolism. Poisonous doses cause fatty degeneration in various organs, and other dis- turbances of metabolism. Various explanations have been offered to account for the more rapid growth observed as the result of the use of arsenic, but it seems possible that the actions on the capillaries and the effects on the general cir- culation together with the stimulation of production of red blood corpuscles or of hemoglobin are concerned in the effects on metabolism. It also seems possible that arsenic may serve to cor- rect some adverse conditions entailed in those feeding experiments in which the greater growth was observed, for it does not seem probable that arsenic would influr ence growth favorably if the animals were kept under the best conditions of living and exercising in the open air. At least, no one would think of advising the rou- tine administration of arsenic to healthy little children living under hygienic conditions. Certain of the organic compounds of arsenic which ionize but little are much less active than the inorganic compounds that have been discussed. Cacodylic acid, which differs from arsenic acid by having two methyl groups in place of two hydroxyls of the latter, has long been known, the sodium salt having been introduced about fifty years ago. Sodium arsanilate was intro- duced into therapeutics in 1902 under the name of atoxyl under the mistaken impression that it was non- toxic. It exerts the arsenic action, though less violently than arsenic trioxid in equal weights, and in addition it is prone to cause blindness through atrophy of the optic nerve. When atoxyl was submitted to the Coun- cil on Pharmacy and Chemistry its composition was investigated, and it was shown that the arsenic is not USES OF ARSENIC 337 present in the trivalent state as had been supposed, but in the pentavalent. Following the introduction of organic compounds of arsenic, Ehrlich investigated a large number with the object of finding one capable of exerting the well- known trypanocidal action of the metal without the toxic action on the host, or at least of finding a com- pound in which the relative toxicity for the parasite and the host would perrnit of the administration of a single dose that would at once destroy all the micro- organisms in the blood. As a result of this search Ehrlich and his co-workers brought out salvarsan, or arseno-benzol, more cor- rectly called arsen-phenol-amine hydrochlorid. It has also been named "606" in reference to the laboratory number given the compound. From the results of the early studies it was announced that a single dose of salvarsan was capable of destroying all of the micro-organisms of syphilis in the human body in suitable cases. It was also highly extolled in the treatment of various other diseases, including relapsing fever, and at the same time it was said to be relatively harmless to man in the dosage advised. The literature relating to salvarsan is already enor- mous, and while it is not feasible to review this even partially, it may be said that a single dose apparently efifects a complete cure only when it is given shortly after infection, if at all, and that it is far from being harmless, numerous deaths being undoubtedly attribu- table to its use even with the most careful technic. Unfortunately, the spirochetes of syphilis may become more resistant than normal to arsenic after repeated doses, and it is usually necessary to combine the use of arsenic with that of mercury. Neosalvarsan is a soluble compound of salvarsan thought by some to be tolerated better than the original product. THERAPEUTIC USES Arsenic trioxid is applied to ulcerated surfaces as an irritant, but its use is attended with severe pain. It has long been used in domestic practice and occa- 338 ARSENIC sionally by physicians as a caustic for the removal of malignant growths, in the form of pastes. The action cannot be controlled accurately, it is very painful and there is some danger of the absorption of a poisonous dose when it is applied in this way. Its use is not rec- ommended. It has long been employed and is still used as an application to ulcerated surfaces and by dentists for destroying the nerves in carious teeth. It is used internally in a variety of disorders in which its mode of action cannot be explained satisfactorily. For example, it is used in neuralgia of a periodic char- acter, and in chorea, in which it is of doubtful value. It is used in anemia, in which it probably stimulates the organs involved (bone marrow) to a more rapid regen- eration of the red blood corpuscles or the hemoglobin. It is also used in pernicious anemia, in leukemia and in Hodgkin's disease (malignant lymphoma, or hyper- trophic disease of the lymphatic glands of the body, attended with anemia). In these diseases its tempo- rary effects are often markedly beneficial, but relapses almost invariably occur. It is often used to improve the nutrition when the disturbance results from obscure causes, but, of course, it is not suited for use in all of those cases. It has been recommended for use in diabetes, but like other drugs, it usually fails in that condition. Arsenic is said to be useful in various skin diseases, such as psoriasis, lichen planus, chronic eczema, pemphigus, dermatitis herpetiformis, chronic urticaria and disturbances involving the sweat glands. It must be remembered, however, that the treatment of skin diseases by the general practitioner involves many diffi- culties because of the obscurity of the etiology in these conditions, hence they should be referred to a derma- tologist when they present unusual difficulties or con- ditions with which the practitioner is unfamiliar. Attention has been called to the fact that the fur of animals used in experiments with arsenic was glossier than that of the controls, and horse dealers have long utilized this action of arsenic in improving the coats of horses. These results suggest the use of arsenic in man when there is faulty nutrition of the skin. USES OF ARSENIC 339 Acute inflammation of the skin contraindicates the use of arsenic. The organic compounds of arsenic have a distinct field of usefulness in various diseases of protozoal ori- gin, including sleeping sickness (trypanosomiasis), malaria, relapsing fever and syphilis, but the side actions, especially that on the optic nerve (with atoxyl), have greatly interfered with its use. Sodium arsanilate (atoxyl) was used extensively for a time in the treatment of sleeping sickness; but numerous cases of blindness resulted, and it has fallen into dis- use for that purpose. Arsenic has long been used in malaria, especially in the chronic forms which have resisted quinin, arsenic and quinin being commonly used together in those cases. The cacodylate attained to some degree of impor- tance many years ago when it was found that it exerts the actions of arsenic over a longer period than the inorganic forms and that it is less toxic. Salvarsan is widely used in the treatment of syphilis ; it is given alone soon after infection or in combination with mercury in the later stages. It is also employed in the treatment of relapsing fever and in many other conditions, sometimes with good results, sometimes with harmful effects. The results reported soon after the introduction of salvarsan raised hopes which subsequent experience proved were far too optimistic, but when the early lit- erature has been discounted sufficiently we still have in it a valuable remedy. Headache, nausea and malaise commonly follow the intravenous injection of salvarsan, the symptoms last- ing from twelve to twenty-four hours. Aside from these after-effects certain nervous effects have been observed. These symptoms — termed nervous relapse — are believed to be due to an increased activity of the spirochetes and they call for another dose of salvarsan or treatment with mercury. Arsenic is sometimes used in the most diverse con- ditions including asthma, tuberculosis, bronchitis, leu- 340 ARSENIC ketnia, splenic anemia, and in numerous other diseases, and one is led to suspect that when improvement fol- lows its use in those conditions it is merely a coinci- dence or that this improvement is attributable to the effects of arsenic on metabolism in general rather than to any direct effect on the diseased organs or the causes of the disease. All forms of arsenic should be used cautiously or not at all in the presence of disease of the eye, espe- cially of the retina, even if it be of syphilitic origin, because of its tendency to induce optic neuritis and blindness, but salvarsan is said to cause optic neuritis in few instances. Arsenic is contraindicated in severe car- diac and renal disease, and salvarsan should be used cautiously in syphilitic infants because of the danger from liberated endotoxins when the spirochetes are destroyed. DOSAGE For ordinary affections of metabolism or for a tonic influence arsenic trioxid is given in doses of from 0.001 to 0.002 gm. (%o to Yso grain). In syphilis the dosage should be regulated according to the effect induced, but it is well to use as large doses as the patient will tolerate. The various forms of inorganic arsenic are fre- quently administered in increasing doses until symp- toms of mild intoxication appear. One may begin with 0.003 gm. (Yzo grain) of arsenic trioxid, three times a day, and increase by 0.001 gm. (%o grain) three times a day : that is, 0.004 gm. (%g grain) three times on the second day, 0.005 gm. (%2 grain) three times on the third, etc., until symptoms of arsenical intoxication are induced. Solution of potassium arsenite and solution of arse- nous acid may be given in doses of 0.2 c.c. (3 minims) three times a day, and increased by 0.05 c.c. ( 1 minim) three times a day. A slight toxic effect is indicated by nausea, colicky pains or a puffiness under the eyes. The presence of albumin in the urine may also be observed. Such symptoms may make it advisable to discontinue the administration of the drug for a time. DOSAGE OF ARSENIC 341 Solution of arsenous and mercuric iodids is usually administered in doses of 0.1 c.c. (U^ minims). Sodium arsenate is given in doses of 0.003 to 0.005 gm. (VoQ to Yio grain) three times a day and increased as with other preparations of arsenic. Of the organic combinations of arsenic, sodium arsanilate, (atoxyl, soamin), is given in doses of 0.02 gm. (% grain) gradually increased, and sodium caco- dylate may be given in doses of 0.03 gm. (% grain). Sodium arsanilate is used only by injection; the caco- dylate is frequently administered hypodermically though it may also be administered by mouth. The dose of salvarsan is 0.5 gm. (7% grains) . Since it is not suited for oral administration it must be given intravenously, subcutaneously or intramuscularly, but intramuscular injections have been followed in several instances by the toxic effects of arsenic ; furthermore, the intramuscular injection is painful and is usually followed by a painful inflammatory nodule which per- sists for some time. It is seldom employed intramus- cularly by those who have mastered the technic of the intravenous injection, and no one should undertake to administer salvarsan intravenously without having mastered the somewhat difficult technic. Salvarsan, being acid, is neutralized and suspended in a neutral fluid for subcutaneous or intramuscular injection. A clear solution in sterile alkaline fluid is used for intravenous injection. The powder decomposes rapidly on exposure to the air, and suspensions and fluids intended for injection should be used at once. If any part of the contents of a tube remains unused when a dose is administered it should under no circumstances be mixed with a subsequent dose but should be thrown away. Even those tubes that are cracked before being used, permit- ting the action of the air, should be rejected. The water used for making intravenous injections should be distilled shortly before being used. Various forms of apparatus are advised by different authorities, but most of the apparatus employed for the injection can be had in any first class pharmacy or instrument maker's shop. 342 ARSENIC MATERIA MEDICA Arseni Trioxidum. — Arsenic Trioxid, U. S. P., for- merly official as arsenous acid, also called arsenic tri- oxid or arsenious anhydrid, AsjOj, occurs as a white powder or in irregular masses of two varieties, one amorphous, transparent and colorless like glass, the other crystalline, opaque and white resembling porce- lain. Arsenic trioxid is very slowly soluble (glassy variety 1 : 30, porcelain variety 1 : 100) in water and practically insoluble in alcohol. It dissolves quite readily in solutions of acids or alkalis, in which form it is very widely employed in preference to pills or tab- lets of arsenic trioxid itself. Liquor Potassii Arsenitis. — Solution of Potassium Arsenite, U. S. P., commonly known as Fowler's solu- tion, is an aqueous solution containing potassium arse- nite, corresponding to 1 per cent, of arsenic trioxid. The preparation has a distinctive color and odor from the addition of 3 per cent, of compound tincture of lavender. The solution is frequently somewhat alka- line and is therefore incompatible with alkaloidal salts. Liquor Acidi Arsenosi. — Solution of Arsenous Acid, U. S. P., is an aqueous solution containing the equiva- lent of 1 per cent, of arsenic trioxid with 5 per cent, of hydrochloric acid.. It occurs as a clear, colorless, odorless liquid, having an acidulous taste and an acid reaction. Liquor Arseni et Hydrargyri lodidi. — Solution of Arsenous and Mercuric lodids, U. S. P., commonly known as Donovan's solution, represents, 1 per cent, of arsenous iodid and 1 per cent, of mercuric iodid. It occurs as a clear, colorless, or pale yellowish, odor- less liquid, having a disagreeable metallic taste. Sodii Arsenas. — Sodium Arsenate, U. S. P., the sodium salt of arsenic kcid, occurs as colorless trans- parent monoclinic prisms, odorless and having a mild alkaline taste. It is freely soluble (1 : 12) in water but nearly insoluble in alcohol. Sodium Arsanilas. — Sodium Arsanilate, N. N. R., also known as sodium anilin arsonate, sodium amino- phenyl arsonate and sodium aminarsonate, is more MATERIA MEDICA OF ARSENIC 343 widely known by one or the other of its trade names ; atoxyl, which is marketed with 3 molecules of water, and soamin, which occurs in trade with 5 molecules of water. Sodium arsanilate, the sodium salt-of arsanilic acid, occurs as white, odorless crystals, having a faintly saline taste and being freely soluble (1:6) in water and only slightly soluble (1:125) in alcohol. When the aqueous solution is allowed to stand it assumes a yel- lowish tint. Sodium arsanilate is incompatible with acids, alkalies and salts of mercury. It is readily decomposed in the stomach and is now administered only by injection, preferably in simple solution. Sodii Cacodylas. — Sodium Cacodylate, N. N. R., is also known as sodium dimethylarsenate, and is the sodium salt of dimethyl arsenic acid. It occurs as a white powder, very soluble (1 : 0.5) in water and freely soluble (1:1) in alcohol. The aqueous solution is alkaline toward litmus paper, but nearly neutral toward phenolphthalein. It is comparatively stable and may be given either in solution or in the form of pills or tablets. Salvarsan. — Salvarsan, N. N. R., also known as arsenobenzol, "606," and arsenphenolamin hydro- chlorid, is 3-diamino-4-dihydroxyl-l-arseno-benzene hydrochlorid. It contains 31.57 per cent, arsenic. It occurs as a yellowish crystalline hygroscopic powder, very unstable in air. It is soluble in water, yielding a solution with an acid reaction. It is marketed only in glass tubes and, as noted above, care should be exercised to see that these tubes are intact and that the powder has not been exposed to air. Neosalvarsan is the name applied to a mixture of sodium 3-diamino-4-dihydroxy-l-arsenobenzene-meth- anal-sulphoxylate with inert, inorganic salts. The arsenic content of 3 parts of neosalvarsan is approxi- mately equal to 2 parts of salvarsan. Solutions of neosalvarsan are more readily prepared than those of salvarsan. Its actions and uses are the same as those of salvarsan, and the same precautions are to be observed when it is employed. 344 • ANTIMONY ANTIMONY The systemic effects of antimony resemble those of arsenic so closely that they do not require detailed discussion,, but it is important to remember that the early vomiting and diarrhea following the use of toxic doses of antimony may be due to local action, though early vomiting usually serves to prevent the occurrence of severe toxic symptoms. The occurrence of diarrhea, on the other hand, indi- cates that the poison has either entered the duodenum or has been absorbed, and both may occur. Should the administration of the usual emetic dose of anti- mony fail to produce vomiting, as sometimes hap- pens, poisoning may result unless the drug is removed from the gastro-intestinal tract. When there is rea- son to fear its toxic action efforts should be directed toward its removal, as in the case of arsenic. Limewater, a pint or less, the oxid or carbonate of magnesia, or tannin should be administered,^' and the stomach washed promptly and thoroughly. If pre- cipitants are not at hand no time should be lost in efforts to get them before washing the stomach. After the stomach has been washed the patient should receive 30 gm. (1 ounce) of magnesium sulphate in about 500 c.c. (1 pint) of water in order to remove any of the antimony that has passed into the intestine. If antimony remains in the gastro-intestinal tract for a sufficient length of time corrosion occurs, with absorption, and the gastro-intestinal symptoms are augmented by the systemic actions of the poison in the way described under arsenic, and in that case washing of the stomach and saline purgatives would be of little use, though they would at least do little harm. Antimony is usually absorbed very slowly indeed, hence its longer sojourn in the gastro-intestinal tract favors the local irritant action, and interferes corre- spondingly with its use for the systemic effects. This slow absorption with the resulting prolonged local gastro-intestinal action is the basis for its use as 27. Cushny advises the use of strong tea as a precipitant for anti- monial salts. ANTIMONY 345 a nauseant, otherwise it would be inadmissible to employ so toxic an agent for that purpose while we have so many harmless agents that are capable of inducing nausea. As little as 0.15 gm. 21^ grains) has caused death when vomiting was delayed or absent, but such an occurrence is rare, and much larger doses have been survived. Severe poisoning seldom follows the therapeutic use of antimony at present, because it is little used except as a nauseant, the dose for this purpose being too small to cause toxic symptoms even though absorp- tion takes place, and emesis nearly always occurs if large doses are employed. Numerous investigators have sought to utilize com- pounds of antimony in the treatment of trypano- somiasis and syphilis, following the observation that tartar emetic is rapidly destructive to trypanosomes in mice. A single intramuscular injection of a suspension of an insoluble salt of trivalent antimony, or of the metal itself, destroys the trypanosomes in mice, but the latter die of chronic antimony poisoning. Antimonous oxid (SbjOs), containing trivalent anti- mony, is destructive to trypanosomes, and may be administered intramuscularly in the form of a 30 per cent, oily suspension. Ointments containing insol- uble compounds of antimony have been used success- fully in the treatment of experimental trypanosomiasis. Compounds containing pentavalent antimony are much less active than those containing the trivalent. But for the difficulty of securing the systemic action without the gastro-intestinal disturbances, antimony might be used for almost any of the purposes for which arsenic is employed. It is still used in psoriasis when the condition fails to yield to other forms of treatment, and it is used occasionally for trypanoso- miasis. The systemic effects are best attained by intravenous injection, the subcutaneous injection being too painful. 346 PHOSPHORUS DOSAGE Certain of the uses and doses of antimony have been discussed under the emetics. Camac states that he used from 0.01 to 0.015 gm. (% to 1/4 grain) of the sodiotartrate about once a week, in the treatment of a case of sleeping sickness which had apparently become resistant to atoxyl. The ointment was formerly used externally but it sometimes produced extensive abscesses and is now rarely employed. For materia medica see Emetics. PHOSPHORUS The action of phosphorus resembles that of arsenic and antimony to a certain extent. Thus the adminis- tration of very small amounts to young animals causes an increase in the growth of bones, apparently through stimulation of the osteoblasts. At the same time it causes the deposit of dense bone in cancellous tissue, but the prolonged administration causes the absorption of the latter. Small doses of phosphorus have much less effect on the bones of adult animals, but these also show some deposit of dense bone. Phosphorus, like arsenic, causes some increase in the red blood cells, though it does not appear to increase the total amount of hemoglobin in the blood. Small doses do not appear to induce other notable pharmaco- logic actions unless long continued. There are usually no symptoms observed immedi- ately after a poisonous dose of phosphorus has been taken by the mouth, but after some hours there is gastro-intestinal pain with vomiting and sometimes diarrhea. The vomited matter has a garlic-like odor, and this with the phosphorescence which it exhibits in the dark, are characteristic and suffice for a diagnosis in otherwise doubtful cases. Following the early symptoms there is usually a period of several days during which the patient suffers no disturbance, after which he may be seized agaitj with vomiting and diarrhea ; the liver is enlarged and tender; the patient is jaundiced and suffers prostra- tion with its attendant circulatory disturbances, partly PHOSPHORUS 347 due to the direct action of the poison on the heart. Hemorrhages occur in various tissues, and the vomitus, feces and urine may contain blood. There is a fatty infiltration of the liver, heart and other organs, secondary to the disturbances of metabo- lism, whereby there is an increased destruction of pro- tein. Death from heart failure occurs in about one week in fatal cases, but severe symptoms may be' fol- lowed by recovery, in which case the organs that have been infiltrated with fat become cirrhotic from the pro- liferation of interstitial connective tissue; but it is said that this occurs more markedly in poisoning by repeated doses than after a single large dose. This cirrhosis affects the liver and gastro-intestinal tract to a greater extent than the kidneys, and these effects of course induce the usual secondary results. Acute phosphorus poisoning sometimes occurs from swallowing rat paste. It is very slowly absorbed from the gastro-intestinal tract, and when the patient is seen shortly after the poison has been swallowed the efforts should be directed toward removing as much of it as possible and oxidizing the remainder. The stomach should be washed with a very dilute solution of cop- per sulphate, 2 gm. (30 grains) in about 500 c.c. (1 pint) of water, or 2 gm. (30 grains) of copper sul- phate dissolved in 50 c.c. (2 fluidounces) of water may be administered as an emetic, and about 0.1 gm. {W2 grains) may then be administered in a glass of water with a view to causing the phosphorus remaining in the stomach to become coated with metallic copper ; this being rapidly converted into an insoluble phosphid. As an alternative to the use of copper sulphate in the wash water, and later, one may wash the stomach with a large amount of solution of potassium permanganate, 0.1 to 0.2 per cent., and later administer a glassful of water containing 0.3 gm. (5 grains) of potassium per- manganate. As this salt attacks organic matter and other readily oxidizable substances, it is much more effective in oxidizing poisons if it be given after the stomach has been washed than if it be given while the stomach is filled with food. 348 PHOSPHORUS Hydrogen peroxid and oil of turpentine are some- times recommended as oxidizing agents in phosphorus poisoning, but the peroxid is decomposed so rapidly in contact with mucous membranes and body fluids that it can act on the phosphorus only if it be brought into immediate contact with it in the stomach, and oil of turpentine is also of doubtful value. Unless the stomach is emptied almost immediately after the phosphorus has been swallowed, some of it will have passed into the duodenum, where it will be out of reach of the antidotal measures just discussed; it is absorbed very slowly indeed, and the intestine should be emptied as promptly as possible, preferably by using a large dose of magnesium sulphate, 30 gm. (1 ounce) dissolved in about 500 c.c. (1 pint) of water. A small dose of copper sulphate may be dissolved in the solution of magnesium sulphate if it be at hand, or it may be administered later. Fats and oils should be avoided while the phos- phorus remains in the gastro-intestinal tract, as they interfere with the efforts at oxidation and favor absorption of the poison. When later symptoms of phosphorus poisoning have developed alkalies should be given, preferably citrates and bicarbonates, to neutralize the large amount of acid formed in the tissues. Workmen employed in factories where white or yel- low phosphorus is used are subject to a peculiar necro- sis of the jaw bone which was formerly attributed to the action of phosphorus that had gained access through carious teeth; but it seems probable that the bone is first affected by phosphorus that reaches it through the circulation, rendering it susceptible to bacterial action. This truly terrible affliction is less common when red "amorphous" phosphorus is used, and is almost unknown when the sesquisulphid of phos- phorus is employed, as it now is quite commonly in the manufacture of matches. THERAPEUTIC USES Phosphorus favors the deposition of calcium in growing bones, and it is probably useful in osteoma- lacia, in rickets and possibly in bone that is undergoing USES OF PHOSPHORUS 349 repair; but the action on the blood corpuscle forma- tion does not justify its use in anemia, in which iron and arsenic are preferable. It has been used in various affections of the central nervous system for its supposedly tonic or stimulant action, but it has little direct action on the central ner- vous system, and there is no evidence of its value in these conditions for which it is recommended prin- cipally by the manufacturers of nostrums intended to supply phosphorus in a form more readily available than that in the inorganic phosphates, and it is used less by educated physicians for such purposes than formerly. The difficulties involved in the therapeutic use of phosphorus in the elemental state have led to the intro- duction of various compounds intended to supply phos- phorus to the organism, and while it is possible that some of these preparations may have therapeutic prop- erties, their advantages are not very obvious ; but, on the other hand, there is no question that rational thera- peutics has been interfered with by the sensational way in which most of them have been advertised. Among the first of these compounds were the hypo- phosphites, which were introduced into therapeutics about half a century ago by Churchill, who supposed that they influenced nutrition favorably and who there- fore advised their use in tuberculosis. It has long been stated that the hypophosphites undergo little or no change in the body and that they are excreted in the urine practically unchanged. Nev- ertheless they continue to be exploited widely in the form of various nostrums. One of the most widely advertised — hence one of the most popular — of these is Fellows' syrup of the hypophosphites. It contains several bases, in combina- tion with hypophosphorus acid, quinin and strychnin, to which is probably due any medicinal value that the preparation may have. It is unnecessary to prescribe an expensive nostrum of this type merely because one wishes to give his patient small doses of quinin or strychnin. The official compound syrup of the hypo- phosphites is little better than the nostrum just men- 350 PHOSPHORUS tioned, and contains nine supposedly medicinal ingre- dients in syrup. It is not in keeping with modern therapeutic teaching to use such complex mixtures. The continued influence of Churchill's teaching is also evident in the formulas of many of the proprietary emulsions of cod-liver oil that are advertised to physi- cians and to the public. Nearly all of them contain mixtures of hypophosphites that can serve no useful purpose, but usually render the