Class Book. 0*s OopightN . COPYRIGHT DEPOSIT. \ HANDBOOK OF PHARMACOLOGY BY CHARLES WILSON GREENE A.B., A.M\, Ph.D.' PROFESSOR OF PHYSIOLOGY AND PHARMACOLOGY, UNIVERSITY OF MISSOURI ; MEMBER AMERICAN ASSOCIATION OF ANATOMISTS, AMERICAN PHYSIOLOGICAL SOCIETY, SOCIETY OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS; FELLOW OF THE AMERICAN ASSOCIATION FOR THE AD- VANCEMENT OF SCIENCE ; ASSOCIATE OF THE AMERICAN MEDICAL ASSOCIATION, ETC., ETC. WITH SEVENTY ILLUSTRATIONS. INCLUDING MANY NEW AND IN COLORS NEW YORK WILLIAM WOOD AND COMPANY MDCCCCXIV .Q-7 Copyright, 1914 By WILLIAM WOOD & COMPANY OCT 14 1914 THE QUINN & BOOEN CO. PRESS RAHWAT, N. J. (U380862 PREFACE The time has arrived in the differentiation of the teaching of medicine when the demarcation line should be more sharply drawn between those courses presenting to the student the scientific prin- ciples underlying the action of medicinal agencies and that phase of his training which deals with the practical use of medicaments in the alleviation of diseases. A parallel, illustrating the matter, can be drawn from the relations- of the subjects of Physiology and Pathology. Physiology undertakes to present the underlying principles govern- ing the reactions of the normal living body. Pathology deals with the reactions of the living body, but under conditions which we loosely classify as diseased, i.e., the reactions of the body when out of normal relations. Both treat of functions, but the two subjects are separated by the inherent nature which classifies one as normal functions, the other as pathological, a line which, of course, cannot be sharply drawn. Just so is it with the broad subject which deals with the reactions of the living body to drugs. The principles underlying this field are best presented from the standpoint of the reactions of the normal body to drugs and drug agents, which is the peculiar province of Pharmacology. The term Therapeutics, in the restricted sense, ought to apply only to that phase of the subject which deals with the reactions of the diseased body to drugs and drug agencies. These two phases of the broad field of Pharmacology and Therapeutics are, of course, intimately related, just as are Physiology and Pathology. And in the pedagogy of medical education they should be kept in their proper sequence, but should be presented in distinct and consecutive courses, as in the instance of Physiology and Pathology. Medical students should have placed in their hands a Textbook on Pharma- cology without being burdened and confused by a mass of matter on practical Materia Medica and Therapeutics while they are getting the principles of the subject of Pharmacology. The desire to carry forward this idea in meeting an organization which has already been well established in the medical curricula of our best schools has led to the presentation of this Textbook. Courses in Pharmacology have been organized along two lines: One represented by that splendid old Textbook on Therapeutics and PREFACE Pharmacology, by George B. Wood, which ran so many editions in the hands of his descendants. This is typical of the group which classifies the drugs primarily according to the physiological symp- toms they induce in the body. This classification, which characterizes a number of pharmacologies of the present, has in an introductory course the pedagogical disadvantage of presenting a confusing array of new facts to the student each time he shifts from one general topic to another. For example, under the chapter on Cardiac Stimu- lants, the student is suddenly brought face to face, not only with the great number of drugs, new and strange to him, which have this characteristic action on the cardiac apparatus, but he must correlate their actions throughout other parts of the body, making the problem doubly complicated. The other type of Textbook, of which Cushny's classical Phar- macology and Therapeutics is our best example, bases the organiza- tion on the twofold nature of pharmacological agencies, viz., the chemical relations of the drugs and the characteristic physiological reactions of particular groups. No method can be strictly logical in presenting such a wide range of facts without involving wasteful repetition. But Cushny 's method has the pedagogical advantage which may be illustrated by the subject of strychnine. Here the student is presented with the characteristic actions of a single new drug typical of a group. But he is asked to trace the reactions over the entire body with the physiology of which he is assumed to be familiar. In short, the student is asked to establish the scientific relations of a new substance or a group of substances within an organism with which physiology has already given him a working acquaintance. In gathering the material for this book, use has been made of the literature of physiology, pharmacology, and therapeutics to the extent called for in the presentation of the underlying principles of the subject. Recognizing that even the most elementary student often desires fuller detail of some phase of the subject, and that the teacher needs a ready reference to sources in the literature used to support given principles, a few references to original sources have been inserted as footnotes. The articles so referred to are, in the main, those which present reviews of the literature or through which the literature may become available. No attempt has been made to give exhaustive reference lists. Free use has been made of the stand- ard textbooks and encyclopedias of the subject, to the authors of which the writer expresses his particular obligation. It is hoped that the number of figures introduced from the litera- PREFACE v ture and from experiments in our own laboratories will be of special aid to both the student and the teacher. They are presented as standards for comparisons in laboratory experimental work as well as for the purpose of elucidating the subject matter of the text itself. For many of these illustrations I am especially indebted to my own students, to whom I here make grateful acknowledgment. Chas. W. Greexe. Columbia, Missouri. September 10, 1914. CONTENTS Chapter I.— GENERAL CONSIDERATION: PAGE Introduction and Definition — The Nature of the Action of Drugs — Relation of Pharmacological Action to Chemical Composition — Physiological Factors Modifying Pharmacological Responses — Nature of the Change Induced by Drugs in the Pharmacological Actions of the Body — The Method of Application of Drugs as Modifying the Changes in Pharmacological Activity — Changes Produced in the Reactive Power of the Individual by the Continued Application of the Drug — Summation and Tolerance — Pharma- cologic versus Therapeutic Action — The Fate of Drugs in the Body 1-18 PART I. ORGANIC DRUGS. A. General Depressant Series. Chapter II.— THE ALCOHOL GROUP: Introductory and Chemical — Alcohol as a Local Irritant : on the skin ; on the mucous membrane of the mouth and stomach; the action of alcohol on the central nervous system; explanation of the nervous symptoms; action on the nervous system of lower animals; dura- tion of the effects on the central nervous system; action on the muscular tissue, on the heart and circulatory system, the respira- tory system, on the digestive tract; the liver in relation to alcohol oxidations; alcohol on metabolism; the elimination of alcohol; the effects of the repeated use of alcohol on the germ-plasm and fer- tility; alcohol habit and disease — Summary 19-38 THE ANESTHETICS. THE ETHER-CHLOROFORM GROUP. Chapter III.— ETHER: Historical — Outline of the General Action of Ether: stages of anes- thetic effects — Details of the Action of Ether: on the central nerv- ous system, on the respiratory center, on the circulatory system and blood-pressure, on voluntary muscle, on the alimentary canal; the absorption, distribution, and execretion of ether — Summary . :}0-49 Chapter IV.— CHLOROFORM: Details of the Action of Chloroform: stages of anesthetic effects: on the central nervous system, on the circulatory system, on the heari ; chloroform on the voluntary muscles, on the alimentary canal; tin- absorption of chloroform; the execretion of chloroform — Sum mary 50-57 Chapter V.— NITROUS OXIDE: Historical and General — Nitrous Oxide on the General Activities of the Body — The Administration of Nitrous Oxide ... 58-62 vii viii CONTENTS Chapter VI.— CHLORAL HYDRATE: PAGE Historical and Chemical — Pharmacological Action : the general symp- toms; chloral hydrate on the nervous system 63-65 Chapter VII.— MORPHINE AND THE OPIUM SERIES: Historical and Chemical — Outline of Pharmacological Action — Details of Action: on the central nervous system, the circulatory system; reactions of the heart and its nervous mechanism; normal move- ments of the stomach and of the intestine; action of morphine on the stomach and intestine; morphine on the eye, on the frog; morphine on metabolism — Action of Codeine, Papaverine, Thebaine, and Heroin — Excretion of the Morphine Group — The Abuse of Opium — Summary 66-83 Chapter VIII.— APOMORPHINE AND APOCODEINE: Historical and Chemical — Outline of Action — Details of Action : on the central nervous system; depressant action on muscular tissue; apocodeine on nervous structures, on the alimentary canal and urinary motor system; apocodeine in support of pharmacological investigation — Irritant Emetics 84-88 B. General Stimulating Series. Chapter IX.— THE CAFFEINE GROUP: Historical and Chemical — Outline of Pharmacological Effects — Details of effects of caffeine: on the central nervous system, the spinal cord, the medulla; action on skeletal muscle, on the circulation: the cardiac mechanism; the vasomotor apparatus; on the respira- tory mechanism; caffeine on metabolism; diuretic action; absorp- tion and excretion — Summary 89-95 Chapter X.— THE STRYCHNINE GROUP: Chemical and Historical — Outline of Action — Details of Action: on the spinal cord, the medulla, on respiration, on the circulation, on skeletal muscle; action on the special sense organs, on the ali- mentary canal, on metabolism; excretion — Strychnine Poisoning — Brucine — Summary 96-106 C. Drugs with Specific Action for Peripheral Parts of the Xcrrous System. Chapter XI.— THE CURARE GROUP: Historical and Chemical — Outline of Action — Details of Action: on the motor nerve endings, on peripheral ganglia; absorption from the stomach — Comparison with Related Drugs .... 107-111 Chapter XII.— THE ATROPINE SERIES: Historical and Chemical — Outline of Pharmacological Action — Details of Action: general symptoms; action on the central nervous system: specific action on the eye; specific action on glands, on the circula- tory system, on the alimentary canal, the stomach, and the in- testine, on the bladder and uro-genital apparatus; excretion — Sum- mary 112-121 CONTEXTS ix Chapter XIII.— THE PILOCARPINE, MUSCARINE, PHYSOSTIG- MINE GROUP: I. PILOCARPIXE. pAGE Historical and Chemical — Outline of Action — Details of Pharmacolog- ical Action : on glands, on the circulatory apparatus, the heart, the blood-vessels, on the respiratory tract, on the central nervous system, the alimentary tract; action of pilocarpine on the iris and the ciliary mechanism of the eye — Summary. II. MUSCARINE. Historical and Chemical — Outline of Action — Details of Action : on the heart and circulatory system, on blood-pressure, on the glands and the alimentary tract, on the eye. III. PHYSOSTIGMIXE OP ESERINE. Historical and Chemical — Outline of Pharmacological Action — Details of Action: on the eye, on the circulatory apparatus, on striped muscle; physostigmine on the muscles of the stomach and intes- tines, on the central nervous system — Summary: comparison of the pilocarpine group 122-135 Chapter XIV.— THE NICOTINE SERIES: Historical and Chemical — Outline of Pharmacological Action — Details of Pharmacological Symptoms — Action: on the central nervous system, the cerebral cortex and medulla, the spinal cord; nicotine on peripheral ganglia, on the circulatory system, on cardiac muscle; the local nervous apparatus of the heart; the vasomotor system; on the glandular apparatus; the action of nicotine on the eye, on the alimentary canal; excretion — The Xicotine Habit: tolerance . 136-146 Chapter XV.— THE CONIINE, SPARTEINE GROUP: I. CONIINE. Historical and Chemical — Outline of Action — Action: on the central nervous system, on the autonomic nervous system, on voluntary motor nerve endings, on the circulatory apparatus, on the respira- tor}* movements; excretion of coniine. II. PYRIDINE AXD PIPERID1XE; III. LOBELINE; IV. GELSEM- IXIXE; V. SPARTEINE ... 147-151 Chapter XVI.— EPINEPHRINE: Historical and Chemical — Outline of Pharmacological Action — Details of Action: on the nervous system: epinephrine on blood-pressure, on the heart, the salivary glands, on gastric and intestinal move- ments, on the eve; adrenaline on the urogenital apparatus, on the eye; glycosuria — General Discussion of Epinephrine — Sum- mary 152-164 Chapter XVII.— THE ERGOT SERIES: Eistorical and Chemical — Outline of Action — Details of Pharmacolog- ical Action of chemically pure principles; ergotoxine; isoamyla- mine; parahydroxy phenylethylamine ; extracts of ergot; ergol on the uterus, on the circulatory Bystem. the heart, on the alimentary canal; effect of ergot on other physiological mechanisms . 166 17:> x CONTENTS D. Drugs with Primary Activity on Smooth Muscle. Chapter XVIII.— BARIUM CHLORIDE: PAGE Outline of Pharmacological Action — Action: on the circulatory system, on the heart, on the peripheral arterioles, on other smooth muscle, skeletal muscle, the central nervous system; local action of barium salts; therapeutic indications 174-177 Chapter XIX.— THE NITRITES AND THE NITRO-GLYCERINES: Chemical — Outline of Action — Action : on the circulatory system, the heart, on the respiratory apparatus ; formation of methemoglobin — Summary 178-180 E. Glucosides of the Digitalis Series. Chapter XX.— THE DIGITALIS GROUP: Historical and Chemical — Outline of Action — Details of Action: on the circulatory system, the heart, on the peripheral arterioles; digitalis on the central nervous axis, as a diuretic; local irritating effect — Cumulative Action — Summary. Bufonine and Buf otaline — Chemical — Action : on the frog's heart, on the mammal, on blood-pressure and the pulse .... 181-104 Chapter XXI.— THE SAPONIN AND SAPOTOXIN GROUP: Historical and Chemical — Sapotoxin: as an irritant; toxic systemic effects; general saponin symptoms; solanin 195-196 F. Drugs, Chiefly Alkaloids, that Primarily Influence General Metabolism. Chapter XXIL— HYDROCYANIC ACID: Chemical — Outline of Action — Details of Action: on the central nervous system, on respiration, the circulatory system; metabo- lism 197-200 Chapter XXIII.— ACONITE: Historical and Chemical — Outline of Action: the systemic action; aconite on the central nervous system, the circulatory system, the blood-vessels, on the glands, as an antipyretic . . . 201-205 Chapter XXIV.— VERATRINE: Historical and Chemical — Outline of Pharmacological Action: vera- trine on sensory and nervous mechanisms, on skeletal muscle, heart muscle, smooth muscle 206-209 Chapter XXV.— COLCHICINE: Chemical: general systemic and toxic effects; colchicine on the white blood corpuscles 210-211 Chapter XXVI.— EMETINE: Chemical — Details of Action — Systemic Actions 212 COXTEXTS xi G. Drugs Poisonous to General Protoplasm. Chapter XXVIL— COCAINE: PAGE Historical and Chemical — Outline of Pharmacological Action — x^ction : on the central nervous system; cocaine on the circulatory system, the peripheral blood-vessels, on the heart, on skeletal muscle; cocaine on the eye; elimination of cocaine; local and anesthetic action; the cocaine habit — Substances which produce anesthesia similar to cocaine: tropacocaine, eucaine, stovaine, holocaine, novocaine — Summary 213-221 Chapter XXVIII.— QUININE: Historical and Chemical — Outline of Action — Details of Systemic Action: action on undifferentiated protoplasm; quinine as an anti- pyretic; action on muscle, on the digestive tract and digestion, the liver, the central nervous system ; elimination of quinine — Summary 222-230 H. The Coal Tar Series. A. Chapter XXIX.— THE COAL TAR ANTIPYRETICS: Historical and Chemical: the general antipyretic action; action of the antipyretics on the central nervous system, on the circulation; variations in susceptibility; comparison of acetanilide, antipyrine, and acetphenetidine 231-236 B. Chapter XXX.— THE COAL TAR ANTISEPTICS: Historical and Chemical — Outline of Pharmacological Action of the Coal Tar Antiseptics. I. THE PHENOLS. Toxicity to protoplasm: on the central nervous system, the circulatory system; the excretion of carbolic acid; toxicology; summary. II. SALICYLIC ACID AND THE SALICYLATES. Toxicity to general protoplasm; action on the central nervous system, on the circulatory system, on the alimentary canal; antipyretic action; acetyl-salicylic acid; summary 237-247 I. Internal Secretions. Chapter XXXI.— THE THYROIDS AND PARATHYROIDS: General Introduction — Internal Secretions of the Thyroid and Para- thyroid Glands. A.— THE THYROID AND THYROIODIN. Historical and Chemical — Outline of Action: effects of the removal of the thyroids; engrafting of thyroid and parathyroid tissue; interrelationship of the thyroids and the parathyroids; feeding of the thyroid tissue and of thyroiodin. B.— PARATHYROIDS. Systemic phenomena following removal of parathyroids; metabolism after parathyroidectomy; theoretical 24 xii CONTENTS Chapter XXXII.— THE PITUITARY GLAND AND THE HYPOPH- YSIS: PAGE Anatomical — Outline of Pharmacological Action — Details of Pharma- cological Action. A.— PITUITARY GLAND. Changes in metabolism following removal of the pituitary; administra- tion of pituitary; clinical evidences from atrophy and hypertrophy of the pituitary; interrelation of the pituitary and other organs.' B.— HYPOPHYSIS. Influence of the hypophysis on the functions of nerve structures, the heart, on smooth muscular structures; hypophysin . . . 255-258 J. Irritants and Counter Irritants. General Introduction. Chapter XXXIIL— THE BACTERIAL TOXINS: Historical and Introductory: nature of the irritant action; the inflam- matory process a physiological response to irritant action; action of bacteria and bacterial toxins; characteristics of toxins; type of toxin action; antitoxins; specificity of toxins .... 259-267 Chapter XXXIV.— IRRITANTS OF THE EXTERNAL SKIN: Introductory — Outline of Action : permeability of the skin to certain irritants; acute inflammation; action of the volatile oils; toxic glucosides of the mustard series; cantharidin .... 26S-273 Chapter XXXV.— THE VEGETABLE CATHARTICS. IRRITANTS AFFECTING THE ALIMENTARY CANAL: Introduction — Outline of Pharmacological Action : nature of the reaction by which the vegetable purgatives produce catharsis; action at the point of contact; action after absorption; the anthracene group; the jalap group; the neutral oil series . . 274-281 Chapter XXXVI.— COUNTER IRRITANTS AND THE PHENOM- ENON OF COUNTER IRRITATION: The theory of counter irritation; conditions which suppress counter irritation; the practical application of counter irritants; counter irritant agents 282-287 PART II. INORGANIC DRUGS. K. Drugs Characterized to Greater or Less Extent hi/ Salt Action. Chapter XXXVII.— UNDERLYING PRINCIPLES OF SALT ACTION: Underlying Principles of Salt Action — Genera] Considerations of the Physical and Chemical Characteristics oi Salts in Solution — Crystalloids and colloids; dissociation; electrolytes-, freezing poinl depression; osmotic pressure and osmosis .... Chapter XXXVIII.— WATER: Action of distilled water on isolated tissues; drinking water; mineral waters; the influence of water on metabolism and on the kidney 294-296 CONTENTS xiii Chapter XXXIX.— ISOTONIC PHYSIOLOGICAL SOLUTIONS: PAGE Physiological saline; perfusions of physiological salines; Ringer's solu- tion; Locke's solution; sera and lymphs; summary . . . 297-303 L. Detailed Action of Salts Normal to the Body Pluids and of Their Chemical Relatives. Chapter XL.— THE SODIUM-POTASSIUM GROUP, INCLUDING THE CHLORIDES, BROMIDES, IODIDES, SULPHATES, NI- TRATES, ETC.: The Sodium Salts: sodium chloride, the bromides, iodides, sodium nitrate, sodium sulphate, sodium phosphate — Potassium Salts — Ammonium Salts: on secretion; on the nervous system; excretion — Lithium, Rubidium, and Cesium Salts 304-309 Chapter XLL— THE SALTS OF THE CALCIUM-MAGNESIUM GROUP, IN COMBINATION WITH VARIOUS ANIONS: Calcium Salts: in relation to the heart; in the coagulation of blood; on nerve tissue; on metabolism; excretion — Magnesium Salts — Barium and Strontium 310-314 Chapter XLIL— THE SALINE CATHARTICS: Nature of the Action of the Saline Cathartics: sodium sulphate; sodium potassium tartrate; magnetism sulphate; the saline cathartics as enemas 315-323 Chapter XLIII.— ALKALIS AND ACIDS: Alkalis: the cauterizing action of the alkalis; the physiological action of the alkalis — Acids: the action of dilute acids .... 324-328 Chapter XLIV.— OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC.: Oxygen : effects of increase of oxygen — The Peroxides . . . 329-332 Chapter XLV.— THE SALTS OF THE HEAVY METALS: The general reactions of salts of heavy metals; absorption of salts of heavy metals; distribution and excretion of the heavy metals in the body 333-337 Chapter XLVL— IRON: The normal relations of iron in the body; absorption of iron; iron- protein compounds; astringent action 338-340 Chapter XLVIL— SULPHUR AND THE SULPHUR COMPOUNDS: Action of sulphur, sulphides, sulphates; the organic sulphur com- pounds 341-342 Chapter XLVIII.— PHOSPHORUS AND THE PHOSPHORUS COM- POUNDS: Historical — Outline of Pharmacological Action — Action: <»t' phos- phorus as a genera] protoplasmic poison; fatly degeneration after phosphorus poisoning; action on the skeletal structures; the in- organic phosphates; organic phosphorus compounds . 343-349 xiv CONTENTS Chapter XLIX.— ARSENIC AND ANTIMONY: PAGE A. Absenic. — Introductory — Outline of Action: general toxicity of arsenic compounds; on the circulatory system; arsenic on the alimentary tract; metabolism; excretion of arsenic — Organic and Synthetic Arsenic Compounds: the arsanilates; salvarsan. B. Antimony. — The irritant action of antimony 350-356 Chapter L.— LEAD SALTS: Historical and Chemical — Outline of Action: the general toxic action of lead salts; chronic lead poisoning; lead on the digestive tract; excretion of the lead by glands; excretion of lead by the kidneys: reaction on the circulatory system, on the nervous system; mus- cular effect 357-363 Chapter LL— ZINC SALTS: General toxic and disinfectant action of copper salts; the local action; the systemic action of zinc 364-365 Chapter LIL— THE SALTS OF COPPER: General toxic and disinfectant action of copper salts; systemic action of copper; the elimination of copper salts 366-367 Chapter LIIL— THE MERCURY SALTS: Chemical — Outline of Pharmacological Action — Details of Action: the absorption of mercury; action on bacteria, on differentiated animal protoplasm, on the alimentary tract, on the central nervous system, on the circulatory and respiratory systems; mercury on the kidney; excretion of mercury; chronic poisoning . . . 368-375 Chapter LIV.— SALTS OF SILVER: The local and antiseptic action of silver salts; the toxic action; sys- temic effects "376-377 Chapter LV.— SALTS OF BISMUTH: The action of soluble bismuth compounds; the action of insoluble bismuth salts 378-380 APPENDIX 381-386 CHAPTER I. PHARMACOLOGICAL FACTORS OF GENERAL BEARING Introduction. Pharmacology is the science which treats of changes in the physiological actions of normal living organisms induced by chemical or physical-chemical agencies. It must be understood that the word has often received a wider range of application in the literature, especially by the older writers. The term Pharmacology has been used synonymously with the term Materia Medica in its broader sense, also to designate the broad field of actions induced in patho- logical as well as in normal organisms. The present tendency in these days of specialization is to restrict the boundary of the field. In this book the term pharmacology is used in the restricted sense expressed by the definition just given. Pharmacology, from this point of view, is not limited by any question of utility or application in the art of healing. It is quite immaterial whether a given agency be destructive of life, or of aid in maintaining life. If the agency is one that primarily influences the otherwise normal physiological processes, inducing reactions that are characteristic and constant, then it belongs to the field of phar- macology. No sharp and all-inclusive boundary can be set around pharma- cological agencies. Schmiedeberg has given a classical definition in which he specifically excludes substances capable of assimilation. Yet many recognized food materials have a decided influence on the normal reactions of the living body. They may be primarily nutritive, yet at the same time they produce changes in the physiological func- tions over and above those of simple nutrition, hence to that extent are pharmacological in nature. Also, many chemical agencies, which are well recognized as of the pharmacological group, for example alcohol or strychnine, are oxidized in the body and thus yield energy, and are to that extent nutritive, therefore foods. Nutritive processes and those of the type indicated as pharmacological shade from the one to the other so that no sharp dividing line can be drawn. 2 PHARMACOLOGICAL FACTORS Pharmacological agencies are, for the chief part, chemicals, i.e., drugs. Many of these chemicals are of practical value in disease. The art of the application of drugs in the modification of the processes of disease with the purpose of recovering the normal functions is known as therapeutics. This term also is used with widely varying meanings by different writers. Occasionally the word therapeutics is given the meaning which includes pharmacology as outlined above and vice versa. The term drugs should be restricted to designate chemicals of therapeutic value. In the restricted interpretation of the relations of this field pharmacology deals with the physiological action of chemicals on the normal body while therapeutics deals with the action of drugs on the diseased body. In therapeutics chemi- cal agencies are used for the purpose of recovering the normal, i.e., in the art of healing. In pharmacology, on the other hand, the whole intent of investigations and procedures is for the scientific purpose of unfolding the reactions induced. That the net results of pharma- cological investigation may or may not yield a body of facts of positive utility is wholly a secondary consideration, though in presenting the subject from the standpoint of the undergraduate medical student it is the commendable practice to choose those materials and drugs which are of most importance in the practice of the art of healing. If the action of the drug is destructive of the living organism it is said to be a poison. The science which deals with the limited field of drugs with poisonous action is termed toxicology. It is a subdivision of pharmacology. Formerly much attention was given to the source and preparation of drugs. These subjects are now of primary interest, chiefly to the manufacturer and professional pharmacist. The present tendency is to eliminate them from other than secondary consideration under the subject of pharmacology. However, the definitions and limita- tions of these subjects may be given here for the sake of a fuller understanding of the general field. Materia Medica deals with the origin, preparation, and composition of drugs. As many of the active drugs are derived from plant tissues, the special field of the study of drug-producing plants is recognized under the title pharmacognosy. The art of preparing and compounding drugs is known as pharmacy. and the skilled druggist who does the compounding is called the pharmacist. With the present great development in the manufacture and preparation of drugs and drug principles we arc rapidly dispens- NATURE OF THE ACTIOX OF DRUGS 3 ing with the services of the pharmacist, who formerly played so large and important a part in the preparation of medicinal agencies. A study of pharmacology assumes a wide and intimate knowledge of the subject of physiology. It is only on the basis of such knowl- edge that one can build the science of pharmacology. Physiology deals with the intricate and complicated reactions of the living body to every change either in the internal or external environment. These changes are constantly shifting throughout the life cycle of the individual organism and these shifting reactions make up the sum total of the physiological life itself. When pharmacological agencies are introduced into the body or brought into contact with living protoplasm by whatever device, the living tissue or organism responds to their presence. In other words, the presence of the special agency is only one of the numerous factors which induce response in the living protoplasm. The study of drug action is, therefore, only a restricted portion of the field of physiology. Modern science has taken up the questions of pharmacology with the same vigor and spirit of investigation which has characterized the development of physiological knowledge during the last three- quarters of a century. In this spirit scientists have studied the details of the changes induced by drugs, thus establishing the facts on a strictly scientific observational basis. This method and the re- sults are in direct opposition to the old empiricism. The findings have been seized upon by the clinician and therapeutist, since they enable him to proceed in the light of definite and known pharmaco- logical actions of the agent. On the assumption that a given drug, which has been proved to induce a change of a certain nature in the normal organism will induce a change in the same direction in the diseased or pathological organism, the clinician can apply a given drug with a definite knowledge of what effects may be expected. This is the rational treatment in opposition to the empirical. Modern medicine and modern therapeutics look to the science of pharmacology for the basic facts for a rational procedure. II. The Nature of the Action of Drugs. The chemical substances that produce pharmacological reactions in the body by virtue of chemical combinations with constituents of the body are properly called drugs. The term is an old and con- 4 PHARMACOLOGICAL FACTORS venient one, though its application is often vague and indefinite. The character of the change in the reactions depends upon many environmental conditions, of which one of the most important is the manner in which the drug is brought into contact with the tissues of the organism. On this basis the drug actions may be either local or general. i. Local actions. — A certain class of changes produced in the body by drugs is dependent upon the fact that the chemical is brought into contact with only a restricted part of the body, hence the restricted action is purely local and for purely mechanical reasons. For example, if strong sulphuric acid comes in contact with the skin it will produce chemical destruction of the tissue of that local spot. While sulphuric acid is generally destructive to protoplasm, in this instance it can act only locally in the same sense that a hot piece of iron will sear only that portion of the body which it touches. 