preparation more disa- greeable to the taste. When it began to be accepted by educated physicians that the hypophosphites were superfluous, other phos- phorus compounds were introduced and glycerophos- phates, lecithin and nuclein were oflEered. Lecithin is abundant in various tissues and is espe- cially abundant in eggs, but it is sometimes claimed that the raw or combined forms of lecithin, such as that existing in eggs, cannot be utilized so well as the uncombined. It is obvious, however, that the healthy organism is capable of obtaining its normal supply from the lecithin-bearing compounds of the food, and there is no evidence that the free substance is ever necessary. The average diet of a healthy man contains from 5 to 15 gm. (75 to 225 grains) of lecithin, and this can be increased easily when patients can take an abundance of egg-yolk. Glycerophosphoric acid consists of phosphoric acid in which an atom of hydrogen has been replaced by the glycerin radical, and has the formula H2(C3H5(OH)2) PO4. The glycerophosphates of calcium and of sodium are described in New and Nonofficial Remedies. Lecithin consists of the ester of oleic, stearic, pal- mitic or other fatty acid with glycerophosphoric acid combined with cholin ; hence it is spoken of as a phos- phorized fat. The lecithins obtained from different sources differ somewhat in their composition, but this does not appear to be of any great importance in regard to their utilization by the body. The nucleins consist of proteins combined with nucleic acid and are derived from the nucleoproteins of cells. Nucleic acid varies slightly but not essentially. DOSAGE OF PHOSPHORUS 351 in its composition, depending on the source from which it is obtained, that from yeast cells — the usual source of commercial nucleins and nucleic acid — containing almost exactly 10 per cent, of phosphorus. The composition of the nucleins varies rather widely with the method of preparation, but nucleic acids are definite chemical substances. They may be decom- posed, yielding phosphoric acid, a carbohydrate, and purin and other bases. Liver, kidney, brain and sweetbread are rich in nucleoproteins, hence in nucleic acids, and these foods may be used when it is desired to administer nuclein or nucleic acid, but lean meats are relatively poor in nucleoproteins. The purin bases derived from nucleo- proteins are the precursors of uric acid; hence brain, liver, kidney, and sweetbread are to be withheld when the formation of uric acid should be limited as much as possible. Lecithin, the glycerophosphates, nuclein and nucleic acid are discussed in New and Nonofficial Remedies. Sanatogen is one of the many compounds that are exploited as containing a particularly active form of phosphorus. This product has been referred to on several occasions in the reading pages of The Journal and is discussed at some length in "Nostrums and Quackery." DOSAGE The average dose of phosphorus is 0.5 mg. (%20 grain), to be given several times daily. A somewhat larger daily dose is recommended in osteomalacia, in which as much as 5 mg. (%2 grain) may be given in the course of a day; but such doses cannot be consid- ered altogether safe. Phosphorus may be given in pills which may be made by using one of the many fairly permanent mix- tures of phosphorus with suet, wax, or rosin, or by triturating phosphorus with a little- sulphur under water, until liquefied; the water is poured off and a suitable excipient added. It may also be given dis- solved in olive oil or cod-liver oil, or in alcoholic solu- 352 PHOSPHORUS tion in the form of an elixir. It may be prescribed for children somewhat as follows : Phosphorus 0.01 gm. % grain Cod-liver oil to make 100 gm. 3 fluidounces Free the oil of contained air by heating to ISO C. and allow to cool, then add the phosphorus and warm to about 80 C. and shake until the phosphorus is entirely dissolved. Two teaspoonfuls of this solution may be given daily, but it is said that even this amount taken daily for several days has caused death, and its use is not recommended. For alcoholic solutions, the phosphorus is preferably dissolved in chloroform and mixed first with absolute alcohol, then with a mixture of alcohol or glycerin and elixir, care being taken to keep well within the solu- bility of phosphorus in the several solvents. Practically all of the preparations of phosphorus^ deteriorate on keeping and, if it is desired to give this substance in an active form, care must be exercised to have the mixtures freshly prepared from materials that will comply with the official requirements. It will also be necessary to see that proper precautions are observed to free the solvent, particularly an oil, a fat or a resin, of air or free oxygen so as to avoid dete- rioration as much as possible. MATERIA MEDICA Phosphorus, U. S. P., occurs in commerce as a semitransparent, wax-like solid, usually in the form of cylindrical sticks. It has a distinct and disagreeable odor and taste, is luminous in the dark when exposed to air and should be kept under water in well-closed vessels, in a moderately cool place, protected from light. Phosphorus is nearly insoluble in water, slightly soluble (1:350) in absolute alcohol or (1:400) in glycerin, and soluble (1 : 80) in fatty oils and in ether; also (1:25) in chloroform and very soluble (1:0.5) in carbon disulphid. The official. or medicinally active form of phosphorus may be converted by means of heat into the red or allotropic modification of the element. This red or MATERIA MEDICA OF PHOSPHORUS 353 "amorphous" phosphorus is permanent in dry air, is insoluble in ordinary solvents, and is generally con- sidered to be non-poisonous. Calcii Hypophosphis. — Calcium Hypophosphite, U. S. P., which occurs as colorless, transparent crys- tals, small lustrous scales, or white crystalline powder, odorless and having a nauseating bitter taste. It is freely soluble ( 1 : 65 ) in water and is practically insol- uble in alcohol. Calcium hypophosphite is incompatible with iodids and oxidizing agents. Caution should be observed in dispensing the substance, as an explosion may occur when it is triturated or heated with substances rich in oxygen, particularly nitrates and chlorates, that may be affected by a powerful reducing agent. It is not recommended for therapeutic use. CHAPTER XL— THE HEAVY METALS AND THEIR SALTS The salts of the heavy metals act locally as astrin- gents, irritants or corrosives, dependent on the nature of the compounds which they form with the tissues; thus the lead salts, which are astringent when used in dilute solution, are corrosive when concentrated solutions are employed. The intestinal mucous membrane acquires a certain degree of tolerance toward irritant action of the metals if small doses are given at first, and gradually increas- ing amounts are employed. The large amounts of arsenic taken by the arsenic eaters of Tyrol afford a well-known example of this acquired tolerance. The salts of metals which dissociate readily into their ions have many actions in common after the absorption of toxic doses into the circulation. The marked differences in the effects commonly observed after their administration are attributable in part to differences in their rates of absorption, in part to dif- ferences in their rates of dissociation. Arsenious acid is absorbed fairly well from the gastro-intestinal tract and it dissociates readily, hence it is actively poisonous, whereas most of the salts of iron and lead are absorbed so slowly that toxic symptoms rarely follow the administration of single doses of them. When soluble salts of the metals are administered they are partially converted in the duodenum into insol- uble carbonates or into albuminates, in which form they may be absorbed, or they may pass into the large intestine, being converted into sulphids. A larger part of the dose of the metallic salts escapes absorption and the sulphid renders the feces black. Slow as the absorption of the metals usually is their excretion is commonly even slower, so that they may accumulate in the body and give rise to symptoms of poisoning. This action is prominent in the case of lead, even when minute amounts are taken over pro- longed periods. LEAD 355 Most of the metals are excreted through the large intestine mainly, and to a slight extent through the kidneys. The irritant action at the seat of elimination in the intestine may give rise to enteritis and diarrhea, aside from any local irritant action and diarrhea induced by the unabsorbed portion, as with calomel. The excretion of metals by the kidneys may give rise to nephritis, this being especially prominent after poisoning with mercuric salts. The intravenous injection of toxic doses of the metallic salts or the rapid absorption of one of the arsenites, such as potassium arsenite, causes a rapid fall of blood pressure due to the direct action on the heart and vessels. This is attended with disturbances of the central nervous system, as profound circulatory disturbances always are. The astringent and irritant local effects of the salts of some of the metals are utilized therapeutically, but the systemic effects just mentioned are of toxicologic, rather than therapeutic, interest. LEAD The systemic effects of lead are of little or no therapeutic importance but they are of toxicologic interest. Acute lead poisoning is not observed frequently, but a single large dose of one of the lead salts may cause gastro-intestinal irritation with nausea, vomit- ing and diarrhea, which may be bloody, or constipa- tion with pain, and in exceptional cases these symp- toms may be followed by collapse. The acute symp- toms are said, in rare instances, to be followed by .chronic poisoning. Chronic lead poisoning is said to be the commonest of all forms of metallic poisoning owing to the wide- spread use of the metal and its constant absorption with slow elimination. It is stated that workers in more than one hundred trades are liable to lead poisoning, especially where suitable precautions are not observed. Dust should be avoided as much as possible in lead works, work rooms should be ventilated thoroughly, and workmen 356 HEAVY METALS— LEAD should avoid putting their hands in their mouths or holding articles between their teeth. Food should not be kept where it can be contaminated with the dust arising from the metal work, and clothes should be changed when the workmen leave the work room. Painters and other workers in white lead are said to be most frequently attacked, and lead smelters, plumb- ers, typesetters, electricians, potters, enamel ware workers and dyers are affected frequently. The use of new lead pipes for conveying drinking water is said to be a common source of plumbism, but this is probably less dangerous than is popularly supposed, for the city of New York requires that lead pipes be used to connect houses with the public water mains, and poisoning seldom results from the use of this water. Wall paper, solder used in sealing canned foods, and even hair dyes are said to be sources of lead poisoning. The cosmetic known as flake white (lead carbonate) is sometimes responsible. Nausea and loss of appetite with a metallic taste in the mouth are among the earliest symptoms of chronic lead poisoning. A bluish line may appear on the margin of the gums but this may be absent when the mouth and the teeth receive proper attention. Anemia is also an early symptom and it may be the only one to attract attention. SoUmann states that at first there may be a pallor due to a constriction of the cutaneous vessels and later a diminution of the hemoglobin and the number of red blood corpuscles. The red blood cells frequently undergo granular degeneration, the granules staining with basophil dyes. If there is extensive destruction of the red cells there may be jaundice and highly colored urine. This granular degeneration of the red cells is characteristic, and may afford the first clue to the nature of the disease. Amenorrhea is not infrequent in women so poisoned and lassitude and weakness are frequently observed. Lead is said to cause gout or a predisposition to it in regions where gout is prevalent. It is well known that abortion is a frequent result of lead poisoning in pregnant women, and Cushny states LEAD 357 that abortion is common among women workers in lead even when they do not show other symptoms of plumbism. Children born to parents either of whom suffers from chronic lead poisoning are weak and seldom live to reach adult life. Various manifestations of lead poisoning are due to its actions on peripheral nerves, but the central ner- vous system may be concerned in certain of these manifestations. Lead causes a general peripheral neu- ritis affecting both motor and sensory nerves, but certain groups of nerves are much more frequently affected than others, and colic, wrist-drop, anesthesia OT excessive tenderness of the skin, arthralgia and dis- turbances of vision are among the most frequent effects of the actions on the nerves. Colic is among the most constant symptoms of chronic lead poisoning and Bastedo cites Starr to the effect that it precedes palsy in more than 90 per cent, of the paralytic cases. The attacks come on suddenly, the paroxysms alternating with periods of relative comfort. During the paroxysms the abdominal mus- cles are tense and hard, the patient often lies face down and obtains some relief by pressing his fists against the region of the umbilicus where the pain appears to be localized. The colic is usually accom- panied by obstinate constipation and attacks of vom- iting, but occasionally there is diarrhea. The parox- ysms of colic are due to spasm of the intestinal wall, but the precise mechanism by which the spasm is induced is not known with certainty. Sollmann attrib- utes it to a stimulation of the nerve endings (vagus) in the intestine as it lacks the peristaltic nature of gangli- onic stimulation and it sometimes yields to atropin, which paralyzes the vagus endings. The intestinal spasms are attended with high blood pressure, which Sollmann also explains as being due to pressure exerted on the splanchnic vessels, whereby the blood is forced into the peripheral circulation. The paralysis of the extensor muscles in the fore- arm is also fairly characteristic of chronic lead poison- ing. The middle and ring fingers are usually involved before the thumb and index and little fingers, the 358 HEAVY METALS— LEAD wrist being aflEected later, the condition being com- monly termed wrist-drop. The neuritis may be fol- lowed by degeneration that extends to the cord and this is followed by rapid atrophy of the extensors, when the unopposed contraction of the flexors gives the hand a claw-like appearance. Bastedo states that the general peripheral neuritis may be similar to that resulting from alcohol and that it may at least superficially resemble locomotor ataxia. Among the sensory disturbances are anesthesia, which sometimes begins suddenly and disappears after a few days, or there may be intense pain in certain joints and muscles near them, or great tenderness over different areas of the skin. Various disturbances of the brain are described under the title of saturnine encephalopathia ; these include intense headache, vertigo and mental depres- sion, but these manifestations are said to be rare when the earlier stages of chronic lead poisoning are treated properly. Lead shares with other metals their irritant actions on the kidneys, and nephritis is a constant result of chronic lead . poisoning ; lead may possibly induce arteriosclerosis. Prophylaxis is of the first importance with refer- ence to lead poisoning, but it is not always possible to foresee when one will suffer from its effects, since many escape under conditions that lead to poisoning in others. Persons who suffer from anemia or general ill health, and those who have suffered from lead poison- ing are especially susceptible to its effects. Those who are exposed to the effects of lead have been advised to take very dilute sulphuric acid with a view to converting any of the metal that may be swallowed into the relatively insoluble sulphate, but this should not be permitted to give a false sense of security and cause the neglect of more important prophylactic mea- sures, and it cannot be understood too well that the insolubility of a substance in water does not neces- sarily mean that it is not absorbable from the gastro- intestinal tract. LEAD 359 An overdose of a soluble lead salt frequerttly causes vomiting that serves to remove practically all of the poison from the stomach, thus preventing further symptoms, but even in such cases it is well to give a dose of magnesium sulphate and wash the stomach in order to remove the resulting sulphate of lead, after which a second dose of magnesium, sulphate may be administered with a view to inducing purgation and removing any of the lead that may have escaped from the stomach into the duodenum. In the absence of sulphate of magnesium or sul- phate of sodium one may administer egg-white or milk in order to form the insoluble albuminate of lead, but in any case the precipitate must be removed as promptly as possible. If vomiting and diarrhea have already resulted from the local action of the lead, magnesium sulphate may be administered in order to convert any remaining lead into the sulphate and hasten its passage through the intestinal tract. Those who work in trades in which lead poisoning is an ever-present danger should be instructed to con- sult a physician on the appearance of the earliest symptoms such as the metallic taste in the mouth and the loss of appetite. When a diagnosis of chronic lead poisoning is made one should not be content to find a single source of the intoxication, but owing to the frequency with which minute amounts of lead find entrance into the body from such a variety of sources, the physician should exercise especial care to exclude all sources of poison- ing, for a lead worker having become poisoned through the pursuit of his trade may at the time be absorbing minute amounts from other sources. These minute amounts might be harmless to one in good health but might be extremely injurious to one already suffering from the effects of the metal. The treatment of chronic plumbism includes the relief of symptoms and elimination of the poison. Atropin paralyzes the vagus endings in the intestine abolishing the intestinal spasm, and with it a non- irritant evacuant, preferably a saline, should be used to empty the bowel. An excessively high blood pres- 360 HEAVY METALS— LEAD sure independent of that caused by the mechanical pressure on the splanchnic vessels is apparently con- cerned in the colic, and a vasodilator, such as amyl nitrite, frequently affords relief. Since the local action of atropin is desired in such cases it would seem better to administer it by the mouth in order that it may reach the nerve endings in the maximum concentration. Since, however, the intense vagus stimulation (if indeed that is the cause of the spasm) may also cause spasm of the pylorus and interfere with the passage of the drug into the intes- tine after its oral administration, it may be neces- sary to inject the drug subcutaneously. Even in that case one may fail to elicit the full effect on the nerve endings, not only because of its greater dilution in the general blood stream but because the anemia attending the intense splanchnic constriction interferes with the drug's reaching the endings in the intestine. In such a case it would seem logical to give amyl nitrite by inhalation or nitroglycerin subcutaneou?ly, followed immediately by atropin intramuscularly, li a single dose of atropin (1 mg. or %o grain) does not relieve, it may be repeated once or even twice. Opium or morphin may be required for the relief of the intense pain attending the paroxysms of colic and for the relief of the joint pains that usually come later in the course of poisoning. Gout occurring at such times requires the same treatment as that aris- ing under other conditions. Lead, like other metals, is excreted in part by the kidney, but mainly by the intestine, and while it is stated that the intestinal epithelium participates in the excretion, the fact that the metal is stored more abundantly in the liver than in the other tissues sug- gests that that organ is responsible for the elimination of the larger part of that remaining in the body after absorption has ceased. Potassium iodid has long been used to hasten the elimination of the metal, but it seems probable that it has little effect on the excretion of the metal stored in other parts of the body, though it may lower blood pressure and assist the action of diuretics. IRON 361 Diuretics are also commonly used to hasten elim- ination and while they, too, have probably but little effect on the elimination of the metal stored in other parts of the body, they may lessen the local action on the kidneys by hastening the process of elimination of that actually stored in them. The foregoing discussion might lead one to sup- pose that the diagnosis of chronic lead poisoning is comparatively easy. While it is an extremely simple matter in typical cases, there are many cases presenting such obscure symptoms that the diagnosis will tax the ingenuity of the most careful physician to the utmost. It must be remembered that traces of lead may be found in the urine and feces of persons in health, and that while its detection in the excreta of persons presenting other characteristic symptoms is strong evi- dence of chronic plumbism, the detection of traces of lead in the urine and feces cannot be accepted as con- clusive proof of poisoning by it. The systemic actions of bismuth, copper, silver and zinc are of some toxicologic interest but they do not require detailed discussion here. Numerous attempts have been made to utilize the systemic effects of colloidal metals, colloidal silver having been exploited widely as a systemic germicide and antiseptic. The use of colloidal copper has also been suggested, but the results are not encouraging. (The therapeutic uses of lead salts are mentioned in the discussion pf astringents.) IRON The normal human body contains some 3 gm. (45 grains) or less of iron, the greater part being present in the hemoglobin of the blood. It is generally stated that only a few milligrams of iron are eliminated from the body daily in the feces and urine, this loss being made good from the iron contained in the food. It is supposed that roughly one-tenth of the hemoglobin of the blood is destroyed daily, the pigments being eliminated in the bile, but the iron is evidently utilized again and again in the formation of hemoglobin, the absorption of extremely small amounts sufficing to make good the loss already mentioned. It is seldom 362 HEAVY METALS— IRON that the normal diet contains an insufficient amount for the daily needs, but in disease there is often a dis- turbance of metabolism which prevents the utilization of the iron of the food and additional supplies are required to be administered therapeutically. Iron has long been used empirically in anemia, but its rational use dates from 1746, when it was discov- ered that it is a constituent of the red blood corpus- cles. Since then there have been many investigations intended to show the form in which iron is taken into the circulation and in which it is utilized in the for- mation of hemoglobin. Bunge believed that only those forms of iron which exist in the food, such as meats and vegetables, were absorbed and he suggested that in the form of nucleo- albuminates they escaped conversion into the insoluble sulphid in the intestine, but that, under certain patho- logic conditions, even these might be attacked by the hydrogen sulphid in the intestine, and their absorption prevented. He suggested further that in such condi- tions the administration of ferrous carbonate, or other inorganic salts of iron, would serve to prevent the action of the hydrogen sulphid on the iron of the food, which would then undergo absorption, as usual. This theory of Bunge's is no longer held by physi- cians or pharmacologists, but it is still urged by certain interested manufacturers as the basis for their claims for the value of their preparations. On this basis is urged the use of preparations of manganese which are employed in anemia, as it is claimed that the manga- nese unites with the hydrogen sulphid, thus sparing the iron of the foods for absorption. One need only remember that iron is absorbed mainly in the duode- num and that there is no hydrogen sulphid in that part of the intestine, to recognize that administration of manganese can not affect the absorption of iron. Bunge calls the iron which exists in the yolk of egg hematogen, and this is evidently the source of iron in the blood of the chick. One manufacturer placed a preparation on the market under the name of hema- togen, but Bunge distinctly states that it is a waste of money to buy this expensive preparation. IRON 363 Schmiedeberg isolated an iron compound from the liver of the pig, supposing this to be the immediate precursor of the iron in hemoglobin. While this may be the form in which iron exists immediately before it is built up into hemoglobin, there is no evidence that it is absorbed any better than other forms of iron. Tartarkowsky bled animals repeatedly until they were unable to regenerate hemoglobin from stores of iron in the body, and fed some of these animals food free from iron, and others the same food with the addition of inorganic iron salts.^* Those which received the iron with their food regenerated their blood and recovered their normal condition ; those which did not, succumbed to the effects of the hemorrhage. He also found that when animals which had been bled in this way received food containing an abun- dance of iron they regenerated hemoglobin as well as others which received similar food with the addition of inofganic iron, showing that in simple anemia organic iron in abundance suffices for the restoration of the blood. It seems probable that when the food does not contain an abundance of iron the addition of inorganic iron may be of benefit in simple anemia. It is significant at least that widely different forms of vegetation are capable of supplying the animal organism with all of the iron which it requires for regenerating hemoglobin, and as this iron is almost certainly broken down before it is absorbed, we must suppose that both organic and inorganic forms may be utilized by the body for building up hemoglobin, but only careful clinical experience will determine which of these is preferable for therapeutic use. At best there can be little difference between the organic and inorganic forms so far as their utilization is concerned, and clinical experience has, as yet, failed to indicate any advantage of one over the other in this particular. 28. Those salts of iron which are precipitated by ammonium sulphid at room temperature are called "inorganic," regardless of whether they contain organic material or not, iron albuminate and peptonate, salts that are not directly precipitated by ammonium sulphid, being classed, as inorganic, or preferably, "masked," 364 HEAVY METALS— IRON The results of various experiments indicate that an amount of iron equal to about 5 mg. (%o grain) is excreted daily in the intestine and about 1 mg. (%q grain) in the urine, and it is evident that the diet should contain at least as much as is eliminated. It is in agreement with these estimates that Stockmann found that the normal daily diet of several healthy persons averaged about 8 to 10 mg. (% to % grain) of iron, while the diet of two chlorotic females con- tained from 114 to 3 mg. (%o to %o grain). The following table adapted partly from Bunge and partly from Stockmann, shows approximately the amounts of iron which various foods contain. Sugar, cream, butter, and white of egg are practically iron- free. IRON CONTENT OF FOODS READY TO SERVE Mg. 1 teacupful of boiled oatmeal 0.2 to O.S Two apples or oranges 0.1 to 0.5 500 gm. (about 1 pound) of grapes 0.4 to 1.0 Yolk of two eggs 2.0 to 5.0 500 c.c. (about 1 pint) of milk 1.0 to 1.5 500 gm. of white bread 2.5 to 5.0 500 gm. of whole wheat bread 5.0 to 15.0 1 teacupful of mashed potato 0.3 to 1.5 1 teacupful of boiled cabb,ige 0.5 to 3.0 1 teacupful of boiled carrots, peas or beans 0.5 to 2.0 1 teacupful of boiled spinach 3.0 to 15.0 500 gm. "blut-wurst" 50.0 to 125.0 100 gm. yellow ox-marrow (dried) 4.0 100 gm. red calf -marrow (dried) 8.7 100 gm. roast beef 4.0 to 12.0 The foregoing table shows that the normal diet need not contain an insufficient amount of iron, but it is not always convenient to order a diet for an invalid which will contain an abundance of it, but when ox-marrow, red meats, eggs, whole wheat bread, spin- ach or "blut-wurst" can be taken there will be no diffi- culty in supplying the normal daily needs. Hazel nuts, almonds and green vegetables are relatively rich in iron. THERAPEUTIC USES The use of copperas, or ferrous sulphate, as a disin- fectant has been mentioned, and the astringent uses of iron will be considered later. Iron is used in various conditions attended with anemia, being especially use- ful in those cases in which the red blood corpuscles IRON 365 individually contain less than the normal amount of hemoglobin.