2. General actions. — On the other hand, when chemical agents are introduced into the body in such manner that they are distributed throughout its extent by means of the circulation, then the reactions that occur are characterized by two general types. The drug may be one capable of inducing change in the physio- logical activities of the body whatever the nature and function of the organs or parts considered. If so, it is said to have a general action. An example is found in alcohol. "When alcohol is absorbed into the circulation and distributed throughout the organism it in- duces a change in function in all parts of the body. Most of the drugs used in practical medicine belong to this class. It cannot be said that the chemicals produce exactly the same change in every type of protoplasm, yet the parts of the body affected are so numerous and widely distributed that the general functions are thrown out of balance, hence the action of the drug is said to be general in its nature. The majority of the physical-chemical changes induced in the body are of this class, especially the purer examples of salt action. 3. Specific actions. — In sharp contrast with these drugs of general action is a different class, namely, the specific drugs. In this class, although the drug may be brought in contact with all the tissues of the body still it shows especial affinity for certain tissues only and not for others. Nicotine is an example of such a drug. This alkaloid picks out especially the nervous tissue. Its specific action is still more detailed in that it forms compounds with that differentiation in nerve tissue represented by the link between the pro- and post- NATURE OF THE ACTION OF DRUGS 5 ganglionic neurons of the autonomic system. While nicotine does enter into reaction to some extent with other portions of the nervous tissue and with the muscular tissues, still the intensity of the action is so much stronger at the particular sjmapsis that the other reactions are overshadowed, thrown into the background as it were. Hence this nicotine reaction is said to be specific. Numerous illustrations of this action can be given. Pilocarpine, acting at the same point, would be antagonistic to atropine, the characteristic curare action on periph- eral motor nerve endings, the action of strychnine on certain synapses in the central nerve axis, and of caffeine on muscle and on nerve, particularly the nerve structures of the higher centers are examples. The behavior of such drugs in the body is always in sharp contrast with those reacting generally throughout the body such as the general protoplasmic poisons. The latter class are characterized by the changes which they induce in the physiological responses of general, i.e., undifferentiated, protoplasm. The specific drugs are characterized by the selective action on highly differentiated points in the structure of the animal body. 4. Indirect action of drugs. — Drugs also induce many changes in the normal functions of the body as indirect actions. That is to say, as a result of the primary action of the drug in the body the balance that exists among the coordinated physiological mechanisms is upset, hence there will follow a chain of effects induced by the shifting in the function of that tissue especially influenced by the drug. These purely secondary effects are physiological rather than pharmacological. Nevertheless they must be understood by the phar- macologist, and especially by the therapeutist who makes a rational application of the drug in disease. A simple illustration of this kind of secondary effect is found in the change of the heart rate produced by atropine. This drug paralyzes the endings of the vagus in the heart, thus eliminating the tonic control of the vagus. As a result the heart rate is greatly increased, not due to any direct effect of the drug, but purely secondary to the action of the drug in eliminating the inhibitory function of the vagus nerve. In like manner many drugs which produce profound changes in the circulatory system are accompanied by secondary effects on the respiratory mechanism or the renal system. Most so-called " tonics " induce their favorable changes in nutrition and metabolism in a purely indirect or secondary way. 6 PHARMACOLOGICAL FACTORS III. Relation of Pharmacological Action to Chemical Composition. When drugs are introduced into the body they produce changes that are in nature either physical-chemical or chemical. In either case the type of reaction will depend in large measure upon the chemical composition of the drug itself. If the drug is of such chemical nature as to produce only physical changes, such as changes in osmotic pressure, etc., then its influence on the physiological be- havior of the organism will be limited to the class of phenomena characterized by a disturbance in surface tension, osmotic equilibrium, etc. If, on the other hand, the chemical nature of the drug is such as will react with the protoplasmic constituents to form new or unusual chemical compounds, then the reactive power of the proto- plasm will be altered, owing to the change in the chemical composition of the protoplasm itself. Physical-chemical changes in the body may be induced in a num- ber of ways, for example the digestive enzymes acting upon the food in the normal process of digestion produce hydrolytic changes in which there is an increase in the molecular concentration in the digest- ing mass. This condition alters the osmotic equilibrium as between the digesting food and the lining tissue of the alimentary tract. The physical result is an enormous increase in the interchange of par- ticles as between these two substances, i.e., the foods and the mucous membrane. The cleavage products of the food will pass into the alimentary epithelial lining in relatively large numbers constituting the process of absorption. If, however, the content of the alimentary tract consists of such substances as magnesium sulphate which readily go into solution, but which permeate the lining cells with difficulty, then the osmotic balance will result in the passage of large quantities of water into the alimentary tract, thus greatly increasing the total mass and its fluidity. Such actions are purely physical-chemical. Chemical changes, especially in those drugs that act specifically on the protoplasm of the organism depend upon a chemical reaction between the drug and some portion of the protoplasm of the living tissue. The chemical composition of some of the drugs has not yet been determined, but the greater number of pharmacological agents have well-known chemical composition. On the other hand, the exact and detailed chemical composition of the protoplasm of the tissues of the body is not known. There are many physiological indications of a high degree of involved and complex differentiation between the FACTORS MODIFYING RESPONSES 7 tissues. These are indicated by the numerous cytological methods of staining, as well as by the details of variation in phenomena of physio- logical reaction. But rarely can one specify what is the particular chemical nature of a given differentiated portion of the living body by virtue of which it is capable of executing its characteristic functions. Nevertheless, we do not doubt that drugs induce changes in physio- logical reaction by a process of chemical reaction. Ehrlich has ad- vanced a widely accepted hypothesis in accounting for the specific effect of toxines and anti-toxines. He and his followers have de- veloped an elaborate artificial scheme to explain the type of reaction of substances of this class. Many different groups of drug actions can be explained along similar grounds, namely, on the assumption that some radical in the protoplasm combines with the drug or some portion of the drug. The new compound changes the nature of the protoplasm with the result that its physiological possibilities are altered. IV. Physiological Factors Modifying Pharmacological Responses. It is evident that the reactions produced by a drug in the body do not depend altogether upon the chemical nature of the drug. The structure of the protoplasm in an animal, especially in the higher mammals, is more complex from the standpoint of chemical structure than any known drug. One only has to consider for illus- tration the enormous differentiations among animal species, differ- entiations which are slight from the individual point of view, but collectively are sufficient to give the characteristic specific qualities. In a similar manner the individuals of the species or races of man himself owe their individual characteristics to variations in proto- plasmic composition throughout the body. These variations are most obviously expressed through morphological characters, but a closer analysis shows that a morphological differentiation is only the machin- ery for an even more subtle physiological differentiation. Even from this broad point of view it is obvious that the responses which one individual will give to a drug are not, in fact cannot be exactly duplicated in another. The details of this phase of the subject can better be appreciated by considering specific factors. i. Age of the protoplasm. — Of all the physiological character- istics influencing the pharmacological reaction of protoplasm age is one of the most important, second only perhaps to that of species. A young individual possesses different capability from the adult, whether 8 PHARMACOLOGICAL FACTORS we make the application to man or to species of lower animals. If one considers a child, for example, at the time say of birth, there are several factors of which the following are important. First of all the differentiations of the body are incomplete at this stage, therefore the interrelations of pharmacological responses are not to be too strictly compared with those of an adult. Detailed changes in sus- ceptibility of the central nervous system to recognized stimulation, such as characterize the adult, cannot be wholly reproduced at this age, hence the detailed variations in responses induced by a drug such as caffeine vary widely from those induced in the adult, a varia- tion which may be compared qualitatively with the differences in response. An even more important factor is found in the greater susceptibility of young protoplasm to biological change in character as between adult man and the lower animals. Classical experiments in biological fields in recent years have fully emphasized the fact that young protoplasm is strongly imbued with the " impulse to growth." This characteristic overshadows the dynamic processes of adult proto- plasm. Keactions of the young are to that extent different in nature. It is obvious that the responses to special conditions such as an environment of drugs will to such extent be fundamentally modified. Among other things young protoplasm is quantitatively, i.e., weight for weight, much more susceptible to drug action. In perform- ing experiments on animals or in the practical use of drugs in thera- peutics this fact has long received recognition. In dose tables allow- ance has to be made, not only for the smaller proportionate size of the young in comparison with the adult in computing the adequate dosage (which is always figured for the adult), but for the difference in susceptibility of the child in comparison with the adult. Physi- cians in practical therapeutics have undertaken to express this rela- tion in formulae for computing the dosage for children which shall take into account both age and weight. Young's formula, which is widely used and is sufficiently accurate for all practical purposes, computes the dosage for a child as follows: The fraction obtained by dividing the age of the child by the age plus twelve gives the proper part of the adult dose to be given, i.e. : ntro Young's formula,=The adult dose X — ^r age + 12. A year-old child would receive,- •* . y A — jg of the adult dose, or a 4 1 four-year old child . , , n =-r the adult dose. 4 + 12 4 FACTORS MODIFYING RESPONSES 9 Children under one year, i.e., infants, must receive even smaller proportionate doses. Fried 's rule, applying to this age, is: The dose for the adult X the age in months -s- 150. Age susceptibility cannot always be figured in terms of formulae. It is well known that young children are peculiarly susceptible to certain particular drugs. These can only be known through the process of experience. 2. Race and species differentiations. — As it is with age suscepti- bility so is it with species or race susceptibility. The very foundation of specific or race variation either in man or animals is expressive of protoplasm deviation in composition of a nature which leads to dissimilar responses to chemical agencies. Although many of our pharmacological tests are made on the common house animals, the cat and the dog, it is well known that these two animals give quite different responses to certain particular drugs, for example morphine. When weight and age and other individual characteristics are taken into account still there remains this qualitative difference, which is racial or due to species. The same type of variation is met with in the different races of man. The colored race, for example, is more susceptible to certain types of toxemia than the white, and vice versa. 3. Individual susceptibility among both man and animals. — A wide range of individual susceptibility to drugs has been noted. Some individuals are especially responsive to certain particular drugs. For example, now and then will be found a person who is peculiarly responsive to the alkaloid strychnine. Even the small quantity of this drug customarily given in the form of a tonic to the average individual, will be sufficient to produce incipient tetany in a highly susceptible individual. This characteristic rests on some form of differentiation in the protoplasm. It is met with in common experi- ence in the fact that one individual may be unable to take milk in his food, another strawberries, or honey, etc. The opposite of this type of variation is found in individual tolerance. Great variations are found in the ability of individuals to throw off the particular action of certain drugs. In common ex- perience the most widely known of these reactions is that of tolerance to alcohol and to nicotine. While certain individuals are intoxicated by minute quantities of alcoholic beverages others can take relatively large quantities without marked evil effects. The particular cause of these variations among individuals cannot now be stated as it still belongs in the realm of the unknown, and for that reason we are in 10 PHARMACOLOGICAL FACTORS position to give it a special name, namely idiosyncrasy. This type of variation, however, rests on an inherent variation in the nature of the tissues of the individual concerned. The term idiosyncrasy is not used to express that type of susceptibility or of tolerance which is acquired by repeated experience. 4. Sex susceptibility. — Sex characteristics are generally stated to be a factor influencing susceptibility to the action of drugs. Though not always admitted, it is currently stated that women require smaller doses of therapeutic agents than do men of equal size. This differ- entiation is, doubtless, to some extent, the same in character as that represented by species differences, though they are more specifically physiological. The physiological life of women is subject to periodic disturbances in poise and under these particular conditions there is often a greater response in the reaction to particular drugs. In the nervous system, in the glandular system, and especially in the uro- genital system which is correlated particularly with the sex develop- ment, we have differences which influence the quantitative reaction of drugs. The more subtle sex differences which have long been recog- nized probably rest not so much on mass differences as on the variations in correlation between the organs of the general bodily functions as influenced by the primary sex organs, chiefly through their in- ternal secretions. In pregnancy there is a very great disturbance of physiological equilibrium. The usual coordinations are thrown far out of balance by the physiological adjustments to the developing fetus and the enlarging uterus. The nerve reflexes are more delicately poised and are stimulated into action by less profound changes in the environ- ment than usual. The responses to pharmacological agents are for these reasons greater. Drugs also pass from the mother to the de- veloping child, whose tissues are more susceptible. A non-toxic con- centration for the tissues of the mother may prove fatal to the child. The child in the uterus may also be profoundly affected by the sec- ondary changes in its nutritive condition, superinduced by the primary responses of the respiratory or circulatory sj-stems of the mother, for example in surgical anesthesia. Preceding and during the menstrual period there is great dis- turbance in the interrelations of the physiological reaction. Drugs displayed at this time produce effects somewhat differently co- ordinated in comparison to the effects ordinarily and normally called forth. The state of the body is comparable to that under many con- ditions of disease and the question of reaction variation is essentially CHANGE INDUCED BY DRUGS 11 one of practical therapeutics. During that crisis in the life of a woman known as the menopause there are somewhat similar physio- logical disturbances that need to be taken account of in the interpre- tation of pharmacological reactions. 5. The influence of mass, i.e., proportionate weight of active tissue. — In the display of drugs in the human body it is found that, other things being equal, there is a response proportionate to the mass of active protoplasm involved. Two individuals of similar type and build, but of dissimilar weights require dosages proportionate to their weight, if equivalent responses are expected. However, weight in itself is not a sufficient guide. Adipose tissue is inactive tissue, hence variation in weight due primarily to adipose tissue must not be taken into account in determining dosage. It is only the active proto- plasm that one can assume gives rise to drug reaction. If, however, the particular drug is of such nature as to enter into solution in the inactive tissue, then to that extent it is lost from the possibility of reaction with the active tissue. In old age there is less active tissue weight for weight than in the younger adult, hence pharmacological dosage must be somewhat reduced. V. Nature of the Change Induced by Drugs in the Pharmacological Actions of the Body. The human body is a highly differentiated mass of tissues and cells. The differentiation has resulted in two general types of struc- ture, first, the generalized tissues such as the skin, connective tissue, bone, etc. ; and second, the specialized tissues, i.e., the nervous tissue, muscular tissue, gland, etc. The first class of tissues is characterized by the possession of protoplasmic properties which retain, to a relatively high degree, the general characteristics of living protoplasm. These are the mobile tissues, the tissues on which growth, repair, and metamorphosis de- pend. These are the tissues which enter largely into the pathological processes, i.e., inflammation, tumor formation, and metastases. The specialized tissues are those that have modified widely from the general type for the effective accomplishment of some one or more of the special functions such as irritability and conductivity in the nervous tissue, contractility in the muscular tissue, and secretion in glandular tissue. These are the tissues which are least easily modified in their form but which are most strikingly involved in the execution 12 PHARMACOLOGICAL FACTORS of specific functions. They are the tissues which, when subjected to the influence of drugs, respond most acutely with changes manifested in the group by dynamic phenomena. Of these two classes of tissue the first is involved in all those phenomena which are characterized by irritative processes. They are the tissues affected by such agencies as turpentine, arnica, dilute alkalies, iodine, cantharadine, etc. Those drugs which act upon the parenchyma, that is the specialized tissues, can produce, and do produce changes in the specific functions. These changes are of necessity of two types, an increase in the function, i.e., stimulation, or a diminution of the normal function, i.e., depressive. Also, this possibility applies to each differentiated part of the body. Therefore the possibilities of change in the total func- tions of an organism are great in proportion to the number of highly differentiated tissues and dependent relations of tissues found in the body. As an illustration, when caffeine is introduced into the general circulation, it increases the functional activity of the nervous tissue by increasing the irritability of that tissue. Under the influence of this alkaloid a smaller stimulus will produce the same nervous reaction as that produced by a much larger stimulus in the normal body. The cerebral cortex is therefore more susceptible to stimuli, hence gives a greater amount of response to the same stimulus. The general activities of the body, as a whole, are proportionally increased or restrained, therefore, because this controlling tissue of the cerebral cortex is increased in its function. Or, if atropine is used in sufficient quantity to depress the activity of the vagus nerve endings, the usual stimulations, which increase the function of the vagus, will fail of their ordinary effects upon the heart. The delicacy of coordina- tion, which is usually accomplished by the cardiac nervous apparatus, is lost owing to the blocking of conduction through the nerve endings. In a similar manner, when the ganglionic synapses of the autonomic system are under the toxic influence of nicotine, there will be a general depression of the delicacy of coordinative responses in the circulatory, respiratory, and glandular systems. Certain drugs, like the glucoside digitalis, increase the function of a large number of parenchymatous tissues at one and the same time. The intensive action of the drug is greater by virtue of this simultaneous action on numerous tissues. In a like manner the depressive action of morphine is greater because it lowers the reactive power of practically all of the tissues of the bodv. METHOD OF APPLICATION OF DRUGS 13 VI. The Method of Application of Drugs as Modifying the Changes in Pharmacological Activity. The method of bringing the drug into contact with the body decidedly influences the character and the rapidity of reaction in- duced. It is possible to control the relative concentration and the sequence with which the drug is brought into contact with the differ- ent tissues of the body. One may exercise a certain amount of control over the rate and the degree of absorption, therefore the relative concentration of the drug in the different tissues at a given moment. The methods of presenting drugs to the tissues of man and mam- mals are briefly reviewed in the following paragraphs. i. Introduction of drugs by way of the mouth. — This method involves the slow process of absorption through the walls of the alimentary canal and is, therefore, a relatively slow method of in- troducing drugs into the general system. As drugs, like the elements of food, are absorbed chiefly in the intestinal tract, it follows that the rapidity with which they are passed into the intestine will de- pend upon the general motility and sensibility of the alimentary tract, particularly of the stomach. Drugs given by way of the mouth produce local effects in the mouth itself and in the stomach long before they reach the general system. All medicinal agencies with strong tastes and with positive odors sharply stimulate the sense organs of the mouth and nasal cavity. Reflexes are thus produced that induce secondary changes in the secretory, respiratory, and circulatory systems. Drugs taken by way of the mouth always reach the stomach and intestine in greater concentration than they will have after absorption. Thus strong alcoholic liquors, such as whiskies and gins, taken undiluted, produce marked local inflammatory processes in the stomach. After the slow process of absorption these alcohols are so far diluted that no general irritant effects occur, hence the characteristic general systemic effects alone are produced. 2. The introduction of drugs by way of the rectum. — The rectal method of introducing drugs rests upon the well-known fact that absorption takes place from this region. Even volatile substances, as ether, have been given by this channel. It has the advantage of avoiding the mouth and stomach, if for any reason such path is un- 14 PHARMACOLOGICAL FACTORS desirable. The local reflexes produced in the mouth and stomach are avoided and the cardiac and vasomotor reflexes are not so strongly aroused. It is well known that artificial feeding may be accom- plished by way of the rectum in instances of marked inanition or for other special reason. 3. Hypodermic injection. — A small syringe provided with a fine hollow needle tip provides a convenient and reliable method of giving drugs. Sterile solutions are injected into the subcutaneous tissues whence they are rapidly absorbed into the general circulation. This method has certain objections, i.e., considerable pain is produced by the mechanical effects of the injection and the pain induces com- plicating reflexes. Certain drugs are marked irritants and set up local inflammation at the point of injection, as for example digitalin. Finally, there is always the risk of infection by the introduction of contaminating germs. Hypodermic injections may be used to secure the local action of drugs as well as to secure their general action after absorption. The best well-known illustration is that of cocaine. This general poison has proved of inestimable value in alleviating pain in operative and other procedures due to the successful hypodermic infiltration of the drug, care always being taken to prevent too rapid absorption so that a toxic quantity at any one time does not get into the general cir- culation. The hypodermic syringe is an invaluable instrument, not only in the determination of the facts of the pharmacological action of drugs, but in the control of drugs in practical therapeutics. 4. Intramuscular injection. — Meltzer has proved that a more rapid absorption of drugs occurs if the injection be made deep into the body of the skeletal muscles rather than into the subdermal con- nective tissues. This method, therefore, is to be employed in all cases where it is desired to introduce the drug in the most rapid way other than intravenous. This method is proving very valuable. By it drugs are rapidly, and, what is often of more importance, evenly introduced into the general circulation. Furthermore there is less pain and a slighter tendency to local inflammation from preparations that tend to irritation. 