^' There are few therapeutic facts that are better established than that iron is useful in chlorosis, and it is also apparently beneficial at times in secon- dary anemias. Organic iron is sometimes found to cause less gastric disturbance than the inorganic forms. Owing to the uncertainties concerning the most absorbable forms of iron one might suppose that the intravenous injection of iron is indicated in those cases in which the oral administration is not followed by improvement, but it must be remembered that iron is extremely poisonous when administered intra- venously, and when the oral administration is without results this is probably due to an inability to utilize the iron in the formation of hemoglobin, rather than to any want of iron in sufficient amounts in the blood- building organs. We have no reason, therefore, to suppose that intravenous injections are ever indicated. It is said that the anemia of ankylostoma yields readily to treatment with iron. One writer records observations on more than 300 cases and states that reduced iron, ferric chlorid, and ferrous sulphate gave better results than organic iron compounds. Iron has been used in numerous conditions in addition to those mentioned, but without sufficient evidence of any bene- ficial action. It has long been taught that moist ferric hydroxid is an antidote for arsenic if it be given while the arsenic is still in the stomach, as iron and arsenic react to form an insoluble compound which should be removed as soon as possible. Later experiments seem to show that this procedure is of doubtful value, as the arseni- cal compound seems to be broken down and the arsenic to be absorbed about as promptly as when no iron hydroxid is given. If the stomach is washed promptly, the antidote is probably of value, as the stomach then contains little but water (if that be used for washing it), and, as previously stated, the arsenic is rendered insoluble in water. When the stomach cannot be 29. William Hunter states that the stored iron in the body is more commonly deficient, and the cause of chlorotic anemia, in the young than in patients in whom the disease occurs after 30. 366 HEAVY METALS— IRON emptied promptly, however, the iron is probably worse than useless. DOSAGE It is obvious that the dosage of iron usually bears little relation to the amount which it is expected will be utilized in the formation of hemoglobin, and the amount administered is frequently regulated with ref- erence to the tolerance shown by the stomach. There is little correspondence between the amounts of iron present in the doses of the different salts as commonly administered: for example, the dose of reduced iron is given as 65 mg. (1 grain) but larger doses are fre- quently used, whereas the average dose of the syrup of ferrous iodid contains less than one sixth as much iron as the average dose of reduced iron. The dose o'f ferrous carbonate is 0.25 gm. (4 grains) ; of the pills of ferrous carbonate (Blaud's pill) two containing 0.06 gm. (1 grain) each of ferrous carbonate, are taken; of ferrous sulphate, 0.2 gm. (3 grains) ; of the dried ferrous sulphate two thirds as much as of the crystalline; of the syrup of ferrous iodid, 1 c.c. (15 minims) ; of iron and ammonium citrate or of soluble ferric phosphate, 0.25 gm. (4 grains) ; of the tincture of ferric chloric^ 0.5 c.c. (8 minims). " The well-known disadvantages of inorganic salts of iron, such as the difficulty of preventing the oxidation of the ferrous and the astringency of the ferric; the tendency of many of them to injure the teeth ; the diffi- culty of securing absorption and their tendency to dis- turb the stomach, have led to the introduction of a very large nuinber of official and unofficial, galenical preparations, while the numerous theories advanced with regard to the form of iron which is utilized directly in the formation of hemoglobin have resulted in the introduction of numerous proprietary prepa- rations of iron, and of manganese intended as substi- tutes for iron, but there is not the least evidence that any of these proprietary preparations,^" even those 30. Examples of the way in which some of the proprietary preparations of iron or its substitutes are exploited are discussed in Jour. Am. Med. Assn., Sept. 23, 1905, p. 934; April 6, 1907, p. 1197, and April 23, 1910, p. 1389. MATERIA MEDICA OF IRON 367 sponsored by eminent investigators, have any advan- tage over the preparations enumerated below. MATERIA MEDICA Ferrum. — Iron, U. S. P., is used in pharmacy in the production of preparations of iron, but in medicine it is used chiefly in the form of : Ferrum Reductum. — Reduced Iron, U. S. P., the official product of which should contain not less than 90 per cent, of pure metallic iron. It occurs as a grayish-black lustrous powder, without odor or taste, that is permanent in dry air. It is insoluble in water or in alcohol and is preferably administered in cap- sules or in the form of recently prepared pills. Of the many salts of iron that occur, the following ferrous combinations are, perhaps, the most widely used: Ferri Carbonas. — Ferrous Carbonate, U. S. P., is usually made by the interaction of ferrous sulphate with a soluble carbonate and is used in medicine chiefly in the form of: Massa Ferri Carbonatis. — Mass of Ferrous Car- bonate, U. S. P. — This mass, better known as Vallet's mass, is a mixture of ferrous carbonate with honey and sugar to form a mass and to act as a preservative. The average dose of 0.25 gm. (4 grains) contains approximately 0.1 gm. (I14 grains) of ferrous car- bonate. Mass of ferrous carbonate is frequently prescribed in combination with strychnin or nux vomica or with arsenic trioxid. The following is a typical combina- tion: Gm. or c.c. Grains R Massa ferri carbonatis 6| 100 Extract! nucis vomicae 0|40 6 vel Strychninae 0|02 Yj M. et fiat pilulas No. 20. Pilulae Ferri Carbonatis. — Pills of Ferrous Car- bonate, U. S. P., popularly known in Blaud's pills, consist of a mixture of freshly formed ferrous carbo- nate and potassium sulphate with sugar and a smaller 368 HEAVY METALS— IRON proportion of tragacanth and althea to make a mass. Each pill represents approximately 0.06 gm. (1 grain) of ferrous carbonate. They should be freshly pre- pared. Ferri Sulphas. — Ferrous Sulphate, U. S. P., and the dried product. Ferri Sulphas Exsiccatus. — Exsiccated Ferrous Sul- phate, U. S. P., are seldom employed for internal administration but are used indirectly as the source of ferrous iron in the preparations of ferrous car- bonate enumerated above. Ferri lodidum. — Ferrous lodid, U. S. P., is com- monly used in medicine in the form of the syrup. Syrupus Ferri lodidi. — Syrup of Ferrous lodid, U. S. P., contains about S per cent, by weight of Fel^. It occurs as a transparent, pale green or yellowish green liquid having a sweet, but strongly ferruginous taste and an acid reaction. Syrup of ferrous iodid is incompatible with alkali carbonates, acid salts and vegetable astringents. It is very susceptible to oxidation and is best kept in small well-sealed vials exposed to diffuse daylight. Syrup of ferrous iodid is preferably directed to be admin- istered alone, well diluted with water. It should not be used when a reddish or yellowish color has devel- oped, indicating that oxidation has taken place. Of the many ferric salts and combinations that have been suggested from time to time the following are fairly representative: Ferri et Ammonii Citras. — Iron and Ammonium Citrate, U. S. P., a scale salt containing ferric iron and ammonium citrate corresponding in amount to not less than 16 per cent, of metallic iron. It occurs as thin, transparent, garnet-red scales, odorless and having a saline, mildly ferruginous taste. The compound is deliquescent in moist air and is readily and completely soluble in water but is insoluble in alcohol. Ferri Phosphas Solubilis. — Soluble Ferric Phos- phate, U. S. P., a compound containing ferric phos- phate corresponding in amount to not less than 12 per cent, of metallic iron. It occurs as thin, bright green, MERCURY 369 transparent scales, odorless, and having a saline, slightly acidulous taste. The salt is permanent in dry air when excluded from light but when unprotected soon becomes dark and discolored. It is freely and completely soluble in water but insoluble in alcohol. Like other soluble salts of iron, these scale salts are incompatible with fixed alkalies, alkali carbonates, and vegetable astringents. They may be administered in either water or syrup, with or without the addition of a small amount of alcohol and a trace of aromatic oil. Ferri Chloridum. — Ferric Chlorid, U. S. P., is used in medicine principally in the form of : Tinctura Ferri Chloridi. — Tincture of Ferric Chlorid, U. S. P., a hydro-alcoholic solution of ferric chlorid, FeCla, containing not less than 13.28 per cent, of anhydrous salt, corresponding to about 4.5 per cent, of metallic iron. Tincture of ferric chlorid occurs as a bright brownish liquid having a slightly ethereal odor, a very astringent taste and an acid reaction. On exposure to light it is gradually reduced with the production of some ferrous salt, hence it should be carefully preserved in glass-stoppered bottles, protected from the light. Because of its objectionable styptic taste and distinct acid reaction it is now seldom employed internally. When so given, care should be taken to protect the teeth either by directing that the diluted tincture be taken through a glass tube or that the mouth be carefully rinsed with a slightly alkaline mouth-wash immediately after taking the medicine. MERCURY When the soluble mercuric salts, such as the chlorid, are taken they may be brought into more intimate con- tact with the tissues than the insoluble salts, such as calomel. This is because the solutions of the mer- curials permit the formation of the albuminate, which is soluble in excess of albumin, such as exists in the tissue fluids. The solubility of the mercurial compound formed, and its toxicity for all cells with which it comes into contact in sufficient concentration permits it to exert its toxic action not only on the mucous membrane of 370 HEAVY METALS— MERCURY the alimentary tract at the time it is swallowed, but also on the cells of the renal tubules and of the intes- tine which participate in the excretion of the metal. It is commonly stated that a metallic taste and a burning sensation in the mouth and throat are the first symptoms observed after a toxic dose of mer- curic chlorid has been swallowed. Animals, however, appear to suffer no discomfort after the introduction of mercuric chlorid through a stomach-tube before the onset of nausea, which is promptly followed by emesis. The vomitus may be tinged with blood within a few minutes after the administration of an excessive dose, showing the rapidity of the onset of the cor- rosive action. The vomiting may be almost incessant or there may be intervals during which an animal gives little sign of actual discomfort. A cat vomited fourteen minutes after the administration through a stomach tube of a 1 : 500 solution containing an amount of the mercuric chlorid corresponding to about 2 gm. (30 grains) for a man. Another cat received about one tenth as much in a 1 : 5,000 solution and though this amount corresponds to an almost certainly fatal dose in man the animal did not vomit or exhibit any symptoms of discomfort during more than forty- eight hours that it was under observation. In man, the onset of nausea and vomiting may be sufficiently delayed to permit notable amounts of the poison to pass into the duodenum, where part of it is absorbed. The remainder being carried into the large intestine causes diarrhea in some cases, but in others this result is delayed for twenty-four hours, that is, until the irritant action of the metal is exerted on the intestinal cells during excretion. The evacuations often resem- ble those seen in arsenic poisoning, and contain blood and shreds of desquamated intestinal epithelium. Excessive doses of mercuric chlorid may cause pro- found collapse through the severity of the gastro- intestinal action. Death may result in a few hours, but the patient usually lives from three to eight days after a fatal dose has been taken, and death may then be due to collapse incidental to the action on the cen- tral nervous system and to gastro-intestinal and renal MERCURY 371 effects. There is little direct action on the heart and central nervous system in many cases, and conscious- ness is commonly retained in acute poisoning until shortly before death, when uremic symptoms with coma result. Aside from the salivation resulting from the nausea that comes on soon after the poison has been taken, there is sometimes an intense activity of the salivary glands. The saliva containing mercury, which is irri- tant, may occasion excoriations and deep ulcerations extending even into the bone of the jaw unless care is given to the mouth. A 2 per cent, solution of potas- sium chlorate is recommended as a mouth-wash in such cases. The salivation and soreness of the gums and mouth are important as they are among the earliest of the symptoms commonly observed in chronic mercurial poisoning when mercury is taken over prolonged periods, or when persons are exposed to its action as in the trades in which it is used (mirror makers). In severe mercurial poisoning the colon and cecum are commonly the seat of ulceration caused by the direct action of the salt before its absorption, or more commonly, during excretion. The small intestine suf- fers comparatively little, probably because the poison does not remain in it long, but is either absorbed or passed on into the cecum. The urine may be increased for a time and later completely suppressed, partly through the action of the mercury on the epithelium of the tubules, partly through the circulatory changes induced by the watery diarrhea. This by withdrawing fluid from the blood increases its viscosity, which with the lowered blood pressure causes further interference with the renal secretion. Attention has been called to the necessity for pre- venting diarrhea when calomel is administered for its diuretic action, and the reasons for this have been explained. It is in keeping with that explanation that when mercurial poisoning is attended with severe gastro-intestinal disturbances with watery diarrhea, there should be less nephritis than when poisoning of 372 HEAVY METALS— MERCURY equal severity is accompanied with comparatively little diarrhea. The various skin lesions observed during chronic mercurial poisoning are due to the irritation caused during excretion in the sweat. In chronic poisoning in long-standing cases (not in those induced by the therapeutic use of mercury), mus- cular tremors of central origin may occur, and a condi- tion of erethism, or increased excitability of certain parts of the central nervous system is described. This erethism is characterized by irritability and alterations in the disposition. The milder forms of chronic mercurial poisoning are induced when any of the mercurial is given over a prolonged period in the treatment of syphilis, and, indeed, the beginning of these symptoms serves as a guide in limiting the administration. More severe symptoms occur among workers in trades in which mercury is used constantly. The continuous admin- istration of calomel is said to give rise to severe stoma- titis more frequently than is the case with mercuric chlorid and other soluble salts of mercury, because it is impossible to control the absorption with any degree of precision in the case of calomel. Undue absorption thus occurs at times, especially when opium is admin- istered to control the diarrhea which calomel causes otherwise. Acute fatal poisoning with mercuric chlorid has become quite common of late, owing to carelessness or the deliberate use with suicidal intent of the "antisep- tic tablets," each of which contains about 7 grains of the poison. There is little doubt that the widespread use of these tablets in solution for preventing conception is responsible for their being present in many households, inviting mistakes and affording opportunities for self- destruction. Various ways have been suggested by which mis- takes with the tablets will be rendered impossible, thus, it has been recommended that they be made of cylindrical shape, or that they be colored distinctly with indigo or ultramarine blue. The distinctive shape MERCURY 373 is preferable, since mistakes are often alleged to be due to taking tablets in the dark. The tablets are threaded together like beads by one manufacturer. Fatal poisoning also results occasionally from the use of solutions of mercuric chlorid as a wash for large wounds and body cavities, and it should be remembered that absorption may take place from any mucous or denuded surface. Fatal poisoning has even followed the local application of the mercurial oint- ment, though this is extremely rare. It is even said that the oral administration of calomel may be fol- lowed by absorption and the typical corrosive action of mercuric chlorid, but this must also be rare. The stomach should be emptied as promptly as pos- sible after a poisonous dose of mercuric chlorid has been swallowed. The stomach tube is preferable for this purpose,'^ for while emesis occurs in the large majority of cases from the action of the drug, this is not sufficiently prompt to prevent the absorption of notable amounts, or to prevent still larger amounts from passing into the duodenum. Egg-white, milk or other readily available form of protein should be administered immediately but not too freely, even before the stomach-tube is passed, and again after the stomach has been emptied as thor- oughly as possible. The portion administered at first is intended to precipitate the poison and stop its fur- ther action on the stomach, and that administered after the stomach has been washed is for the purpose of protecting the mucous surface and precipitating any mercuric chlorid that may have escaped precipi- tation in the first case. Immediately after washing the stomach, 30 gm. (1 ounce) of magnesium sulphate should be dissolved in 500 c.c. (1 pint) of water and administered in order to dilute any of the poison that passes into the duode- num and to hasten its evacuation in the feces. Egg- white or milk may be added to this solution in order to precipitate any mercuric chlorid that may exist in 31. The danger of perforating the stomach, while attempting to pass the stomach-tube after corrosives have been sv^allowed, has probably been much exaggerated. Of course, one should exercise caution in passing the tube under any conditions. 374 HEAVY METALS— MERCURY the alimentary tract, and egg-white or milk should be administered from time to time for the same purpose. One cannot be certain that the most energetic treat- ment will suffice to prevent the absorption of a poi- sonous dose of the salt, hence attention should be given to its elimination and to the treatment of symp- toms that may arise. Since mercury is eliminated by all of the channels of excretion, it would appear to be logical to promote all the secretions so far as pos- sible, and diaphoretics and diuretics should be used freely. Attention has been called in previous chapters to the copious diuresis that may be induced by the intra- venous injection of large amounts of a 2 per cent, solution of sodium sulphate. While this procedure is not justified by the mere suspicion that a toxic dose of mercuric chlorid may have been absorbed, it would probably prove beneficial if used early in the course of poisoning after absorption has taken place and before severe nephritis has developed. We are not aware of any case of mercurial poisoning having been so treated, but when a fatal outcome appears almost certain in the presence of the usual methods, it would at least seem justifiable to employ any means of hastening the elimination that does not jeopardize the patient's welfare. The diarrhea and its attendant pain that result dur- ing the excretion of mercury may require the admin- istration of opium, but the evacuations must not be checked altogether since that would prevent the elimi- nation of the poison. It is often asserted that potassium iodid facilitates the elimination of mercury from the body but no sat- isfactory evidence exists that it exerts any marked effect in this way. THERAPEUTIC USES The disinfectant, diuretic and cathartic actions of mercury have been discussed. Its use in syphilis remains to be considered. In this disease its value has been established beyond question. Its well-known disadvantages and the over- shadowing literature of salvarsan, however, together USES OF MERCURY 375 with the sensational introduction of the latter as a cure for syphilis have tended of late to create the impression that mercury is of only secondary impor- tance. In truth mercury is indispensable still, even though there are some cases of syphilis which may possibly yield to arsenical treatment, for mercurial treatment becomes necessary in the larger proportion of cases. It seems probable that it will be used more and more in conjunction with arsenic when the tech- nic of their cdmbined use is perfected. Preference has been given at one time or another to nearly every one of the better-known salts of mer- cury, including those that have been introduced in the effort to overcome some of the disadvantages of the other mercurials. The value of mercury in the treat- ment of syphilis depends on getting enough of it into the circulation to destroy (or to enable the body to destroy) the Spirachaeta pallida, the causative organ- ism. Since mercury is toxic to all of the cells of the human body with which it comes in contact in sufficient concentration, it follows that whatever method of administration is chosen the toxic effects of the metal must be exerted at .the points of absorption and elimi- nation. It is therefore apparently impossible to secure the therapeutic action of mercury without at the same time subjecting the patient to some of its disagreeable side actions. The literature dealing with the treatment of syphilis and the best methods of administering mercury is extensive, but the general practitioner will usually depend on oral administration despite its many dis- advantages, until better means of administering the remedy are perfected. Many specialists prefer the intramuscular injection of an insoluble salt such as the salicylate, as a sufficient quantity can be given at two injections to produce an influence which will last a week, thus saving much time. This method, however, has the great disadvantage of resulting in a variable rate of absorption, so that the dosage cannot be regu- lated satisfactorily. The pain attending the injection is said to be less severe but to last longer than that following the injection of mercuric chlorid. A few 376 HEAVY METALS— MERCURY specialists prefer the mercuric chlorid for intramus- cular injection. It has the advantage of insuring rapid absorption with satisfactory regulation of the dosage, but it causes severe pain and the injections must be made every day. Inunction is practiced in some institutions where the services of trained attendants are available. The ointment of mercury is rubbed into the various parts of the body successively. It is extremely untidy and it gives rise to much discomfort. Mercurial vapor baths would appear to have decided advantages were it possible to regulate the dosage sat- isfactorily. Calomel, mercury and chalk, mass of mercury, and the "proto" or yellow iodid are insoluble forms of mer- cury that may be administered by the mouth in pills or capsules. They all cause diarrhea, usually neces- sitating the use of opium to secure sufficient absorp- tion, and they have the disadvantage of being variable in absorbability even then. Mercuric chlorid, or red mercuric iodid may be given in solution. Mercuric chlorid and potassium iodid are commonly prescribed together, the soluble double salt of mercury and potassium iodid being formed. When arsenic is used in the treatment of syphilis an effort is made to destroy all of the spirochetes in the blood with one dose. It would therefore seem logical to use the largest doses of mercury that the patient can stand in order that the micro-organisms may be destroyed as rapidly as possible, but the tox- icity of mercury for the host and its many side actions are so important that they must be taken into con- sideration in the method of treatment. A lack of agreement also exists concerning the best methods of procedure with the various mercurials. The administration of mercurials during the latter months of pregnancy may induce abortion, or the new- born may suffer from chronic mercurial poisoning. The simultaneous occurrence of syphilis and tubercu- losis offers additional difficulties in the administration of mercury but it does not wholly contraindicate its use. DOSAGE OF MERCURY 377 Mercurial ointment is also used for destroying para- sites, especially body lice, but there are other methods that are equally effective and more cleanly. A solu- tion of mercuric chlorid, 1 : 500 in vinegar, diluted acetic acid or diluted alcohol may be applied cau- tiously; but absorption may occur if too much of the solution is used, hence not more than one fluidounce of such solution should be applied during a day. Ointment of ammoniated mercury is antiseptic and a local stimulant ; it is used to excite a healthy inflam- matory reaction in psoriasis, and it is also applied to areas of suppurating dermatitis. DOSAGE The single dose of the various mercurials varies widely with the method employed. Larger single doses of the salicylate are given when injections are made intramuscularly twice a week than of the mer- curic chlorid when used daily. On the other hand, it is obvious that the amount of calomel or one of the other insoluble mercurials that will be required to induce a given effect will vary considerably with the measures taken to prevent its rapid removal by purga- tion. It is probable that the amount of mercury nec- essary to be absorbed in a given length of time to pro- duce the desired therapeutic effects, that is, the destruction of the spirochete, does not vary nearly so widely as the total amount which may need to be administered. The oral dose of mercuric chlorid (corrosive sub- limate) is 0.002 to 0.01 gm. (%o to % grain) in pill or preferably in dilute solution. Attention is again called to the much greater irritation caused by con- centrated solutions than by dilute ones containing equal amounts of irritant salts. The maximum oral daily dose is 0.06 gm. (1 grain). The daily dose by intramuscular injection should not exceed 0.01 gm. (% grain). Solutions of from 1 : 1,000 to 1 : 2,000 are used to excite dermatitis and exfoliation ; care should be taken to avoid absorption of large amounts, hence such solu- tions should be used only with caution and they should be discarded should there be evidences of absorption, SIlpVl ns salivatinn nr a mptallip taet(> in tVip mniitVi 378 HEAVY METALS— MERCURY It is difficult to state the dose of calomel in exact terms with such strict limitations as in the case of the mercuric chlorid. The administration is regulated rather by the symptoms induced and evidence of absorption than by mere figures. The single dose varies from 0.06 to 0.12 gm. (1 to 2 grains) and from 3 to 5 grains daily until slight mercurialism is induced when it is employed in the treatment of syphilis. Soluble iodids, such as sodium or potassium iodid, are contraindicated during the administration of calo- mel as they react with it to form metallic mercury and mercuric iodid. The yellow mercurous iodid, also called the green iodid, or the protiodid, is little used except for the treatment of syphilis ; it has less tendency than calomel to cause diarrhea. It is best administered in pill form after meals in doses of 0.015 gm. (^ grain) three times daily, increasing gradually by 0.008 gm. (% grain) till the symptoms indicate that the limits of tolerance are being approached. The appearance of salivation, diarrhea and pain is the signal for inter- rupting the administration or diminishing the dose. Red mercuric iodid is given by the mouth in doses of 0.003 gm. (%o grain) three times daily. It is commonly prescribed in a liquid form by directing mercuric chlorid and potassium or sodium iodid in solution somewhat as follows: Gm. or c.c. 1^ Hydrargyri chloridi