5. Intravenous injections. — The quickest and surest way of bringing a drug into contact with all the tissues is by introducing it directly into a vein. It thus passes throughout the whole circulatory system in a few seconds. Solutions are driven from a hypodermic needle or through a canula ligated into a vein. In either case pre- caution must be taken ; first, not to introduce air and thereby produce METHOD OF APPLICATION OF DRUGS 15 air emboli ; second, not to introduce vigorous acting drugs too rapidly, lest they reach the heart in too concentrated form and lead to un- desirable reactions before general distribution is accomplished ; third, when either of these methods is practiced on man, or on any animal when the life is to be conserved, the whole procedure should be under aseptic conditions. 6. Transfusions. — The transfusion of blood from one person to another is a most valuable clinical method of saving life. It is practiced in cases of extreme anemia, or where there has been great loss of blood under conditions from which the individual does not rally. In this method an artery, generally the radial of the donor is directly connected with one from the recipient, and blood is allowed to run directly from the vessels of the one to the other. In transfusion we now know that only the blood of individuals of the same species can be safely transfused (see literature on Animal Sera, Toxins, etc.). The method of transfusion is a reliable method of pharmacological testing as applied to animals. Valuable information as to the re- actions of epinephrine, or sera, etc., has been secured by this method. 7. Inhalation and insufflation. — Everyone is familiar with the method of introducing volatile drugs by inhalation and insufflation as practiced in anesthesia. The volatile anesthetics, ether and chloro- form, as well as the gases, as nitrous oxide, carbon dioxide, or the poisonous carbon monoxide, are readily absorbed through the lining epithelium of the lungs. They are taken up by the blood in the pul- monary vessels and quickly distributed to all parts of the body. It is also possible to introduce substances which can be atomized and inhaled with the respiratory air. Such atomized particles come in contact with the pulmonary epithelium and are fairly readily absorbed. ' Volatile oils which are carried off on steam belong to this class of materials. 8. Local application of drugs. — A favorite method for bringing drugs into contact with particular parts of the body is that of local application. This method is chiefly limited to external sur- faces of the body or those portions of the body that are readily reached through the external openings. Deeper portions of the digestive tract, such as the stomach and the rectum, admit of a limited application of drugs by this method. Also in hypodermic injections, as for example cocaine, drugs can be so manipulated as to produce strictly local effects. One of the best illustrations of the local application of drugs is 16 PHARMACOLOGICAL FACTORS that of atropine to the surface of the eye. The alkaloid is slowly absorbed into the tissues of the cornea and the underlying parts, ' where it ultimately comes into contact with the musculature of the iris and ciliary processes. In this locality the atropine penetrates to the nerve endings of the smooth muscles involved in the act of ac- commodation where it produces its selective toxic action. It is true the atropine is absorbed into the general circulation, but only very slowly, and it does not reach the general tissues in concentration great enough to produce noticeable changes in organs other than the eye. If an excess of atropine be applied to the eye and its application too long continued, then there may be enough absorbed into the general circulation to become active. The method of local application is capable of wide use, especially in the group of irritants. Drugs that would be very toxic if introduced into the general circulation may be used by this method. Contact restricted to a local area, may still be associated with extensive and general physiological effects on the organism as a whole. These effects are, for the greater part, reflex in character, hence fall on the factor of coordination influences within the body. One of the chief values of the method of local application depends upon this reflex influence, an example of which is found in the reactions of the group of counter- irritants. VII. Changes Produced in the Reactive Power of the Individual by the Continued Application of the Drug — Summation and Tolerance. If drug doses are given in succession, two changes may follow in the intensity of the physiological reaction produced. First, if the doses follow in too rapid succession so that elimination is incom- plete there will be summation, or cumulative effects. This is illustrated by the usual therapeutic administration of digitalis. Mostrom and McGuigan x have explained certain increased sensitiveness of animals to strychnine as ' ' habit, ' ' or as Sollmann - puts it ' ' The system appears also to be subject to what might be called an ' educa- tion ' to the effects of the drug." However, the more striking and more common phenomenon is the 1 Mostrom and McGuigan: Jour. Pharmacology and Exp. Therapeutics, Vol. III., p. 515. "Sollmann: Textbook of Pharmacology, 2d edition, p. 131, 1906. PHARMACOLOGIC VS. THERAPEUTIC ACTION 17 great decrease in susceptibility as the dose is repeated, known as acquired tolerance. Acquired tolerance differs from individual tol- erance in that it implies an individual readjustment to the new agency. It is most strikingly illustrated in the instance of the numerous drugs that are abused leading to the formation of drug habits. The origi- nally sensitive tissues acquire an immunity whereby the organism may withstand the toxic action of a dosage many times greater than the ordinary fatal quantity. This is illustrated by the widespread nicotine habit, so prevalent in America, or the opium habit of the Orient, or by the worldwide prevalence of the alcohol habit. A few cubic centimeters of whiskey will produce incipient intoxi- cation in an individual not accustomed to its use, whereas a con- firmed toper may consume more than a pint or even a quart a day and still maintain his equilibrium. The organism acquires tolerance in several ways. There is an actual decrease in the protoplasmic sensitiveness to the drug as in the case of nicotine. Or the presence of the drug may lead to the strengthening of the defenses of the organism expressed in the in- creased oxidative power as with alcohol, or, in the production of neutralizing substances as in the case of the toxins. VIII. Pharmacologic versus Therapeutic Action. Pharmacological action is defined above as change induced in the normal physiological functions, whereas therapeutic activity is change induced in the pathological functions with the object of aiding the recovery of the normal. Eational therapeutics assumes that these two types of change are in the same direction, are alike in kind. How- ever, pathological states induce great changes in an organism along two lines. There are changes in the protoplasm itself, and these are more or less responsible for changes in the interrelations of parts, hence in the functional coordinations. The diseased condition is the sum of these two classes of changes. Pathological protoplasm will not always give the same quantitative responses to a drug as does the normal, in fact there are certain qualitative variations as well. In general the response is of a similar quality, but varies more widely quantitatively. The greatest difference lies in the change in the type of responses in the great coordinative mechanisms. It is evident that familiarity with pharmacological action is a necessary foundation 18 PHARMACOLOGICAL FACTORS for therapeutic applications. But the latter must take into considera T tion the changes induced by the pathological states produced by dis- ease, hence the corresponding variations in the response to drugs. This field is now rapidly being brought to a more accurate scientific basis by the development of the newer field of experimental therapeutics. IX. The Fate of Drugs in the Body. Drugs are disposed of by the body in several ways. Certain drugs, as alcohol or morphine, are largely oxidized by the tissues. From 90 to 95 per cent, of the alcohol of liquors is oxidized, leaving only a small percentage to be disposed of in other ways. Excretion by the kidney, the skin, the lungs, in volatile substances, or by the alimentary tract is the usual fate of most substances. The material may be excreted unchanged or it may be partially oxidized and then excreted. Substances that are excreted by the alimentary tract are partially resorbed by lower divisions of the tube, hence their elimination by this route is through an ever-repeating circle and slow. Morphine is an example. It is excreted freely into the stomach and reabsorbed from the intestinal tract further on. The heavy metals, which form very fixed chemical combinations in the body, are dissociated and eliminated only with extreme difficulty and in minute quantities at a time through the kidneys or the alimentary tract. Most volatile substances are rapidly eliminated through the pulmonary epithelium and carried off in the expired air. Ether and chloroform are typical of this class. The chief excretory channel for the great majority of drugs is the kidney, the substance being eliminated hr solution in the urine. PART I. ORGANIC DRUGS. A. General Depressant Series. CHAPTER II. THE ALCOHOL GROUP. I. Introductory and Chemical. Introduction. — Of the alcohol chemical series the form most in- teresting from the pharmacological standpoint is ethyl-alcohol, C 2 H 5 OH. This alcohol is the particular constituent of a long series of fermentive beverages and has been known since the beginnings of history. The use of alcohol and alcoholic beverages in medicine also dates to the earliest known period. It does not seem necessary in this connection to trace the historical steps down to the present time in relation to either the medical or social use of alcoholic prep- arations. Perhaps it is sufficient to say that in the last few years the reactions of alcohol in the body have been studied both quali- tatively and quantitatively in the light of our modern advances of physiology and physiological chemistry. The result has been to give this substance a much more rational position in the list of phar- macopeial remedies than it has ever known before. Solutions and chemical relationships. — Ethyl-alcohol is derived from the fermentation of different sugars by yeast. The reaction that takes place in general can be represented by the formula : — Glucose Alcohol Carbon dioxide CH O = 2 C H OH + 2 CO 6 12 C 2 5' 2 Absolute alcohol is a transparent, highly volatile substance with a specific gravity of 0.797. It boils at a temperature of 78.5° C. The ordinary commercial alcohol contains about 95 per cent, absolute alcohol. The alcohols used in medicine are rarely pure alcohols. Instead 19 20 THE ALCOHOL GROUP are used the alcoholic liquors, such as whiskey, wines, brandies, etc. Liquors contain a varying percentage of alcohol depending upon the particular class to which they belong. Brandies, whiskeys, and rum 40-60% alcohol. Wines 6-22% Beer 3-6 % Ales 2-5 % Liquors always contain a number of principles more or less volatile which bear a close chemical relation to or are developed during the fermentation of the alcohol. It is these substances that give the characteristic aromas and flavors peculiar to the different types of liquors. The development of the flavoring materials depends largely upon the type of yeasts fermenting the fruits and grains, but to some extent upon the character of the fruits and grains used. It is this characteristic of the local brews of liquors from special localities which is prized so highly by connoisseurs, as for example in the different Rhine or Spanish wines. The alcohol series varies in toxicity or in intensity of pharma- cological action somewhat in relation to the structural formula of the particular alcohol. In general it can be said that the intensity of the toxic action increases as we go up the aliphatic series. The toxicity -of the first five members is as follows, according to Baer: Methyl CH g OH Toxicity . 8 Ethyl C H OH " 1,0 Propyl C 3 H ? OH " 2.0 Butyl CH g OH " 3.0 Amyl C.H^OH " 4.0 In the higher members of the series the solubility of the substances in the body fluids becomes relatively less and therefore the toxicity falls off, the paraffins being wholly insoluble and inert. II. Alcohol as a Local Irritant. i. The local effects of alcohol on the skin. — When alcohol is applied to the skin at any point on the surface of the body in relatively concentrated form it produces a local irritative process in the epidermal tissues. Under ordinary conditions the alcohol evaporates before the irritation proceeds very far and the effect is ALCOHOL AS A LOCAL IRRITANT 21 slight and evanescent. But if the alcohol is kept from evaporating, then the irritation may proceed even to advanced stages of inflam- mation. The alcohol itself penetrates the skin rather freely due to its solubility in the oils of the surface. As it comes into contact with the deeper layers of the epidermis it extracts water and tends to precipitate the cell proteins, changes that account for the in- flammatory process. The local action is twofold. In the first place, it produces a primary stimulative effect on the processes of repair and growth. If the primary action of the alcohol is intense enough there may follow in definite pathological sequence the changes which characterize the development of inflammation. In the second place, an immediate stimulation is produced on the nerve endings in the local portion of the skin. The result of the stimulation is a series of reflexes which may affect not only the local circulation of the part, but also the general circulation, and, in the more extreme cases, the processes of respiration and the general bodily movements. The secondary effects are of course not peculiar to or characteristic of alcohol only, since they are characteristic of any local stimulative agent. 2. The local effects of alcohol on the mucous membrane of the mouth and stomach. — Alcohol and alcoholic liquors produce distinct physiological responses when taken by way of the mouth. These responses are more marked with the liquors than with the pure alcohol, due to the fact that they contain esters and other volatile constituents which produce striking reflex stimulations. The local effect of the strong alcohol as such on the moist mucosa of the mouth and of the stomach is much more irritative than in the case of the skin. These membranes have a higher water content and the living protoplasm is not separated from the alcohol by a thick layer of dead tissue as in the skin. Therefore, the changes produced are immediate and stimulative leading to marked nervous reflexes through the medullary centers. It is at this point that one can make the strongest claim for the clinically beneficial effects of certain classes of alcoholic liquors. The mild stimulation of the taste buds in the mouth, and of the olfactory membrane of the nose, produces secretory reflexes through the medulla which not only increase the secretion of saliva but also induce the primary secretion of the gastric juice in the stomach, and possibly also the secretion of the pancreas. The painful and burning sensation of the stronger alcohols in the mouth may set up to some extent the same reflexes, but they are not so normal or beneficial. 22 THE ALCOHOL GROUP In the stomach the mild irritation of the mucosa produces some degree of reflex secretion of gastric juice, a matter that has been adequately determined by Chittenden. Undoubtedly the stronger alcohols, especially when oft repeated, produce more profound processes leading to inflammation and ofttimes to necrosis. The necrotic ulcers of the chronic alcoholic are sufficiently well known. Certainly in such cases the gastric mucous membrane has long since passed into a pathological state in which even a normal secretion cannot take place, much less the favorable physiological reflexes. This local action of alcohol rests on its toxicity to general proto- plasm. It is this factor which makes of alcohol a valuable antiseptic. Isolated organisms, such as bacteria, protozoa, etc., have their proto- plasm precipitated by alcohol of sufficient strength and are therefore killed. III. Detailed Systemic Effects of Alcohol. i. The action of alcohol on the central nervous system. — Alcoholic liquors have long enjoyed a popular reputation as stimu- lants for the nervous system. Experimental tests have been made which claim for alcohol in very moderate quantities some acceleration of mental reactions, when tested by psychological tests and methods. Yet, writers working under such stimulus have not consistently found an increased brilliance of their products judged under calmer conditions. The question can safely be considered as still in doubt as to whether alcohol in such quantities favors or hinders the process and reactions of the central nervous system, the phenomena of which are expressed in mental or psychical states. It is generally admitted that larger doses of alcohol depress intellectual functions, and along with this depression will come marked changes in the general physiological reactions of the body. We are, in America at least, all too familiar with the details of the successive stages of the toxic effect of alcohol. However, some of the salient phenomena will be re-enumerated for the sake of clearness of discussion. In the first stage or in mild alcoholic action the individual changes in his personal estimate of his activities. The drinker fools that he is more brilliant, whether or not he be so. There is a greater vivacity, especially in company, usually associated with de- ALCOHOL ON THE NERVOUS SYSTEM 23 creased reserve and self-restraint. The individual has what super- ficially appears to be a keener appreciation of humor and wit, that is, he gives greater responses to these stimuli. He shows a tendency to much talking, to free laughter, and also to accelerated neuro- muscular activities. The respiratory rate is generally somewhat accelerated, as is also the heart rate. An increased flushing of the skin, especially noticeable in certain portions of the face, is one of the first indications of mild alcoholic effects, an index which comes even earlier than those symptoms noted above. In the second or successive stage of alcoholization there comes on a more marked degree of incoordination of mental processes indi- cated by less logical sequence of thought. This characteristic is shown in the responses to wit, humor, etc., i.e., in responses to social intercourse. Along with these symptoms there is an increasing lack of neuro-muscular control revealed by some unsteadiness of move- ment as indicated in the process of writing, in the movements of walking and the like. With the still greater increase in the effects of alcohol there is a marked depression of the entire bodily functions. This is char- acterized bj r a progressive loss of muscular control to the point of narcosis, associated with increasing loss of normal reflex nerve re- actions, a depressed respiratory rate, a slower heart, and inefficient circulation. In this stage, especially when much prolonged, there is a decided lowering of the general body temperature. 2. Explanation of the nervous symptoms induced by alcohol. — Two schools have arisen for the explanation of the influence of alcohol expressed through the nervous system. These two schools are led by the two great pharmacologists, Binz and Schmiedeberg. Binz and his followers believe that the incipient effects of alcohol on the central nervous system, including the cerebral cortex, are actual stimulation, that the functions are really accelerated. They of course admit that the later effects are narcotic. Schmiedeberg and his followers, on the other hand, believe that the incipient effects of alcohol on the central nervous system are narcotic and not stimulative. They explain the phenomenon of apparent accelerated function by the view that the narcotic effect of alcohol is progressively toxic, beginning with the highest portions of the cerebral cortex and extending in a descending direction, a process that characterizes certain dementias and is known as dissolution. The higher processes of the association centers of Flechsig through which the processes of reasoning, of attention, and mental association are executed will be first attacked by alcohol 24 THE ALCOHOL GROUP and, by Schmiedeberg 's view, should be lowered in efficiency. Numerous later observers have found evidence to indicate that this as- sumption holds. Simple mathematical processes take place less readily when the computer is given a small quantity of alcohol. Also com- putations of distance as well as acuteness of perception are depressed. Typesetters do less work, i.e., place fewer type and with less accuracy, on days when they receive a small measure of alcohol. The accelerations of simple motor processes, which in their most complex form are associated with psychic reflexes, are explained on this view by the elimination of the inhibitive regulative control which the psycho-motor centers receive from the higher centers of the cortex. In progressive alcoholism there will come, therefore, a time when the association centers will have been narcotized just sufficiently to depress their inhibitive regulative control over the basic motor centers. These centers, therefore, will be physiologically freer to respond to the incoming sensory stimulations of whatever kind. The resultant reflex motor responses will be greater. The alcoholic therefore talks more volubly, laughs more freely, and responds more strongly to the stimulations of his social environment. These in- creased responses are by this line of reasoning to be considered as evidences of lack of control rather than positive stimulation. If one follows the progressive influence of alcohol in its inter- mediate and advanced stages he will note that the marked depres- sion of function appears successively in certain nerve centers, and this order is surprisingly near the ranking one would make on physiological evidence when asked to classify these centers in a descending series. There is first a loss of psychological activities, perhaps even of consciousness itself. This is followed by lack of motor control, especially of the arms, legs, and vocal apparatus in which the complexity of nerve structure and function is unques- tionably of later physiological development. Finally there is loss of function of the trunk musculature, therefore of the respiration, and a marked depression of the circulation, together with paralysis of those medullary centers controlling the same. 3. The action of alcohol on the nervous system of lower animals. — The general influence of alcohol on intelligence as expressed by the action of the cerebral cortex has been tested on dogs by Hodge of Clark University. He found decided changes in the mental characteristics of dogs, particularly indicated by a great increase of timidity and fear, the especial symptom of the neurosis in man. The evidence of intellectual power he tested in four dogs of the same ALCOHOL OX THE NERVOUS SYSTEM 25 species, by the method of retrieving. Two alcoholics, that is dogs receiving a definite quantity of alcohol in their food each day. and two normals were used. These dogs retrieved a ball on the gymnasium floor. The alcoholic dogs were far less efficient than the normal. Of a series of 1400 balls thrown "The two normal dogs retrieved 922. the alcoholics 478. This gives the alcoholics an efficiency of 59.8 per cent, as compared with the normals." Of the two male dogs the ability of the alcoholic was only 32 per cent, of the normal. The pair of alcoholics " gave evidence of very much greater fatigue." Of course the greater efficiency of the normal dogs in these tests rests in part in physical agility and muscular endurance as well as on nervous characteristics. 4. The duration of the effects on the central nervous system. — The duration of the effects of alcohol varies with the size of the dose. If the amount of alcohol has been sufficient to produce the second set of changes previously outlined, then the body will not recover its former degree of activity for some fifteen to twenty-four hours or even more. The duration of the change is longer than has generally been supposed. Experiments have been carried forward to prove these effects on quantitative work as well as on qualitative. Dyna- mometer experiments by which one measures the amount of muscular work given off in voluntary muscular contractions tend to show that the effects of alcohol are recovered from very slowly. Voluntary muscular effort has in it two factors, the nerve stimulation and the muscular response. The action of alcohol is not the same on the two tissues. Hence the results of this type of test have been a little confusing. Jacobi's observation, that an individual could more clearly estimate small differences in weight when under small doses of alcohol than in the normal state, can be explained on the ground that the muscle itself is rendered less stable by the drug. It was shown by Lee and Salant that muscles execute the simple muscular contractions more quickly when subjected to moderate quantities of alcohol. In Jacobi's experiment it is not necessary to assume an increased sensi- bility of the nervous part of the apparatus, i.e., of the motor centers. An interesting observation was made by C. C. Stewart * showing that alcohol brought about a change in the amount of Xissl substance in the cells of the different portions of the brain, tending to diminish the content of the Xissl substance. Illustrations of the change in the pyramidal cells is shown by Figure 1. In light of later work- on the structural changes in nerve tissue under the influences of 1 Stewart, C. C. ? Journal of Exp. Med., Vol. I., p. 623, 189(». 26 THE ALCOHOL GROUP activity, drugs, etc., it is probable that this stage of change rep- resents only a mild degree of acute activity quite comparable to that shown by vigorous activity of ordinary type. Whether or not alcohol produces the more profound changes observed under other conditions remains yet to be learned. 5. The action of alcohol on muscular tissue. — The muscular apparatus consists of the muscle fibers, the controlling motor nerves, and the nerve endplates which unite the two. The evidence showing the action of alcohol on the nervous tissue applies to the motor cells of the spinal cord and brain stem, though these cells are Fig. 1. — Alcohol on the amount of Nissl suhstance in pyramidal cells ; 1, normal ; 2, alcohol for 50 minutes ; 3 and 4, alcohol for 54.5 hours. Stewart. somewhat less sensitive than other portions of the nervous system. Nerve fiber itself can be narcotized by alcohol as has been shown by Waller, in this instance preceded by evidence of stimulation. Muscle has been studied extensively by Lee and Salant, 1 who showed that there is a distinct increase both in the sensitiveness of the muscle to stimulation and in the amount of work which a muscle will do under repeated stimulation. Also, the number of contrac- tions which can be completed in a given time is greater, since the individual contractions are quicker. These three effects are observed only on muscle which has received a relatively moderate quantity of alcohol, preferably through the blood vessels. When the dosage is greater, then the reverse of the above effects is true. Lee and Salant compared the two gastrocnemii of the frog, one of which received alcohol, the other none. When after a mild injection of alcohol both are stimulated uniformly with single induction shocks repeated, say, every two seconds, which allows time for a complete relaxation of the muscle after each stimulus, and if the stimulation be kept up until the muscles are exhausted the alcoholic muscle will give off a Lee, F. S., and Salant, W„ Am. Jour. Physiol, Vol. VIII., p. 61, 1902. ALCOHOL ON THE HEART 27 greater amount of work than the non-alcoholic. Comparison of the two records shows that the alcoholic muscle lifts the same weight through a greater height and that the number of contractions is greater. On the other hand, if a strong dose of alcohol be used just the reverse results are obtained. The alcoholized muscle does the least work. These results, which have often been repeated and con- firmed in our pharmacological laboratory, seem to prove that the muscle substance as such is a little less stable under the influence of a mild amount of alcohol. The decrease in stability permits a quicker response upon stimulation, a result that can be explained on the assumption of increased irritability. Fig. 2. — Curves of simple muscle contraction from the gastrocnemii of the frog. The quick contraction, after 0.08 cc. of 10 per cent, alcohol to 1 grm. of body weight. The slower contraction, the normal muscle before alcohol. Lee and Salant. It would seem, therefore, that skeletal muscle as such may receive a true stimulation by alcohol. This is of little practical value, however, since all voluntary muscular activity calls for the nervous stimulating factor. Nerve cells have already been shown to be nar- cotized by alcohol. These two antagonistic effects upon the neuro- muscular apparatus have served to suppress the real truth for each, and have led to confusing interpretations in many lines of experi- ments such as voluntary muscular work. No evidence has yet been adduced showing any favorable influence of alcohol on smooth muscle, and in cardiac muscle alcohol is on the whole depressant. 6. Alcohol on the heart and circulatory system. — " Alcohol, when circulating in the blood stream, causes a gradual progressive lowering of blood pressure, with decrease in amplitude, but increase in the rate of the heart beat," according to Brooks whose experiments were uncomplicated by the presence of anesthetics. This systemic effect is due to a series of factors involved in the circulation, namely, those which on the one hand control the action of the heart, and on the other control the size of the blood vessels, and therefore the peripheral resistance to the flow of blood. The reaction on the circulatory 28 THE ALCOHOL GROUP system is abundantly complicated, however, by physiological factors set in action by the local stimulation by alcohol and the alcoholic liquors when taken by the mouth. v a. The reactions of the heart. — The heart is a complicated apparatus, physiologically consisting of the musculature of the heart, the local nervous apparatus, and the nerve centers and connections with the central nervous system. There are well defined methods in vogue in physiological and pharmacological laboratories for study - Fig. 3. — Alcohol on ventricular muscle. The strip contracts rhythmically in physi- dlogical saline 9 parts plus Ringer's solution 1 part. During the time indicated by the marker 2 per cent, alcohol in the normal solution was applied. The time record, intervals of 10 seconds. The second test was depressing. New tracing by Summers. ing each of these portions of the cardiac apparatus. To determine the effects of alcohol on cardiac muscle two methods have been used. One method depends upon the isolation of the muscle itself, heart strips as free as possible from nervous elements, and the immersion of these strips in solutions of alcohol made up in normal or artificial physiological liquids. The other method consists in per- fusing alcoholic solutions through the isolated heart or through the heart in place in the body cavity. Studies on the strips of cardiac muscle, for which the heart of the terrapin is especially favorable, show that alcohol depresses both the rate and amplitude of the mus- cular contractions. Stimulative effects, as indicated by accelerated rhythm, very seldom occur, in not over 10 per cent, of the experiments. These accelerations are produced by relatively strong solutions of alcohol and only at the moment of immersion. This suggests the type of local irritative effect rather than a pharmacological stimulation. ALCOHOL OX THE HEART 29 Increase in amplitude, which is so characteristic of the isolated skeletal muscle, does not often occur on isolated strips of heart muscle. The exceptional reaction is presented in Figure 3. Perfusion of alcohol through the heart of the frog has, in the main, given confirmation of the observations from the muscle strips taken from the terrapin. The amplitude of the frog's ventricle diminishes and the rate becomes slower and often ceases, even with the weaker solutions. It is admitted by all that the stronger con- centrations, 1 per cent, and over, are depressant. The auricles are even more sensitive than the ventricle. They dilate and become extremely feeble. Conduction of the auriculo-ventricular wave diminishes or is blocked. Experiments on the isolated mammalian heart have, in the main, given essentially the same results as those listed above for the cold- blooded animals. Martin and Stevens 1 were the first to investigate the behavior of the isolated mammalian heart under the influences of alcohol added to the blood perfusing through it. Their results are indicated in the following quotation : " When defibrinated blood containing one-half of one per cent, by volume of ethyl-alcohol is supplied to an isolated dog 's heart, which has been hitherto working with uniformity, the invariable result is a very rapid and marked diminution in the work done (indicated by the quantity of the blood pumped out from the left ventricle) by the heart in a given time. When the blood contains only one-fourth of one per cent, of alcohol the result is, in most cases, the same, but sometimes is little or none. After the action of the alcohol has been fully manifested the heart can, in many cases, be restored to its original working state if supplied with defibrinated blood containing no alcohol. Blood containing but one-eighth of one per cent, of alcohol exerts no influence upon the work done by the heart, at least for several minutes/ ' Leo Loeb's experiments on the perfused and isolated heart showed that when alcohol was added to the perfusing fluid to the amount of 1 per cent, and more the solution became injurious to the heart. There was diminution in the rhythm and weakening of the force of the contraction. "When he used solutions of 0.3 per cent, or less he sometimes found a stronger heart beat. This was particularly true if the heart was in a weakened condition. Dixon 2 further 1 Martin, N. H., and Stevens, L. T., Jolins Hopkins Biol. Bull, Vol. II. , p. 485, 1883. 2 Dixon. W. E., Jour. Physiology, Vol. XXXV., p. 346. 30 THE ALCOHOL GROUP elaborated this point and secured a decided improvement in the cardiac flow and rhythm by concentrations of alcohol from 0.05 to 0.3 per cent. The favorable influence on the heart action was decidedly greater when the hearts were in a weakened condition. Cushny, in his Pharmacology and Therapeutics, publishes a splendid instructive figure (Fig. 3), which shows the unfavorable influence of alcohol as falling more strongly on the contractile power of the auricle. This effect would markedly influence the volume and therefore the efficiency of the cardiac discharge even though the ventricle were less pro- foundly affected by the drug. Isolated hearts contain local ganglia as well as muscle. But such stimulations as do occur can scarcely be claimed as specific or constant enough to be attributed to the nervous elements. Hence, whichever view one takes of the cause of the heart rhythm and sequence, the pharmacological explanation of the direct action of ■■■■ LI?!'!! i ■ ■■■!* p IG . 4. — Isolated Rabbit's heart perfusing with Ringer-Locke solution. A, normal ; B, after two minutes with 0.4 per cent, alcohol ; C, alcohol 0.8 per cent. Time in seconds. Dixon. alcohol on the heart is the same, namely, primary depression of function. o. On the cardiac centers of the medulla. — It has been diffi- cult to determine the direct action of the weaker doses of alcohol on the cardiac medullary centers because of the complicating reflexes. Also in an experimental procedure on mammals the medullary center is almost always rendered somewhat narcotized by the anesthetics employed. Dixon, however, has published results of experiments in which he used the beheaded dog. He injected alcohol into the carotid artery but toward the medulla. His published figures show a prompt but temporary rise of blood pressure and a change in the heart beat. A previous injection of 5 cc. of 30 per cent, alcohol in the jugular vein led to a marked fall of blood pressure. Dixon's figure presented ALCOHOL OX BLOOD VESSELS 31 herewith gives his evidence for assuming that the inhibitory cardiac centers are directly stimulated by alcohol. Brooks gave alcohol by the mouth, through a gastric fistula, and intravenously. The rise of pressure which he found on giving alcohol by the mouth he ascribes to a reflex stimulation. Brooks, by a more normal method, excludes any direct stimulative action on the niedul- Fig. 5. — Dog, cerebrum destroyed, but medulla uninjured. The records from above downward are respiration, intestinal volume, and blood-pressure. At the mark X 10 cc. of 30 per cent, alcohol was injected into the femoral vein. The right and left vagi were cut at the marks indicated to the right. Time in seconds. Dixon. lary center. Here again, therefore, we have the matter still in dis- pute and one must draw his conclusions guardedly. c. On the peripheral blood vessels. — The arteries are under a partial tonic contraction controlled by the nerves emanating from the vasomotor centers. Under the influence of alcohol these muscles relax, thus leading to a dilatation of the blood vessels. Dixon has reinvestigated this question, showing that there is with light doses an associated vascular constriction in the viscera. This positive visceral reaction he believes to be largely central, involving an asso- ciated alcoholic stimulation of the heat regulative centers. The stronger and semitoxic concentrations tend toward a general vascular paralysis, not only in the skin but in the viscera as well. The cutaneous dilatation is shown in the blush that comes in the 32 THE ALCOHOL GROUP cheeks and face of those who use alcoholic liquors even very sparingly. This blushing takes place more or less throughout the whole skin and gives rise to the feeling of warmth and glow which characterizes the early effects of alcohol. Undoubtedly the sensation is one second- arily produced by the slight rise in temperature of the skin associated with the dilated blood vessels. It is this factor which makes possible the great loss of heat even in the mild stages of alcoholism. It is an oft observed fact that those who take a " bracer " of alcoholic liquors in bitter cold weather cannot resist the extreme cold nearly so well as those who refrain. The dilated cutaneous blood vessels lead to a greater loss of heat than the body can supply, hence a lowering of the body temperature. Continued use of alcohol tends to a permanent paralysis of the cutaneous blood vessels. This paralysis is particularly striking in the cheeks and especially in the nose in chronic alcoholism. It is accompanied by degeneration of the active muscular tissue of the smaller arterioles, probably associated with decreased endothelial resistance and with fibroid thickening of the vascular walls, all of which contribute to a pathological condition of the tissues of the part. 7. The action of alcohol on the blood. — ' ' Alcohol has a harmful action on the white blood cells, the agents of natural defense against infective microbes " (Metchnikoff). The corpuscles are rendered less motile and therefore are decreased in their phagocytic action. Certain microbes, especially those of erysipelas, are shown to more readily gain a foothold in the body when the phagocytes are ren- dered relatively inert by alcohol, and it is also shown that alcohol users are prone to suffer from this disease. As was to be expected, the blood complements have also been shown to be distinctly reduced in users of alcohol. The importance of this change in the blood can scarcely be over-estimated in its relation to the establishment of immunity. Neither do the red corpuscles escape injury by alcohol, due to the relative solubility of alcohol in the red corpuscle substance. As a result, large numbers of corpuscles are weakened and ultimately destroyed. The continued display of alcohol therefore has a tendeney to the production of anemia. A not unimportant secondary influence of the consumption of large quantities of the lighter alcoholic liquors is its influence on the volume of the blood. The continued absorption and disposal of large quantities of fluid tend to raise the total volume of the ALCOHOL ON THE DIGESTIVE TRACT 33 blood and this reacts in the complex of the circulatory system to increase the work of the heart. The prolonged effect of this condition is great hypertrophy of that organ. Such liquors are generally asso- ciated in the long run with sufficient concentration of alcohol to produce muscular degeneration so that the beer drinker's heart becomes, not only excessively hypertrophied, but also weakened by fatty degeneration and infiltration. 8. Responses of the respiratory system to alcohol. — Alcohol affects the respiratory mechanism at two points, namely, the ap- paratus which controls the volume of air expired, and, second, that which controls the carrying power of the blood as regards its oxygen, Binz has given evidence indicating that alcohol slightly stimulates the respiratory centers, especially in the case of wines. Measure- ments have been made indicating that the total respiratory volume is increased with small doses of alcohol. Attention must again be called to the effect of alcohol on the nervous system. If one accepts the view of the depressant action of alcohol of the Schmiedeberg school, then it is obvious that this increase of respiration would take place as a secondary effect of the alcohol, either from the progres- sive narcosis of cerebral centers, or from reflexes arising in the mouth and stomach. In any case the acceleration of respiration is evanescent, passing quickly into a stage of depressed rate and amplitude, and the total air breathed is less. Dixon's figure shows primary respiratory depressant action, Figure 5. The influence of alcohol on the blood whereby the total amount of hemoglobin is diminished produces a chronic diminution in the internal respiration. Such an effect would not follow after a single dose. 9. The action of alcohol on the digestive tract. — The local irri- tating effects of alcohol on the alimentary tract and the secondary reflexes produced thereby have already been discussed. It should be remembered that the acute secondary effects of alcohol produced through stimulation of the nervous mechanism which controls the secretion of both the salivary and the gastric glands are favorable. When alcohol has been absorbed and, through the blood, reaches these glands and their nervous mechanisms, secretory action is apparently accelerated in the gastric glands but not influenced in the salivary glands, according to Chittenden. Alcohol mixed with the foods in the digesting stomach produces an increase in the absorbing powers of this organ. This is to be attributed to the direct effect of alcohol on the superficial epithelial 34 THE ALCOHOL GROUP cells whereby these cells are rendered more permeable than normal. Extensive experiments have been performed to show the action of alcohol on the digestive enzymes as such. These experiments indicate that the total efficiency of the digestive enzymes is decreased only after an alcoholic concentration of from 5 to 10 per cent. If one adds the two factors, increase in the total secretion of enzyme and the decrease in the efficiency of the enzyme present, it is obvious that the total efficiency of the digestive enzymes as such may be accelerated or weakened pretty much in proportion to the concentration of the alcohol. In therapeutic quantity and with guarded administration the medicinal balance is favorable in certain maladies. Excessive quantities of alcohol tend to diminish the motility of the stomach and intestine, a change that is unfavorable to digestion. If the peristalses of the stomach fail to occur in the normal number and intensity then the food will be relatively stagnant in the stomach and fermentive and other changes are induced which are detrimental. This is an important factor in the development of secondary toxic substances. Where the local action of alcohol has resulted in exten- sive gastric ulcers both secretion and motility are interfered with, and digestion is rendered correspondingly less efficient. io. The liver in relation to alcohol oxidations. — The physiolog- ical importance of the liver is very great, a fact that is realized when one recalls the numerous functions accomplished by this organ. The discovery of the glycogenic function of the liver by Claude Bernard in the middle of the last century gave such importance to this func- tion as to overshadow the several no less important functions that have been explained in more recent times. Of all the complex func- tions of the liver one cannot overestimate the part it plays in the elimination of nitrogenous wastes. Urea and uric acid are oxidized to their final form through the agency of the liver. The other nitrogenous wastes are oxidized or their elimination facilitated through the agency of enzymes which are present in the liver. Chittenden warns in the following terms : " It is, I think, quite plain that while alcohol in moderate amounts can be burned in the body, thus serving as food in the sense that it may be a source of energy, it is quite misleading to attempt a classification or even comparison of alcohol with carbohydrates and fats, since, unlike the latter, alcohol has a most disturbing effect upon the metabolism or oxidation of the purin compounds of our daily food. Alcohol, therefore, presents a danger- ous side wholly wanting in carbohydrates and fats. The latter are simply burned up to carbonic acid and water, or are transformed ALCOHOL ON METABOLISM 35 into glycogen and fat, but alcohol, though more easily oxidizable, is at all times liable to obstruct, in some measure at least, the oxidative processes of the liver. ' ' The evidence indicates that the oxidation of alcohol itself takes place largely through the agency of the liver. In the presence of alcohol a relatively large amount of uric acid and a decreased quantity of urea are produced by the body. Clinically it is a well-known fact that certain diseases of the liver are associated with chronic alcoholism. Of these one of the most common is cirrhosis. The drug not only acts on the peripheral hepatic blood vessels and parenchyma directly, but the view has been offered that the energy of the liver is consumed in the oxidation and elimination of alcohol. There is, therefore, an accumulation of nitrogenous wastes that weakens and poisons, not only the body, but the liver itself. The excessive accumulation of uric acid is offered as an explanation of the tendency to gout in alcoholics. ii. The effect of alcohol on metabolism. — The oxidation of alcohol by the body sets free its latent energy, which no doubt is utilized. However, the presence of the alcohol interferes with the metabolic processes of the body itself. In a general way it tends to depress these changes. Alcohol, when given with a fixed ration, produces a diminution in the output of nitrogen and of the total sulphur which are perhaps the best measures we have of the influence of the drug on metabolism. The variations in the specific functions of so many different mechanisms, as outlined above, all point in the same direction. The use of alcohol, therefore, as an energy producing material, is overbalanced by its toxic injuries. Even the energy which it gives is more than compensated by the weakening of the oxidizing organ, the liver. Hunt has more recently given us an insight into the nature of the change in metabolism initiated by alcohol. He has worked with minimal and non-toxic doses fed to different species of animals through relatively long periods. He has shown, for the first time, that such temperate use of alcohol leads to marked changes in the by-products of metabolism. Proceeding on the theory that tolerance presupposes increased ability of the tissues to oxidize alcohol, he established his point by tests with methyl cyanide which on oxidation liberates toxic substances. In his tests a mouse which recovered from a dose of 0.5 mg. of methyl cyanide per gram of weight, after a month's feeding with small quantities of alcohol in the food, quickly succumbed to a dose of 0.2 mg. Furthermore, Hunt found that the ethereal sulphates were relatively strongly increased, 3 to 50 per cent., 36 THE ALCOHOL GROUP under alcohol feeding, indicating failure of complete oxidations. This discovery, together with Edsall's observation of unoxidized phenol in the urine of chronic alcoholics, may also be explained as indicating injury to liver metabolism under alcohol. 12. The elimination of alcohol. — Alcohol is practically all oxidized in the body as shown by the calorimetric determinations of Atwater, except when excessive quantities are introduced. Of the remaining alcohol a trace only is eliminated by the lungs as shown by Cushny, and the remainder is excreted through the kidney. The excretion of alcohol by the kidney, especially when excessive amounts are taken, leads to certain cumulative effects which produce irritation. This produces a tendency to nephritis, which interferes with the normal functions of that organ. 13. The effects of repeated use of alcohol on tolerance, and on the germ-plasm and fertility. — Alcohol, like a number of the al- kaloids, when used repeatedly leads to the production in the tissues of a degree of tolerance. The body protoplasm acquires an increased power of oxidation and becomes less responsive to the drug. This accounts for the ability of a chronic user to consume such large quantities of alcohol without intoxication. Unfortunately these protoplasmic changes are associated with an unconquerable desire for the alcohol. The nervous tissue gets into such a state that the will power is no longer able to withstand the craving, and the individual consumes an excessive amount of alcohol. The moral and ethical side of this question is emphasized in voluminous literature. One of the most important changes produced in the body by alcohol is that on the germ-plasm. Both man and animals show a great decrease, not only in fertility, but in the number of normal offspring. Hodge has bred dogs from alcoholic parents in comparison with normal dogs and finds that the alcoholics show an average fertility of one-half, namely, 50 per cent. Of the young produced by normal parents an average of 90.2 per cent, were normal young. In alcoholic dogs this percentage of normal offspring is reduced to 17.4 per cent. Hodge quotes an instance of a study made on human parents showing that the number of viable children from alcoholic parents was 17 per cent, as against 88.5 per cent, from normal parents. The alcoholic families of both man and dogs produce a high percentage of defective and deformed offspring, many of the young in fact being born dead. The strength and development of the human embryo are dependent upon two factors, inheritance from the germ-plasms and nutrition during embryonic life. That alcohol influences the inheritance factor. SUMMARY OF EFFECTS OF ALCOHOL 37 through the father as well as through the mother, is indicated by the number of deformed and defective children born of parents of which one alone is alcoholic. Of the children born many are non-viable, that is, for one reason or another they are unable to take nourishment and do not develop normally. Possibly these defects are due to failure of full development of some internal structure. 14. The alcohol habit and disease. — Physicians, as well as lay- men, now take into account the habit-forming tendency produced by alcohol. "With its repeated use the tissues not only acquire power to oxidize and dispose of the alcohol, but there results a change which leads to a craving that cannot be satisfied. It is this factor which often leads to a rapid disintegration of an otherwise apparently strong and healthy individual. Through its effects on the defensive qualities of the blood, i.e., the phagocytes and the anti-toxins pro- duced by them, as well as because of the general changes in the effi- ciency of the circulatory apparatus, the profound changes in the metabolism of the liver, the tissues in general are rendered non- resistant to the invasion of disease. Germs which otherwise would be successfully combated and eliminated from the body are able to gain a foothold. This factor was especially emphasized by the obser- vations of Hodge on alcoholic dogs. An invasion of disease into his experimental kennels resulted in the death of several of his alcoholic dogs, whereas the normals recovered after relatively light attacks. Similar observations have been made at the various clinics on men. In quite recent years it has become a well-established fact that the excessive users of so mild an alcoholic drink as the Munich beer, are rendered more liable to disease and show a higher death rate. IV. Condensed Summary of the Effects of Alcohol on the Human Organism. Alcohol is a local irritant, acting on the skin of the mouth and on the mucosa of the stomach. It produces secondary reflex effects when so applied, some of which are quite favorable. When introduced into the general system, alcohol produces a narcotic effect, especially on the nervous tissues. It diminishes the activity of the cortex in its most complex relations, as shown by decrease in intellec- tual power, emotional control, and will power. The lower centers of the central nervous axis are temporarily released from the inhibitive 38 THE ALCOHOL GROUP control of the cerebral cortex, but later are depressed in function and ultimately paralyzed. Alcohol diminishes the efficiency of the vital organs, like the heart, blood vessels, the blood, and their nervous mechanisms, in certain cases with an initial but evanescent stimula- tion. In acute use it favors the reflex increase of the digestive secre- tions, but with a decrease in the amount of enzyme present in a given quantity of secretion. It also diminishes the digestive efficiency of the enzyme. Alcohol produces irritation and ulceration of the stomach after prolonged use, especially in the concentrated form. It also diminishes the motility of the stomach and the intestine. It inter- feres with the metabolism of the body, especially with the oxidations in the liver of the by-products of protein and nuclear metabolism. It tends to produce local inflammation in the kidney. It leads to the formation of the alcohol habit, and, in prolonged and chronic use, changes the germ-plasm and thereby diminishes both fertility and the viability of offspring. It breaks down the resistance of the body to disease by destroying the efficiency of the phagocytes, and leads to premature death of the individual. THE ANESTHETICS. CHAPTER III. ETHER I. Historical. Members of the group of anesthetics are characterized by the physical property of volatility, also by the physiological property of producing unconsciousness, and therefore loss of pain without any great danger to life. They have proven an invaluable boon to suffering humanity in their use in surgical anesthesia. The anesthetic properties of ethyl ether were introduced to the public by the activities of Morton in Boston in 1846. Chloroform was introduced the next year, 1847, by Simpson at Edinburgh. Nitrous oxide soon after came into popular use for periods of short anesthesia. In determining priority it appears that the anesthetic action of both nitrous oxide and of ether had previously been discovered, and had been used in isolated cases; but for one reason or another this knowledge had not become public property. Jackson demonstrated the anesthetic power of ether in 1841, and Long first used ether in surgery in 1842. But the honor of introducing ether into public use really belongs to Morton, not as its discoverer, but by virtue of his success in the public demonstration of its surgical value. It is now well known that even the ancients produced a degree of anesthesia or insensibility to pain in surgical operations. They used alcohol, some plant infusions, and in some cases a degree of asphyxiation, thus securing carbon dioxide anesthesia. But the intro- duction of drugs as a regular routine in relieving pain in surgical operations dates from the popular demonstration of ether in Boston by Morton in 1846. The anesthetics, by virtue of their great volatility and ready absorption by the tissues, are peculiarly adapted to surgical purposes. Inhaled, they come into intimate contact with a relatively large absorbing surface, the pulmonary capillaries. They quickly pass into the blood and are as quickly distributed throughout the body. 40 ETHER On the other hand, their elimination is by the lungs, a process which is at first equally rapid and efficient. Volatility with ready absorp- tion and elimination gives an immediate and advantageous control of the degree of narcosis quite impossible with non-volatile drugs that must be introduced by the slow process of gastric and hypodermic absorption, and eliminated by the even more retarded paths of general excretion. The relative action and safety of ether and chloroform have aroused a great amount of investigation throughout the surgical world. In Europe chloroform gained the greater favor, and has been used most extensively down to comparatively recent years. In America ether has been in greater favor and, at the present time, is used almost exclusively, except where it is contraindicated in special surgical cases. It is difficult to determine the relative danger of the two and our statistics depend almost entirely on figures derived from hospitals where conditions are most safe for its successful adminis- tration. Statistics from St. Bartholomew's from the years 1875 to 1890 show a death list for: Chloroform, in 18,526 cases, 13 deaths, 1 death to 1,502 Ether in 8,491 " 3 " 1 " " 2,830 Gas and ether in 12,941 " 1 death, 1 " " 12,941 In the cases collected by Julhard, the death-rate was: Chloroform 1 to 3,258 for 524,507 cases Ether 1 to 14,987 for 314,738 cases. The above figures indicate that the chloroform is about five times more fatal than ether, but that neither