corrosivi Potassi iodidi 6 Aquae 100 06 grains i 00 3 iss 00 3 iii Red mercuric iodid may be injected intramuscularly, in a solution in a bland fixed oil containing from 0.2 to 1 per cent. The daily intramuscular dose is about 0.005 gm. (%o grain) or 1 c.c. (15 minims) of a 0.5 per cent, solution. Mercuric salicylate has come into use largely for intramuscular injection suspended in liquid paraffin or other oleaginous menstruum. Of a 10 per cent, suspension, containing 0.06 gm. (1 grain) of mer- curic salicylate, 0.6 cc. (10 minims) is injected intra- muscularly about twice a week or once in four days. MATERIA MEDICA OF MERCURY 379 Mercury with chalk is given in doses about equal to those in which calomel is used. The action of mercury with chalk, the mass and the ointment, con- taining the metal in fine division, is quite dififerent from that of the metal in mass, since the finely divided globules of mercury are partially oxidized. Metallic mercury was formerly administered in sub- stance in large doses, but it is seldom given now in the pure form. MATERIA MEDICA Hydrargyri Chloridum Corrosivum. — Corrosive Mercuric Chlorid, U. S. P., more popularly known as corrosive sublimate, occurs in the form of heavy colorless crystals or a heavy white powder having an acrid and persistent metallic taste. It is permanent in the air and is quite soluble (1:13) in water and freely soluble (1:3) in alcohol. Ammonium chlorid, sodium chlorid, tartaric and citric acid increase its solubility in water. Mercuric chlorid is precipitated from its aqueous solutions by albumin, but redissolves in a large excess of the albumin solution. In administering tgg white as an antidote this property of albumin should be borne in mind. Mercuric chlorid is also incompatible with soluble carbonates and hydroxids forming insol- uble mercuric oxid. With soluble iodids it forms mercuric iodid or complex salts. It is incompatible with many alkaloids and other organic compounds and is reduced to calomel or metallic mercury by iron, zinc and other reducing agents. Hydrargyri Chloridum Mite — Mild Mercurous Chlorid, U. S. P., more popularly known as calomel, occurs as a white impalpable powder, becoming yel- lowish-white on trituration with strong pressure. It is odorless, tasteless and permanent in air. Mild mer- curous chlorid is practically insoluble in water, alcohol or ether. It undergoes change when exposed to the action of light or under the influence of alkaline chloridS; bromids or iodids; by which mercuric salts are more or less rapidly formed. For intramuscular injections it may be directed to be suspended in liquid petrolatum or a bland, fixed 380 HEAVY METALS— MERCURY oil and the equivalent of 0.1 gm. (1% grain) injected once a week. Hydrargyri lodidum Flavum — ^Yellow Mercurous lodid, U. S. P., also known as protiodid of mercury and popularly, though erroneously, called green iodid of mercury, occurs as a bright yellow amorphous powder that is odorless and tasteless. By exposure to light it becomes darker, in proportion as it under- goes decomposition into mercuric iodid and metallic mercury. It is almost insoluble in water and wholly insoluble in alcohol. Yellow mercurous iodid is usu- ally administered in the form of pills. It is incom- patible with oxidizing agents, alkalies and the haloid salts of the alkali metals, which tend to decompose it with the formation of mercuric salts. Alkali iodids decompose mercurous iodid with the formation of metallic mercury and soluble alkali mercuric iodid. Hydrargyri lodidum Rubrum — Red mercuric Iodid, U. S. P., popularly known as biniodid of mercury, occurs as a scarlet red powder that is odorless and tasteless. It is permanent in air, and nearly insoluble in water but slightly soluble (1:116) in alcohol; also slightly soluble in fatty oils. Red mercuric iodid may be given internally in the form of solution with potas- sium or sodium iodid or administered in the form of pills. For intramuscular injections the solution in a bland, fixed oil is frequently used. Mercuric iodid is incompatible with alkalies and their carbonates and alkaloids and their salts. The addition of an alkaline iodid produces a water-soluble complex salt. Hydrargyri Salicylas — Mercuric Salicylate, N. N. R., occurs as a white amorphous powder, tasteless and odorless and neutral to litmus paper. It is nearly insoluble in water or alcohol but is soluble at the ordinary temperature in solutions of sodium hydroxid or sodium carbonate, with the formation of a double salt. Mercury salicylate is incompatible with iodids. Like the mild mercurous chlorid it is used for intra- muscular injections in the form of a suspension (1 : 10 to 1 : 20) in liquid petrolatum or other fixed oil, and is administered in doses of about 0.1 gm. (l^^ grains). MATERIA MEDICA OF MERCURY 381 Hydrargyrum — Mercury, U. S. P., in its ordinary form is a shining, silver-white, volatile and fluid metal without odor or taste. In medicine it is used at the present time largely in the forms in which it is reduced to a fine state of subdivision. It is capable of absorp- tion either by the skin or mucous membranes and produces the ordinary pharmacologic efifects of its salts. Among the several official forms of mercury are: Hydrargyrum Cum Creta — Mercury with Chalk, U. S. P., a powder popularly known as gray pow- der, containing 38 per cent, of mercury with clarified honey and prepared chalk. It occurs as a light gray, slightly adhesive powder, with little odor and a slightly sweetish taste. It is insoluble in water but is partially dissolved by diluted hydrochloric acid, the residual mercury being left in a finely divided state. Massa Hydrargyri — Mass of Mercury, U. S. P., is popularly known as blue mass, and is a mixture containing 33 per cent, of mercury, with glycyrrhiza, althea, glycerin and honey of rose. The mercury should be reduced to such a fine division that globules are not visible under a magnification of 10 diameters. Unguentum Hydrargyri — Mercurial Ointment, U. S. P., is a mixture of 50 per cent, of mercury with prepared suet, benzoinated lard and 2 per cent, of oleate of mercury. The mercury should be reduced by trituration to such fineness that globules are no longer visible under a lens magnifying 10 diameters. Unguentum Hydrargyri Dilutum — Blue Ointment, U. S. P., is a diluted mercurial ointment made by mixing approximately 2 parts of mercurial ointment and 1 part of petrolatum. Hydrargyrum Ammoniatum — Ammoniated Mer- cury, U. S. P., is a mercuric ammonium chlorid pro- duced by the precipitation of a solution of mercuric chlorid by a solution of ammonia. It should repre- sent not less than 78 nor more than 80 per cent, of metallic mercury. It usually occurs in the form of white pulverulent pieces or a white amorphous pow- der, having an earthy, afterwards styptic and metallic taste. It is practically insoluble in water or ;n alcohol 382 HEAVY METALS— MERCURY but is gradually decomposed by washing with water. It is readily soluble in warm adds with decomposition. Unguentum Hydrargyri Ammoniati — Ointment of Ammoniated Mercury, U. S. P., is a mixture of 10 per cent, of ammoniated mercury with white petro- latum and hydrous wool-fat. CHAPTER XII -DEMULCENTS, EMOL- LIENTS, ASTRINGENTS, IRRITANTS AND CAUSTICS DEMULCENTS, EMOLLIENTS AND OTHER PROTECTIVES The word "demulcent" is derived from "demulceo" meaning "to smooth"; the word "emollient" from "emoUio" meaning "to soften." Mucous membranes rarely require softening though they sometimes require agents to render their surfaces smoother. When, however, an inflamed skin becomes hard it requires softening, hence we speak of applying demulcents to mucous membranes and emollients to the skin, the same agent usually being both demulcent and emollient. Petrolatum is used for both purposes, but when used internally it is commonly spoken of as a lubricant for the intestinal tract. Cushny states that the number of demulcents, emol- lients and astringents in common use might be cur- tailed considerably without loss to therapeutic prac- tice, and the physician will find that "Useful Drugs" contains all that he needs of this group. Acacia, tragacanth and other gums are colloidal substances that can be dissolved in water or made to absorb many times their weight of it, forming mucilages that serve to protect mucous membranes against irritants of various kinds. They form a coat- ing that protects the surface mechanically against solid particles, and they retard the movement of liquids that are incorporated with them so that absorption and penetration into the mucous membranes are delayed. Poisons, such as strychnin, are less active when dissolved in solutions of colloids than when dissolved in water, the slower absorption from the former per- mitting of the simultaneous excretion of a portion of 384 DEMULCENTS, EMOLLIENTS, ETC. the poison. Sweet and sour substances have less taste when dissolved in solutions of colloids than when dissolved in water, because of their slower penetra- tion into the organs of taste in the tongue. That such dissolved substances are more slowly absorbed, also explains the protective action of demul- cents against soluble poisons in the gastro-intestinal tract, but, on the other hand, when such colloid solu- tions remain too long in contact with inflamed and infected surfaces they offer opportunities for bacteria lo develop. This does not apply with so much force to the mouth, nose and throat, in which the natural secretions and frequent washing suffice to remove bacteria, but to the gastro-intestinal tract, where the rapid multiplication of putrefactive organisms together with the delayed digestion of food and absorption of the products of digestion may result in further injury to the inflamed mucous membranes. Demulcents may be added to solutions of irritant drugs, such as hydrated chloral, to lessen or prevent gastric irritation, thus avoiding emesis and permitting the drug to be absorbed. For this reason they are sometimes added to nutrient enemas, as enemas are prone to set up peristalsis, thus causing their expul- sion. The colloids retard or prevent this, affording time for the absorption of the nutriment. It is sometimes difficult to relieve thirst when the stomach has become so irritable that even small amounts of water are rejected. Demulcents may be added to water in such cases, and when large amounts of water are to be administered by the mouth to induce diuresis, the use of demulcents and flavoring prevents nausea and facilitates the passage of water into the duodenum, where it is absorbed. Albumin water, made by adding the white of an egg to a glass of water with a little lemon juice or barley water, serves the double purpose of introducing water and nitrogenous or car- bohydrate food, though the food value may be slight. Demulcents are also used to allay the irritation of the gastro-intestinal tract in poisoning with such metal- lic salts as those of mercury. . The possibility of bac- terial infection should be borne in mind and in such DEMULCENTS 385 cases the combination of an antiseptic and colloid is probably preferable. Glycerite of starch serves as a demulcent, but is digested without becoming a nidus for the growth of bacteria. The objection to the use of demulcents in the treatment of diarrhea is the same as in other inflammatory conditions of the intes- tine. This applies with even greater force when it is evident that pathogenic bacteria are already doing harm. Petrolatum would seem to have a special field of usefulness in such cases, at least on theoretic grounds, but protectives, such as bismuth salts, that are also astringent and antiseptic, are usually pre- ferred for use in combination with the mucilaginous demulcents. The skin is kept soft and pliable under normal con- ditions by its natural secretions, but there are innumer- able ways in which the pliability is destroyed and it is rendered hard, the hardening being followed by cracking and greater or less irritation. The hands especially are subject to innumerable minor injurious influences such as frequent washing with alkali soap; frequent wetting and drying ; the action of cold winds ; of various chemicals, including acids and alkalies in various trades; of tannin in vegetables in domestic service ; of dust and ashes. Probably the majority of occupations involve a certain degree of injury to the skin of the hands, and while this is not so serious as to demand medical treatment, the frequent use of harmless demulcents adds much to the comfort of many persons. All bland oils are emollient, but they become rancid on exposure to the air, and ordinarily they are incon- venient to use on the hands unless they are thoroughly rubbed into the skin. Even this may be troublesome ; petrolatum for this purpose is quite inconvenient, though commonly used. Many people find glycerin irritant, especially women and children who have sensitive skin. Others find it a most convenient emol- lient when diluted with at least an equal volume of water. It is applied after washing and wiping the hands but while they are moist. A mixture that has been found useful consists of equal parts, by measure, 386 DEMULCENTS, EMOLLIENTS, ETC. of glycerin, water and solution of hydrogen peroxid. Rose water in equal amount may be substituted for the water or a small amount of benzoin or other flavor- ing may be added. Among the emollients that do not require detailed discussion, vai-ious ointment bases may be mentioned. Lard becomes rancid, hence the pharmacopeia directs that it shall be treated with benzoin, which prevents rancidity. Lanolin, or hydrous wool fat, does not become rancid, but it is not pleasant to use. Wild reported to the therapeutic research committee of the British Medical Association recently on the availability of certain ointment bases in common use. While the subject is not fully understood, he holds that the fats such as lanolin and lard are absorbed more readily than petrolatum, but that we have little knowledge of the rates at which incorporated sub- stances leave these substances to go into the tissues. While this has little bearing on the use of ointment bases as demulcents it is obviously important when the use of ointments as a means of applying drugs for their systemic action is considered. The melting point of the ointment is held to be of first importance, gradual melting being desired, hence Wild prefers a mixture of ointment bases with differ- ent melting points. Certain other mechanical protectives serve the same purpose as the mucilaginous and oily demulcents and emollients ; for example, the insoluble salts of bismuth, which are usually taken in a fine powder suspended in mucilage, form a thin layer on the mucous membrane of the stomach and intestine. Dusting powders, such as starch, lycopodium, talcum and boric acid serve much the same purpose on the inflamed skin. The salts of bismuth are usually classified as astringents, among which they will be mentioned later. They do not appreciably dissolve in the gastro-intestinal tract as a rule, but pass through it unchanged exerting their protective action throughout its length. The subnitrate has long been the most popular of the salts of bismuth, but its popularity over the subcar- bonate is apparently due to force of habit, for their DEMULCENTS 387 beneficial actions are similar, while the subcarbonate does not cause poisoning as the subnitrate does occa- sionally. This poisoning is due in part to the absorp- tion of nitrites resulting from the decomposition of large doses of the subnitrate by bacteria, in part to the systemic action of the metal bismuth. Bastedo administered bismuth subnitrate to dogs and after several hours found the bismuth in a flocculent state coating the mucous membrane very uniformly as far as the ileocecal valve. He also administered bis- muth subnitrate with a test breakfast to a patient and at the end of the hour found the salt in a flocculent state and uniformly mixed with the extracted stomach contents. It separated slowly from the food. Cannon introduced the practice of administering the salts of bismuth and observing their progress through the alimentary tract by means of the fluoroscope, as an index of gastro-intestinal movements. The subcar- bonate or the subchlorid is to be preferred to the subnitrate for this purpose because of the danger of using such large amounts of the latter as would be required (60 gm. or 2 ounces). Bismuth salts are partly converted into the sulphid in the colon and this may act as an irritant; like the sulphids of many other metals it colors the stools black. The soluble salts of bismuth, such as bismuth and ammonium citrate, are apparently wholly superfluous, as the soluble salts are converted iijto insoluble ones in the gastro-intestinal tract, and absorption is never desired. Linseed or flaxseed is used in the form of an infusion as a demulcent. The mucilaginous outer wall of the seed swells or dissolves in water to a pleasant tasting mucilage. The crushed or ground linseed is used in the form of cataplasms as an emollient and, because of its property of retaining heat, for the relief of inflammatory conditions generally. The insoluble salts of zinc, more particularly the oxid and stearate, are used externally in the form of a dusting powder or an ointment to protect the skin and to allay irritation. To absorb the discharge in eczematous conditions or to check excessive perspiration, mixtures of equal 388 DEMULCENTS, EMOLLIENTS, ETC. parts of zinc oxid or zinc stearate with starch and boric acid or one of the insoluble bismuth salts may be used. The composition of such dusting powders should be varied to meet the particular indications or needs. THERAPEUTIC USES The therapeutic uses of demulcents are indicated to a large extent by the preceding discussion. Attention has been called to the fact that they retard the absorp- tion of fluids with which they are mixed, and they may check diarrhea by lessening the irritation of the intes- tinal mucous membrane, thereby diminishing peristal- sis and prolonging the time allowed for absorption of fluid so that less passes into the large intestine. The fluid may also be retained so tenaciously by the demul- cent, as in the case of compound licorice powder, that the bulk of the intestinal contents is increased and normal peristalsis is stimulated.- In this case the laxa- tive action is due partly to the irritation of the mucous membrane caused by the hyrogen sulphid or sul- phurous acid formed in the intestine from the sulphur of the powder. Demulcents are commonly used for the relief of cough and sore throat. It sometimes happens that the continued use of demulcent lozenges causes the tongue to become coated with insoluble matter from the loz- enges, and it will be found advisable in such cases to use a gargle or spray for the throat and to wash the mouth with solution of hydrogen peroxid. The salts of bismuth are used to allay vomiting from gastric irritation and to check diarrhea arising from irritation due to decomposing food; to protect the gas- tric mucous membrane in hyperacidity and in gastric ulcer ; in gastro-intestinal catarrh and in ulcerative enteritis. Bismuth subnitrate and subcarbonate are used exter- nally for ulcers and suppurating wounds. A paste made of bismuth with petrolatum has long been used in treating old sinuses and fistulous tracts. It is injected once a week in cases of chronic tuberculous cavities but not in acute conditions. Poisoning has resulted from its use in this way and the use of the paste should USES OF DEMULCENTS 389 be discontinued on the appearance of symptoms indi- cating tliat absorption is taking place. These symp- toms include headache, nausea, stomatitis, with occa- sionally a blue line on the gums. In such cases the cavities should be irrigated thoroughly with warm olive oil and filled with the oil, which is allowed to remain for twenty-four hours, after which the washing with the oil is to be repeated daily until symptoms of poisoning abate. Dusting powders including the insoluble salts of bis- muth, starch, boric acid, zinc oxid and zinc stearate are used to protect inflamed skin, and collodion and oiled silk are used to exclude the air from inflamed surfaces. Flexible collodion affords an impervious covering which may be used on cuts and small non-infected wounds. Lime liniment is specially used in the treatment of burns, promptly relieving the pain, but it has the great disadvantage of being uncleanly and difficult to remove and of permitting the development of bacteria beneath it. MATERIA MEDICA Acacia. — Acacia, U. S. P., commonly known as gum arable, is soluble in water but practically insoluble in alcohol. It is frequently used in the form of : Mucilago Acaciae. — Mucilage of Acacia, U. S. P.,- containing about 34 per cent, of acacia. Tragacantha. — Tragacanth, U. S. P., swells on addi- tion of water and gradually forms a cloudy gelatinous mass or viscid mucilage. Linum. — Linseed, Flaxseed, U. S. P., unground, forms a thin mucilage with water. When ground and mixed with from two to three times its weight of boiling water it yields a rather firm mass much used as a poultice. Amylum. — Starch, Corn Starch, U. S. P., occurs in the form of a fine white powder or as irregular friable white masses. It is insoluble in water or alcohol, but when boiled with water it yields a gelatinous mixture which, depending on the amount of water present, may be used as a cataplasm, a paste or a mucilage. Starch 390 DEMULCENTS, EMOLLIENTS, ETC. itself is widely used as a dusting powder and as a diluent for active substances. Among the fats, bland oils and related substances that are used as emollients are: Adeps.—'Lsxd, U. S. P. Adeps Benzoinatus. — Benzoinated Lard, U. S. P. Adeps Lanae Hydrosus — Hydrated Wool Fat, U. S. P., better known as lanolin, a mixture of 3 parts of water with 7 parts of wool fat. Petrolatum. — Petrolatum, U. S. P. Petrolatum Liquidum. — Liquid Petrolatum, U. S. P. Glycermum. — Glycerin, Glycerol, U. S. P., occurs as a clear colorless liquid of syrupy consistence miscible in all proportions with water or alcohol. Among the drugs that are used as dusting powders are: Acidum Boricum. — Boric Acid, U. S. P. Bismuthi Subcarbonas. — Bismuth Subcarbonate, U. S. P. Bismuthi Subgallas. — Bismuth Subgallate, U. S. P., also known as "Dermatol." Bismuthi Subnitras. — Bismuth Subnitrate, U. S. P. Bismuthi Subsalicylas. — Bismuth Subsalicylate, U. S. P. Zinci Stearas. — Zinc Stearate, U. S. P. Zinci Oxidum. — Zinc Oxid, U. S. P. The latter two substances are frequently used in the form of ointments. One of them is official as: Unguentum Zinci Oxidi— Ointment of Zinc Oxid, U. S. P., a mixture of zinc oxid 20, with benzoinated lard 80 parts. ASTRINGENTS Astringents precipitate proteins and cause shrinking of mucous membranes. When applied to inflamed sur- faces they cause diminished permeability of the smaller superficial vessels and allay pain due to sensory irri- tation. They lessen the secretory activity of the gastro-intestinal and other mucous glands, this action being of some importance when the astringents are used in the treatment of diarrhea. ASTRINGENTS 391 The vegetable astringents act mainly by means of tannins, a group of ill-defined substances characterized by an astringent action and the property of forming black precipitates with ferric salts. The official tannic acid is soluble in the gastric juice, and in solution combines with the proteins present in the stomach or attacks the gastric mucous membrane. The tannin of gambir (gambir replaces catechu of the pharmacopeia of 1890), however, is protected by the presence of gum and extractives. When gambir is administered it passes into the intestine, on which it exerts its astringent action, lessens the intestinal secretion and modifies the conditions under which bacteria develop during the inflammation of the mucous membrane. Certain of the metallic albuminates, such as that of mercury, are soluble in the tissue fluids and by means of its corrosive action the metal destroys cells with which it comes in contact, this action being especially pronounced with mercuric chlorid and zinc chlorid. Albuminate of lead is insoluble in the tissue fluids and when the lead salts are applied in suitable concentra- tion they form an impervious protective coating to the inflamed surface. The actions of astringents, irritants and caustics differ largely in degree, many of the caustics being astringent when applied in sufficiently dilute solution, and the astringents causing irritation when they are used in too great concentration. PICRIC ACID Picric acid has recently attained some prominence as an external application in the treatment of various inflammatory conditions of the skin, but it is not a new remedy, crystalline picric acid having been pre- pared more than a century ago. It was used inter- nally and externally with little discrimination, and fell into disrepute owing to the dangers that attended its use. It has been included in "Useful Drugs" because of its value as an external application, more particularly in the treatment of burns, and this recognition should 392 DEMULCENTS, EMOLLIENTS, ETC. not be understood as an endorsement of the claims that have been or are being made for it in all sorts of diseases. Overdoses cause irritation of the gastro-intestinal tract with nausea, vomiting and diarrhea. When absorption occurs, there is a characteristic staining of the skin and mucous membranes which may simulate jaundice, but differs from it in that there is no bile in the urine. This staining of the skin and mucous mem- branes is due to the extraordinary affinity of the acjd for epithelium. Its presence in the skin gives rise to itching and sometimes to erythema. It destroys red blood cells when it is adniinistered to animals in large doses, but it is said that this has not been observed in cases of poisoning in man. The irri- tant action on the kidneys induces nephritis. Fatal doses cause convulsions and collapse, with death by paralysis of the respiratory center. It is excreted by the kidneys in the form of picras- mic acid (CeH20HNH2(N02)2), which is closely related chemically to picric acid. The urine is colored yellow or reddish. Like phenol, it is antiseptic and anesthetic, and on these and its astringent actions (in dilute solution) its value as an external application depends. Concen- trated solutions are irritant. THERAPEUTIC USES The astringents are not used in the treatment of the diarrhea of infants nearly so much as formerly, the complaint being now treated mainly by diuretic mea- sures. Tannin as such, or in one of the preparations of gambir (catechu), kino or krameria, is sometimes used internally in the treatment of diarrhea ; but owing to its tendency to cause nausea and vomiting, especially when given in too great concentration, one of the com- binations of tannin with protein, such as tannalbin, is commonly preferred. Tannin is used in the form of a gargle or troches in relaxed conditions of sore throat. A solution is some- times used to harden the skin over bony protuberances to prevent bed-sores. USES OF ASTRINGENTS 393 Tannin is sometimes used in the form of an ointment (20 per cent.) or of suppositories, each containing 0.3 gm. (5 grains) for the relief of painful bleeding inter- nal piles, and for prolapse of the rectum. It is irra- tional to employ opium locally in this way, despite the fact that the well-known galls and opium ointment does afford relief, since the ointment of tannin alone is equally efficacious. Tannin is frequently directed to be used as a pre- cipitant in poisoning with alkaloids, but the official tannin is not usually readily available in the household and tannin-bearing household articles, such as tea and coffee, are not dependable for this purpose. Tannin is widely distributed in the vegetable king- dom and many pharmaceutic preparations of vegeta- ble drugs have a wide range of incompatibilities. It is therefore better to avoid prescribing ferric salts and alkaloids especially, with such preparations. The systemic actions of iron, lead and other metals have been discussed, but their uses as astringents and styptics remain to be considered, lead being employed therapeutically only for its astringent action. Lead acetate is sometimes used with opium in the treatment of diarrhea, but its use should not be long continued lest chronic poisoning.be induced. A dilute solution of lead subacetate is used in inflammations and for sprains and bruises, but it should not be applied to the broken skin. The well-known lead and opium wash is popular as a local application, but the alkaloids of opium are not absorbed to any appreciable extent under these condi- tions and they have no local analgesic action. A com- press wet with lead water will probably answer any purpose that the lead and opium wash serves, and it is more cleanly. Alum is seldom used internally, though a solution containing from 1 to 5 per cent, is sometimes used as a gargle, but the teeth should be protected against its injurious action. Exsiccated alum is actively astrin- gent and even caustic; it is applied to cankers in the mouth and to chronic ulcers. 