is especially dangerous. The eases do not, however, take into account the toxic influence on the organs produced by the anesthetic, such as develop secondary changes that may lead to death at some later period. Chloroform is generally recognized as much more dangerous from this latter point of view. II. Outline of the General Action of Ether. i. Stages of anesthetic effects. — Since ether and chloroform are used primarily for the production of anesthesia, it will be desirable to present at once the successive general stages recognized in the process of anesthetizing. These stages have been described by numerous STAGES OF ETHER ANESTHESIA 41 writers, and somewhat variously classified. However, four phases of action may be recognized as described in the changes in the general functions of the whole body. These are: 1. The excitement stage, 2. The intermediate stage, 3. The surgical anesthesia stage, 4. The toxic stage. The excitement stage is characterized by the presence of profound reflexes which are induced by the action of the ether on the mucous membranes of the respiratory tract. These lead to irregularities and some acceleration of the respiration, and often to violent cough- ing. Kespiration may occasionally be completely inhibited for several seconds, even producing considerable cyanosis. These periods are followed by deep and spasmodic respiration in which deep draughts of relatively saturated ether vapor are drawn into the lungs. There is reflex irregularity of heartbeat with considerable quickening of the pulse. There is a tendency to emotional states coupled with mental incoordination. In the late stages of this period analgesia is produced. The intermediate stage is usually short, but is associated with mental delirium, often strong muscular contractions or even spasms. There is great irregularity of respiration characterized by deep in- spiratory gasps. The cutaneous blood vessels are dilated, and narcosis and unconsciousness quickly supervene. The stage of surgical anesthesia is characterized by complete loss of pain sensations, complete relaxation of the voluntary muscles, and loss of general muscular reflexes. The breathing becomes regular as in a deep sleep, the pulse is regular, somewhat rapid, and the blood pressure medium. The light reflexes are lost and the pupil widely dilated. The corneal reflexes are present in light anesthesia, dropping out in the deep stages, a valuable indication of the degree of anesthesia. The temperature of the body is lowered, due to the greater dilation of the cutaneous blood vessels and to lowered metabolism. The anatomic mechanisms are still intact and respond to reflexes in the usual way, except in the very deep and profound anesthesia. The toxic stage or danger stage is indicated by a marked slowing followed by complete cessation of respiration. The blood pressure becomes low with paralysis of the vasomotor center, the heartbeat is weak from direct muscular anesthesia. The respiratory center often en. tirely ceases; even when the blood-pressure is relatively high, the heart will continue beating for some seconds. In mammals the circulation is kept up until the blood becomes strongly cyanotic, at which stage 42 ETHER there usually occurs a series of respiratory gasps in response to the direct effects of the highly venous blood on the respiratory centers. TABULATION OF THE CHARACTERISTICS OF THE STAGES OF ANESTHESIA. r coughing respiration accelerated pulse quickened vertigo -< occasional sharp reflex cardiac inhibition emotional tendency incoordination dilated pupil L analgesia 1. Excitement stage 2. Intermediate stage delirium muscular spasms respiratory irregularity dilated blood-vessels narcosis unconsciousness ' pain sensations lost muscular relaxation with loss of muscular reflexes regular breathing regular pulse with medium blood-pressure 3. Surgical anesthesia stage -{ light reflexes lost, pupil widely dilated corneal reflexes present in lighter stages absent in deeper temperature lowered by greater loss of heat I alimentary reflexes present except in deepest stage 4. Toxic stage f respiratory center becomes slower and ceases blood-pressure very low with paralysis of the vaso- motor center heart weak from direct muscular anesthesia III. The Details of the Action of Ether. i. The action of ether on the central nervous system. — The changes in the function of the central nervous system are the ones most important to surgical anesthesia, and many of the details have already been given in the summary above. From this list it is obvious that the narcosis is a descending one. It begins with the suppression of function of the higher or cortical centers, and is closed with the loss of function of the great vital centers in the medulla. There is an evident similarity of action to that produced by alcohol, also to that produced by chloroform as will appear later. Ether narcosis is preceded by a short stage of stimulation or accelerated function. Waller has demonstrated this point by a direct ETHER OX THE NERVOUS SYSTEM 43 study of nerve fibers. He determined the volume of the nerve impulse as measured by the action current which was given in response to a constant stimulus. This he found to be sharply increased at the initial stage of the action of ether. If this principle were accepted in general it would account for a number of phenomena noted in the stimulation stage in anesthetizing. However, many of the phenomena can also be accounted for largely on the basis of descending nerve narcosis, the principle considered in the study of alcohol. Many of the effects, when ether is first inhaled, are produced, not by the action of the ether on the central nervous system, but by Fig. 6. — Ether vapor on nerve irritability. A muscle nerve preparation is so ar- ranged as to subject the nerve only to ether vapor, which was applied between the arrows. Electrical stimulation at 10 second intervals. The first two contractions of the muscle are normal. The successive five contractions during the application of ether vapor. Slow recovery occurs on the removal of the vapor by a stream of fresh moist air through the apparatus. New tracing by Wallace. reflexes started by the local irritant action on the mucous membrane of the mouth, nasal cavity, and respiratory tract. Some anesthetists avoid this action in hypersensitive individuals by a preliminary nar- cotic, by cocaine sprayed into the upper portion of the respiratory channel, or by nitrous oxide gas. In the deeper stages of anesthesia, sensory stimuli no longer arouse the more complex centers of the central nervous system. Certain centers in the spinal cord, and especially in the medulla, are still capable of executing reflexes. Experiments of Bernstein indicate that local anesthesia of the spinal cord produces a block for sensory nerve impulses for spinal nerves of the anesthetized region, whereas reflexes still occur through the anesthetized region upon stimulation of sensory nerves of a non-anesthetized region. This indicates that the block to reflex nerve impulses occurs primarily in some of the sensory connecting links, rather than in the motor cells of the cord and brain stem. In the deeper anesthesia the motor cells also lose their irritability. The nerve centers in the medulla respond to reflex stimulation long after the cerebral cortex is narcotized, and after sensory reflexes 44 ETHER through the cord are lost. In animal experimentation the stimulation of the various sensory nerves, as, for instance, the sensory fibers of the vagus, produces, not only respiratory effects through the medul- lary center, but cardiac and vasomotor effects through their respective centers located in the same region. The retention of reflex irritability under ether anesthesia is of great surgical importance. It permits reflex stimulations during operations that may be, and generally are, important factors in pro- ducing the undesirable condition of shock. In recent practice certain accessory drugs, i.e., urea, quinine, or novocain, are being used to block the course of sensory nerve impulses, thus eliminating the un- desirable reflexes. 2. The action on the respiratory center. — In the excitement and intermediate stages the respiratory center undergoes great change, chiefly due to secondary stimulations developed by local peripheral irritation. In the toxic stage these cells are directly affected and are markedly depressed, respiration ultimately ceasing from loss of function of the cells of the respiratory center. Eecovery of the irritability of the respiratory center in ether paralysis is always possible so long as there is a considerable amount of blood-pressure, a factor that has been emphasized by Dixon. This is one of the chief points in favor of ether versus chloroform. Anesthesia so deep as to suspend the function of the respiratory center rarely causes a fall of blood-pressure of more than 50 or 60 per cent., usually much less. Artificial respiration will, therefore, generally recover the case. 3. The action of ether on the circulatory system and on blood- pressure. — The blood-pressure is maintained at a rather high level dur- ing ether anesthesia. Just at the beginning of the action of ether the blood-pressure rises slightly, i.e., during the stimulation stage, a change that is chiefly secondary in character. Occasionally there may be a reflex fall of pressure, see the heart action discussed below. In surgical anesthesia the blood-pressure is slightly below normal, though generally strong and effective. At death from ether the pres- sure falls slowly until the respiratory center ceases, then it usually drops rapidly to 20 to 30 per cent, of the normal. The early general pressure fall is followed by a secondary or asphyxial rise of variable amount, then a final sharp fall to approximately zero. 4. The action of ether on the heart.-AEther produces changes in the heartbeat both by direct action on the heart muscle and through the ne rvou s mechanism.^/ The first effects on the heart are reflexes which arise from the irritant stimulation of portions of the ACTION OF ETHER ON THE HEART 45 respiratory tract. Occasionally there will be a complete inhibition of the heart following the first two or three whiffs of ether. This usually lasts for only a moment, after which the heart resumes its beating with the usual vigor. In the intermediate stage, as the ether is distributed through the system, there is generally a slight acceleration of the heartbeat from direct muscular stimulation. In the late toxic stages the heart ceases to beat also from direct muscular action. These facts can be beautifully illustrated by the laboratory methods for studying the isolated heart, f The perfused frog's heart almost always shows an appreciable acceleration in rate when a Fig. 7. — The action of ether on the isolated heart of the dog when perfused through the coronary arteries, 2 per cent, hy volume in Ringer-hlood solution. The composition of the Ringer's solution was NaCl 0.9 per cent. + KC1 0.042 per cent, -f- CaCl 2 0.026 per cent. Time in 5 second intervals. New tracing by Kruse, Boutwell, and Heldt. weak ether solution is used. If the solution is made stronger then the acceleration is followed by a marked slowing, often by complete stopping. "With still stronger solutions slowing and stopping occur at once.\ With slowing of the frog's heart there is a decrease in the amplitude of the contractions and a dilation of the heart chambers. Undoubtedly these are direct muscular effects. Isolated strips of turtle's heart muscle exhibit similar phenomena, the ventricle becom- iDg slower and weaker, and the sinus also losing its waves of tonic contraction. The isolated mammalian heart also shows a characteristic picture of anesthesia, as does the heart studied in the complex of the body. Leo Loeb studied the effect of ether on the isolated mammalian heart, showing that 0.4 per cent, ether in solution in the blood leads to a stoppage of the rhythm. 5. Ether on the blood vessels. — In the stimulation stage of ether 46 ETHER anesthesia there is a marked flushing of the skin, an effect that is a secondary reflex response to the local sensory stimulation of the respiratory tract. However, this stage is quickly followed by the direct systemic action of the ether on the blood vessel walls and on the vasomotor center of the medulla. The latter is lowered in its sensitiveness to the usual medullary reflexes, thus leading to a loss of vascular tone. The decrease in peripheral resistance to the blood Fig. 8. — Ether, 4 per cent, solution in physiological saline, on the isolated cardiac muscle of the terrapin. Time, 5 seconds. New tracing by Summers. flow results in most of the fall of blood-pressure noted under ether. The vasomotor center, fortunately, does not completely lose its reflex irritability, in fact this irritability is only slightly diminished to the great mass of autonomic reflex stimulations. The peripheral vascular actions of ether are not uniform throughout the whole body. Along with the marked flushing of the skin, Kemp has shown that in the dog the blood vessels of the kidney are con- stricted. Of course such a constriction leads to an interference with the secretion of urine, and may produce complete anuria. It is possible that this renal action is due to the direct local action of the ether during excretion. The kidney is an important organ in the elimination of ether, especially during surgical anesthesia, when the concentration in the blood is greatest. The local concentration during excretion leads to local irritation and therefore inflammation, mild nephritis, or in prolonged anesthesia marked nephritis will result, a condition that is later associated with albuminuria, which is its characteristic symptom. ETHER ON MUSCLE 47 6. Action of ether on voluntary muscle. — It is easy to demon- strate by laboratory experiments that voluntary muscle is anesthetized as well as is nerve. If a muscle-nerve preparation be suspended in a moist chamber and the nerve alone be surrounded by ether vapor, the nerve shows a decreased irritability as judged by the response of the muscle to maximal and minimal stimuli. If the muscle alone be subjected to ether vapor it also shows a decrease in irritability lasting for some moments after the ether vapor is replaced by pure air. Ether narcosis of the nerve is preceded by a brief and slight increase in irritability, a fact which has not been shown for muscle. 7. Action of ether on the alimentary canal. — The effects of ether on the alimentary tract are also twofold, namely, systemic and local irritant with its corresponding reflex changes in function. In ordinary procedure the most marked stimulations occur in the mouth and upper respiratory tract, the reflex effects of which have already been discussed in relation to respiration and circulation. Important alimentary reflexes are produced through the various secreting glands connected therewith. The salivary glands, for instance, are markedly stimulated and a marked increase in the secretion of saliva follows. The smaller glands of the mouth and of the walls of the bronchial tubes also have their secretions increased. The movements of the alimentary canal are depressed by ether, especially in the deeper stages where they may be stopped altogether. But " Ether can be given sufficient to prevent any movements of skeletal muscle without interfering with the alimentary canal " (Cannon). Meltzer has recently called attention to the possibilities of anes- thetizing per rectum. While ether is absorbed in this locality it is not considered a very favorable method of anesthetizing, owing to the high local irritant action of the anesthetic. No specific effects of ether on the efficiency of the alimentary tract as a digesting mechan- ism have thus far been shown. 8. The absorption, distribution, and excretion of ether. — Over- ton and Meyer have advanced theories accounting for the absorption of ether and chloroform. Their view is that the anesthetics produce their characteristic action by virtue of great solubility in the cell lipoids. The fats and fatty compounds of the cells dissolve the ether and this changes the physical-chemical constants of the cell protoplasm, thereby interfering with its normal function. Such tissues as the nerve cells, which have a high content of lecithins, etc., would by this theory receive a greater quantity of ether than other tissues, as for example, the skeletal muscles. This theory furnishes a good working 48 ETHER hypothesis, though there is considerable evidence against its complete acceptance. In any case the ether markedly interferes with the metabolism of the cell protoplasm. Heat production is diminished and nitrogenous metabolism also. That the protoplasmic structure is to some extent disorganized is shown by the degenerative changes, fatty infiltrations, etc., which follow deep anesthesia. The kidney, the heart, the nerves, all have been shown to undergo varying degrees of fatty degeneration following surgical anesthesia. This is evidence of the degeneration of protoplasm, and of the fact that the drug is toxic in a chemical sense as well as in a physical. Ether is primarily eliminated by the same channel by which it enters the body, namely, the respiratory tract. Its great volatility favors its elimination from the body by this channel. Complete elimination takes place only very slowly, and ether can be detected in the breath for many hours after only a mild inhalation. Elimina- tion also takes place through the kidney where ether is excreted with the urine. The slow passage of the urine along the tubules favors irritant action of ether on the renal cells, thus producing inflamma- tion and fatty degeneration, i.e., nephritis. IV. Condensed Summary of the Action of Ether on the Body. Ether is a most reliable surgical anesthetic. It produces complete loss of consciousness, is relatively free from danger, and permits of rapid recovery when the drug is eliminated. The stages of anesthesia are (1) an excitement stage characterized by accelerated respiration and heartbeat, slight rise of blood-pressure, a local irritation of the respiratory tract with reflex dilatation of the pupil, a confusion of mental impressions. This stage is followed by (2) an intermediate one in which there is mental incoordination, a tendency to muscular reflexes that are uncoordinated in character, irregularity of respira- tion, analgesia, and finally complete unconsciousness, passing over into the third stage of surgical anesthesia. This is characterized by complete muscular relaxation, insensibility to pain, loss of muscular reflexes, regular respiration and heartbeat, an even blood pressure, loss of eye reflexes in the deep stages, but retention of the function of the medullary center. The final or toxic action of the drug is charac- terized by slow respiration with final stoppage, slight fall of blood- SUMMARY OF ACTION OF ETHER 49 pressure with slow and weak heart, which continues to beat for some moments after respiration ceases and before final death. Ether produces the most profound effects on the nervous system, but prac- tically all the other tissues are anesthetized. The heart is reflexly inhibited, but finally slowed and paralyzed by direct action. > The glandular tissues are reflexly stimulated to secretion, especially the salivary glands and the glands of the respiratory tract, with later depression. The kidney is directly and locally irritated, with a tendency to vascular constriction and suppression of urine, followed in the after period by albuminuria. Local actions in the lungs are irritation with a slight predisposition to inflammatory processes. Fatty degeneration may follow as a sequence in the liver, the kidney, and the heart. On the whole, ether is relatively safe, about four to five times safer than chloroform. CHAPTER IV. CHLOROFORM I. Details of the Action of Chloroform. i. Stages of anesthetic effects. — With chloroform, as with ether there are well-marked stages of effect during the production of anesthesia. These stages are characterized by very definite symp- toms which are similar in character to those produced by ether. Chloroform is much more toxic than ether and must be administered with its vapor well diluted with air. On this account the excitement stage and also the intermediate stages as described for ether are very much foreshortened with chloroform. It is generally stated that the local effects of choloroform are less irritant than in the case of ether. However, this difference does not preclude the local stimulations of the mucous membrane of the respiratory tract and the production, therefore, of all the local reflexes described for ether. These, it will be remembered, are interference with the respiratory rate and depth often with a temporary complete inhibition of respiration, increased reflex secretion of saliva, and marked irregularity of the circulation due primarily to reflex cardiac inhibition. A few deep whiffs of concentrated chloroform vapor at the beginning of its inhalation often lead to complete but temporary inhibition of respiration. In surgical anesthesia the greater intensity of action of chloroform is still operative, therefore there is a much narrower margin between the light and the deep stages, and between the anesthesia and the toxic stage. It is evident that slight variations in the proportion of chloroform vapor and of air will produce relatively great variations in the degree and intensity of anesthesia. In short, it requires a greater degree of skill on the part of the anesthetist to maintain a uniform and safe chloroform anesthesia. The percentage of saturation of chloroform vapor in the inspired air has been investigated by Rosenfeld. 1 His results on rabbits are given in part in the following table : — 1 Rosenfeld, Max, Archiv fur Pathologie und Pharmakologic, Vol XXXVII., p. 52, 1896. 50 ON THE CENTRAL NERVOUS SYSTEM 51 The Rapidity of Onset and Degree of Chloroform Anesthesia in Rabbits in Re- lation to the Percentage of Concentration of Chloroform in the Air. Exp. Per cent, by volume of Time before complete anesthesia, and notes. No. chloroform vapor 6 0.54—0.69 No anesthesia in 1 hr. Reflexes present, 43 min. Heart rate depressed. 5 0.93—1.01 Anesthesia in 40 min. Respiration regular for 4 hrs. 4 0.93—1.01 te " 53 " Heart rate accelerated. 3 1.16—1.22 ee " 31 " Respiratory failure in 1 hr. 56 min 2 1.41—1.47 te " 36 " Heart markedly depressed. Respiratory failure in 1 hr. 13 min. 1 1.63—1.65 te " 11 " Respiratory failure in 45 min. 2. The action of chloroform on the central nervous system. — With chloroform as with ether the narcosis of the nervous system is in a descending direction. The higher cortical functions pass through a very slight and brief stimulation stage, followed by a complete, but temporary loss of function. The suspension of func- tion involves, first the cerebral cortex and the great tracts of the sensory and the association centers, later the spinal reflexes, and finally the great vital centers of the medulla. Many of the early effects produced by chloroform are accomplished through variations in the reflexes of different portions of the nervous system. Keflexes that have their origin in primary stimulation of sensory surfaces of the respiratory tract can, to some extent, be depressed by previous treatment that lowers the sensibility of the cutaneous nerve endings, as for example by cocaine spraying or previous appli- cation of other drugs with local depressant action. Of the reflex effects the most profound are those which react through the respiratory center and through the cardiac inhibitory center. Some animals, as for example the rabbit, are especially sensitive in this regard. A whiff of chloroform vapor is often sufficient to inhibit respiration in the rabbit for many seconds. Occasional clinical experiences of the anesthetist show that a certain percentage of individuals of the human species also respond more completely to these local stimulations. In the later stages of chloroform anesthesia, the vital centers which are involved in the early reflex responses are narcotized by the direct action of the chloroform on the nerve cells. If the narcosis be deep then the sensitiveness of the centers to the usual sensory stimuli is lowered and the responses are correspondingly diminished. The danger stage of anesthesia depends chiefly on paralysis of the respiratory center. As a rule the irritability of the respiratory center can readily be recovered if the anesthetic has not produced too great 52 CHLOROFORM a fall of blood-pressure. However, chloroform has a profound effect upon blood-pressure, and, unfortunately, tends to a marked lowering of pressure at a time somewhat preceding the paralysis of the respiratory center. On this account, deep chloroform anesthesia is much more dangerous than that with ether. Artificial respiration \i\ Rate 48 Rate 96 a 1 l I 45 90 C I I I I I 36 79 d i i i i 42 90 33 78 / I i i Fig. 9. — The mild influence of chloroform on blood-pressure, heart rate, and on respiration. The respiratory and cardiac rates are indicated on the tracing. Between the successive portions indicated from a to f there have been omitted 10, 10, 15, 40, and 100 seconds, respectively. New tracing by Gullion. will often suffice to recover activity of the respiratory center when its function has been lost by a temporary toxic stage. This recovery is, however, much more difficult to attain than in the case of ether. 3. The action of chloroform on the circulatory system, — blood- pressure. — Chloroform tends to lower blood-pressure. In mammalian experimentation one rarely notices any initial rise of blood-pressure. The fall of pressure is accompanied, perhaps caused by an initial reflex slowing of the heart. Deep anesthesia is accompanied by narcosis of the musculature, not only of the heart, but of the arterial system as well. During surgical anesthesia the blood-pressure is considerably below that of the normal. If the anesthetic is pushed far, then there will be a marked and sudden fall of blood-pressure, with a slow and weak heartbeat and ultimate death. In mammals, as a rule, the respiratory center ceases its action before paralysis of the CHLOROFORM OX BLOOD-PRESSURE 53 heart is complete. This, however, depends upon the rapidity with which the chloroform is given. 4. The action of chloroform on the heart. — The first effect of chloroform on the heart is a reflex slowing produced by the local irritation of the sensory nerves of the mouth and naso-pharyngeal region. This slowing usually passes away after the anesthetic induces its systemic effects. During the initial systemic action there is a brief Fig. 10. — The influence of chloroform on the contractions of the isolated heart of the cat. The chloroform was in Ringer-hlood solution, 0.03 per cent, by volume. There is some lag before the chloroform solution reaches the heart tissue, also a slight mechanical displacement at the time the solution was turned on. Time, in 5 second intervals. Perfusion as marked. New tracing by Boutwell, Heldt, and Kruse. period of slight irregularity of the heart accompanied by periods of accelerated rate. 'Chloroform has a marked depressing action upon the functions of the heart muscled In deep anesthesia this depression accounts in large measure for the slow and weak pulse. Rhythmic beating strips of heart muscle cut from the ventricle of the terrapin respond very delicately to chloroform anesthesia. The amplitude is quickly diminished and the rate rapidly slowed and inhibited after suffi- cient vapor is used. } ( If the anesthetic reaches the stage of complete inhibition of rate then the rhythm is restored only after a long latent period.'l Chloroform and ether are usually in sharper contrast in this respect than shown in Figures 8 and 11. The mammalian heart is also very susceptible to chloroform vapor, presumably on account of the muscular effects of the drug. Isolated mammalian hearts show a diminution in rate and a great decrease in the amplitude when weak solutions of chloroform are added to the perfusing liquid. When simultaneous cardiograms are made from 54 CHLOROFORM the auricle and from the ventricle of an experimental mammal these effects on the rhythm and amplitude are shown in fine contrast. Cushny, and Gottlieb and Meyer, have published figures on this point. Cushny, especially, has demonstrated a more marked influence on the excursions of the auricle than on the ventricle. Ventricular contractions will be medium strong and vigorous at a time when the auricular contractions are reduced to a minimum. The more profound stages of chloroform suspension of function of Fig. 11. — Chloroform 0.1 per cent, in physiological saline on the rhythm of the ventricular muscle of the terrapin. The marked decrease in amplitude and rate is characteristic. This strength of chloroform will often completely inhibit the rate within five to ten seconds. Compare with Fig. 8 showing the effect of ether. Time in 5 seconds. New tracing by Summers. the cardiac muscle do not immediately destroy the vitality of the tissue. The function can be reestablished, though with much greater, difficulty than with ether. However, a pronounced toxic effect upon the protoplasm follows after such deep stages. A certain proportion of the heart protoplasm is killed, as indicated by the fatty degenera- tions which follow after a lapse of two or three days. These degenera- tions are in fact of great vital importance, hence very deep chloroform narcosis is to be avoided under all circumstances. 5. Action of chloroform on the blood-vessels. Following the first few inhalations of chloroform vapor there is a reflex vaso- dilation shown by the flushing of the skin. This stage is quickly followed by a direct systemic action of the drug on both the vaso- motor center and the blood-vessel walls. The vasomotor center loses its delicacy of response to the usual stimulations, thus allowing a CHLOROFORM ON MUSCLES 55 passive dilation of the blood-vessels. The smooth muscles of the blood-vessel walls are directly narcotized. This leads to relaxation and dilation and to a corresponding fall of blood-pressure. Local organs are affected by the dilation of the peripheral blood- vessels and the fall of blood-pressure. The kidney, for example, is markedly affected. The dilation of the renal vessels immediately allows greater carrying volume of blood, though this is more than counterbalanced by the general fall of blood-pressure. The general result is that the solution of chloroform vapor in the blood is brought into contact with the renal tissue in relatively greater amount, i.e., the slow speed of the blood through the vessels allows of proportionately greater time for local absorption, hence the renal tissue is correspondingly deeply anesthetized. This is shown, in part, through the partial suspension of function of the kidney. In a word, the somewhat more sluggish stream of blood through the kidney is, not only in itself unfavorable to the excretion of urine, but is favorable to the production of anesthesia of the renal tissue, still further reducing the power of excretion. As chloroform is excreted by the renal tubules it follows that there will be a somewhat con- centrated action of the drug at this point. Other organs, such as the liver, are similarly affected. Doubtless this is the explanation of the tendency to fatty degeneration in the kidney, liver, etc., following prolonged or deep chloroform anesthesia. 6. Action of chloroform on the voluntary muscles. — Voluntary muscles are directly anesthetized by chloroform. This is readily shown by the decrease in irritability of the muscles to direct stimula- tion during anesthesia. When isolated skeletal muscle is anesthetized with chloroform to the point of complete loss of irritability it can be recovered only by complete removal of the vapor and after pro- longed treatment with air or oxygen. The anesthesia stage for skeletal muscle is deeper and more profound for chloroform than for ether. 7. The action of chloroform on the alimentary canal. — Chloro- form will anesthestize the tissues of the alimentary tract as it does every other tissue thus far examined. These effects are, as in ether, both indirect through the reflexes and direct. The direct effects come only after the chloroform is absorbed into the blood and has passed through the circulation. This stage is characterized by a depression of function, i.e., by anesthesia of the muscles of the stomach and intestine and by a suspension of the secretion of the digestive glands. The reflex effects are accomplished chiefly through the local action of chloroform on the naso-pharyngeal and mouth regions. These 56 CHLOROFORM reflexes last only a brief time and consist in the increase in the secre- tion of the saliva and probably of gastric juice. The normal peri- stalses of the stomach and of the intestine are suppressed by chloro- form, though the matter has not been sufficiently investigated for full statements. 8. The absorption of chloroform. — The great volatility of chloro- form favors its administration admixed with air by way of the res- piration. Though it has a relatively low solubility in water and in the watery content of the cells, i.e., a saturation factor of one part in two hundred, 0.5 per cent., still this is well above the efficient con- centration for anesthetic purposes. Its solubility in the cell lipoids also favors its absorption by the tissues. Probably, as Meyer and Overton have indicated, this lipoid solubility is a factor in the dis- tribution and relative intensity of action of chloroform on the tissue. This would account for its specific effects on the nervous tissue, the red blood cells, etc. Roaf gives good evidence to show that the re- actions of chloroform in the body are not entirely physical. Metabolism is lowered by chloroform. This is evident from the great diminution of the output of nitrogen as well as the lowering of functional activities which characterize chloroform anesthesia. Chlo- roform tends to destroy the protoplasmic organization ; this undoubt- edly is the contributing factor which leads to more or less fatty degen- eration after its administration. If the destruction of the tissue is slight, then ultimate repair occurs and no untoward effects follow. If the injury is marked, then fatty degeneration occurs with its chain of pathological disarrangements from which death will occasionally follow. Unfortunately these delayed effects are not always charged up to the primary cause, i.e., chloroform anesthesia. 9. The excretion of chloroform. — Chloroform, like ether, is elimi- nated from the body by the respiratory tract and by the kidney. The respiratory tissue through which the chloroform vapor enters and in a large measure leaves, and the kidney are relatively deeply anesthetized. They, therefore, feel the evil effects of the anesthetic as expressed in degenerative changes. II. Condensed Summary of the Action of Chloroform on the Body. Chloroform is a widely used surgical anesthetic, comparing in value with ether. It produces complete loss of consciousness and a descend- SUMMARY OF ACTION 57 ing elimination of function of the great divisions of the central nervous system. Rapid elimination and recovery follow when the drug is removed. The stages of anesthesia are the same as with ether, except that the excitement stage and the intermediate stage are passed over more quickly. Chloroform vapor must be administered with great dilution in air. Slight variations in the concentration of the vapor produce more profound variations in the degree of anes- thesia. Chloroform is several times more toxic than ether, therefore, more dangerous. In the danger stage there is complete loss of mus- cular reflexes, great weakness of the respiratory activity, slow and weak heart, dilated blood-vessels, and correspondingly low blood-pres- sure. The toxic stage is marked by a cessation of respiration through direct action on the respiratory center and a quick fall of blood-pres- sure and weak heart. Recovery of the toxic depression of the res- piratory center is rendered very difficult because of the associated low blood-pressure. [The heart is directly anesthetized, greatly slowed, and finally paralyzed. ) The alimentary tract is at first reflexly stimu- lated though slightly, and later depressed because of the direct action of the drug on the smooth muscle. The kidney parenchyma is directly anesthetized, and, to some extent, undergoes toxic degeneration follow- ing chloroform anesthesia. The nervous tissue responds in a similar manner. Fatty degeneration of the kidney, of the liver, and of the heart muscle characterizes the after-affects of prolonged chloroform narcosis. Chloroform is many times more intense in its action, there- fore more dangerous than ether. CHAPTER V. NITROUS OXIDE. I. Historical and General. The anesthetic action of nitrous oxide, N 2 0, was discovered at the end of the eighteenth century. It is therefore the oldest of the anesthetics unless one give consideration to the use of alcohol along this line. The action of nitrous oxide was first noted by Davy. Like many other valuable observations this one was not followed up, hence the peculiar value of this agency was not utilized until after the introduction of ether and chloroform. Wells in 1844 rediscovered the action of nitrous oxide, though again this act did not result in its immediate introduction into general use. Nitrous oxide produces anesthesia, but only when administered in concentrated form. This fact has led to considerable discussion of the nature of nitrous oxide action. It is claimed by some that the gas does not produce anesthesia, but instead does produce a degree of asphyxiation by the exclusion of oxygen. However, experiments by Kemp and others have shown that the nitrous oxide has a direct effect upon the nervous tissue. Kemp experimented on dogs, allow- ing them to breathe nitrous oxide mixed with oxygen in known con- centrations. He found that when an animal was anesthetized with nitrous oxide mixture and then allowed to breathe a mixture of nitro- gen and oxygen in the same proportions, it quickly recovered from the anesthetized condition. Kemp analyzed the gaseous content of the blood and thereby proved that there was sufficient oxygen present to maintain life, provided an indifferent diluting gas only was present. These experiments indicate that asphyxiation cannot account for the anesthetic effects and that nitrous oxide is a true anesthetic. II. The Action of Nitrous Oxide on the General Activities of the Body. If nitrous oxide is inhaled in concentrated form for a few minutes, it quickly produces a degree of intoxication followed by unconscious- 58 THE ADMINISTRATION OF NITROUS OXIDE 59 ness. The early symptoms are not unlike those of alcoholic intoxi- cation except that a leading characteristic is that of uncontrolled laughter. It is this that has led to the name ' ' laughing gas. ' ' There is a marked lowering of response to sensory stimuli and a decrease in the acuteness of pain sensations. This condition is characterized hy a lack of coordination of the voluntary muscles and a lowering of the sensibility of the central nervous system in general. This stage is followed by complete unconsciousness in which respiration is weak and in which there is a tendency to dyspnea. The circulation con- tinues even though there oe temporary stoppage of respiration. If the gas is removed, unconsciousness lasts only a brief period, 40 to 60 seconds. Kecovery is almost instantaneous, and the individual suffers no untoward after-effects. The maintenance of prolonged anesthesia with nitrous oxide is difficult, owing to the high concentration of the gas required. How- ever, for brief operations, the nitrous oxide has proven a valuable anesthetic to be recommended, because of the ease of application and because of the lack of danger in its use. Practically no instances of death have been recorded which are attributable directly to the anesthetic. Its freedom from danger makes it invaluable for such operations as the extraction of teeth or for minor surgical operations, but its use has been largely restricted to dental work. This gas has no characteristic special actions in the body. Such symptoms as occur other than general anesthesia can be largely attributed to the disturbance of the respiratory balance. Partial anesthesia produces in the body secondary physiological effects as detailed in the discussion of the reactions from ether and chloroform. Nitrous oxide responses show a large percentage of disturbance of this type. There is, therefore, a marked rise of blood-pressure, increase of the heart rate, disturbances of the respiration rate, etc. III. The Administration of Nitrous Oxide. The surgical administration of nitrous oxide is best accomplished with a controlled admixture of gas with pure oxygen. This mixture is secured by a mechanical apparatus, of which there are several de- vices in use in various institutions. With such an apparatus as that invented by Hewitt it is possible to administer nitrous oxide of any concentration. His apparatus contains three chambers, nitrous oxide 60 NITROUS OXIDE in one, pure oxygen in one, and from these cylinders mixtures can be made in any proportion in the third chamber. A close fitting face mask is connected by means of a wide tube with the chamber con- taining the mixed gas, from which inhalations take place. However, the later forms of apparatus have a rubber bag attached to the mask Fig. 12. — Application of Hewitt's nitrous oxide and oxygen apparatus in surgical operation. After Hewitt. (which is preferable), or to a side tube on the connecting tube. The inhalation of external air is controlled through a side valve. In practice it is best to fit the mask and then allow the patient to breathe pure air until everything is tested. The gas bag is then filled with pure gas and this is breathed for from 10 to 15 breaths^ a quantity usually sufficient to put the patient thoroughly asleep without inducing cyanosis. The gas bag is then refilled with oxygen THE ADMINISTRATION OF NITROUS OXIDE 61 and gas in the proportion of 1 to 6 or 8. 1 Great variation exists in the individual requirements as to the percentage of gas and oxygen. In starting the anesthesia with pure gas, great care must be taken not to allow cyanosis, and if such appears during the anesthesia, the Fig. 13. — Chart showing nitrous oxide anesthesia associated with local infiltration of 1 to 400 parts novocain. The chart shows the chauges in blood-pressure and pulse rate during a three-hour operation for the resection of the right half of the colon. Bloodgood. practice is to allow the patient to have one or two breaths of pure air, thus tending to keep the blood-pressure under uniform control. When nitrous oxide is the only general anesthetic used, then a local analgesic is applied at the point of incision or wherever intense nerve stimulation may occur. For this purpose use novocain in 1 to 400 parts. 2 1 For details given in this place I am indebted to several papers by Dr. J. C. Bloodgood, and to personal information from Dr. J. E. Stowers, who has assisted Dr. Bloodgood in numerous operations. 2 Bloodgood, J. C: Annals of Surgery, Vol. LVIII., p. 721, 1913. 62 NITROUS OXIDE An illustration of the practical use of nitrous oxide gas by this method is given in the preceding chart, Figure 13. Nitrous oxide is being more and more used as a preliminary anesthetic to chloroform or ether. It has the effect of producing a quick partial anesthesia, thus enabling the patient to pass more safely and comfortably over the excitement stage of ether and chloroform. This procedure has also the economic value of reducing the quantity of ether required. There is practically no danger from the adminis- tration of nitrous oxide for brief anesthesia. Yet the disturbances of the circulation induced by the temporary degree of asphyxiation are associated with some little danger in atheroma, or in certain types of cardiac irregularity in which nitrous oxide is to be excluded. CHAPTER VI. CHLOKAL HYDRATE. I. Historical and Chemical. In 1868 Liebrich described chloral hydrate as a new hypnotic, since which time it has become a reliable and widely used drug for that purpose. Chloral hydrate is a representative of the methane series, with the structural formula: CC1 .COH.H 0. 3 2 ( Trichloracetaldehyde ) The discovery of the physiological effects of this drug has led to the examination of numerous other representatives of the series, and has given us a group of drugs with general narcotic powers. In general they are characterized by a change in function more nearly resembling that in sleep and hence known as hypnotic. Chloral hydrate is far less volatile than either chloroform or ether. How- ever, it is very soluble in the body fluids, hence can be absorbed readily from the alimentary tract. There is a numerous series of represent- atives of the hypnotic group, but none have become of primary im- portance. Of this series may be mentioned chiefly chloral hydrate, urethan, veronal, and sulfonal. II. Outline of Pharmacological Effects of Chloral Hydrate. 1. It produces a narcosis resembling deep sleep. 2. The narcosis is characterized by a lowering of sensibility to stimulation with diminution of pain. 3. There is a marked lowering of blood-pressure with slowing of the heart rate and a tendency to a diastolic pause. 63 64 CHLORAL HYDRATE III. Details of Pharmacological Action. i. The general symptoms. — The general symptom complex pro- duced by chloral hydrate is remarkably like that of natural sleep in a profoundly fatigued individual. There is at first inertia, drowsi- ness, with sluggishness in response to severe stimulation. This stage passes into a sleep-like stage of unconsciousness. The sensory mech- anisms remain irritable and the patient reacts to strong stimuli which may still arouse in him consciousness, unless the amount of chloral ad- ministered be excessive. 1 to 1.5 grams produces drowsiness with sleep, while a dose of 4 to 5 grams produces a profound degree of unconsciousness from which it is very difficult to arouse the patient, even with excessively vigorous stimulation. Since chloral greatly lowers the stimulation threshold, pain sensations are diminished. Re- covery from chloral is relatively slow, 4 to 5 hours after a gram dose, 10 to 12 hours after a 5-gram dose. It is for these general symptoms that the members of the group have their special value, namely, as depressants of the central nervous activity. 2. Chloral hydrate on the nervous system. — The general symp- toms described above are in fact nervous system effects. Chloral hy- drate seems to specifically depress the functional activity of nerve cell groups in the central nervous system. Of these groups those cells in the cerebral cortex are of the most profound importance since the de- pression of their sensibilities leads to diminished responses to the usual inflow of sensory impulses. The influence, however, is more profound in that the coordinative activities of the neurons in the cor- tex are depressed. Such responses as result in the basic nuclei of the nervous system from chemical or possibly hormone reactions are proven to be lowered. Of these nuclei those located in the medulla are the most important. For example, the respiratory center in the medulla has recently been shown by Cushny x to be lowered in its sensibility to carbon dioxide stimulation. It is true that this center is still responsive to afferent nerve stimulation while under the influence of chloral hydrate. The change in the nerve cells produced by chloral hydrate comes on only slowly and under the influence of a rather strong dosage. Eabbits make little response up to a dose of Cushny, A. R.: Journal of Pharmacology and Experimental Therapeutics, Vol. IV., p. 380. CHLORAL HYDRATE ON THE NERVOUS SYSTEM 65 0.17 gram per kilo given intravenously. "When the dosage reaches 0.28 gram there is a distinct fall of respiratory rate, and after 0.4 gram a sudden fall in the rate together with an increase in the depth of respiration accompanied by forced breathing. Under this condi- tion of mild chloralization, i.e., 0.17 grams per kilo, " the reflex movements and general activity are very much diminished and the carbon dioxide production must fall in corresponding measure." 1 ' As the dose is increased the excitability of the nerve center is so far reduced that it can no longer maintain the rate even under the double stimulus of carbon dioxide and anemia, but it continues to deepen. Finally its rate is reduced to one-ninth of the normal, while its depth is doubled. " Chloral hydrate narcosis does not, however, lower the rate of oxidations of sea urchin eggs. CHAPTER VII. MOEPHINE AND THE OPIUM SERIES. I. Historical and Chemical. The dried juice of the poppy, Papaver somniferum, contains a series of some twenty alkaloids of which morphine is present in greatest amount. The juice or milk is obtained by scarring the unripe seed pods. The exudate is evaporated in the open air, and the dried product is known as opium. Opium is produced in largest amount in the Asiatic countries. Turkey, Persia, East India, and China, and also Egypt are the great producers of opium. In recent years an increased quantity has been grown in Europe, and its culti- vation is now being introduced into the United States. The medicinal reactions of opium have been known since ancient time. The alkaloid morphine is of special interest as being the first alkaloid chemically isolated in pure form, 1804. Of the series of alkaloids present in opium, the following are the most important: Morphine C H NO r 17 19 3 Codeine C HNO o 18 21 3 Papaverine C H NO r 20 21 4 Narcotine . C H NO, 22 23 7 Thebaine C H NO 19 21 3 The percentage of the different alkaloids present in opium varies extremely, depending upon the country and climate, and upon the method of gathering and drying. Opium contains from 10 to 20 per cent, of morphine, the former being the average requirement of the medicinal drug. Opium on the market, however, may contain from 3 to 18 per cent, of morphine, 1 to 10 per cent, of narcotine, 1 to 2 per cent, of codeine with traces of the large number of alkaloids that have been isolated from this mixture. The chemical relationships of the opium alkaloids is complex. 66 HISTORICAL AND CHEMICAL 67 The structural formula of morphine, for example, is still in question. It is apparently a derivative from a hydrated phenanthrene nucleus, and has been given by Knorr as follows : OH v >C H oh/ 14 10 0-CH 5 I CH 2 I KCH 3 Codeine and thebaine differ from morphine in that the hydrogen of the hydroxyls is substituted by methyl, one methyl in the former, two in the latter alkaloid. With this substitution the change in the physiological action approaches that of the caffeine group, where an increase of methyl in the series produces the same type of physio- logical change in the action. The chemical relationships may be expressed by the following formulae: HO v >C II ho/ 14 10 CH 3 ^C H ho/ 14 10 -0-CH, I CH 2 I KCHs Codeine CH 3 0. \q h CHsO/ 14 10 Thebaine In modern synthetic chemistry a series of products have been built up by substituting radicals for one or more of the hydrogen atoms in morphine. Of these heroin is of chief importance from the pharmacological and therapeutic point of view. Heroin is a diacetyl morphine of the following formula: CHsCO.Ov CH3CO.O / C,JI.( -0-CH 2 I C1I 2 , N.CH3 Heroin Morphine as an alkaloid is very insoluble in water, while its salts are quite soluble, six per cent, or more. The salts have the same pharmacological action, and are generally used, the sulphate being official. 68 MORPHINE AND THE OPIUM SERIES II. Outline of Pharmacological Action of Morphine and the Opium Series. 1. Morphine produces a marked depression of the central nervous system in the descending direction preceded by slight initial stimula- tion. The change of greatest importance is the great decrease of the perception of pain. 2. Depression of the blood-pressure with marked cardiac depres- sion after larger doses. 3. An initial increase followed by marked decrease of the peri- stalses of the alimentary canal associated with pyloric stricture. 4. A constriction of the pupil from central action, with dilation in the paralytic stage. III. Details of Pharmacological Action. i. The central nervous system. — The action of morphine on the central nervous system varies greatly. In animals there is a marked variation in response by the different species, especially among the mammals. In man the general picture is one of slight initial increase of function followed by very marked depression. The first and primary effect on man of a mild dose of morphine, and especially of opium, is a gradual diminution in the activity and control of the higher psychic centers. There is a marked decrease in the power of attention, followed by a dreamy, sleepy, imaginative state which is the condition desired by the opium abuser. This stage is characterized by lack of power of consecutive thought, a diminution of acuteness of judgment, and inability to long maintain effort if it involve logical sequence. The picture evidently indicates a selective action on the association centers and other higher psychic centers of the cerebral cortex. There is a certain degree of excitement some- times shown in the so-called imaginative stage somewhat similar to that produced by certain alcohols, especially absinthe. However, mor- phine is much more sedative and does not lead to the excessive mus- cular activities produced under the former drug. Morphine greatly reduces the power of self-control, therefore leaves the individual in the position of a reflex animal. In the incipient stages of morphine intoxication there is a delay ACTION ON THE NERVOUS SYSTEM 69 in the facility with which intellectual acts are accomplished. This is quickly followed by a languid state in which the individual is aroused only by much more vigorous stimuli than are usually required. He may pass into a dreamy, sleepy state in which the sensations of pain are greatly blunted. The usual reflexes from stimulation of the skin are very greatly decreased though not eliminated. The change > Voluntary MovemtntUet Cannot Control movement \ Ga.nn.ot jump Unableto reeover pos ition when laid,, on t£s back. Pig. 14. — Dorsal view of the frog's brain. The legend shows the progressive effect of morphine and other narcotics which destroy the higher functions of the brain in the descending direction, i.e., in the reverse order of" their racial development. Dixon. depends upon the central depression rather than any direct effect upon the peripheral sensory apparatus. The chief value of morphine as a medicinal agent depends upon this characteristic reduction of the sensitiveness of the central nervous system to pain stimulation. In fact, morphine is probably the best known and most valuable alle- viator of pain in the whole category of drugs. With excessive doses of morphine the person lapses into a deep sleep from which he is awakened only with extreme difficulty, and even then only into a semi-conscious state. However, even in the advanced toxic stage, i.e., until respiratory paralysis is approaching, he can be aroused sufficiently to move around. Power of voluntary movement is only lost in the final toxic stage. In this deeply toxic 70 MORPHINE AND THE OPIUM SERIES condition the centers of the spinal cord have their irritability very sharply diminished, also the controlling medullary centers. The toxic action of the morphine falls very heavily upon the reflex mechanism within the cord without completely paralyzing it, hence this mechan- ism can be set into action, but only with the most profound cutaneous stimulation, a fact to be remembered in the treatment of morphine intoxication. The depression of the medullary centers falls most largely upon the respiratory center. The respiratory rate is greatly diminished according to Cushny 1 without suppressing the responses of the center to sensory stimulation and to the direct stimulation of carbon dioxide, 0" 20' 40" 100' 120" 140' 160' 180" Fig. 15. — The influences of C0 5 inhalations on the respiratory rate and amplitude before and after morphine. The tests of carbon dioxide were given 6 minutes before morphine, and 21 minutes after morphine. The rate and depth of respirations are represented by the ordinates. Time in 20 second intervals. Cushny. — — — depth before morphine. respiratory rate before morphine. depth after morphine. respiratory rate after morphine. though this latter response is greatly lessened in absolute amount. The amplitude is little decreased except in the very toxic degree of action. In the late stages of morphine intoxication the rhythm en- tirely ceases and death follows from the respiratory failure. 2. Morphine on the circulatory system. — The responses of the circulatory system to morphine are complex, since the drug acts at several points in that system. Blood-pressure studies on mammals show, as a rule, a marked fall of pressure if morphine is injected intravenously in a relatively strong dose. The fall is accompanied by a large beat, but very slow heart rhythm, together with a peripheral vascular dilation. If the vagus nerves are severed the heart rhythm is more rapid, although a decided fall in the pressure still occurs. 