394 DEMULCENTS, EMOLLIENTS, ETC. Aluminum acetate solution is widely used as an astringent application to infected wounds. The irritant action of copper sulphate and zinc sul- phate explains the use of those salts as emetics. Dilute solutions of zinc acetate and sulphate are used as astringent applications in the urethra, in the eye and in the vagina. The chlorid of zinc is corrosive; the oxid and stearate are mild astringents and are used as dusting powders on ulcers and inflamed surfaces of the skin. The tincture of ferric chlorid is commonly used in gargles for sore throat, especially in combination with potassium chlorate. It has been suggested that the alcohol in the tincture be evaporated and replaced with water, the resultant mixture to be used on tampons for checking uterine hemorrhage. The tincture of fer- ric chlorid or the solution of the subsulphate is some- times added to glycerin and painted on the throat. A hot saturated solution of potassium chlorate has often been used as a gargle and mouth wash. Tinc- ture of myrrh is sometimes added to mouth washes and gargles. In recent years potassium chlorate has been used as the active constituent of tooth pastes and powders. The assumption is that in contact with putrefying organic matter the salt liberates nascent oxygen and thus acts as an antiseptic as well as an astringent. This theory is highly improbable. Bismuth subcarbonate, subgallate and subnitrate are commonly discussed among the astringents. Their use, however, in the treatment of diarrhea seems to depend on their capacity for forming a mechanical protective covering for the intestinal mucous mem- brane rather than on any slight astringent action that they may exert. Bastedo states that they act in a purely mechanical manner as a protective and demul- cent to the mucous membrane of the stomach and intes- tine. More than twenty-five years ago Harnack called attention to the neglect of certain well-known drugs by clinicians and attempted to explain the therapeutic actions of lime water in the treatment of diarrhea and USES OF ASTRINGENTS 395 as a solvent for diphtheritic false membrane. It is unfortunate that more pharmacologists and clinicians do not devote their energies to the investigation of some of the simple remedies of proved value, but which we understand all too little. Lime water is useful in the treatment of infantile diarrhea because of its astringent effect, and in some cases, because it neutralizes the acid secretions attend- ing the condition. The insoluble calcium salts formed serve to close the finer openings through which bacteria would penetrate. They lessen excretion in the same way, and further, they form a protective covering for the mucous membrane. The calcium soaps formed with the higher fatty acids are insoluble and have a caoutchouc-like con- sistency. It has been suggested that their action on the cell lipoids and intercellular substance is a tough- ening one. Calcium salts are supposed to lessen the permeability of the smaller blood vessels even in those parts of the body that they reach only through the circulation. This systemic action may be induced and the intestinal catarrh controlled when lime water is taken by the mouth, though this action must be rather slight, for, as already stated, most of the calcium is converted into insoluble salts in the intestine — but not in the acid secretions of diarrhea. Harnack emphatically praises lime water in the treat- ment of diphtheritic sore throat, in which it dissolves the mucin in the false membrane, permitting the fibrin to fall apart, after which the lime water acts as an astringent. Lime water is sufficiently alkaline to be irritant to a sore throat. Ichthyol penetrates the unbroken skin to some extent and constricts the superficial blood vessels, hence it is used to lessen hyperemia in a variety of inflammatory conditions of the skin including erysipe- las, and acne vulgaris. Grossly exaggerated thera- peutic claims have been made concerning its use in a wide variety of conditions, but it has not gained greatly in favor during the past few years. Drugs containing tannin are no longer used to the extent to which they were at one time and it is now 396 DEMULCENTS, EMOLLIENTS, ETC. generally recognized that tannic acid or one of the albumin compounds of this substance will answer practically all indications for a vegetable astringent. Picric acid is commonly used in the form of a solu- tion composed of 1 part of picric acid, 10 parts of alcohol and ISO parts of water. Cloth or gauze is wetted with this solution and applied to the part affected several times a day, or small areas of the skin may be kept wet with it if care is exercised to see that absorption does not occur. This solution is said to be especially useful in the treatment of bums, in which case it is advised that the injured area be cleansed, and a cloth saturated with this solution be applied. A pad of absorbent cotton is fastened over the cloth by means of a light bandage. The dressing dries rapidly, and may be left undisturbed for several days. It is painful in some cases. It should not be applied to large surfaces because of the danger of absorption. H. B. Wilcox states that in acute eczema with pro- fuse exudation, excoriation, and formation of crusts, the application of solution of picric acid caused almost immediate lessening of the itching and pain with a reduction of the serous exudate. It was less useful in the subacute and chronic types. He states that the danger of absorption is negligible, though he applied the solution several times a day and allowed it to dry in mild cases, but applied wet dressings of the acid held in place by a facial mask in the more severe ones. According to Sollmann* it is useful in the treatment of "bakers' eczema." Picric acid solution is also used in various condi- tions of the skin, such as intertrigo, herpes labialis, erysipelas, ringworm, and for fissured nipples. A saturated solution (about 1.5 per cent.) has been applied to the eruptions in pellagra, and a weaker solu- tion (1 : 200) has been used as a gargle in that disease. The intense staining of the clothing and skin con- stitutes a serious annoyance when picric acid is used. • Personal communication to the authors. MATERIA MEDICA OF ASTRINGENTS 397 Its poisonous nature must be remembered, and care should be taken to avoid absorption, even when it is applied to the skin. MATERIA MEDICA The astringents most widely used are : Acidum Tannicum. — Tannic Acid, U." S. P., tannin, occurs as a light yellowish powder very soluble in alcohol, water and glycerin. Glyceritum Acidi Tannici. — Glycerite of Tannic Acid, U. S. P., is a 20 per cent, solution of tannic acid in glycerin. Typical of the albumin compounds of tannic acid that are receiving recognition at the^present time is: Tannalbin. — Tannalbin, N. N. R., tannin albuminate, insoluble in the gastric juice and becoming effective only when it reaches the intestine. Plumbi Acetas. — Lead Acetate, U. S. P., popularly known as sugar of lead, occurs as crystalline masses or a heavy white powder, freely soluble (1:2) in water and soluble ( 1 : 30) in alcohol. For external use the preparation usually preferred is the following: Liquor Plumbii Subacetatis. — Solution of Lead Sub- acetate, U. S. P., an aqueous solution containing not less than 25 per cent, of lead subacetate. As a wash it is usually diluted with from 15 to 30 times its bulk of water. Other mineral astringents that are used for various purposes are: Alumen. — ^Alum, U. S. P., a crystalline product con- taining 12 molecules of water. Alumen Exsiccatum. — Exsiccated Alum, U. S. P., the anhydrous product which occurs in the form of a white granular powder. Alumini Acetas. — Used principally in the form of: Liquor Alumini Acetatis. — Solution of Aluminum Acetate, N. F., a clear, colorless solution containing about 8 per cent, of basic aluminum acetate. 398 DEMULCENTS, EMOLLIENTS, ETC. Cupri Sulphas. — Copper Sulphate, U. S. P., popu- larly known as blue vitriol, occurs in crystalline form, is soluble (1:22) in water but only slightly soluble (1:400) in alcohol. Zinci Sulphas. — Zinc Sulphate, U. S. P., occurs in small crystals or as a granular powder, is very solu- ble (1:0.53) in water, but practically insoluble in alcohol. Zinci Acetas. — Zinc Acetate, U. S. P., occurs as soft pearly crystals, is freely soluble (1 : 2.5) in water and soluble (1:36) in alcohol. Zinci Chloridum. — Zinc Chlorid, U. S. P., when properly kept, occurs as a white granular powder, is very soluble (1 : 0.5) in water and in alcohol. Ferri Chloriduw.— Ferric Chlorid, U. S. P., has been used in medicine in the solid form and as an aqueous solution, but principally in the form of: Tinctura Ferri Chloridi. — Tincture of Ferric Chlorid, U. S. P., a hydro-alcoholic solution containing not less than 13.28 per cent, of the anhydrous salt representing about 4.5 per cent, of metallic iron. Potassii Chloras. — Potassium Chlorate, U. S. P., occurs as crystals or as a white granular powder. It is soluble (1 : 16) in water but nearly insoluble in alcohol. Potassium chlorate forms an explosive mixture with oxidizable material, and due caution must be observed in manipulating it. Ichthyol. — Ichthyol, N. N. R., an aqueous solution of ammonium sulpho-ichthyolate, occurs as a reddish brown or brownish black syrupy liquid that is miscible with water but is incompletely soluble in alcohol. Acidum Picrictmi. — Picric Acid (CoH^.OH (N02)g) N. N. R., an acid obtained by nitrating phenol, occurs as yellow crystalline needles or scales having an acid reaction, a bitter taste and imparting an intense yellow color to aqueous solutions. It is soluble (1:81) in water and freely soluble (1:10) in alcohol. Picric acid forms insoluble compounds with many alkaloids and precipitates albumin in the cold. PHARMACOLOGY OF RUBEFACIENTS 399 RUBEFACIENTS Inflammation is a local reaction to irritation that •tends to limit the area of injury, to remove the injurious substance and the tissues that may be destroyed, and to repair the damage. There is increased permeability of the smaller vessels with the other well-known symptoms of inflammation including redness, heat, swelling and tenderness or pain. While inflammation is sometimes a useful process it may be present when it is not useful or it may exceed the limits of usefulness. Evidence is abundant that inflammation results from the irritation of sensory nerves, but the precise mechanism by which this is brought about is not understood. In therapeutic practice irritants of vari- ous types are used to induce different stages of inflammation, most frequently that of redness only, and the agent so usee}, is termed a rubefacient. If a somewhat more intense action is elicited, a blister is formed by the collection of the transudate under the horny layer of the skin. This is termed vesication. Pus formation is rarely induced intentionally at present, but pustulants were formerly used to some extent. Caustics destroy the tissue to which they are applied, hence they are used mainly for the removal of callus and for application to small areas when it is desired to remove exuberant growth. Rubefacients are appUed to the skin for the purpose of causing an increased blood supply to relieve organs in which congestion due to diminished circulation has caused inflammation to reach the stage of pain. Since this is accomplished through causing irritation at the seat of application such agents are called counter- irritants. Ross, Mackenzie, and more especially Head, have put the use of rubefacients on a rational basis. Ross observed the location of painful cutaneous areas com- plained of by patients who suffered with visceral disease and he suggested that pain was referred along the distribution of somatic nerves which came off from the same part of the cord as the sensory sym- 400 DEMULCENTS, EMOLLIENTS, ETC. pathetic fibers to the organs affected. Head was stimulated (to use his own expression) by Ross' sug- gestion to make careful observations of the areas of cutaneous tenderness in sixty-two cases of herpes zoster, and was surprised to find that these areas correspond exactly with those with which he was familiar in visceral disease. Head mapped out the cutaneous surface of the body and limbs, dividing it into 'areas each of which corresponds to the distribu- tion of nerve fibers given off from a segment of the spinal cord. He suggested that the skin is tender in visceral disease because impulses (not painful) pass up the sensory nerves from the diseased organ and set up a disturbance in the segment of the cord to which they are conducted. When a secondary impulse from the skin is conducted to that disturbed segment of the cord the impulse will be altered and exaggerated, so that a stimulus that would not be painful under ordinary circumstances now becomes so, for example, the application of slight warmth then causes a burning sensation. When there is congestion of an internal organ the application of a rubefacient or more active irritant to the corresponding area of the skin causes vaso- dilatation in the viscus with relief of the congestion and the attending pain. We do not know the exact mechanism by which this is accomplished, but we do know that the application of rubefacients does often relieve pain and congestion in internal organs in this way. Head suggests that the head of a common pin — not the point — be used in eliciting tenderness in the skin, or that this may be done by pinching the skin gently between the thumb and forefinger. The number of irritants is very large and the choice is often determined by convenience of application, care being taken to limit the action of the more active members of the group when they are used. Among the rubefacients most commonly used are: Alcohol, ammonia, camphor, chloroform (causes blis- tering readily), capsicum, iodin, menthol, mustard MATERIA MEDICA OF RUBEFACIENTS 401 and oil of turpentine. Croton oil is sometimes used as a rubefacient but it tends to produce pustulation. Heat in its various forms is probably the most com- monly used of the rubefacients. The various therapeutic applications of the rube- facients cannot be discussed in this place, but an understanding of the principles involved is necessary for their rational use. Nearly all textbooks of therapeutics and pharmacology give the cutaneous areas corresponding to the internal organs as deter- mined by Head. MATERIA MEDICA Rubefacients are used principally in the form of liniments or solutions for external application. Among the widely used official liniments are: Linimentum Ammoniae. — Ammonia Liniment, U. S. P. A mixture of ammonia water (35), alcohol (5), and a fatty oil (60). Linimentum Camphorae. — Camphor Liniment, U. S. P. Camphorated Oil, a solution of Camphor (20) in cottonseed oil (to make 100). Linimentum Saponis. — Soap Liniment, U. S. P. A solution of soap, camphor and oil of rosemary in a mixture of alcohol and water. Soap liniment is used quite extensively as a vehicle for active rubefacients, such as chloroform, oil of turpentine, oil of mustard, tincture of capsicum, menthol, ammonia, or croton oil, all of which it dis- solves more or less readily. A type of this form of preparation is found in the official: Linimentum Chloroformi. — Chloroform Liniment, U. S. P. A mixture of chloroform (30) with soap liniment (70). The solutions used for external application are chiefly alcoholic solutions of the rubefacients men- tioned above. A type of these solutions is the official. Tinctura lodi. — Tincture of lodin, U. S. P. 402 DEMULCENTS, EMOLLIENTS, ETC. An alcoholic solution, each 100 c.c. of which con- tains 7 gm. of iodin and 5 gm. of potassium iodid. VESICANTS When it is desired to. carry irritation to the stage of vesication cantharides or cantharidin is commonly used. The action develops slowly, eight hours being frequently required before vesication is induced. When cantharides is employed for a short time it acts as a rubefacient, but in such cases it has no apparent advan- tage over the more rapidly acting members of the group, such as mustard. Cantharidin, the active principle of cantharides, is excreted by the kidneys after its absorption into the circulation and gives rise to irritation of the genito- urinary tract — a circumstance that has led to its abuse in some instances. Cantharides is sometimes added to liniments and to hair tonics, and while it may enhance the rubefacient action of these it probably has no specific action on the scalp or hair follicles, and is therefore probably useless as a hair restorative. MATERIA MEDICA The more important vesicants are: Cantharis. — Cantharides, U. S. P., which is fre- quently used in the form of: Ceratum Cantharidis. — Cantharides Cerate, U. S. P. Usually applied as a plaster. Sinapis Nigra. — Black Mustard, U. S. P. Used in the form of a plaster or as : Charta Sinapis. — Mustard, U. S. P., which con- sists of a layer of black mustard on well-sized paper. Oleum Sinapis Volatile. — Volatile Oil of Mustard, U. S. P., obtained from black mustard by maceration with water and subsequent distillation; also made synthetically. CAUSTICS OR CORROSIVES Strong acids and alkalies and certain of the metallic salts destroy the tissues and dissolve them. Phenol in concentrated solution precipitates the proteins of cells and destroys them. CAUSTICS 403 Acids, alkalies, phenol and certain other caustics are of some toxicologic interest because of the frequency with which they are swallowed accidentally. In such cases the gastro-intestinal injury may result in shock or in perforation with peritonitis. The corrosive action in the mouth and throat may be followed by cicatricial contraction, and esophageal stricture has frequently resulted from swallowing concentrated alkalies and acids and perhaps from phenol. The stomach should be washed as promptly as pos- sible after a corrosive has been swallowed, using a large amount of water and the appropriate antagonist in dilute form. Thus, if a mineral acid has been swal- lowed, a weak alkali such as magnesium oxid, lime water or weak soap solution, should be added to the water used to wash the stomach; if a caustic alkali has been swallowed then a weak acid, such as dilute vinegar, should be administered with the wash water. After the stomach has been washed, demulcents, including butter, cream, milk, white of egg or a bland oil, such as olive oil, should be administered. Bismuth subcarbonate suspended in water affords a useful pro- tective covering for the mouth, throat and mucous membrane of the stomach in such cases. It is generally held that sodium bicarbonate liberates too much gas to justify its use after a caustic acid has been swallowed, but it is commonly at hand in the household and it should be employed in an emergency if lime water, magnesia or pure castile soap is not available. Strong nitric or glacial acetic acid is sometimes used for cauterizing sores and for the removal of warts. The surrounding tissue is coated with petrolatum and the acid applied to the wart with a stick or glass rod for a short time. Corns are commonly treated with salicylic acid dis- solved in collodion, which insures the continued caustic action of the acid. The coating is removed after having been applied for about twenty-four hours. The treatment is painful, however. Lunar caustic, or molded silver nitrate is a con- venient caustic for the destruction of exuberant granu- lating tissue. 404 DEMULCENTS, EMOLLIENTS, ETC. Concentrated solutions of silver nitrate, even up to 50 per cent., are used in the treatment of sore throat and tonsillitis. The solution is painted on the throat or swollen tonsils and the throat is immediately gar- gled with salt solution in order to neutralize the excess of silver nitrate by converting it into the insoluble and harmless silver chlorid. This is said to be espe- cially efficacious in severe forms of tonsillitis. Extreme care must be taken to insure that none of the solution is swallowed and that the excess of the caustic is neutralized immediately with sodium chlorid solution. MATERIA MEDICA Among the available caustics and corrosives are: Argenti Nitras. — Silver Nitrate, U. S. P. Lunar Caustic, occurs in colorless crystals which become gray or grayish black on exposure to light. Silver nitrate is very soluble (1:0.54) in water and soluble ( 1 : 24) in alcohol. It fuses when heated and this property is frequently utilized to form a coat- ing of the caustic material on the end of a silver wire or probe. It is also used in making : Argenti Nitras Fusus. — Moulded Silver Nitrate, U. S. P., occurs as a white hard solid containing a small proportion of silver chlorid for the purpose of toughening the mass. Acidum Aceticum. — Acetic Acid, U. S. P. The glacial acetic acid which contains not less than 99 per cent, by weight of absolute acid is sometimes used. Acidum Nitficum. — Nitric Acid, U. S. P. A liquid containing about 68 per cent, by weight of hydrogen nitrate, occurs as a colorless, fuming, caustic and corrosive liquid. Care should be exercised to control the corrosive action. Potassii Hydroxidum. — Potassium Hydroxid, U. S. P., and Sodii Hydroxidum. — Sodium Hydroxid, U. S. P., are sometimes used as caustics for the removal of warts, corns and other excrescences, but their corrosive action is not readily controlled, CHAPTER XIII.— MISCELLANEOUS SALTS, ACIDS AND ALKALIES MISCELLANEOUS SALTS The systemic actions of a soluble salt are determined, as a rule, either by the anion alone or by the cation, but both ions are concerned in the actions of some salts. Sodium and potassium are of physiologic impor- tance but we know little of their actions that would indicate that one should be used therapeutically rather than the other in any given condition. It is often stated, however, that certain important differences are observed between the actions of sodium bromid and those of potassium bromid. The rapid injection of large amounts of potassium salts directly into the circulation induces cardiac paralysis, but this action is not observed when the potassium salts are used therapeutically. It is some- times maintained that the salts of ammonium or sodium should be used when cardiac depression from the action of potassium salts is to be feared. Lithium is of neither therapeutic nor physiologic importance, but has become popular to a certain degree because of -the erroneous belief that it is capable of dissolving uric acid calculi in the bladder. This mis- conception arises from the fact that salts of lithium do promote the solubility of uric acid and urates when tested under conditions that can never obtain in the bladder. None of the salts of lithium are of sufficient impor- tance to merit inclusion in the Council's list of "Use- ful Drugs." The erroneous belief concerning the efficiency of lithium salts as solvents for uric acid has led to con- ditions that would be ludicrous were they not of a nature so little to our credit as physicians. Numerous 406 MISCELLANEOUS SALTS, ETC. proprietary preparations of lithium salts have been exploited widely as uric acid solvents and this action has been urged as the basis for their use in innumerable conditions in which it is claimed that uric acid plays an important role. The absurdity has reached its cli- max in the exploitation of so-called lithia waters. It has been shown that about two hundred thousand gal- lons of Buiifalo Lithia Springs water contains an amount of lithium equal to only one therapeutic dose. The rapid intravenous injection of large doses of ammonium salts causes strychnin-Hke convulsions, but these effects are never seen when those salts are admin- istered by the mouth because they are decomposed in the body or eliminated almost as rapidly as they are absorbed. Hence after their oral administration their concentration in the blood never reaches the degree required to cause convulsions or hyperexcitability. A fleeting stimulation of the central nervous system by ammonium is attained in the use of smelling salts in the treatment of fainting. Ammonium carbonate is frequently used to stimulate the respiratory center when this is depressed and when there is mechanical interference with respiration, as in asthma and espe- cially in pneumonia. The use of ammonium acetate as a diaphoretic has been mentioned, the effect being attributed to its action on the central nervous system. The use of ammonium chlorid in the treatment of sore throat and cough has been mentioned in connection with other expectorants. Calcium is an important element in the body, small amounts being found in the blood in which it is essen- tial for the beat of the heart, and much larger amounts are found in the bones. The normal diet probably contains more calcium than the body requires, but when calcium is withheld from the food of growing animals symptoms resem- bling those seen in rickets and osteomalacia are induced. This has led to the administration of calcium in the treatment of those conditions. It appears, how- ever, that these conditions arise from an inability to utilize calcium, rather than from a deficiency of it in the food in most cases, hence calcium used therapeu- CALCIUM 407 tically frequently fails to cause improvement. Emer- ich and Lowe believe that the daily food is often defi- cient in calcium and they recommend the routine use of as much as 1.5 gm. (22 grains) of calcium chlorid daily in health, and as much as 10 gm. (2% drams) daily in disease. It is difficult to believe that such amounts are often indicated. A diminution of calcium below normal in the circu- lation causes nervous irritability. Such a depression of the central nervous system as is sometimes observed when magnesium salts are used subcutaneously in very large doses, as in the treatment of tetanus, can be relieved at once by the subcutaneous or intravenous injection of calcium chlorid. Doses of from 0.30 to 0.40 gm. of calcium chlorid per kilogram of body-weight, corresponding to from 300 to 400 grains for a man, injected subcutaneously, gradually produce a fatal result in animals. The intravenous injection of calcium salts into ani- mals reduces their susceptibility to local irritants such as mustard, probably because of a lessened permeability of the smaller blood-vessels. While normal dogs are resistant to the experimental induction of moist eczema their resistance is reduced by the injection of oxalates which precipitate the calcium in the circulation. It has thus been suggested that calcium salts should be used therapeutically in the treatment of moist eczema in man. It is also used on the same basis in the treatment of urticaria and to prevent serum rashes. When administered by the mouth, a part of the salts of calcium are absorbed, but the larger portion is converted into insoluble phosphate or carbonate and excreted in the feces, the part that is absorbed being usually insufficient to exert any marked systemic effect. The salts of calcium are administered to. prevent or control hemorrhage during typhoid fever, and in hemophilia because of their supposed power to increase the coagulability of the blood. Calcium chlorid will usually suffice for the adminis- tration of calcium, though there is no particular reason why one of the other salts should not be used if pre- ferred for any reason. Calcium lactate has been rec- 408 MISCELLANEOUS SALTS, ETC. ommended by many because of its being less irritant than the chlorid and therefore preferable for subcu- taneous injection. Calcium hypophosphite is wholly superfluous and its use should be discouraged as it tends to perpetuate a mistaken idea of the value of the hypophosphites in general. DOSAGE The average dose of calcium chlorid is 0.5 gm. (71/^ grains). If larger doses are required to abolish the paralytic action of magnesium salts when such action is induced accidentally, small doses should be given subcutaneously and repeated if necessary, or a dilute solution (1:200) may be slowly injected intra- venously until improvement occurs or until the full therapeutic dose has been administered. Concentrated solutions must not be injected subcutaneously as they cause abscesses. Calcium lactate may be given in doses of from 0.5 to 2 gm. (7% to 30 grains). Lime water, a solution of calcium hydroxid, is an antacid and has been used as a solvent for the false membrane of diphtheria, but it is not used to produce the systemic action of calcium. Attempts have been made at various times to popu- larize the salts of strontium but these have no advan- tage over the corresponding salts of the alkalies and none of the strontium salts has been admitted to "Useful Drugs." MATERIA