3. The reactions of the heart and its nervous mechanism. — The heart is affected by morphine in two ways, primarily by change in 1 Cushny, A. R.: Jour. Pharm. and Exper. Therap., Vol. IV., p. 363, 1913. THE REACTIONS OF THE HEAKT 71 the functional influence of the nervous complex, and secondarily through the direct action of the drug on the cardiac muscle. The heart rate is reduced to half or even less of its normal rate with a characteristic large and swinging amplitude, when a small to medium dose of morphine is given an otherwise undrugged animal. This effect comes from a primary and sharp stimulation of the inhibitory center in the medulla. If, in a mammal, the vagus nerves are sec- tioned before morphine is injected, the heart rate instead of slowing is markedly accelerated, a fact which may be interpreted as a direct stimulation of the accelerator center, see Figure 17. In this latter case there is still a great fall in the blood-pressure which is indicative of a general vascular dilation, an effect that can be explained by either of two conceptions, namely, vasodilator stimulation or vasocon- strictor paralysis. In light of the positive evidence as regards the cardiac centers one is inclined to consider the phenomenon a positive vasodilation. With the stronger intoxication from morphine these stimulative reactions on the medullary vascular centers pass into depression, i.e., narcosis. Morphine directly influences the rhythm, the contractility, and probably the conductivity of cardiac muscle. The rhythm is more profoundly depressed, though the amplitude may be, and generally is greatly diminished. Isolated portions of cardiac muscle, when bathed by relatively strong solutions of morphine may have the rhythm com- pletely obliterated. This influence is of the nature of a narcosis and can be slowly removed by eliminating the contact of the drug. Un- doubtedly this direct influence of morphine on heart muscle is a factor in the complex of the symptoms with all stronger doses of morphine, but does not appear in the reaction to therapeutic con- centrations. Recently Eyster and Meek x have shown that the intravenous and subcutaneous administration of morphine to dogs not only slows the heart, but produces characteristic irregularities in the cardiac action. Intravenous injections of 30 to 60 milligrams of morphine usually slightly increase the pulse for a few minutes, then there comes on a marked slowing of the rhythm. Still later there develops arrythmia in which there may be a sino-auricular block or an auriculo-ventric- ular block. " Electrocardiographic records indicate that the slowing and arrhythmia are due to disturbance of conduction between the point of origin of the cardiac impulse and the auricle, and between 1 Eyster and Meek, Heart, Vol. IV., p. 62. 72 MORPHINE AND THE OPIUM SERIES the auricle and ventricle. ' ' At any time during the irregularity of the heart rhythm the administration of atropine completely recovers the regular rhythm. This antagonism of atropine for the morphine effect leads the authors to conclude that the peripheral cardiac change is a vagus effect. This view has been strengthened by the known fact that vagus stimulation may lead to similar blocks of cardiac conduction. EFFECT OF MORPHINE ON THE ELECTROCARDIOGRAM (EYSTER AND MEEK) Exp. Normal After Morphine P Q R s T RT P Q R s T RT 6 3 6 25 6 -7 0.192 1.5 2 19 6 +6 0.227 7 3 14 27 -5 0.240 2 8 28 -1 0.280 8 2 9 33 6 +2 0.207 1 6 30 6 +2 235 9 3 8 30 6 -4 0.185 0.5 6 24 5 +3 235 10 2 6 25 6 -2 0.243 1 2 19 6 +3 0.262 4. A review of the normal movements of the stomach and in- testine. — The stomach is divided into the two great cavities, the Fig. 16. — Intravenous injection of 2 cc. of 1 per cent, morphine on blood-pressure and respiration. Vagi intact, dog. The respiratory rates and heart rates as shown. Time in seconds. A, 10 seconds before morphine. D, after 4 1-2 minutes. B, 30 seconds after morphine. E, after 7 minutes. C, after 2 minutes. F, after 2S minutes. fundus and the pylorus. These cavities are bounded by muscular bands, the cardiac sphincter, between the esophagus and the stomach, and the pyloric sphincter at the boundary between the pylorus and MOVEMENTS OF THE STOMACH 73 duodenum. A cardiac-pylorus sphincter between the fundic and pyloric parts has been described but is questioned. The muscular walls consist of the general circular and longitudinal muscle coats, the special muscular sphincters being only thickened modifications of the RATE 13 RATE 157 B RATE 10 RATE 140 Fig. 17. — The influence of morphine on blood-pressure and respiratory rate. Vagi cut. Experiment on same animal as Fig. 16. A, immediately after injection of mor- phine ; B, 1 1-2 minutes later ; C, 6 minutes later. Still later stages of this experiment show slow but gradual recovery similar to but not so rapid as in Fig. 16. The respiratory rates and heart rates as shown. circular muscle. "When the stomach is completely relaxed the sphinc- ters are passive, but when the stomach is filled as with food, then they are thrown into tonic contraction. Cannon has recently shown that the regulation of the contractions of the cardiac and of the pyloric sphincters is dependent upon an acid stimulation, the " acid closure." The acid of the gastric juice, largely secreted in the ot,.n ' -N CH 3 N Theobromine— 3.7. dimethylxanthine HN OO HN- CO I c— -NH >co NH Uric acid II. Outline of Pharmacological Effects. Caffeine is one of the purest stimulating agencies acting on physiological mechanisms which has thus far been described. Its primary effects are: — 1. The excitability of the central nervous system is increased in the descending direction, stimulation primarily of the cerebral cortex and later the centers of the spinal cord and the medulla. 2. It increases the power of muscular contraction of all kinds of muscle. 3. It is a cardiac and vasomotor stimulant. 4. Caffeine is a vigorous diuretic. III. Details of Pharmacological Effects. 1. Caffeine on the central nervous system. — The alkaloids of the caffeine group increase the irritability, and therefore the volume of the reactions, through the central nervous system at all points. Its stimulating effect falls, first and primarily, upon the cerebral cortex, especially on the higher psychic functions of the association centers of the cortex. It increases the delicacy of sensory perception by increasing the sensitiveness of the mechanisms of the cortex. As a result a given sensory stimulus produces a greater volume of psychic reaction during caffeine than before the use of this drug. The association of ideas is facilitated^ As a net result, the ability to do mental work and the volume of work done are both increased. It is evident that caffeine produces a change in the nervous complex, which facilitates the passage of nerve impulses, hence there is a tendency to alertness and fatigue is displaced by a feeling of com- fort. But, while caffeine is favorable to the greater production of psychic activity under stress, attention must be called to the fact that such a nervous whip is not without its exhausting after effects. ACTION ON THE SPINAL CORD 91 The amount of physical work which a man can do depends, not only upon his muscles, but upon the neuro-muscular mechanism as a whole. Caffeine by its influence upon the nervous side of the machine alone, greatly increases the amount of physical work and endurance. Thus, in modern army regulations the well-known beneficial effects of caffeine are recognized by the addition of coffee to the ration dur- ing the execution of forced marches. A part of this influence of caffeine falls upon the muscular tissue, as will be explained later, but the main effect is in the stimulation of the central nervous system. With larger and especially with excessive doses of caffeine, ex- treme restlessness and nervous excitability occur and severe headache develops. In extreme cases there is some confusion of thought with a tendency in the toxic intensity of action to delirium and convul- sions. Many individuals are hypersensitive to caffeine and cannot endure the larger doses to which the average person gives only a moderate response. 2. The spinal cord. — Caffeine and other members of the group add to the sensitiveness of the spinal cord. Reflex excitability is in- creased, though not to anything like the extent produced by strych- nine. Even the lower vertebrates show a greater response to cutaneous stimulations, in some cases approaching tetanus. These effects are shown more delicately on toads, Bufo, than on the usual laboratory frog, Rana esculenta, partly due to the characteristic motor activities of the former. 3. The medulla. — Caffeine stimulates the nerve centers of the medulla, especially the cardiac inhibitory and the respiratory centers. In the case of the respiratory center the alkaloid apparently acts directly on the nerve cells, greatly increasing their sensitiveness. Respiratory stimuli, therefore, produce markedly greater discharges of motor nerve impulses. The respiratory rhythm is also sharply accelerated. 4. The action of caffeine on the skeletal muscle. — Caffeine in- creases the amount of muscular work which can be voluntarily accom- plished, as shown by ergographic records. A percentage of this bene- ficial effect is due to central nervous action as previously mentioned, but apparently the larger part is due to the influence of the series on the muscular tissue. The most striking demonstration of this point is had from parallel records from the work of two gastrocnemii. If one muscle be allowed to absorb caffeine through the normal cir- culation while the other is kept free from the drug, and if parallel records be taken of the contractions in response to repeated stimuli 92 THE CAFFEINE GROUP of the same intensity applied to each muscle, it will be found that the drugged muscle will do from ten to thirty per cent, more work than the normal muscle. Skeletal muscle is also rendered more sensi- tive to stimuli so that the minimal stimulus has a smaller intensity in a caffeinized muscle. Larger, i.e., toxic, doses produce a persistent contraction and rigor, a fact that is of diagnostic value in dis- tinguishing between caffeine and strychnine in physiological toxi- Fig. 22. — The influence of caffeine 0.1 per cent, in blood-Ringers solution on the contractions of the isolated heart of a cat perfused through the coronary, arteries. The irregularity which appears in the last portion of the tracing continued to increase, showing periodical groups of extremely rapid rhythm. The regular rhythm was soon re-established. On repeating the experiment the rhythm was enormously increased and accompanied by even a more marked increase in amplitude. Time in seconds. New tracing by Boutwell, Miller, and Peeler. cology. This rigor can be produced by the different members of the series, including xanthine itself. Smooth muscle and cardiac muscle are similarly influenced by caffeine. 5. Caffeine on the circulation. — The effect of caffeine on the general circulation is to produce a rise of blood-pressure. The degree of change is influenced by the somewhat antagonistic physio- logical effects of the stimulation of different parts of the circulatory mechanism. Therapeutic doses of caffeine produce a favorable rise, while the strong doses are apt to be followed by irregular results. This is explained by the details which follow. CAFFEINE ON THE VASOMOTOR APPARATUS 93 6. Caffeine on the cardiac mechanism. — Caffeine and the other members of the series stimulate both the nervous mechanisms con- trolling the heart and the cardiac muscle, as shown in heart strips and in the isolated mammalian heart. There is an increase in the rhythm and a stronger contraction. This increases the discharge of blood from the ventricles, both from the increased volume of a single beat and from the increased number of beats for a unit of time. Undoubtedly this favorable influence on the function of the heart is due to direct action on the muscular tissue. This is proven by the influence of caffeine on isolated ventricular muscle from the lower animals. Xanthine, which is a product liberated in the mammalian body, also markedly stimulates the mammalian heart as shown by Kobert. Strips of terrapin's ventricle produce stronger contractions, and usually an acceleration of rhythm when bathed in graded strengths of solutions of caffeine. This favorable activity on the heart muscle is also shown in the perfused isolated frog's heart preparations where the amplitude is markedly increased and the rate slightly accelerated. In the frog's heart there is a tendency to systolic contracture, espe- cially in the late stages of the after effects. Cushny has demonstrated the favorable action of caffeine on the heart by direct records from the heart of mammals in situ. Caffeine produces both acceleration and increased amplitude under these conditions. The heart rhythm is often slowed by therapeutic doses of caffeine. This apparently contradictory action is due to a preponderant stimu- lation of the vagus center in the medulla. In the therapeutic dose the medullary stimulus is greater than the direct cardiac, hence there is relative slowing. By laboratory experiments it can be shown that minimal inhibitory stimuli for the vagus become subminimal after the injection of caffeine, which is due to the greater activity of the cardiac muscle and not to depression of nerve function. 7. Caffeine on the vasomotor apparatus. — The vasomotor ap- paratus is stimulated by caffeine both centrally and peripherally. The vasoconstrictor center is set into greater tonic activity, which leads to increased peripheral constriction. The drug also produces a greater irritability of the smooth muscle, which adds to the periph- eral constriction of the arterioles. Hence there is a marked increase in the vascular resistance with a corresponding rise of blood-pressure. With excessive doses this peripheral constriction amounts to a vascu- lar spasm, and may thus influence the reactions of the tissues in secondary ways. 94 THE CAFFEINE GROUP 8. The action of caffeine on the respiratory mechanism. — The acceleration of the discharge of nerve impulses from the respiratory center under the influence of the caffeine series was mentioned while discussing the medulla. But the favorable reaction is in part due to the peripheral influence on the respiratory muscles. In all marked depressions of the respiratory mechanism, as from alcohol or in mor- phine narcosis, caffeine forms a splendid antagonistic drug. Con- siderable quantities of caffeine may be administered in such cases without running the risk of collapse in the after stages, of the kind which characterizes the effects of over-stimulation from strychnine. 9. Caffeine on metabolism. — The study of the central nervous system, of the musculature, and the great circulatory and respiratory mechanisms, all indicate greatly increased functional activity under the influence of caffeine. It is obvious that metabolism in these special tissues is accelerated thereby. The metabolic increase is further indicated by the greater output of carbon dioxide and of nitrogen, and also by the rise in general body temperature. 10. The diuretic action of caffeine. — Therapeutic quantities of caffeine, and especially of theobromine, produce marked diuresis in man and the mammals. The diuretic action may increase the output of urine per unit of time several hundred per cent., as demonstrated by Cushny on the rabbit. In man this increase may amount to fifty per cent, or more. Associated with the greater water output, there is an increase in the solids of the urine, both inorganic and organic. Considerable discussion has arisen as to how the favorable influ- ence of caffeine is accomplished. By some it is held that the diuretio action is secondary to the favorable action on the circulation. This, however, will scarcely account for the greater volume of urine some- times observed in low blood-pressure. It is more probable that the caffeine members act to increase the irritability of the renal epithelium in a way not unlike their action on muscular and nervous tissue. With toxic doses of caffeine there is occasionally complete suppres- sion of the urine, a result that is explained by the production of arterial spasms with shutting off of an adequate renal blood flow. 11. The absorption and excretion of caffeine. — The alkaloids of the caffeine series are readily absorbed from the alimentary tract. They are excreted by the kidney, but only in small part unchanged. The greater part of the caffeine undergoes oxidation in the body, with loss of methyl, being converted into dimethyl or into monomethyl- SUMMARY OF ACTIOX OF THE CAFFEINE GROUP 95 xanthine. The xanthine of caffeine origin is undoubtedly further oxidized in the body in the same way as the xanthine of animal origin. IV. Condensed Summary of the Action of the Caffeine Group. Caffeine is a primary nerve stimulant. Its action is char- acterized by descending stimulation, falling first upon the cerebral cortex and later upon the centers of the medulla and spinal cord. It produces a primary acceleration of psychic activity, a greater sensitiveness to the inflow of stimulation, which arouses, or at least supports, intellectual work. Caffeine also stimulates the motor nervous mechanisms of the spinal cord and the medulla. It increases the power of the skeletal muscle to do muscular work. Therefore it has a favorable influence over conditions of fatigue and exhaustion, coupled with a minimum of deleterious after effects. Respiratory activity is markedly accelerated, due to increased sensi- tiveness of the respiratory center and in part to an increase in the irritability of respiratory muscles. The circulation is favorably augmented by a rise of blood-pressure, and a slightly slower but stronger heartbeat. Heart muscle itself is rendered more irritable and its contractions more vigorous, but in therapeutic doses of caffeine, the stimulation of the inhibitory center overcomes the muscular ac- celeration. The arterioles are constricted, partly from direct mus- cular action and partly from increase in the tone of the vasomotor center. Metabolism in general is favored and the body temperature increased. Diuresis is produced by caffeine through primary stimu- lation of the renal epithelium. Anuria may result from an over- stimulation by the production of stricture of the arterioles. Caffeine loses its methyl and is oxidized down to monomethyl xanthine and uric acid in which forms it is largely excreted. A portion may be excreted unchanged. CHAPTER X. THE STRYCHNINE GROUP. I. Chemical and Historical. Strychnine is an extremely toxic alkaloid, found together with its relative brucine in the various species of Strychnos. These alkaloids are present in the largest quantity in the seeds, but are also found in portions of the bark and wood. The best known species from which the alkaloids are obtained are Strychnos nux vomica, and Strychnos ignatia. The seeds of Ignatia contain about two per cent, total alkaloid, three parts strychnine, and one part brucine, of nux vomica from 2.6 to 3.9 per cent, of the two alkaloids, about equally distributed. Strychnine is much more toxic than brucine, in about the ratio of 1 to 50. The chemical formulae of the two alkaloids are : C21H22N2O2 = C20H22O — CO Strychnine r C 23 H 26 N 2 04 = C2 H2o(OCH 3 ) 2 0— CO M Brucine The brucine differs from strychnine in that it contains two oxy- methyl groups. Both alkaloids are very insoluble in cold water, but they readily form salts, which are soluble. II. Outline of Pharmacological Action. 1. Strychnine increases the irritability of the spinal cord and the central nervous system. 2. It causes convulsions and tetanus in toxic doses. 96 DETAILS OF PHARMACOLOGICAL ACTION 97 3. It increases the sensibility of special sense organs. 4. Tonic reflexes are produced by the bitter taste. III. Details of Pharmacological Action. Nux vomica has for a long time enjoyed a favorable reputation as a vigorous stimulating agency. Hypodermic preparations of the strychnine salts are given more or less indiscriminately in emergency cases, not only as legitimate nerve tonics, but too often on the mis- taken theory that they are vigorous cardiac stimulants. With strych- nine, as with numerous other medicinal agencies, there has been a tendency to generalize the use of the drug from insufficient data. Strychnine is, as a matter of fact, a tremendous nerve stimulant. On the other hand, its use on the heart and circulatory system as an emergency stimulant is partially, if not wholly, irrational. i. The spinal cord and brain-stem. — With strychnine in thera- peutic quantity, up to 2 milligrams of strychnine nitrate, there is a great increase in the reflex irritability of the centers of the spinal cord and brain-stem. This produces an increase in the sus- ceptibility to the ordinary normal stimuli with a corresponding in- crease in the volume of discharge of motor nerve impulse. The slight acceleration of the cerebral cortex and of the higher nerve centers, produced through the action of this factor, is relatively insignificant. Strychnine action on the spinal cord seems almost specific, in that the effect is selective on the spinal structures. If the brain be removed strychnine still produces the same qualitative effects. Reflexes take place through the cord in response to milder stimuli than in the normal, and there is a tendency to the involvement of larger and larger areas of cord until, with toxic doses, even the mildest stimulus enter- ing at any sensory point, may set the whole neuro-muscular mechanism into tetanic spasms. By tetanic convulsions one understands spasmodic and persistent contractions of the entire voluntary musculature. The individual muscles exhibit series of very rapidly following contractions with imperfect relaxations. The usual well coordinated alternate contrac- tions of the opposing muscles no longer occur, but instead, the exten- sors contract at the same time and stronger than the flexors. The effect is that the trunk and limbs are thrown into an extended posi- tion. The entire body thus becomes stiff and rigid. The muscular cramps involve the respiratory mechanism, hence, when they follow 98 THE STRYCHNINE GROUP each other too rapidly they tend to produce asphyxia. Man and mammals usually die after a short series of convulsions, largely be- cause of an asphyxial paralysis of the respiratory center. Frogs may endure tetanic contractions for days and even weeks, due to the fact that adequate respiration is maintained through the skin in these animals. In attempting to explain the mechanism of the strychnine cramps, it has been shown that complete severance of all the sensory nerves Fig. 23. — Von Kolliker's scheme of neuron relations in the spinal cord. Orange, afferent or sensory ; red, efferent or motor ; and black, central or connecting neurons. leads to failure of the development of the spasms. Central stimula- tion of the end of a sensory nerve sets up strychnine contractions. In like manner, cocainization of the entire skin will eliminate strych- nine spasms when the body is otherwise so senstive that even a slight current of air is sufficient stimulus to initiate the contractions. It is perfectly evident that sensory stimulation is necessary to the develop- ment of the tetanic contractions, but that the tetanus does not depend upon the toxic change in that mechanism. Houghton and Muirhead ' 1 Medical News, 1895. ACTION ON THE MEDULLA 99 determined experimentally that strychnine specifically poisoned the receptive, i.e., connecting, neurons of the spinal cord. They ex- posed the spinal cord of the frog, having excluded the circulation, and painted a local area with strychnine solution. The area painted soon became hypersensitive, showing the usual general tetanic re- sponses to cutaneous stimulation. The tetanus involved, not only the local area, but also the motor area of the unpoisoned parts of the cord. On the other hand, stimulation of portions of the skin connected with an unpoisoned portion of the cord led only to the usual normal reflexes. Since direct stimulation of the motor cells themselves can- not produce tetanic spasms, it is to be inferred that the toxic influ- ence falls especially on the connecting nerves lying between the afferent sensory and efferent motor neurons of the cord. The alteration of the protoplasm produced in these cells by strychnine does not lead to automatic discharge of nerve impulses by the cells in question, but the cells are rendered so very unstable that the least sensory stimulus sets them into maximal discharges. The nerve impulses are strong enough to break down the usual physiological resistance to the diffusion through the differential mechanisms of the cord. Sherrington x has called attention to the physiological fact that the stimuli leading to contractions of the flexor muscles of the body are associated with inhibitory processes for extensor muscles, and vice versa. Whenever an extensor is reflexly stimulated the flexor will be inhibited. In other words the stimulative processes for an agonist are associated with an inhibition of the antagonist. Strych- nine undoubtedly destroys this normal antagonistic action of the two sets of muscles. One may assume that in strychnine tetanus the physiological resistances through the cord which maintain the balance between the agonistic and antagonistic groups are so broken down by the drug that all power of coordinative reaction is lost. This general effect of strychnine characterizes the reaction of the entire vertebrate series, though the sensibility of the cold-blooded animals is considerably less than that of the mammals. 2. The medulla. — Strychnine produces similar changes in the medulla to those noted in the spinal cord, though the cord is more sensitive to the drug than the medulla. The nerve centers of greatest importance in this connection are the respiratory, the vasomotor, and the cardiac inhibitory centers. These are all increased in sensitive- ness by the therapeutic action of strychnine, hence give a greater volume of response to the usual sensory stimuli. Sherrington: Phil. Trans. Royal Society, 1898, Vol. OXC, p. 1G0. 100 THE STRYCHNINE GROUP 3. On respiration. — The influence of strychnine is to increase the respiratory activity due to the increased sensitiveness of the respira- tory center and the central connecting mechanisms of the cord in- volved in respiratory movements. Strychnine is therefore in thera- peutic quantity a good antagonist for pathological or pharmacological effects which tend to depress the central mechanism of the respiratory apparatus. The converse holds under restricted limits only. That is, the late or toxic paralysis of strychnine must be guarded against, lest Fig. 24. — Sherrington's diagram to indicate the anatomical basis for the physio- logical control of stimulative and inhibitive processes in the spinal cord. R. and L., right and left pairs of antagonistic muscles. a, <£, afferent paths, which, when stimulated, produce coincident stimulations, +, and inhibitions, — , as shown. This orderly reaction is broken down by strychnine. this stage of its action be additive to that produced by the primary acting narcotic. 4. On the circulation. — Therapeutic doses of strychnine produce changes in the circulatory apparatus only by causing variation in the delicacy of response in the central portions of the nervous mechanism controlling the heart and blood-vessels. This point cannot be too ACTION ON THE CIRCULATION 101 strongly emphasized, owing to the general and often indiscriminate practice of administering strychnine in cardiac emergency. The heart is indeed influenced in its rhythm and amplitude, but only through changes in the reflex sensitiveness of the cardiac centers of the cord and medulla. In the otherwise normal animal the heart, as a rule, contracts with a somewhat slower rhythm and stronger amplitude, typical of increased vagus activity. The changes in the heart rhythm under ordinary tonic and therapeutic doses of strych- nine, are relatively insignificant; in the subtoxic doses permissible in mammalian experiments the heart rate is often markedly slower. This statement is applicable to experiments on the otherwise normal animal under surgical anesthesia. If a mammal be curarized and artificial respiration be maintained, then the variation in cardiac rhythm under the influence of strychnine may be demonstrated. The curarized animal is especially instructive in other regards. For example, in a mammalian experiment, on the animal used in the experiment represented in Figure 25, there were intermittent periods of very slow cardiac rhythm, alternating with periods of striking accel- eration. Considering the fact that strychnine following nicotine and atropine, which together eliminate the function of the major por- tion of the autonomic system, produces no change in either cardiac rhythm or blood-pressure, it is a logical deduction that the drug is acting through the controlling nervous mechanisms. Further, strych- nine produces its changes through the central portions of these nerv- ous mechanisms. Referring back to the alternate retardation and acceleration of the heartbeat mentioned above, it is obvious that these two nerve mechanisms are both strongly influenced by strych- nine, i.e., by action on the centers. Slight variations in external con- ditions may give one mechanism the controlling hand at one time, the other at another time, since both vagus and accelerator centers are known to be in tonic action. 1 Cardiac muscle, on the contrary, is not only not stimulated, but decidedly depressed both in amplitude and rhythm under the influence of strychnine. If, for example, the frog's heart be perfused with strychnine solution, its rhythm and amplitude are both decreased. Following normal perfusion, there is a very slow and prolonged but gradual recovery from the toxic effects on the cardiac protoplasm. Similar reactions are noted on the isolated mammalian heart. The amplitude of its contractions is depressed without a preliminary rise. It would seem from the above facts and arguments that the bene- a Hunt, Reid: Jour. Exp. Med., Vol. II., p. 151, 1897. 