MEDICA The soluble salts of calcium in popular use are : Calcii Chloridum. — Calcium Chlorid, U. S. P. It occurs as white translucent fragments having* a sharp saline taste. It is very deliquescent, is freely soluble (1:1.3) in water and also (1:8) in alcohol. The unpleasant acrid taste of calcium chlorid is diffi- cult to mask and it is best administered in dilute solu- tion flavored with syrup of citric acid or the official elixir of orange. Calcii Lactas. — Calcium Lactate, N. N. R. It occurs in white crystalline masses or a compara- tively fine powder, odorless and tasteless. It is solu- ble (1 : 15) in water but only slightly soluble in alco- BROMIDS 409 hol. The large doses of calcium lactate frequently given may be directed to be suspended in water, or the substance may be dispensed in powder or in cachets. The soluble salts of calcium are incompatible with carbonates, phosphates, tartrates and sulphates and are preferably dispensed in simple solution. THE BROMIDS Animal experiments have failed to throw much light on the actions of the bromids on the central nervous system because of the comparatively slight action on the centers in animals unless doses are used that cause other toxic actions. The bromids of the alkalies are irritant to the stomach and sometimes cause nausea and vomiting, especially when they are given in concentrated solutions or in the form of tablets. Tablets are convenient for dis- pensing but they should be dissolved in at least fifty times their weight of water before being taken. The bromids cause mental depression with dulness and confusion of ideas, hence they are not so useful as hydrated chloral in simple wakefulness unattended with pain or nervous irritability, but they are useful in combination with hydrated chloral when these symp- toms are present. The bromids depress the centers in such a way that reflexes are diminished, while impulses passing from the brain to the periphery are said to be unaffected. They are therefore efifective in controlling the reflex excitability of strychnin and may abolish the convul- sions unless the dose of the strychnin has been exces- sive. Large or frequently repeated doses of the bromids often give rise to a condition known as bromism, the readiness with which such symptoms develop in differ- ent individuals being subject to wide variation. The symptoms of bromism include various skin eruptions, acne of the face being very common, and digestive disturbances which are sometimes attributed to the hydrobromic acid that is excreted into the stomach, but which are probably due largely to the local irritant action of the salt. The memory suffers 410 MISCELLANEOUS SALTS, ETC. severely and the other mental disturbances already mentioned are exaggerated. Muscular tremors also occur. The symptoms usually disappear if the drug is discontinued, but the patient is said to be more sus- ceptible than normally to certain infectious diseases while suffering from bromism. The bromids depress the respiratory center, and the sexual appetite is diminished or abolished. The bromids are absorbed readily from the gastro- intestinal tract and they may be detected in the urine within a few minutes after their administration. The larger part of the drug, however, is fixed in the tis- sues, apparently displacing as much as one fourth of the chlorids of the blood when saturation is said to have taken place, and the elimination thenceforth keeps pace with absorption. The bromid that displaces the chlorids in combination with protein is eliminated slowly, so that some weeks may elapse after the admin- istration is discontinued before the last of the bromid is eliminated. Other tissues beside the blood also show the replacement of chlorids by bromids. Saturation with the bromids is reached more rapidly if chlorids are withheld while the bromids are being administered and, as saturation is desired when the bromids are used in the treatment of epilepsy, it is customary to limit the chlorid ingestion at such times. Saturation with bromids is indicated by the appearance of hydro- brOmic acid in the stomach, and probably by the elimi- nation of a larger amount in the urine. The mutual displacement of chlorids and bromids indicates the treatment of bromid poisoning by chlorids. It has been suggested that the toxic symptoms of the bromids may be due, at least in part, to the absence of the chlorids that are displaced, rather than to any direct action of the bromids themselves. The bromids are found in nearly all of the body fluids and excretions, and bromism may be induced in a nursing infant whose mother is taking bromids. THERAPEUTIC USES The bromids are used as hypnotics when sleepless- ness results from nervous irritability; they are fre- quently used with hydrated chloral, in which case their DOSAGE OF BROMIDS. 411 depression of the reflexes probably enhances the hyp- notic action of the chloral. They are especially useful in the treatment of epi- lepsy, in which they greatly diminish the number of seizures, or these may be abolished during the period that saturation with bromids is maintained. The attacks usually recur when the administration of the bromids is stopped. The bromids are sometimes used for several days before operations on the throat and before examina- tion with the mirror for adenoids. They are also used to quiet nervous excitability in neurasthenia and in hysteria. A more or less widespread belief exists that a mix- ture of bromids is preferable to any one of them, and the widely known epilepsy mixture of Brown-Sequard contained the bromids of sodium, potassium and ammonium together with some others. There is no evidence that such mixtures have any advantage over potassium bromid alone. Certain organic compounds of bromin have been introduced as hypnotics, but there is no satisfactory evidence that these are better than the inorganic. DOSAGE The average dose of sodium or potassium bromid is usually given as 1 gm. (15 grains), but 0.3 to 0.6 gm. (S to 10 grains) is the dose commonly used as a hypnotic with hydrated chloral. In the treatment of epilepsy it is advisable to begin with doses of 1 gm. (15 grains) and increase until as much as 10 gm. (2y2 drams) are taken daily, until saturation is attained or until symptoms of bromism indicate the limits of tolerance. The bromids are sometimes given in doses varying from 0.3 to 0.6 gm. (5 to 10 grains), dependent on the age of the child, three times daily for a week, in order to lessen the sensitiveness of the nasopharynx in prepa- ration for mirror examination for suspected adenoids. MATERIA MEDICA The more widely used bromids are : Potassii Bromidum. — Potassium Bromid, U. S. P. 412 MISCELLANEOUS SALTS, ETC. It occurs as colorless crystals or a granular powder having a strongly saline taste. It is freely soluble (1 : 1:5) in water but only slightly soluble (1 : 180) in alcohol. Sodii Bromidum. — Sodium Bromid, U. S. P. It has the general physical characteristics of potas- sium bromid, but is more hygroscopic. It absorbs moisture from the air without deliquescing. It is freely soluble (1: 1.7) in water and soluble (1: 12.5) in alcohol. The solution is devoid of the bitter taste of potassium bromid. The alkali bromids are preferably given in aqueous solutions, with or without syrup. The ready made preparations such as the elixirs of bromids, usually contain considerable quantities of alcohol and are objectionable for this reason. The bromids of the alkalies are incompatible with mineral acids, the salts of mercury, spirit of nitrous ether and oxidizing substances generally. lODIDS Our knowledge of the pharmacologic actions of the iodids does not permit of a systematic discussion of them as a basis for their therapeutic uses. The systemic effects frequently observed after the administration of the iodids are commonly described under the term iodism, and these are often seen after small doses as well as after larger ones. It is even asserted that when they appear after sm"'l doses they may disappear if the dose is increased. This may be true but it has not been demonstrated satisfactorily that the disappearance in such cases is due to the increase in dosage. Catarrh of the respiratory passages is probably the commonest of the symptoms of iodism. There is often swelling of the larynx with edema that interferes with respiration, occasionally necessitating tracheotomy, and rarely causing death. Bronchitis is not infrequent, and the eyes are commonly suffused. The respiratory symptoms are sometimes attributed to the liberation of free iodin by minute amounts of nitrites in the saliva and by carbon dioxid. It seems improbable that enough iodin could be liberated in this lODIDS 413 way to give rise to the symptoms, for the larger part of a dose of iodid leaves the circulation promptly and the amount that can be detected in any of the tissues except the blood is extremely small. Skin eruptions of the most various character occur more frequently after the drug has been administered for some time; these include erythematous patches, papular eruptions that may become pustular, eczema, bullae, pemphigus, purpura and many others. It is said that frequent bathing with scrupulous regard for the cleanliness of the skin lessens the severity of the skin manifestations. The iodids of sodium and potassium are absorbed promptly from the gastro-intestinal tract. The larger portion is excreted rapidly in the urine unchanged, a portion remaining fixed in the tissues for some time, much as in the case of the bromids. The excretion of the iodids in the urine begins within a few minutes, reaches its maximum in about two hours, and within twelve hours the greater part of a small dose is eliminated, but several days may be required for the practically complete elimination of a large dose. The elimination may be hastened by the administration of chlorids but not by simple diuretics, such as caffein. Small amounts of the iodids appear in the saliva and other secretions. THERAPEUTIC USES The iodids are used in combination with mercury in the treatment of the second stage of syphilis, and alone, or in combination with mercury in the third stage. Various explanations have been offered to account for the improvement that they induce, but no adequate explanation has been given of the truly remarkable effects that often follow their use in the treatment of ^syphilitic manifestations affecting internal organs. ilOther obscure manifestations of syphilis, such as neu- ralgia and disturbances of the central nervous system, often yield readily to iodid treatment. They are extensively used in the treatment of chronic rheumatism, but the benefits they cause are unexplained. The effects of iodids on the thyroid, and 414 MISCELLANEOUS SALTS, ETC. indirectly on conditions aifected through the thyroid, will be mentioned when the thyroid is discussed. The iodids are frequently used in arteriosclerosis partly perhaps because of their supposed capacity for lowering arterial tension, but there is no satisfactory evidence that they lower blood pressure appreciably. Their usefulness in this condition as in aneurysm is probably limited to their capacity for causing the absorption of syphilitic deposits in the walls of the vessels. These salts have long been of special repute in the treatment of chronic poisoning by lead and mercury, and while some old experiments seem to show that they facilitate the elimination of lead, and possibly of mercury, the mechanism of the action is not known. The iodids are sometimes used in the treatment of asthma. It has been suggested that they paralyze the vagus endings in the bronchi, thus relieving the spasm. While large doses of the iodids do depress the vagus endings, it is hardly conceivable that the small doses usually employed can have any such action. They are commonly used with belladonna or some other member of the atropin group, compared with which they can act only feebly, on the vagus. The iodids are contraindicated in tuberculosis, but they are used, nevertheless, in syphilis complicating tuberculosis. The increased susceptibility of the tuber- culous to the iodids should be remembered when they are used in such conditions. They have long been used in the treatment of actino- mycosis and they are also of especial value in sporo- trichosis and blastomycosis. In all of these they pro- mote the absorption of granulomatous lesions. Numerous organic compounds of iodin have been introduced for use in place of the alkaline iodids. Although these lack certain disadvantages of potassium iodid clinical experience shows that they are weaker than potassium iodid in the doses commonly used. These compounds of iodin with proteins and with fats seem to irritate the stomach less than potassium iodid. It is asserted that they induce symptoms of iodism less readily, but these claims have not been sub- DOSAGE' OF lODIDS 415 stantiated in cases in which they are used in amounts sufficient to produce the full therapeutic effects. Numerous compounds of ipdin with protein and others with nonprotein substances are described in New and Nonofficial Remedies. DOSAGE Potassium iodid is used in nonsyphilitic conditions in doses of 0.3 to 2.0 gm. (5 to 30 grains) but much larger doses are employed to promote the absorption of the gummatous exudates in tertiary syphilis, in which S gm. (75 grains) and even larger amounts are used unless symptoms of iodism appear. It may be prescribed in doses of 0.3 c.c. (5 minims) of a saturated solution administered three times a day after meals (at which time the stomach con- tents lessen the irritation) with a daily increase of 1 drop in each dose. While a saturated solution is convenient for measuring the dose it should be ■remembered -that saturated, or even somewhat less concentrated solutions of salts are irritant to the stom- ach, hence these should be diluted with from half a glass to a glass of water before being taken. Bland fluids, such as milk, are better than water, and even with such dilution they should be taken only after food. When symptoms of iodism occur the drug should be discontinued for a time and smaller doses used when the administration is resumed. MATERIA MEDICA The iodids in general use are : Potassii lodidum. — Potassium Iodid, U. S. P. It occurs as colorless or opaque white cubic crystals or a granular powder having a pungent saline, after- ward bitter taste. The salt is slightly deliquescent in moist air. It is very soluble ( 1 : 0.7) in water and soluble (1:12) in alcohol. Sodii lodidum. — Sodium Iodid, U. S. P. It occurs as colorless crystals or white crystalline powder having a saline taste, practically devoid of bit- terness. In moist air it deliquesces and frequently undergoes decomposition. It is very soluble (1 : 0.5) in water and freely soluble (1:3) in alcohol. 416 MISCELLANEOUS SALTS, ETC. The alkali iodids like the bromids are incompatible with mineral acids, spirit of nitrous ether and oxidiz- ing substances generally. They are also incompatible with bismuth salts and ferric salts, and should not be prescribed in solution with salts of alkaloids or with preparations of drugs having alkaloidal constituents. The iodids are preferably prescribed in concentrated solutions that may be measured out in drop doses and directed to be taken well diluted with water or with such liquids as milk, or solutions of egg albumin. The following is a typical formula for securing a concen- trated solution of an alkali iodid: gm. or c.c. 1} Potassii iodidi 251 1 ounce av. Aquae destillatae q. s. ad 25| 1 fl. S When larger doses of dilute solutions are used the disagreeable taste of the iodid may be masked by the addition of the compound syrup of sarsaparilla. ACIDS When an acid is taken into the mouth it acts reflexly to cause a flow of saliva, and it is partly neutralized thereby; the acid that passes into the stomach excites gastric secretion, and if in sufficient amount induces increased gastric movements. Free acid is fixed by proteins and is absorbed, or a part of it may pass into the duodenum, causing the produc- tion of secretin and promoting pancreatic and biliary secretion; but the latter actions are fleeting, and probably of no therapeutic importance. If a moderate amount of free acid enters the duo- denum, it is neutralized by alkali, the salt thus formed acts as a laxative or it undergoes absorption and causes diuresis if in sufficient amount. If a large amount of free acid enters the duodenum, it acts as an irritant and sets up peristalsis with diarrhea. When mineral acid is taken internally, it diminishes the alkalinity of the tissues, causing the elimination of acid salts in the urine, but none of the free acid exists in the circulating blood, of course. With the elimination of the acid salts, the proportion of nitro- gen that is eliminated in the form of ammonia is ACIDS 417 larger than normally, and there is a corresponding decrease in the amount eliminated in the form of urea. The acid salts lessen the solubility of the urates, and promote the solubility of the phosphates in the urine; but preformed phosphatic calculi are not brought into solution. The diminished alkalinity of the blood is attended by dyspnea and other symptoms of acidosis. These symptoms may be relieved by the intravenous injec- tion of a solution of sodium carbonate or by the rectal injection of a 3 per cent, solution of sodium bicar- bonate in small amounts (250 c.c, 8 fluidounces) as frequently as possible without causing its expulsion, or by the slow continuous method. Citric acid is oxidized in the body with the forma- tion of carbonates. A case is reported of a woman's having taken at least 12 gm. (3 drams) of tartaric acid in concentrated form. This was followed by severe pain, vomiting, diarrhea, and later by delirium, weak pulse, subnormal temperature, and death on the seventh day. THERAPEUTIC USES Citric acid is sometimes used in place of lemon juice in making lemonade, and citric and tartaric acids are used in making granular effervescent salts. Acetic acid is seldom used internally, but it may be given well diluted with water, as a diaphoretic and diuretic. The only advantage that it has over potassium acetate when used in this way is that it has a less disagreeable taste. Mention has been made elsewhere of the use of acid sodium phosphate (NajHPO^) for increasing the • acidity of the urine, especially when hexamethylenamin is used as a urinary antiseptic. The corrosive and astringent actions of acids are discussed elsewhere. MATERIA MEDICA Acidum Aceticum. — Acetic Acid, U. S. P., a solu- tion containing 36 per cent, by weight of absolute acetic acid (H.C2H3O2). The diluted acetic acid of the pharmacopeia contains 6 per cent., and the glacial 418 MISCELLANEOUS SALTS, ETC. acetic acid 99 per cent, by weight of absolute acetic acid. Acidum Citricum. — Citric Acid, U. S. P., a tribasic organic acid, HgCjHsO,, HgO. It forms transparent crystals having an agreeable acid taste. It is very soluble (1 : 0.54) in water, and freely soluble (1 : 1.5) in alcohol. ALKALIES The alkalies neutralize acids, dissolve mucus, com- bine with proteins to form soluble compounds, saponify fats, and alter the solvent powers of various fluids in which they are dissolved. Their eflfects on metabolism vary with conditions that are not understood. Dilute solutions of the alkalies in contact with mucous membranes dissolve the superficial layers and concentrated solutions of the hydroxids, destroy the entire membrane within a few seconds, and deep cor- rosion of the mouth, throat, esophagus and stomach, with perforation of the latter may follow the swallow- ing of a solution of potassium or sodium hydroxid. When small amounts of these concentrated liquids have been swallowed, the corrosion is frequently followed by gastric ulcer and by cicatrices in the throat and esophagus that prevent swallowing. If the amount of a dilute alkali taken is not exces- sive, it is neutralized in the stomach, and the chlorid formed is absorbed, the alkali causing no "effect except that due to interference with gastric digestion and the temporary increase in the alkalinity of the blood and urine. Somewhat larger amounts pass into the duo- denum and are absorbed, the character and intensity of the actions depending to a great extent on the concentration in which the alkalies are taken. It was formerly taught that the administration of therapeutic doses of the alkalies causes increased gastric secretion, but they appear to have no impor- tant effect on the activity of the secretory apparatus. Obviously, if they are taken during digestion they will neutralize the acid in the stomach and interfere with peptic digestion, but if they are taken some time before eating they may serve to dissolve an excess of ALKALIES • 419 mucus that may be present in the stomach, and thereby promote digestion without directly influencing the secretory activity of the stomach. The effects of alkalies in the intestine are partly direct and partly indirect. The gastric juice destroys many bacteria, and when the acidity has been neutral- ized, many of these organisms escape destruction and they may multiply enormously in the intestine. In like manner the neutralization of the gastric juice interferes with the production of secretin, and thus indirectly with the pancreatic secretion; but with small amounts, or even with fairly large single thera- peutic doses, this effect is slight. The alkalies increase the alkalinity of the tissues even though they are completely neutralized in the gastric juice, since they spare a corresponding amount of carbonates in the intestine that would otherwise be used for neutralizing the chyme, and the carbonates so spared are absorbed. The normal degree of alka- linity of the blood and tissues is restored rapidly through the elimination in the urine of a larger pro- portion of dibasic phosphates than normally. The increased alkalinity of the body fluids persists for periods varying with the amount of alkali taken and the rates of absorption and elimination. The urine is usually alkaline or only very slightly acid, for nearly twenty-four hours after one has taken a seidlitz powder, which contains sodium and potassium tartrate with molecular proportions of sodium bicar- bonate and tartaric acid. This is of some importance when hexamethylenamin is being used as a urinary disinfectant. There is an extensive literature dealing with the effects of alkalies on metabolism and secondarily on numerous diseases, much importance having been attached to the fact that the ammonia of the urine is often diminished during the administration of alkalies, while the urea is increased correspondingly. The alkalies do not appear to have any constant or important influence on the elimination of uric acid, which is sometimes increased and sometimes decreased by them. 420 MISCELLANEOUS SALTS, ETC. There is a widespread belief that alkaHes increase tissue waste, a belief that has been fostered by those interested in mineral waters, and several of the resorts where obesity is treated have gained wide celebrity. The effects obtained in such cases are due more to the laxative effects of the waters, to the diet imposed and the mode of life followed than to any direct effects of the alkalies on tissue waste. THERAPEUTIC USES The alkalies (usually the bicarbonates) relieve gas- tric hyperacidity and are given preferably about an hour after meals, but they are sometimes used an hour before meals when there is continuous secretion and for the purpose of dissolving mucus, as in alcoholic gastritis. A solution of potassium bicarbonate often afifords almost instantaneous relief in sour stomach when there is an accumulation of gas that proves very distressing. Potassium or sodium bicarbonate is frequently used to lessen excessive acidity of the urine that irritates the bladder, or to alkalinize the urine for the purpose of dissolving mucus. This solvent action is said to explain the occasional breaking down of calculi, into fragments, that had been held together by mucus. Sodium carbonate is used intravenously, and sodium bicarbonate is often administered by the rriethod known as the "drop enema" in acute acidosis, as well as in acidosis accompanying diabetic coma; but the striking effects seen in the acute form are in marked contrast to the slight or temporary improve- ment seen in the late stages of diabetes. Alkalies are commonly used in the treatment of rheumatism and gout, though some authorities main- tain that they do harm in gout. Their mode of action is not known. They are also used empirically in the treatment for gallstones and in jaundice. A solution of sodium bicarbonate is commonly used externally as a solvent for dried exudates in various skin diseases, and as a local application for burns, and other conditions in which the skin is irritated. (The caustic actions of alkalies are considered elsewhere.) DOSAGE OF ALKALIES 421 DOSAGE Sodium hydroxid and potassium hydroxid are never used internally in the solid state, and their solutions are used less frequently than the bicarbonates. A solution containing only 1 per cent, of sodium hydroxid is disagreeably alkaline to the tongue.- One part of a 1 per cent, solution of sodium hydroxid will neutralize about 5 parts of 0.2 per cent, hydrochloric acid; 1 gm. of sodium bicarbonate will neutralize more than 200 c.c. of such dilution of hydrochloric acid, or of gastric juice. As much as 15 gm. (4 drams) of sodium bicar- bonate may be given in a day by the mouth in the treatment of acidosis, and 50 gm. (nearly 2 ounces) may be given in 3 per cent, solution by the drop enema. When sodium carbonate is given intravenously, care must be exercised in order that none escapes around the vein, as it causes abscess. When a solution of sodium bicarbonate is boiled in order to sterilize it, it becomes more strongly alka- line to "the taste, through the loss of carbon dioxid gas, but its capacity for neutralizing acid is not altered. In the treatment of rheumatism, the administration of sodium bicarbonate is pushed to the point of ren- dering the urine alkaline, the actual amount required varying with dififerent individuals. Doses up to 1.5 gm. (22 grains) have been recom- mended for bringing up blood and mucus from the stomach in cases in which nausea persists after operation for adenoids. Potassium bicarbonate is used in doses of 0.2 to 0.3 gm. (3 to 5 grains) dissolved in a small amount of water for the relief of sour stomach with its accumulation of gas. MATERIA MEDICA The ofiScial alkalies in the order of their popu- larity are: Sodii Bicarbonas. — Sodium Bicarbonate, U. S. P., NaHCOj, a white, opaque, odorless powder having a cooling, mildly alkaline taste. It is soluble ( 1 : 12) in water but insoluble in alcohol. The solution, even 422 MISCELLANEOUS SALTS, ETC. at ordinary temperatures, gradually loses carbon dioxid, and at boiling heat the salt is converted into the normal carbonate. Potassii Bicairbonas. — Potassium Bicarbonate, U. S. P., KHCO3, occurs as colorless, odorless, transparent crystals having a saline and slightly alkaline taste. It is freely soluble (1:3) in water, but practically insolu- ble in alcohol. Like sodium bicarbonate, this salt in solution gradually loses carbon dioxid, and on boiling is converted into the normal potassium carbonate. Sodii Carbonas Monohydratus. — Monohydrated Sodium Carbonate, U. S. P., NajCOa.HjO, occurs as a white, granular powder having a strongly alkaline taste. It is freely soluble (1:3) in water, but prac- tically insoluble in alcohol. It should not be con- founded with the commercial sodium carbonate, which contains (when uneffloresced) 10 molecules of water of crystallization, and therefore less than half as much NajCOs as the official salt. Potassii Carbonas. — Potassium Carbonate, U. S. P., K2CO3, occurs as a white granular powder having an alkaline taste. It is very soluble (1:1) in water, but practically insoluble in alcohol. Potassii Hydroxidum. — Potassium Hydroxid, U. S. P., KOH, occurs as white sticks or fused masses having a very acrid and caustic taste. It is very solu- ble (1:0.5) in water and soluble (1:2) in alcohol. Because of its caustic properties it is used internally only in the form of: Liquor Potassii Hydroxidi. — Solution of Potassium Hydroxid. An aqueous solution of approximately 5 w/v per cent, of KOH. Sodii Hydroxidum. — Sodium Hydroxid, U. S. P., NaOH. Like potassium hydroxid, this substance occurs in the form of sticks or fused masses. It is very soluble (1:1) in water and in alcohol. Inter- nally it is used only in the form of a solution, prefer- ably a dilution of the official : Liquor Sodii Hydroxidi. — Solution of Sodium Hydroxid. An aqueous solution of about 5 w/v per cent, of NaOH. PHARMACOLOGY OF OXYGEN 423 OXYGEN Leonard Hill and Flack found that the administra- tion of oxygen restored vigor in a striking way, send- ing the "done" man back into the boxing ring after the third round full of "fire and energy," and reviving the well-nigh exhausted swimmer. Students were caused to run up and down stairs carrying apparatus that supplied ordinary air or oxygen without their knowing which they breathed, and the performance of the tasks was compared. A greater capacity for doing work was shown by those who breathed oxygen than by those who breathed air, but the differences were not great, and were only such as one might expect, for there is always some embar- rassment when one who is untrained performs violent physical effort, because the air way is not sufficient to admit enough air to supply the required oxygen with- out some extra effort, which was not required when pure oxygen was breathed. In other words, the breathing of oxygen in such cases is equivalent to enlarging the air way and alveolar capacity. Hill and Flack believe that the inhalation of oxygen prevents the discomfort due to the washing out of carbon dioxid in forced breathing after severe physical effort. THERAPEUTIC USE Oxygen is used therapeutically to supply a deficiency in respiration due to mechanical obstruction of the air passages. The hemoglobin of the blood is incapable of taking up oxygen to the normal degree in poisoning with car- bon monoxid (illuminating gas), and if oxygen be sup- plied under pressure in such cases, as much as 3 per cent, may be dissolved in the plasma, and this supple- ments that which is taken up by the corpuscles while the oxygen is displacing the carbon monoxid with which the hemoglobin is bound. Oxygen is used very commonly to relieve respiratory embarrassment in pneumonia, but it is seldom capable of saving life in that disease. Naturally, less labor is required to breathe the requisite amount of oxygen in concentrated than in diluted form through narrowed 424 MISCELLANEOUS SALTS, ETC. air passages, but in severe distress in pneumonia the trouble lies in the diminished surface available for oxygenation of the blood. MATERIA MEDICA Oxygenium Compresswrn. — Compressed Oxygen, N. N. R., gaseous oxygen O2 in a compressed state, is marketed in several forms of container. The amount of gas present is usually determined by weight, and the degree of pressure of necessity regulates the size and the nature of the cylinder in which the oxygen is sold. Oxygen is a colorless, odorless, tasteless gas, slightly soluble in water and neutral to ordinary indi- cators. For medicinal purposes, compressed oxygen, should be neutral toward litmus and free from chlorin compounds or ozone. The extemporaneous production of oxygen from peroxids, while possible, is not usually considered economically practicable. THYROID The removal of the thyroid glands is rapidly fatal in dogs; in man it results in a train of symptoms closely resembling, if not identical with, those seen in myxedema. These include dulness of mentality and a characteristic collection of mucus-like substance in and about the connective tissue of the body. The symptoms that result from the removal of the thyroid gland can be abolished by the oral admin- istration of the dried gland or of a nonprotein com- pound containing iodin that may be obtained from the gland and which is probably secreted by it. This iodin compound as separated by Kendall contains 62 per cent, of iodin and is thought to be a di-iodo-di- hydroxy-indole. The oral administration of iodin or alkaline iodids may give rise to symptoms indicative of increased thyroid activity in those who show a tendency toward hyperthyroidism, or Graves' disease, and this would suggest that the activity of thyroid prepa- rations might be increased by the addition of iodin or iodids to them, but this simple addition of iodin compounds to the thyroid preparations does not THYROID 425 increase their activity. Such sophistication can be detected by chemical analysis, and biologic tests may be used to determine the activity of commercial prep- arations so that one can be satisfied that there has been no sophistication. Four general methods have been followed in the investigation of the actions of thyroid preparations. These are: 1. The administration of thyroid sub- stance to thyroidectomized animals. 2. The adminis- tration of the gland or preparations of it to patients suffering with myxedema. 3. Metabolism experiments during thyroid feeding. 4. Investigations of the effects of thyroid administration on the circulation. The results of the oral administration of thyroid substance to thyroidectomized animals and man afford striking proof of the presence of some substance in the gland that is necessary to health, and the results obtained by the therapeutic use of the gland substance or idiothyrine in myxedema, in cretinism and in cases in which the gland has been removed have few par- allels in the whole range of therapeutics. These brilliant results have led to the use of the gland sub- stance in innumerable other conditions in which the failure is as complete as the success that attends its proper use. Moderate doses of thyroid have comparatively little effect on normal persons, but with continued administration there is usually some loss of adipose tissue and some increased protein metabolism with loss of weight. The action with reference to the increased metab- olism of fat and protein is not the same in different individuals. In some there is a marked reduction of fat with relatively little loss of body protein, this being especially common in those persons who accu- mulate fat readily even when the diet is moderate and exercise is taken habitually. When thyroid substance is taken for the reduction of fat an abundance of protein should be taken, but there is often a serious disturbance of the nervous 426 MISCELLANEOUS SALTS, ETC. system with marked destruction of body protein even when this precaution is observed. The injurious effects of excessive thyroid feeding include palpitation with tachycardia and a sense of fulness in the head. There may be lassitude, trembling of the limbs, fever, sweating and sleeplessness. There is usually some looseness of the bowels or severe diarrhea; frequently there is some respiratory depres- sion and there may be exophthalmos. These symp- toms are seen in Graves' disease and are almost certainly due to hyperactivity of the gland. Reid Hunt found that the administration of thyroid substance to mice increased their resistance to poison- ing with isonitrile, the degree of the increase in resis' tance affording an index of the activity of the thyroid used. Unfortunately, we do not know the mechanism by which this tolerance is induced. The injection of an extract of thyroid substance into the circulation causes slowing of the normal pulse rate, apparently through stimulation of the vagus center in the medulla, but with the appearance of toxic symptoms the vagus loses control of the heart rate and tachycardia results, as previously stated. The thyroid gland of the sheep is official in the U. S. Pharmacopeia VIII, but sheep are often goiter- ous, in which case the iodin content and the activity of the gland are low, and much of the older work done with thyroid substance is rendered valueless by the fact that the activity of the substance used is not known. "New and Nonofificial Remedies" contains a descrip- tion of a proprietary preparation known as iodo- thyrine, or thyroiodin, which consists of a milk-sugar trituration of a substance, or mixture of substances, for which it is claimed that 1 gram of the preparation contains 0.3 mg. of iodin. This corresponds fairly well with the official dried thyroid gland. THERAPEUTIC USES The uses of thyroid gland have been suggested in part by the discussion that precedes this. First in importance in the use of thyroid stands its employment THYROID 427 in those conditions in which there is a deficiency of normal thyroid activity, including myxedema, sporadic cretinism and patients having enlarged but feebly act- ing thyroid. Of less importance, so far as real value is concerned, is its use in obesity though it is probable that it is used for this purpose more frequently than for any other, especially in the form of nostrums advertised directly to the public. Curiously, its use in myxedema requires greater care than is necessary when it is administered to a normal person. It may then give rise to circulatory disturbances with weak and rapid heart, even when small doses are employed. The cause of these side actions is not known, but it has been suggested that during the course of myxedema and other conditions of deficient thyroid activity certain substances may accumulate in the organism and that these substances may be broken down, or otherwise rendered harmful, by the thyroid, in a manner analogous to the liberation of endotoxins when pathogenic bacteria are destroyed in large numbers in the body during the course of treatment of an infectious disease. It is probable that the proper regulation of the diet and exercise can always accomplish better results than thyroid in the reduction of superfluous flesh. The symptoms of thyroid poisoning should be borne in mind when one is called on to treat a patient who may be suspected of having resorted to the use of an obesity cure. It would not be profitable to attempt to discuss the many dififerent conditions in which thyroid has been used with asserted benefit. DOSAGE The average dose of desiccated thyroid gland is said to be 0.1 to 0.6 gm. (1% to 10 grains), but it is evident that the dose must be adjusted carefully for each patient. 428 MISCELLANEOUS SALTS, ETC. MATERIA MEDICA The gland is official as: Glandulae Thyroideae Siccae — Desiccated Thyroid Gland, U. S. P. One part of the desiccated gland, in the form of a yellowish amorphous powder, represents approx- imately 5 parts of the fresh glands of the sheep. To insure greater uniformity it is proposed that the powder be required to yield from 0.17 to 0.23 per cent, of iodin in thyroid combination. The preparation is preferably administered in the form of capsules or cachets. ANTITHYROID These may be mentioned here briefly though their use is still in the experimental stage. A somewhat more extended discussion of these preparations will be found in "New and Nonofficial Remedies." These preparations are obtained from the milk or blood of animals which have been deprived of their thyroid glands. Their use is based on the theory that the thyroid secretes substances that are toxic but which neutralize, and are neutralized by, other toxic substances formed in the body. Removal of the thyroid is supposed to favor the accumulation of these toxic body substances (not those of the thyroid, of course) in the blood and milk, hence the blood and milk of such animals with the contained hypothetic accumulation are supposed to counteract the effects of hyperthyroidism (Graves' disease) or to interfere with the activity of the gland. CHAPTER XIV.— SUBSTANCES USED TO INFLUENCE THE APPE- TITE AND DIGESTION BITTERS Innumerable bitter drugs have been used with asserted benefit in the treatment of a great number of diseases though ^here is no satisfactory evidence that they are curative in any of these conditions, and it seems probable that the only benefit derived from their use is to be explained by the improvement in the appetite that they cause. The group of drugs known as simple bitters are now used by educated phy- sicians only for improving the appetite. That the appetite and digestion are closely related hardly required experimental demonstration, but Paw- low and his co-workers have shown that gastric juice is secreted when a dog is allowed to smell meat, but that food introduced into the stomach through a fistula might remain long undigested. Bitter substances stimulate the taste buds in the tongue and cause the secretion of saliva, but Carlson and his associates have shown that they do not cause hunger contractions in the stomach, but on the con- trary, that when they have any effect they tend to diminish these contractions. These experiments car- ried out on normal men and on one with a permanent gastric fistula of long standing, leave the question of the influence of the bitters on the appetite, as dis- tinguished from hunger sensations, undecided. Abundant clinical experience seems to show that the bitters taken shortly before meals improve the appetite in suitable cases. From this it follows that the subject is one for clinical, rather -than purely pharmacologic discussion. 430 BITTERS, CARMINATIVES, ETC. Bitters are classified conveniently as simple and aromatic. There are innumerable simple bitters, but the list of drugs in this class now recognized by the Pharmacopeia is much smaller than formerly and "Useful Drugs" contains orriy one — ^gentian — that may be classified as a simple bitter, since others, including nux vomica and cinchona, that may be used as such, have more important actions. Chamomile, bitter orange peel and serpentaria are frequently added to alcoholic beverages or "bitters" in domestic practice, but none of these aromatic bitters has been included in "Useful Drugs." Gentian is administered a few minutes before meals in such a way that the bitter taste is utilized, for, as previously stated, it has no therapeutic effect aside from this bitter taste. DOSAGE Gentian is rarely used in substance ; the dose of the solid extract is 0.25 gm. (4 grains) ; that of the com- pound tincture is 4 c.c. (one teaspoonf ul) . MATERIA MEDICA Extractum Gentianae. — Extract of Gentian, U. S. P., is an aqueous extract of gentian evaporated to pilular consistence. As suggested above, this preparation is of no direct value as a bitter unless dissolved in water and its continued use as a diluent in the making of pills is probably due to a misapprehension. Tinctura Gentianae Composita. — Compound Tinc- ture of Gentian, U. S. P., is a hydro-alcoholic tincture representing 10 per cent, of gentian with bitter orange peel and cardamom used for flavoring. It should be directed to be well diluted, but not followed with water, so as to allow the bitter taste to become evident. AROMATIC CARMINATIVES Under this classification are included various drugs that are related to other groups. Bastedo enumerates no less than eighteen therapeutic groups in which the carminatives may be classified. These include: CARMINATIVES 431 1. Anticolics, especially for infants (anise, ginger and peppermint). 2. Odors and flavors. 3. Correctives of irritant cathartics. 4. For tympanites — in typhoid fever, pneumonia, etc. 5. Anthelmintics (oil of chenopodium). 6. Stimulants of mucous membranes. 7. Antiseptics and anesthetics. 8. Counterirritants. 9. Stimulants in chronic skin diseases. 10. Stimulants to the growth of hair (oil of mace). 11. Antirheumatics (methyl salicylate). 12. Antihysterics (asafetida, camphor). 13. Antiasthmatics (cubebs in powder for cigarets). 14. Bronchial stimulants. 15. Diuretics. 16. Urinary antiseptics. 17. Emmenagogues. 18. Leprosy (oil of chaulmoogra). Some of these have been discussed and a few remain to be considered. The aromatic carminatives increase gastro-intestinal peristalsis and serve to hasten the passage of gas through the stomach and bowel. They induce hyper- emia of the gastro-intestinal mucous membranes and probably increase the appetite and digestion. Capsicum enjoys a special reputation in the treatment of atonic dyspepsia due to chronic alcoholism; carda- mom is used as an aromatic carminative and the com- pound tincture is also used to give a handsome appear- ance to alcoholic mixtures. Oil of cloves is very com- monly used for the relief of pain in carious teeth. Cinnamon is especially popular as a flavor. Mustard is most commonly used as a condiment; its use as a counterirritant has been mentioned. Ginger is prob- ably the most popular .member of the group for the relief of colic. 432 BITTERS, CARMINATIVES, ETC. DOSAGE The average dose of tincture of capsicum is 0.5 c.c. (8 minims) ; that of tincture of cardamom is 5 c.c. (75 minims) ; of tincture of ginger 2 c.c. (30 minims). Oil of cloves is seldom used internally and oil of cinnamon is used mainly for flavoring. The dose of oil of cloves is 0.2 c.c. (3 minims) ; that of oil of cinnamon is 0.1 c.c. (2 minims). MATERIA MEDICA Among the more widely used preparations that are ■generally classed as carminatives, we have : Tinctura Capsici. — Tincture of Capsicum, U. S. P., a 10 w/v per cent, preparation with 90 per cent, alcohol. Tinctura Cardamomi. — Tincture of Cardamom, U. S. P., a 20 w/v per cent, solution in diluted alcohol. The compound tincture of cardamom, Tinctura Car- damomi Composita, is a 2.5 w/v per cent, diluted alcohol preparation of cardamom with cinnamon and caraway, colored red with cochineal. Tinctura Zingiberis. — Tincture of Ginger, U. S. P., a preparation containing 2 w/v per cent, of the drug in alcohol. Oleum Caryaphylli. — Oil of Cloves, U. S. P., a vola- tile oil containing about 80 per cent, of eugenol. Oleum Cinnamoni. — Oil of Cinnamon, U. S. P., a volatile oil required to contain about 75 per cent, of cinnamic aldehyd. PEPSIN, PANCREATIN AND HYDROCHLORIC ACID There are few chapters on therapeutics that reflect less credit on us than that dealing with the abuse of the digestive ferments. Many physicians have clung tena- ciously to the idea that intestinal digestion can be pro- moted by the administration of pancreatin or mixtures of pepsin and pancreatin, despite the frequent reitera- tion of the fact that pepsin destroys pancreatin in the presence of a suitable acid. Pepsin may be given to secure the digestion of pro- tein food in the stomach when there is a deficiency of PEPSIN, PANCREATIN, ETC. 433 pepsin in the gastric secretion, but this seldom occurs, pepsin being secreted even where there is a deficiency of hydrochloric acid in the stomach. Pepsin acts only in acid mediums and its action is inhibited when the concentration of hydrochloric acid exceeds 0.3 per cent. It is destroyed rapidly by pan- creatin in alkaline mediums. Pepsin is used in acute indigestion when there is no absence of hydrochloric acid in the gastric secretion but in chronic conditions it should be used only when it has been shown that pepsin and hydrochloric acid are both deficient in the gastric secretion. Pancreatin is not often suited for oral administra- tion for the reasons just mentioned, and it is useful mainly for preparing partially digested protein and starchy foods. It may be administered with sodium bicarbonate in achylia gastrica, and it has been administered in the form of pills coated with salol or in gelatin capsules that have been hardened in formaldehyd, but this method of administration is not very promising. Milk may be partially peptonized by adding a small amount of pancreatin and bicarbonate of sodium and allowing it to stand for a few minutes at body tem- perature. The process may be stopped by heating the milk rapidly to 65 C. (ISO F.). If the process is carried too far the taste becomes excessively bitter. As previously stated, there is a deficiency of hydro- chloric acid in the gastric secretion more frequently than of pepsin. It is commonly given in doses of 1 c.c. (15 minims) of the diluted acid with water. MATERIA MEDICA The above drugs are official as : Pepsinum. — Pepsin, U. S. P., the ferment or enzyme obtained from the stomach of the hog, capable of digesting not less than 3,000 times its own weight of freshly coagulated and disintegrated tgg albumin. Pancreatinum. — Pancreatin, U. S. P., a mixture of enzymes contained in the pancreas of warm-blooded animals capable of converting not less than 25 times its own weight of starch into substances soluble in water. 434 BITTERS, CARMINATIVES, ETC. Acidum Hydrochloricum Dilutum. — Diluted Hydro- chloric Acid, U. S. P., should contain 10 per cent, by weight of absolute hydrochloric acid. COD LIVER OIL Cod-liver oil may be considered in this place, though it is not a drug, its value depending on its nutrient property. The taste is so disagreeable to most persons that it is commonly dispensed in the form of a sweetened and flavored emulsion. Cod-liver oil has long enjoyed a special reputation in the treatment of tuberculosis. Practically all pro- prietary emulsions of cod-liver oil contain the useless and extremely disagreeable hypophosphites. The following formulas may be used by those who prefer to prescribe the emulsion of cod-liver oil without useless salts : gm. c Cod liver oil 250 ■ Acacia 60 Syrup 60 Methyl salicylate 2 Water; a sufficient quantity make SOD flS viii Sii flSii TTlXXX flSxvi The flavoring may be varied to suit the individual taste; oil of sassafras, oil of peppermint, oil of cinna- mon or oil of bitter almond may be used in varying quantities. In the event that oil of bitter almond is used that without hydrocyanic acid should be specified. An emulsion made with yolk of egg has had consid- erable vogue at times and may be made as follows : gra. c Cod liver oil 250 Fresh yolk of eggs 45 Glycerin 60 Syrup 60 Methyl salicylate 2 Water, a sufficient quan- tity to make 500 flS viii 3 jss 5ii flSii in, XXX flSxvi In making this emulsion the yolk of eggs is triturated in a mortar with the glycerin added gradually. The oil is then added to this mixture, small portions at a time, followed by the syrup, the flavoring and finally FLAVORS AND VEHICLES 435 a sufficient amount of water to make the required quantity. MATERIA MEDICA The oil is officially described as : Oleum Morrhuae. — Cod-Liver Oil, U. S. P., a fixed oil obtained from the fresh liver of various species of cod. FLAVORS, DILUENTS AND VEHICLES SACCHARIN Saccharin (benzosulphinid) is used by diabetics as a substitute for sugar, though it is not at all satisfactory. It is frequently stated that saccharin is nontoxic, and very large amounts have been administered to a dog during a period of ten days without inducing percep- tible ill effects. It has also been used to replace sugar to a large extent in sweetened beverages, but unfor- tunately we do not know whether its continued use is capable of inducing deleterious effects under abnor- mal conditions, and in the present state of our knowl- edge it should not be used in place of sugar unless the latter is contraindicated. It is unfortunate that our knowledge of the subject is so limited, because many persons who crave sweets are singularly intolerant of sugar and are subject to attacks of indigestion with headache and other evidences of severe intoxication after even moderate indulgence in sugar. Commercial saccharin is variable in composition, and is usually sold on the basis of its sweetening power compared to sugar. The product is official as : Benzosulphinidum. — Benzosulphinid, saccharin, U. S. P., the anhydrid of ortho-sulphanid-benzoic acid or benzosulphonic-imid, having approximately 500 times the sweetening capacity of sugar. It occurs as a white crystalline nearly odorless powder having an intensely sweet taste. It is soluble (1:25) in alcohol but only slightly soluble ( 1 : 250) in water. The addition of an alkali materially increases the solubility, and the prod- uct usually sold as "soluble saccharin" is made by neu- tralizing a solution of saccharin with sodium carbonate or bicarbonate and evaporating to dryness. 436 BITTERS, CARMINATIVES, ETC. This soluble form of saccharin is generally sold in the form of compressed tablets or of tablet triturates containing the equivalent of 15, 30 or 60 mg. (i^. V2 or 1 grain) of pure saccharin. The tablet containing 30 mg. is equivalent to 15,000 mg., 15 grams or approx- imately 1 tablespoonful of sugar. The proportion usually employed is 0.03 gm. (^ grain) of saccharin or 0.6 gm. (1 grain) of soluble saccharin to 200 to 250 gm. (6 to 8 ounces) of fluid. In practice it will usually be found necessary to use rather more than the actual sweetening capacity of saccharin unless some addition in the form of milk, albumin, gum, gelatin or casein can be made to the liquid to increase its density. In lieu of the tablets of soluble saccharin, an alcoholic or hydroalcoholic solution of saccharin itself may be directed to be used, or an extempora- neously prepared solution of saccharin may be pre- scribed as follows : gm. or c.c. gr. xlv 5 gr. xxii fl. Svi Saccharin 3 Sodium bicarbonate 1 , Water, a sufficient quantity to malce....200 Dissolve the' saccharin and sodium bicarbonate, by means of gentle heat if necessary. One teaspoonful of the resulting solution is equivalent to about 0.06 gm. (1 grain) of saccharin. The following substances that have been included in the list of "Useful Drugs" do not require detailed discussion : Mentha Piperita. — Peppermint, U. S. P. The leaves and tops of Mentha piperita. Peppermint is practically never used therapeutically in substance, but is sometimes employed pharmaceutically to give a green color to alcoholic preparations, such as spirit of peppermint. Aqua Menthae Piperitae. — Peppermint Water, U. S. P. A saturated solution of peppermint oil in water. It is used largely as a vehicle, especially for the bromids. Oleum Menthae Piperitae. — Oil of Peppermint, U. S. P. This is actively carminative. The dose is 0.2 c.c. (3 minims) administered on sugar preferably. Spiritus Menthae Piperitae. — Spirit of Peppermint, U. S. P, It contains 10 per cent, of the oil in alcohol FLAVORS AND VEHICLES 437 colored with the herb. It is sometimes used as flavor- ing, but it is also actively carminative. The dose is 2 c.c. (30 minims), diluted with water or syrup and water. The flavor of spearmint is preferred by many to that of peppermint.- Spearmint herb, oil, spirit and water are also official. These correspond to the preparations of peppermint in activity. Rosa. — Rose, U. S. P. It is seldom used therapeu- tically in substance. Aqua Rosae. — Rose Water, U. S. P. A solution of the volatile oil of rose in water. It is much used as a perfume in lotions and toilet articles. Oleum Rosae. — Oil of Rose, U. S. P. It is used to perfume ointments, 1 or 2 drops being sufficient for an ounce of ointment. Saccharum Lactis. — Sugar of Milk, U. S. P. It is used as a diluent, especially for powders and tablet triturates. It is also used extensively for modifying milk in infant feeding, and of late it has come into use in the high calory diet in typhoid fever as advocated especially by Shaffer and Coleman. Syrupus Sarsaparillae Compositus. — Compound Syrup of Sarsaparilla, U. S. P. A mixture of fluid- extract of sarsaparilla (20 c.c), fluidextract of glycyr- rhiza (1.5 c.c), fluidextract of senna (1.5 c.c.) and aromatics, with syrup (sufficient to make 100 c.c). Compound syrup of sarsaparilla was formerly used as a so-called blood purifier, or alterative, but at pres- ent it is used as a vehicle, especially for potassium iodid. A simple syrup of sarsaparilla affords a thick froth with "soda water," and this is commonly used for the administration of castor oil. The compound syrup may be used for the purpose, but it is too bitter to be pleasant to children. Sugar and syrup are widely used in pharmacy, but they do not require further mention here. Sarsaparilla (the root) is of no therapeutic interest except that it contains saponin. CHAPTER XV.— ANTHELMINTICS Anthelmintics are agents that kill intestinal para- sites or facilitate their expulsion with the aid of evacuants. The ideal anthelmintic would kill or stupefy the parasites but would not be absorbed from the gastro- intestinal tract of the host, nor would it irritate the stomach or the bowel more than enough to cause pur- gation. Unfortunately, the best of the anthelmintics at our disposal are far from being ideal, and all of them are capable of causing the death of the patient if used without care, while none of them is certain in its action on the parasites. The round worm (Ascaris lumbric aides) and. pin- worm (Oxyuris vermicularis) are probably the most common of this type of parasite in the bowels of chil- dren, if we except the hookworm, which is very preva- lent in certain parts of the country, while the tape- worm, including the Taenia and Bothriocephalus latus (or broad tapeworm) are found more commonly in adults than in children, but taeniae are occasionally reported as occurring in children and a case of Taenia saginata has been very recently reported as occurring in an infant. Gross parasites of this nature can be guarded against more easily than the bacterial infections, and the more common sources of infection should be understood more generally than is the case. The so-called head, which is of minute size, is the real tapeworm, all the remainder, the segments, con- sisting of generative buds containing matured sexual organs. These are constantly breaking off and passing out of the bowel, the ova being swallowed by other ani- mals in which they develop in various organs. For example, the hog is commonly infested with Taenia solium, which becomes encysted, forming what is known as "measles," and when a person eats raw measly pork he becomes the host of a tapeworm. ANTHELMINTICS 439 Taenia solium. It is probably the tapeworm most commonly found in this country. Taenia saginata may infest beef in the same way. Bothriocephalus latus is very much more common in Europe, but it is occasionally seen in this country. The dog is commonly infested with intestinal para- sites, which are sometimes present in large numbers. Other domestic and wild animals are similarly infested. While the eating of raw meats, especially pork, is probably the commonest source of infestation, the pos- sibility of having the hands contaminated by pets should be borne in mind. All active cathartics tend to remove worms and other intestinal parasites in the evacuations, but while this may occasionally succeed in ridding one of the so-called head of the tapeworm, as a rule only a smaller or larger number of segments are thus gotten rid of and these segments are rapidly replaced. As previously stated, none of the anthelmintics is either certain in its action or free from danger ; hence every precaution should be taken to insure the most favorable conditions for the expulsion of the parasite when medication is undertaken. Medication should be preceded by a diet calculated to weaken the parasite as much as possible without greatly weakening the patient. Meat and other pro- teins are withheld or given in small amounts while carbohydrates are given in abundance. It is said that sharp particles, such as seeds of strawberries, and pungent substances, such as mustard, tend to cause the parasite to loosen its hold ; hence these may be utilized as a preliminary to active treatment. Tapeworms are provided with suckers, hooks or ser- rated margins by which they attach themselves to the mucous membrane of the intestine, and the best that can be accomplished by anthelmintics, as a rule, is to stupefy the parasite or paralyze its musculature so that its hold on the intestinal mucous membrane is released, at which time it may be swept out in a copious watery evacuation. The patient should fast for about twelve hours before taking a taeniafuge, such as aspidium or pelle- 440 ANTHELMINTICS tierin, but a cup of coflfee may be taken in the morning on arising, that is, shortly before the administration of the drug. A laxative may be administered previously so as to insure the almost complete emptying of the intestine, but an entirely empty tract facilitates the absorption of the drug by the host. The parasite is usually caused to loosen its hold within an hour or two after the administration of an effective dose of aspidium; hence the purgative is usually given either at the same time or shortly after the anthelmintic. The pinworm, or threadworm {Oxyuris vermicu- laris), is a very small parasite that inhabits the lower parts of the intestine in great numbers. It does not attach itself to the intestinal mucous membrane and may be dislodged from the bowel by cathartics and enemas. Bastedo mentions the following as being used for irrigating the colon to remove the pinworm : infusion of quassia ; lime water ; quinin bisulphate 1 : 2,000 ; a solution of tannin or alum 2 gm. (30 grains) to 500 c.c. (1 pint) of water; or 15 c.c. (% ounce) of oil of turpentine to 1 liter (1 quart) of soap suds. He states that the Taenia nana is often mistaken for pinworm and one of the dwarf tapeworms is said to be the commonest of the tapeworms of childhood. ASPIDIUM Our knowledge of the chemistry of aspidium is unsatisfactory, but there are several substances, includ- ing amorphous and crystalline filicic acid, on which the anthelmintic actions of the drug seem to depend. Whatever the nature of the active principles, they are present in the oleoresin, in which form aspidium is now commonly employed. Under favorable conditions but little of the oleoresin (or its active constituents) is absorbed into the circu- lation in man, but when absorption does occur severe, and even fatal, poisoning may result. Nausea and even slight vomiting are not infrequent consequences of therapeutic doses, and this may even PELLETIERIN, SANTONIN 441 prevent the desired action of the drug. With absorp- tion and severe poisoning there are violent vomiting and purging with pain in the intestines, muscular weak- ness and convulsions, followed by stupor passing into coma. Castor oil is sometimes administered with aspidium or afterward in order to induce purgation, but there seems to be little doubt that, because of the readiness with which it dissolves the active principles of aspidium, it promotes absorption unless purgation is prompt. It is stated that aspidium is less effective against taeniae than against Bothriocephalus. It is unfortu- nate that this point has not been determined with cer- tainty, for aspidium is widely used for tapeworm regardless of the species infesting the patient. PELLETIERIN TANNATE The bark of pomegranate root has long been used in the treatment of tapeworm, but it contains an abun- dance of tannin and this often gives rise to vomiting when an infusion is employed in the dose necessary to act as a taeniaf uge — from 30 to 60 gm. ( 1 to 2 ounces) — hence the tannate or sulphate of the alka- loid, pelletierin, is now almost always used instead of the bark. Pelletierin is sometimes absorbed from the gastro- intestinal tract, causing stimulation of the central ner- vous system, and a veratrin-like action on the muscles. It seems probable that a similar action on the muscu- lature of the tapeworm explains its efficiency as a taeniafuge. Poisonous doses of pelletierin cause diz- ziness and sometimes disturbance of vision in addition to the muscular weakhess. SANTONIN Santonin is probably the most effective anthelmintic available for the expulsion of the round worms of childhood. According to von Schroeder santonin does not kill the worm but renders the intestinal contents unpleasant, causing the parasite to seek the large bowel, from which it is expelled by the cathartic that is used in the treatment. 442 ANTHELMINTICS Sodium santoninate is soluble and this is probably absorbed into the circulation of the patient more rap- idly than the insoluble santonin; hence the coarsely powdered crystals of santonin are generally directed to be used. Santonin is always absorbed to some extent and gives the urine a deeper yellow or red color if it be alkaline. Poisoning rarely follows the administration of suitable doses of santonin, but frequently objects appear vio- let colored and later yellow, after its administration, and convulsions may result from poisonous doses. OIL OF CHENOPODIUM Oil of chenopodium or oil of American wormseed has long been used in the treatment of round worms of children, and of late it has attracted attention in the treatment of hookworm. Two investigators reported that they used it in the treatment of nearly 1,500 cases of hookworm with more frequent success than was attained with thymol or other means. They administered three doses, each containing 16 drops of oil of chenopodium, at intervals of two hours, and after another interval of two hours they adminis- tered a tablespoonful of castor oil to which they added a large dose of chloroform. The oil of chenopodium does not kill the parasite but narcotizes it and it must be expelled by means of a cathartic, castor oil being employed frequently. Several cases of severe or fatal poisoning by oil of chenopodium have been recorded and the drug should be used with caution. THYMOL Thymol has come to be used widely in the treatment of hookworm disease, but the danger of poisoning with the large doses required leaves much to be desired. At the present time the supply of thymol is said to be extremely limited, and there would appear to be no reason why the generally safer oil of chenopodium should not be used in its place. THYMOL 443 DOSAGE The average dose of oleoresin of aspidium is given as 2 C.C. (30 minims), but larger amounts are fre- quently used. The average dose of pelletierin tannate is 0.25 gm. (4 grains) and it is stated in "Useful Drugs" that not more than 0.3 gm. (5 grains) should be given at once, as that amount has caused paralysis, but Meyer and GottUeb state that doses of 0.3 to 0.4 gm. (5 to 6 grains) of the sulphate or the tannate usually act efficiently without causing severe symptoms of poisoning. These authors advise the administration of 0.5 to 1 gm. (8 to 15 grains) of tannin with the tannate or sul- phate to insure that the alkaloid be maintained in the intestine in the form of the insoluble tannate. It may be given preferably in the form of capsules after the usual preliminary attention to the diet and emptying of the intestinal tract, and it is best followed in two hours by a brisk cathartic, such as castor oil or magnesium sulphate. The average dose of santonin is 0.065 gm. (1 grain). Since santonin does not kill or even severely injure the worm it is better practice to give the drug for several days. Lozenges, containing 0.03 gm. (% grain) san- tonin may be given to a child morning and evening for three days; twice as much is used for an adult. The last dose is to be followed by a purgative such as calomel, or a laxative dose of calomel, 0.005 gm. (K2 grain), may be administered with each dose of santonin. The dose of oil of chenopodium is given as 0.2 c.c. (3 minims) in the pharmacopeia, but this appears to be rather too conservative. But it would be wise to avoid the use of large doses of chloroform after maximal doses of the oil, for chloroform, which is itself an active anthelmintic in large doses, is usually considered too poisonous for common use for this pur- pose. The dose of thymol in the treatment of hookworm disease is as follows : For children under 5 years, the fine powder is given in doses of 0.5 gm. (8 grains) ; from 5 to 10 years, 1 gm. (15 grains) ; from 10 to 15 444 ANTHELMINTICS years, 1.5 gm. (22 grains) ; from 15 to 20. years, 2 gm. (30 grains) ; and over 20 years, 3 to 4 gm. (45 to 60 grains). It is especially necessary to prevent its absorption when such large doses are used; hence oils and fats should be avoided in the diet. MATERIA MEDICA Of the preparations used as anthelmintics, the more popular are: Oleoresina Aspidii. — Oleoresin of Aspidium, U. S. P., a semisolid dark green extract. On standing it usually deposits a granular crystalline substance which should be thoroughly mixed with the liquid portion before use. Pelletierinae Tannas. — Pelletierin Tannate, U. S. P., a mixture of alkaloids, obtained from pomegranate, which occurs as a light, odorless amorphous powder that is only slightly soluble (1 : 235) in water, but solu- ble (1:12.5), in alcohol. Santoninum. — Santonin, U. S. P., the inner anhydrid or lactone of santonic acid, a glucosid obtained from santonica. It occurs in colorless crystals that become yellow on exposure to light and air. Santonin is very insoluble (1:5,300) in water, but soluble (1:35) in alcohol. Oleum Chenopodii. — Oil of Chenopodium, U. S. P., a limpid, yellowish liquid having a peculiar somewhat camphoraceous odor and a pungent, slightly bitter taste. Thymol. — For materia medica of thymol see under Antiseptics and Disinfectants. CHAPTER XVI.— SERUMS, VACCINES AND VIRUSES Serums, vaccines and viruses constitute one of the most important groups of remedial agents in the materia medica, but the comprehensive discussion of their uses belongs to a special department of medicine, and only the briefest consideration of them is required here. (A brief but somewhat more extended discus- sion of this class of agents will be found in New and NonofHcial Remedies for 1915, p. 279.) The commercial manufacture of these agents is under the supervision of the United States Public Health Service. Standards of potency are provided for antidiphtheric and antitetanic serums, but there is no standard of therapeutic efificiency for the other serums, or the vaccines or viruses. They are exam- ined to see that they are not contaminated with bac- terial or other harmful substances, but this does not insure the usefulness of any of them, since many of them are in themselves capable of doing harm. MATERIA MEDICA AND DOSAGE In the order of their introduction into the medicine, the several more widely used products may be arranged as follows: Virus Vaccinum. — Vaccine Virus, N. N. R., is defined as the material obtained under aseptic con- ditions from skin eruptions of calves having vaccinia. It is usually marketed in capillary tubes or as glycerin- ated points, and is used for immunization against smallpox, the contents of one tube or point constitut- ing the dose, which is usually applied endermatically with the usual surgical precautions. Antirabic Vaccine or Antirabic Virus, N. N. R., is the virus of rabies rendered practically nonvirulent for man by passage through a series of rabbits. The material used consists of sections of the spinal cords 446 SERUMS, VACCINES, ETC. of the infected rabbits dried for dififerent periods of time and preserved in glycerin. For use, this material is emulsified in physiologic saline solution and injected into the subcutaneous tissue of the anterior abdom- inal wall to develop an immunity to rabies before the normal incubation period of the disease is concluded. As the individual dose should be prepared shortly before injection, the material is usually obtained direct from the producer. A list of the laboratories licensed to make antirabic vaccine will be found in N. N. R.* TubercuUnum. — ^Tuberculin, N. N. R. This prod- uct essentially represents the toxins of the tubercle bacillus, and is marketed in a variety of forms, either as a filtered extract of the bacilli or as the pulverized insoluble substance of the dead bacilli themselves. The tuberculins are used in the diagnosis, treatment and prophylaxis of tuberculosis; a number of the more widely used or more prominent forms are enumerated in N. N. R. Tuberculin is of value principally as a diagnostic agent. The characteristic properties of the trade product to be used should be studied closely before it is employed. Serum Antidiphthericum. — Antidiphtheric Serum, Diphtheria Antitoxin,' U. S. P., a fluid separated from the coagulated blood of the horse immunized through the inoculation of diphtheria toxin. Anti- diphtheric serum is now being marketed in the form of the normal serum, the purified serum or antidiph- theritic globulins, and the dried serum. It is required that the potency of these products shall be stated in terms of the standard unit established by the United States Public Health Service. Diphtheria antitoxin has the power of combining with, and of neutralizing the toxin formed by, the diphtheria bacillus. The important object in the administration of the antitoxin is to give it early enough and in sufficient dosage to nullify the toxin as it is produced. For the average case of diphtheria, it is customary to administer 10,000 units of antitoxin subcutaneously, as soon after the discovery of the ♦ Facts and Problems of Rabies (Hyg. Lib. Bull. 65, U. S. P. H. S.) will be found interesting. SERUMS, VACCINES, ETC. 447 disease as possible. For cases more than twenty-four hours after onset, or cases already well developed or which seem to be of a virulent, rapidly spreading type, this dose must be materially increased. Serum Antitetanicum. — Antitetanic Serum, or Tetanus Antitoxin, U. S. P., a fluid separated from the coagulated blood of the horse actively immunized against tetanus toxin. Its physical properties are similar to those of diphtheria antitoxin, and like the latter, it is being marketed in the form of normal serum, purified serum or antitetanic globulins and dried serum, all of which are labeled to show the number of standard antitoxin units as defined by the United States Public Health Service. Tetanus antitoxin is used chiefly as a prophylactic in connection with deep or lacerated wounds, espe- cially those exposed to dust or dirt. The antitoxin may be administered subcutaneously or may be intro- duced directly into the wound, in the form of the dried serum, as a part of the dressing, or both. As a curative agent, in the developed disease, it is gen- erally agreed that the antitoxin should reach the nerve centers as quickly as possible and in as high a concen- tration as possible; therefore, intraspinal injection is usually employed. As a prophylactic agent, antitetanic serum is admin- istered in doses of 1,500 units, injected subcuta- neously, and repeated in twenty-four hours if thought necessary. As a curative agent, it is administered in doses of 5,000 units intraspinally, or 10,000 units intra- venously, to be repeated subcutaneously as indicated. Vaccinum Typhosum. — Typhoid Vaccine, N. N. R., prepared from Bacillus typhosus, with or without the addition of Bacillus paratyphosus A and Bacillus para- typhosus B. Typhoid vaccine is of recognized utility in the prevention of typhoid fever. The immunity produced may persist from two to four years or longer. It is also of service in the treatment of typhoid car- riers, though its use in the treatment of typhoid fever itself has given very inconclusive results. As a preventive, typhoid vaccine should be adminis- tered only to healthy persons. The initial dose usually 448 SERUMS, VACCINES, ETC. represents 500 million bacilli, and is followed in from seven to ten days by a second injection representing approximately 1,000 million bacteria. Some authori- ties recommend that a third injection of the same size be given in from seven to ten days after the second. Vaccinum Staphylococcicum. — Staphylococcus Vac- cine, N. N. R., may be prepared from Staphylo- coccus aureus, Staphylococcus pyogenes albus, or Staphylococcus pyogenes citreus, or from all three. Staphylococcus vaccine is used in carbunculosis, fur- unculosis, sycosis and certain cases of acne, as a cura- tive agent. An autogenous vaccine is usually con- sidered to be preferable, but if this cannot be pre- pared, it is desirable to at least determine the nature of the infection by bacteriologic examination. For the initial dose, it is customary to administer the equivalent of from 200 to 500 million organisms, followed by double this dose in from seven to ten days. INDEX PAGE Acacia and mucilage of acacia 389 Acetaldehyd 122 Acetanilid 83, 87, 88 Acetanilid, antipyrin and phenacetin group 83 Acetic acid 404, 417 Acetphenetidin 83, 87, 88, 89 Acetyl-salicylic acid 149, 156, 159 Acids 416 Acidum benzoicum, boricum, etc.; see Benzoic acid. Boric acid, etc. Aconite 240, 244, 245, 247 Aconitin 240 Adeps 390 Adrenalin; see Epinephrin. Aether; see Ether. Aethylis chloridum; see Ethyl clilorid. Agar-agar 305, 306 Alcohol 92, 100, 102, 237 Aldehyds 122 Alkalies 418 Aloes 280, 282, 284 Aloin 281 Alum 393 preparations 397 Aluminum acetate solution. . . .*. 394 Alypin 138 Ammonia, aromatic spirit of 329 liniment 401 Ammoniated mercury 182 Ammonium acetate solution 263, 264 carbonate 328 chlorid 327, 328 Amyl nitrite 237, 242, 244, 246 Amylura 389 Analgesics 72 Anesthetics, general ; . 103 local '. 128 Anthelmintics 438 Anthracene derivatives 279 Antidiphtheric serum 446 Anti-emetics 321 Antimony 344 Antimony and potassium tartrate 313, 318, 320 Antipyretics 72 Antipyrin 83, 86, 87, 88, 89 Antirabic vaccine 445 Antiseptics and disinfectants 141 Antitetanic serum 447 Antithyroid preparations 428 Aspidium 440, 443, 444 Apomorphin and apomorphin hydrochlorid 54, 68, 314, 318, 320 Appetite, substances used to influence 429 Aqua camphorae 46 450 INDEX PAGE Aqua hydrogenii dioxidi 174 Argenti nitras 166 Aristol 152, 162, 167 Aromatic elixir , 102 Arsenic 330 preparations 342 Arseno-benzol 337 Aspirin 83, 87, 88 Astringents 390 Atophan 149, 156, 160 Atoxyl 341 Atropin and atropin sulpiiate 26, 39^ 301 Balsam of copaiba 165, 166 of Peru 178, 180, 181 of Tolu 329 Belladonna 34 preparations 40 Benzene, derivatives of 143 Benzoates 149 Benzoic acid 146, 149, 160 Benzoinated lard 390 Betanaphthol ; 152, 157, 162 Bile 306 Bismuth salts 387, 388, 390 Bitters 428 Blue mass , 287 Blue ointment 182 Blue vitriol 320, 398 Borax 175, 177 Boric acid 175, 177, 390 acid ointment 177 Bromids 409 Cacodylic acid '. 336 Cailein 46, 49, 50, 234,257 group 46, 252 preparations 51 Calcium 406 clilorid 408 liypophosphite . . . , .• 353 lactate 408 oxid 172 Calomel 258, 287, 289 Calx 172 chlorinata 168, 172 Camphor 43, 45, 235 liniment 401 Camphorated oil 401 Cannabis indica 66 Cantharides and cantharides cerate 402 Cantharidin 402 Capsicum 431 tincture of 432 Carbo lisni 178 Carbolic acid 143, 154, 155, 157, 158 Carbon dioxid snow 140 Cardamom, tincture of 432 Carminatives, aromatic 430 Cascara sagrada 280, 281, 283, 284 Cassia, oil of ■. 175 Castor oil 272, 273 INDEX 451 PAGE Catechu 392 Cathartics 266 Caustics ■ 403 Cephaelin 312 Chamomile 430 Charcoal 178 Chenopodium, oil of 442, 443, 444 Chloral 117 hydrated 117, 123, 124, 125 Chlorinated lime 168, 172 soda (and solution) 172 Chloroform 112, 115 and ether group 103 liniment 401 Cholagogues 306 Chrysarobin '. 179, 180, 182 Cinchona SO Cinchonidin 78 Cinnamon, oil of 175, 431, 432 Circulatory depressants, diuretics and diaphoretics 236 Citric acid 417, 418 Cloves, oil of 175, 431, 432 Cocain 128, 133, 135, 137 hydrochlorid 137 substitutes 138 Codein 64, 67 preparations 69 Cod liver oil 434, 435 Colchicein 247 Colchicin .' 247, 249 Colchicum 247, 248, 249 Colocynth ' 275, 277 preparations 278 Copaiba ^ 165, 166 Copper sulphate 312, 318, 320, 394, 398 Copperas 169, 173 Corn starch 389 Corrosive sublimate 170, 173 Corrosives 402 Creosote : 151, 156, 161 Cresol 156, 160 Cresol, compound solution of 160 Cresols 150 Croton oil 272, 273, 274 Demulcents 383 Depressants, circulatory 236 of central nervous system 53 Dermatol 390 Diacetyl-morphin 66, 67 hydrochlorid 70 Diaphoretics 260, 262 Diethyl-barbituric acid 122, 123, 126 Digalen 233 Digestion, substances used to influence 429 Digipoten : 233 Digipuratum 233 Digitalis 214, 225, 227 preparations 231 Diluents '. 437 Dionin 65, 70 4S2 INDEX PAGE Diphtheria antitoxin 446 Disinfectants and antiseptics 141 general 166 miscellaneous 169 used in skin diseases 178 Diuretics 249 Donovan's solution 342 Dover's powder 64, 69, 263, 264 Effervescing powder, compound 299 Elaterin 275, 277, 278 Elixir aromaticum 102 Emetics 308 Emetin and emetin hydrochlorid 312, 320 Emmenagogues 211 Emollients 40, 177, 182, 183, 383 Emplastra; see names of drugs. Epinephrin 184, 190, 193, 194 Epsom salt 139, 292, 295, 296, 297 Ergot and fluidextract of ergot 200, 206, 207 Ergotoxin 201 Erythrol tetranitrate 243 Ether 112,114 and chloroform group 103 Ethyl chlorid 114 morphin hydrochlorid 65, 70 Eucalyptol 175 Eucalyptus, oil of 175 Euquinin 82 Evacuants 266 Expectorants 325 Extracts; see names of drugs. Ferric chlorid, tincture of 394, 398 Ferrous sulphate 169, 173 Ferrum ! 361 Flavors 437 Flaxseed 387, 389 Fluidextracts; see names of drugs. Formaldehyd 168, 172 Gambir 392 Gastric sedatives 321 Gentian and gentian preparations 430 Ginger and tincture of ginger 431, 432 Glauber's salt 296, 297, 303 Glonoin (nitroglycerin) 238, 243, 245, 246 Glycerin (glycerol) 303, 390 Glycerite of boroglycerin 177 of tannic acid 397 Glycerophosphates 350 Glyceryl nitrate (trinitrate, nitroglycerin) 238, 243, 245, 246 Guaiacol 151, 156, 161 carbonate 161 Halogen derivatives 116 Halogens and their combinations 167 Heroin 66, 67 hydrochlorid 70 Heart, drugs which act mainly on 214 Hemorrhage 191 Hexamethylenamin 163, 165 Homatropin 29 hydrobromid 39 INDEX 4S3 PAGE Hydrargyrum; see Mercury and Mercurials. Hydrastin 209 Hydrastinin 209 Hydrastis and fluidextract Hydrastis 208, 210 Hydrochloric acid 432, 434 Hydrocyanic acid 323 Hydrogen peroxid 171, 174 Hyoscyamus 35, 41 Hypnotics 115 Ichthyol : 395, 398 Indian cannabis 66 lodids 412, 415 lodin 171 tincture of 401 Iodoform 167, 172 lodotbymol 167 Ipecac 311, 317 and opium 64, 69, 263, 264 preparations 319 Iron .'. 361 preparations , . , . 367 Irritant diuretics 251 Jalap and compound powder of jalap 275, 277, 278 Kairin 83 Kino 392 Krameria 392 Labarraque's solution 172 Lanolin 390 Lard 390 Laxatives 266 Lead 355 acetate 393, 397 and opium wash . .- 393 subacetate solution 397 Lecithin 350 Lime 172 chlorinated 168, 172 liniment 389 water 395, 408 Liniments: see names of drugs. Linseed 387, 389 Liquores; see names of drugs. Lithium 405 ' Lobelia and tincture of lobelia 41, 42, 43 Lunar caustic 403, 404 L-suprarenin synthetic 184 Magnesium carbonate 294, 296, 298 citrate and solution 293, 297, 299 oxid 294, 296, 298 sulphate 139, 292, 295, 296, 297 sulphate, effervescent 297 Malo-urea; see Veronal. Medinal (sodium diethyl barbiturate) 123, 126 Menthol 139 Mercurial evacuants 287, 289 ointment 181, 182 Mercuric chlorid 170, 173 454 INDEX PAGE Mercury 369 ammoniated and ammoniated mercury ointment 182, 183 preparations . . . .* 291, 379 Metals, heavy, and their salts 354 Methyl salicylate 156, 158 Milk sugar 437 Mindererus, spirit of .'.263, 264 Morphin 53 and opium 64 preparations 68 and scopolamin 70 Mucilage of acacia 389 Mustard 431 preparations 403 Naphthol 152 Narcotics, hydrocarbon 90 Neosalvarsan 343 Nervous system, central, drugs which act on 13 Nicotin 303 Nitric acid 404 Nitrites 237 Nitroglycerin and spirit of nitroglycerin 238, 243, 245, 246 Nitrous ether, spirit of 243, 245, 246, 263 Novocain 138 Nux vomica and preparations 24 Oils, evacuant 272 volatile 174 Oleum santali 166 Opium and preparations 68 Orange peel, bitter 430 Orthof orm-new 139 Ouabain, crystalline 230 Oxgall 307 Oxygen 423 compressed-. 424 Pancreatin 432, 433 Paraffin, liiiuid 305 Paraformaldehyd 173 Paraldehyd 122, 124, 127 Pelletierin tannate .441, 443, 444 Peppermint and peppermint preparations 436 Pepsin 432, 433 Petrolatum 390 liquid 305, 306, 390 Phenacetin 83, 87, 88 Phenol 143, 154, 155, 157, 158 liquefied 158 Phenolphthalein 281, 283, 286 Phenyl salicylate 148, 155, 156, 159 Phosphorus 346 Physostigmin and physostigmin salicylate : 300, 301 Picric acid 391, 396, 398 Pilocarpin 261, 263, 264, 300 Pituitary extract 196, 199, 200 Fix liquida 179, 180, 181, 182 Plumbi acetas 397 Plumbum: see Lead. Podophyllum 275, 278 INDEX 4S5 PAGE Potassium acetate 238, 259 arsenite 340 bicarbonate 422 bitartrate 259, 299 bromid 411 carbonate 422 chlorate 394, 398 citrate 259, 294, 297, 299 citrate, effervescent 259, 299 hydroxid and solution 404, 422 iodid 415 permanganate 170, 173 salts 405 and sodium tartrate 296, 299 Powders: see names uf drugs. Protargol 165 Prunus virginiana 329 Pulvera: see names of drugs. Purgatives 266 Quinin 73 preparations : SO substitutes 82 Quinolin 83 Resin anhydrids 274 Resorcinol 179, 180, 182 Rhamnus purshiana 280, 281, 283, 284 Rhubarb : 280, 281, 283, 285 Rochelle salt : 296, 299 Rose and rose preparations 437 Rubefacients 399 Saccharin 435 Salicylic acid and salicylates 146, 155 Salol 148, 155, 156, 159 Saloquinin 83 Salts, miscellaneous 405 Salvarsan 337, 341, 343 Santal oil 165 Santonin . ., 441, 443, 444 Sarsaparilla« compound syrup of 437 Scopolamin and morphin 70 hydrobromid 35, 37, 39 Sedatives, gastric 321 Seidlitz powder 299 Senna 281, 285 Serpentaria 430 Serums 445 Silver nitrate and molded silver nitrate 164, 165, 404 Skin diseases, disinfectants used in 178 Soamin 341 Soap 303, 304 liniment 401 Sodium acid phosphate 298 arsanilate 341, 342 arsenate 341, 342 benzoate 160 bicarbonate 421 borate 177 bromid 412 cacodylate 343 carbonate, monohydrated 422 456 INDEX rAGE Sodium chlorid 294, 296, 297 diethyl barbiturate 123, 126 hydroxid and sodium hydroxid solution 404, 422 iodid 415 nitrite 238, 243, 245, 246 phosphate 295, 297 phosphate, effervescent 298 salicylate 147, 156, 158 sulphate 296, 297, 303 sulphite 179, 183 thiosulphate 183 Spearmint 437 Spirits: see names of drugs. Staphylococcus vaccine 448 Starch 389 Stimulants 14 Stovain 138 Stramonium 41 Strophanthin 230 Strophanthus 232 Strychnin 14, 25, 301, 302 preparations 25 Sugar of milk 437 Sulphonal 120, 123, 124, 126 Sulphonethylmethane 120, 123, 124, 126 Sulphonmethane 120, 123, 124, 126 Sulphur 173, 179, 181, 182, 286 preparations 287 Suprarenalin 184 Sweet birch, oil of 156 Sympathetic endings, drugs which stimulate 184 Tannalbin 397 Tannic acid 397 Tannin 392 Tar and tar ointment 179, 180, 181, 182 Tartar emetic 313, 318, 320 Terpin hydrate 329 Thallin 83 Thebain 53 Theobromin 46, 50, 257 preparations 52 Thymol 152, 157, 442, 443 Thymol iodid 152, 162 Thyroid 424 gland, desiccated 428 Tinctures: see names of drugs. Tolu, syrup of 329 Tonics 429 Tragacanth 389 Trional 120, 123, 124, 126 Tropacocain 138 Tuberculin 446 Turpentine, oil of 175 Typhoid vaccine , 447 Unguenta: see Emollients and names of drugs. Urinary antiseptics and disinfectants 163 Vaccine virus 445 Vaccines 445 Valerian and tincture of valerian 212, 213 Vasodilator diuretics 250 INDEX 437 FAOE Vasodilators 237 .Vehicles 437 Veratrum viride 244 Veronal 122, 123, 126 Veronal-sodium 123, 126 Vesicants 402 Viburnum 212 Viruses 445 Wild cherry 229 Wintergreen, oil of 156 Zinc acetate and zinc chlorid 394, 398 Zinc oxid 387, 390 Zinc stearate 387, 390 Zinc sulphate 312, 318, 320, 394, 398