102 THE STRYCHNINE GROUP ficial effects of strychnine on the circulatory system, that have been claimed in therapeutic practice, must rest wholly on the changes in the reaction delicacy through the central nervous mechanisms. By an increase in the irritability of the cardiac inhibitory and ac- celeratory centers, normal stimuli may produce more profound and beneficial changes in the musculature of the cardiac apparatus. It must be remembered, however, that even this favorable cardiac re- WWW Stryehnine eurarlzed dog \4?J** S%$tr zn t niinnniiiim r i nii> i iiLiimnii i nmmiin> ii mtimMMn»H = d i n n i n ii n i M MM i >in i minnm i ii i iMnimuMU > nn i> )M iiii|ii Mi i i i in i n iii >n Fig. 25. — The action of strychnine on the vascular nervous complex as shown in the blood-pressure and pulse changes. Two experiments, a and b are presented in this figure. The experiment was performed on an ether anesthetized dog under the influence of curare, and with artificial respiration. Experiment a shows the influence of an initial dose of 1 mg. of strychnine injected into the venous system. Experiment & represents the effect of a repetition of this dose after several minutes. Between a and & the pulse rate varied greatly, showing periods of slow rhythm, as indicated in the initial rate in &, interspersed with periods of extremely rapid rhythm. The slow rhythm at the beginning of tracing & is due to inhibition. * Gross variations in blood- pressure independent of respiratory rhythm occurred. These are well shown in 6. In a succeeding test during a period of slow rhythm the vagus nerves were cut, the heart rate leaped forward to 210 per minute. The scale to the left measures the pressure in experiment a from a zero at the time line at the bottom. The zero and time line of experiment 6 falls on the 20 millimeter pressure level of the first experiment, hence, deduct 20 millimeters of mercury to read the scale for 6. Time in seconds. New trac- ing by Kruse, Boutwell, and Heldt. sponse to strychnine is somewhat antagonized by the depression of the cardiac muscle tissues. In a similar way the vasomotor center is found to be more sensi- tive to reflex stimulation when under the influence of strychnine. This leads to an increase in blood vascular tone, though the benefit is relatively more slight than the changes induced in the heart. In the tetanic stage of the reactions of skeletal muscle it is claimed that the ACTION ON THE SKELETAL MUSCLE 103 vasomotor center is also thrown into tetanic discharge, thus producing vascular cramps. A slight rise of blood pressure is usually noted during the muscular tetani, a fact also explained on mechanical grounds, i.e., through the mechanical pressure changes in the abdomen and thorax. My experience is that the mechanical factors play a very small part in vascular changes induced by strychnine. This fact is borne out by the influence of strychnine after nicotine and atropine. Although muscular cramps will be produced as usual, they are not accompanied by more than slight mechanical changes in blood- pressure. 5. On skeletal muscle. — The greater volume of muscular con- tractions noted in an animal, when under the influence of strychnine, Fig. 26. — Strychnine on muscle irritability and muscle work. Little change is shown on irritability of the muscle, but the work is increased. Frog 18 grams, dose 0.1 cc. of 0.1 per cent., allowing 10 minutes for absorption, load 75 grams. Time in 2 second intervals. New tracing by Summers. has generally been explained as due wholly to the influence of the alkaloid on the central nervous system. However, parallel experi- ments on the amount of work which the isolated gastrocnemii of a frog will do under rhythmically repeated stimuli applied directly to the muscle, show that the strychninized muscle will accomplish a greater amount of work than the normal muscle. In fact, the muscle substance becomes somewhat more sensitive to stimuli ; in other words, the minimal stimulus on the drugged muscle is reached by a stimulus of weaker intensity. It has not yet been clearly shown whether the muscle substance or the " receptive substance " is really the point of favorable action. In the toxic stage strychnine produces a paral- ysis of the motor end plates in a way comparable to curare, with which the drug is chemically related. This last point suggests that 104 THE STRYCHNINE GROUP the receptive substance may be the point stimulated in the therapeutic dosage. 6. Action on the special sense organs. — Experimentation has produced cumulative results indicating a definite beneficial influence on the sensitiveness of the special sense organs. The sense of smell is rendered more acute, and a change in the character of odors has been noted. In the same way the senses of sight and of hearing are rendered more acute, the usual tests of hearing are perceived at a greater distance than normally, and the visual field is enlarged. The sense of touch is rendered more delicate. This increase in delicacy is noted both in relation to the strength of the threshold of the stimulus and in the accuracy of localization. However, it is not clear just what portion of the sensory mechanism is acted upon by the drug. We are inclined to believe that the change is chiefly, if not wholly central rather than peripheral, though unilateral action claimed for the eye cannot be explained by this view. 7. On the alimentary canal. — Strychnine has long enjoyed a reputation as a bitter tonic. This is due primarily to the extremely bitter taste, which can be detected one part in 600,000, but there is a factor of systemic action involved. The bitter taste leads to pro- found physiological reflexes involving the mouth and gastric glands, also the motor apparatus of the stomach. When strychnine is ab- sorbed, even in extremely small quantity, the secretory and gastric motor mechanisms of the central nervous system are rendered more susceptible to stimuli, hence an increase in tone results. The general influence on metabolism, especially of sluggish tissues, as in vascular and in alimentary atony, is favorable. 8. On metabolism. — Since strychnine produces a general rise in tonus of the neuro-motor mechanisms of the body and increases the volume of response to the usual stimuli, it is obvious that it will pro- duce a general rise in metabolic activity. There is a tendency to a rise of body temperature, though it is controlled by the heat regu- lating mechanism. The increased metabolism is secondary rather than primary. Hence skeletal muscle, the plain muscle, and the glands are thrown into greater activity through the greater delicacy of poise of the centers of the central nervous system. Strychnine is fixed by the tissues of the body, probably by the lipoids. Koch suggests that the intensity of action of strychnine bears a relationship to the percentage of lipoids in the particular tissues most strongly influenced by the alkaloid. 9. Excretion. — Strychnine is excreted unchanged in the urine, STRYCHNINE POISONING 105 although a portion is greatly delayed in its excretion, due to its fixa- tion in the tissues, and a proportion is ultimately oxidized. This latter point was established by Meltzer, who found that nephrectomized rabbits were able to withstand strychnine in toxic amounts, provided it were given in broken doses. IV. Strychnine Poisoning. The too frequent cases of strychnine poisoning make it desirable to discuss the antidotes and treatment. Accidental and suicidal poisoning usually occurs by the method of taking the drug into the stomach. The first step then is to produce evacuation of the stomach, either by vomiting or by means of the stomach pump. Precipitants such as tannic acid or strong tea may be given for temporary fixation of the strychnine, but this must be removed just the same. Strych- nine is not readily absorbed from the stomach, but disappears readily when it reaches the intestine. After convulsions have begun or are approaching, it may be very difficult to introduce the stomach tube. A slight spray of cocaine in the mouth-pharynx region is beneficial or ether or chloroform may be given lightly, in order to pass the tube. Evacuation of the stomach should be followed up with systemic treatment, which consists in the use of antagonists, such as ether or a small quantity of chloral. Ether is preferable to morphine because of the greater ease of its control. Chloral and morphine by their prolonged action become dangerous in the paralytic stage of strych- nine action. Meltzer has recently emphasized the value of artificial respiration in strychnine poisoning. The administration of large quantities of fluid and of diuretics is favorable, though the excretion of strychnine is relatively slow at best. Brucine. Brucine has an action very similar to that of strychnine except that it is much weaker. It requires a dose of brucine about fifty times larger to produce similar effects. In one regard, brucine is relatively more toxic, namely, in its curare-like paralysis of the motor nerve endings. Thebaine, one of the alkaloids of opium, it must be remembered, has also an action similar to strychnine. It also brings on strychnine- 106 THE STRYCHNINE GROUP like spasms, though these spasms come somewhat later and are less intense. Condensed Summary of the Action of Strychnine. Strychnine is a convulsant alkaloid, acting primarily on the cen- tral nervous axis and specifically on the connecting neurons between the sensory and motor neurons. Its action falls most heavily on the spinal cord, and on the medulla. In therapeutic quantity it produces great increase in the reflex irritability of the cord and of the great vital centers of the medulla. It has a slight though important similar effect on the higher portions of the brain and cortex. In toxic dose it breaks down the central resistance so that the mildest of sensory stimuli produce profound and general tetanic contractions of the entire skeletal musculature. The smooth muscle of the circulatory system and of the alimentary tract take little part in the tetanic cramps. Respiration is accelerated, the heartbeat somewhat slowed, and the vasomotor tone somewhat increased — all due to increase in sensi- tiveness of the corresponding nerve centers. The rhythm and ampli- tude of heart muscle are both decreased without preliminary stimula- tion. Hence beneficial cardiac tonic effects do not occur directly, though there are some favorable actions on the nervous mechanisms, chiefly the vasomotor. Skeletal muscle (of the frog) is more sensi- tive after strychnine and yields larger contractions to normal stimuli. Motor endplates are paralyzed by the toxic dose. C. Drugs with Specific Action for Peripheral Parts of the Nervous System. CHAPTER XL THE CURARE GROUP. I. Historical and Chemical. The South American Arrow Poison, Curare, stands as an example of a series of toxic preparations that have long been known by the aboriginal inhabitants of the northern portion of the South Ameri- can continent, especially the valley of the Amazon. At the time of the earliest explorers these people were using arrow poisons, both in the hunt and in war. Efforts have been made by whites to discover the exact plants from which these concoctions were made, but the matter has been made difficult by the fact that the Indians hold the prepara- tions secret. The toxic principles are apparently derived, almost exclusively, from members of the Strychnos family, of which Strychnos toxifera and Strychnos castelnasa are the chief. Boehm has isolated several toxic principles, curine C 18 H 19 N0 3 , tubocurarine, C 19 H 21 N0 4 . The former is slightly different in its action, while the latter produces the results typical of the crude preparations. Both are strongly toxic. The native preparations are put up in containers typical of the differ- ent localities. Boehm 1 has examined these preparations and finds that they contain, in different proportions, a number of related alka- loids. Beside the above may be mentioned protocurine, C 20 H 23 NO 3 , protocuridine, C 19 H 21 N0 3 , and protocurarine, C 19 H 25 N0 2 . These alka- loids readily form crystalline acid salts. II. Outline of Pharmacological Action. 1. Specific paralysis of the motor nerve endings in skeletal muscle. 2. Paralysis of the pre-post ganglionic synapses of peripheral ganglia when large doses are used. 1 Boehm: Festschrift zu Carl Ludwig's 70. Oeburtstagc, 1886. 107 108 THE CURARE GROUP III. Details of Pharmacological Action. i. Specific action on the motor nerve endings. — Curare owes its physiological action almost exclusively to the specific toxic paralysis of the connecting substance, linking motor endings and skeletal muscle. This fact was demonstrated in the middle of the last century by Claude Bernard, 1857, by the method which has become classic in physiological literature. The method slightly modified as now prac- ticed is: First, shut off the circulation in one leg of the frog by a ligature around the thigh, excluding the sciatic nerve; second, in- ject curare into the lymph sacs and allow absorption to take place, whereby the alkaloid passes into the general circulation, going into all parts of the body with the exception of the muscles and tissues of the ligated leg. Paralysis of all the voluntary mechanisms takes place. The point of action of the drug is demonstrated by the follow- ing steps in the physiological analysis : 1. Stimulation of the sciatic nerve of the curarized leg produces no contraction of its muscles. 2. Stimulation of the sciatic nerve of the unpoisoned side below the point of the ligature naturally produces contractions, since no drug has come into contact with this part of the apparatus. 3. Stimulation of the sciatic nerve of this side above the ligature, where the nerve has been irrigated by the blood containing the curare, also produces contraction of the muscle, showing that the nerve fibers are not directly poisoned. 4. Upon direct stimulation of the muscle of the poisoned leg contraction results, demonstrating that the curare has not paralyzed the contractile muscle substance. Bernard drew the conclusion that the toxic effect is upon the protoplasmic substance of the motor end plates, for which, therefore, the poison is specific. Kuhne later, 1886, gave a beautiful demonstration in this way: He noted that the motor nerve of the gracilis muscle of the frog branches before it enters the muscle. By cutting the muscle between the two branches a double preparation is secured, in which the parts are innervated by one nerve, but the end plates and muscle substance form two physiologically separate preparations. When curare is painted on one preparation stimulation of the common nerve fails to produce contraction in that division only. When the CURARE ON PERIPHERAL GANGLIA 109 poisoned muscle, with its contained nerve filaments, is stimulated and recurrent conduction carries the nerve impulse around, and never fails to produce contractions in the unpoisoned slip. Exces- sive use of curare later destroys the irritability of these nerve fila- ments, indicating that nerve fiber does ultimately succumb to the poison. Langley x has more recently examined the point of action of curare. He argues that the poison is not toxic to the nerve endings, but rather is toxic to a differentiated secondary constituent of the muscle fiber, which he designates the " receptive substance," a substance that receives the stimulus from the nerve and transmits it to the proper contractile substance. Strength is given his position by the fact that curare antagonizes certain muscle-stimulating substances after motor nerve degeneration occurs. Bernard showed also that the sensory mechanism of the reflex arc is not injured by ordinary doses of curare. Stimulation of the skin on the poisoned side of the curarized frog leads to reflex contraction of the muscles of the unpoisoned leg. If the sensory nerves in the skin were paralyzed such a reaction would be impossible. 2. Curare on peripheral ganglia. — Strangely enough curare does not poison the striated muscle of the heart, though large doses do eliminate the function of the vagus nerve. This effect is accom- plished by a poisoning of the pre-ganglionic connections around the cells of the cardiac ganglia, a nicotine-like effect. Other autonomic ganglionic endings are similarly poisoned by large doses of curare, as, for example, the vasomotor paths, the secretory nerves of the salivary glands, and the nerves controlling the muscles of the iris and ciliary apparatus. Curare leads to a fall of blood pressure in the mammal because the paralysis of the pre-ganglionic endings eliminates vasomotor tone. Such effects are not very profound, nothing comparable to the intensity of action on the skeletal motor nerve relations. 3. Absorption of curare from the stomach. — It has long been known that curare is comparatively inactive when taken by way of the stomach. There is a sharp contrast as between the intensity and rapidity of action from subcutaneous administration. Hence its inertness in the stomach has called for explanation. Several views have been offered, but that of Bernard is most probable and would account for the facts. Bernard's view is that the absorption takes place so slowly from the stomach and that the active principle of 1 Langley, J. N.: Journal of Physiology, Vol. XXXIIL, p. 374, 1905. 110 THE CURARE GROUP the drug is excreted so rapidly that its toxic effects do not materialize. Some evidence has been found to show that curare is destroyed either by the digestive action of the stomach or by the changes that occur during absorption. Another factor enters here, namely, the fact that the venous blood from the stomach passes through the liver where the parenchyma tends to fix this alkaloid as it does many others. This would hold back the passing of curare into the general circula- tion, hence would be favorable to its elimination before a fatal toxic action took place. IV. Comparison of Curare with Related Drugs. Curare stands at one end of the series of drugs and nicotine at the other as follows : Nicotine, coniine, gelseminine, sparteine, curare Ratio of stimulating effect on the central nervous system and of paralysis of peripheral ganglia. < > Relative toxicity to peripheral nerve endings. Nicotine produces preliminary stimulation of considerable in- tensity followed by marked paralysis. Curare produces practically no central stimulation. Nicotine has slight effect on peripheral nerve endings. Curare has pronounced and specific toxic effects on the endings (or receptive substance) of skeletal muscle. Nicotine and curare both are toxic to peripheral ganglia, though nicotine is much more toxic than curare. There are a number of drug groups which have characteristic actions on peripheral parts of the nervous mechanism, and some- times on particular motor nerve tissues. These drugs interfere with physiological activity by a selective combination with the differ- entiated structures of some portion of the parts of the body involved. They are in the highest degree specific in action. Their specificity depends upon a greater chemical affinity with the physiologically differentiated constituents of certain morphological structures. It is not to be understood that the reaction is limited exclusively to these COMPARISON" OF CURARE WITH RELATED DRUGS 111 parts and that other portions of the body are inert toward the drug, but rather that the degree of selection depends upon the greater intensity of action at some particular morphological point. In the therapeutic use of such drugs it is comparatively easy to accom- plish a change in the function of the part specifically attacked great enough to be of clinical value without materially interfering with the functions of other non-specific reacting parts of the body. Of this series the most characteristic from the pharmacological point of view are atropine, nicotine, coniine, curare, and the pilocarpine series. CHAPTER XII. THE ATROPINE SERIES. I. Historical and Chemical. The atropine series contains a number of alkaloids of extremely bitter taste, found in the plants of the order Solanaceae. Of the species yielding alkaloidal principles should be mentioned Atropa, Datura, Duboisia, Hyoscyamus, etc. Atropa belladonna, deadly nightshade, contains atropine, hyos- cyamine, and hyoscine. Datura stramonium, or thorn apple, contains atropine, hyoscya- mine, and hyoscine. Duboisia myoporoides, contains duboisine and hyoscine. Hyoscyamus niger, or henbane, contains atropine, hyoscyamine, and hyoscine. Mandragora autumnalis, or mandrake, contains mandragorine, and hyoscyamine. Atropine itself is extracted chiefly from the roots and leaves of the plant Atropa belladonna. It is associated with hyoscine and hyoscyamine. The drug is readily decomposed into tropine and tropic acid. Hyoscyamine is isomeric with atropine; in fact, atropine is now con- sidered to be a mixture of dextro- and levo-rotary hyoscyamine. The chemical relationship of the elements is expressed in the formula : Ha H H 2 C C C CH C 17 H 23 N0 3 = >NCH 3 >CHO- CO- CH 2 OH / / I C C C GeHs H 2 H H 2 Atropine Tropine Tropic acid II. Outline of Pharmacological Action. 1. Paralysis of the peripheral endings of the secretory nerves, the cardiac inhibitory nerves, the constrictor nerves of the pupil, and of the motor nerves of the stomach and intestine. 112 DETAILS OF PHARMACOLOGICAL ACTION 113 2. Initial stimulation of the motor apparatus of the alimentary canal and urinary bladder, thought to be muscular. 3. Mild initial stimulation of the cerebral cortex and of the cen- ters of the brain-stem and cord, followed by depression and later by paralysis. 4. Toxic direct paralysis of the medullary centers. III. The Details of Pharmacological Action. Other alkaloids of the atropine series differ in their effects from atropine only in a mild quantitative way. Hence the description of atropine will serve as a type for all the members of the series. i. General symptoms of the action of atropine. — The therapeutic dose of atropine is from 0.5 to 1 milligram. These or slightly larger doses produce in man a perceptible acceleration of the heartbeat, a mild dilation of the pupil, a general dryness of the throat and skin, accompanied by difficulty in swallowing, thirst, and general discomfort from the lack of secretions of the mouth and naso- pharyngeal region. If the symptoms are severe there is nausea, oc- casionally dizziness, and general mental discomfort. There is an initial slight increase of cerebral functions, which passes into incoherence, garrulousness, delirium, or semi-consciousness, but without loss of muscular control. In extreme cases there may be convulsions. In toxic conditions this effect may be followed by deep stupor, labored respiration with a tendency to asphyxiation, and even asphyxial death. This general picture is complicated by the specific peripheral effects of atropine expressed in combination with those on the central nervous system. 2. Action of atropine on the central nervous system. — The evi- dences of stimulation and excitement with the respiratory and circula- tory disturbances indicated above show that atropine has a profound influence on the central nervous system. Unlike caffeine, which acts primarily on the higher cortical centers, and strychnine, which acts earliest on the spinal cord, atropine produces its effect through a general more uniform action on the whole nervous system — a little more profound on the medulla, if any distinction is to be drawn. In the later or more intense stages of atropine action, the motor side of the central nervous mechanism is the more profoundly influenced, and it is this that leads to increased physical activity, garrulousness, or convulsions. In animal experimentation one rarely observes 114 THE ATROPINE SERIES cortical nervous accelerator effects due to atropine. Yon Bezold and Blobaum * first established the stimulating action of atropine upon the respiratory center. They injected atropine peripherally into the carotid artery, so that the alkaloid was first brought into direct contact with the central nervous mechanism. They noted an immediate quickening of respiration. This effect would seem to Fig. 27. — Diagrammatic representation of the nerves of the intrinsic muscles of the eye. Sup. Corp. Quad., superior corpora quadrigemina. Xuc. Ill, nucleus of the third cranial nerve. Sup. Cerv. G., superior cervical ganglion. Circ. M., circular muscles of the iris. Rad. M., radial muscles of the iris. Ciliary G., ciliary ganglion. follow from the direct action of atropine upon the respiratory center, a fact that has been confirmed. There was also an increase in the respiratory volume of from 100 to 300 per cent. The primary effects of atropine are followed by a deep depression of function with ulti- mate paralysis of the central nervous system. The paralysis of the respiratory medullary center may, if artificial respiration is main- tained, be overcome. The life of the animal is thereby prolonged, and the recovery, if it occurs, is due to the fact of rapid oxidation of atropine by the tissues. 3. The specific action of atropine on the eye. — Atropine applied to the eye locally produces dilation of the pupil and loss of the power of accommodation. The toxic systemic effects on the respiratory center are produced before complete loss of function of the accom- modating mechanisms occurs, hence in practical ophthalmology it is 1 Von Bezold and Blobaum: v. Bezold's Untersuchungoi, Vol. I.. 1ST". ACTION ON GLANDS 115 customary to apply atropine by dropping it on the surface of the eye in a one per cent, solution. After about 15 minutes the effects are maximal and last for many hours. The ciliary mechanism and the iris of the eye are innervated by two sets of nerves, as shown in the Figure 27. The third cranial or oculomotor nerve distributes branches to the muscles of the ciliary ap- paratus, and the circular muscles of the iris. Stimulation of this nerve leads to an act of accommodation adjusting the eye for near vision, and to a constriction of the pupil. The cervical sympathetic also distributes branches to the eye. These innervate the radial muscles of the iris and produce dilation of the pupil when stimulated. The loss of the power of accommodation from local application of atropine is explained on the ground of a toxic paralysis of the. nerve endings of the oculomotor fibers on the ciliary muscles. The dilation of the pupil can be accomplished physiologically by either of two methods: contraction of the radial fibers through stimulation of the cervical sympathetic nerve, and relaxation of the circular fibers by elimination of function of the oculomotor. A direct paralysis of the circular muscles in the absence of effect on the radials would, of course, accomplish a dilation of the pupil. That atropine does not poison the muscles themselves can be easily shown by the re- sponse of the muscles of the iris to stimulation by the direct applica- tion of electrodes. It would seem, therefore, that in the local applica- tion of atropine to the eye the functional disturbance is due to paral- ysis of the oculomotor nerve. Direct stimulation of the oculomotor nerve either proximal or distal to the ciliary ganglion, is no longer effective after the application of atropine. This indicates a poisoning in the junction between the nerve and the muscle, according to Langley's views at the " receptive substance." The paralysis of the nerve endings of the ciliary mechanism of the eye by atropine persists for two or three days, and often for six to ten days in the case of the iris. The artificial alkaloid, homatropine, produces the same ocular effects, but is not so persistent, hence is to be preferred under certain therapeutic conditions. 4. The specific action on glands. — The dryness of the mouth and throat produced by atropine is due to a decrease in the secretions of the salivary and other buccal glands, as well as those of the throat. Atropine accomplishes this effect by an elimination of the control of the secretory nerves. Since direct stimulation of the chorda tympani or of the tympanic branch of the hypoglossal produces no secretion of the salivary glands, it is apparent that the action of 116 THE ATROPINE SERIES the drug is peripheral. The stimulation of the cervical sympathetic in the dog still produces its scanty secretion after atropine. Here, therefore, as in the eye, only one set of nerves is paralyzed, and that by a toxic elimination of the function of the terminal nerve endings and not by paralysis of the gland cells. Other glands have their secretion diminished by atropine, es- pecially the gastric, pancreatic, and to a much less extent the mam- mary glands. Thanks to the work of Pawlow, we now know that the gastric glands produce their secretion under a well-coordinated nervous control. The vagus is proven to be the secretory nerve for the gastric glands. Atropine produces a profound inhibition of gastric secretion, both in the Pawlow dog and in man (Riegel). In like manner atropine in weaker doses inhibits the pancreatic secretion. Modrakowski 1 has emphasized the fact that very large doses of atropine in the dog call forth a voluminous pancreatic secre- tion — a fact difficult of explanation by the laws of nerve control. The secretion of pancreatic juice, which is controlled through the hormones, indicates that hormone reaction, in general, is not inter- fered with by atropine. In the case of the secretion of milk, the therapeutic action of atropine is demonstrated clinically, though in the present state of our knowledge of the physiological mechanism of the mammary glands, it is not fully understood what structure the atropine affects. The development of these glands and of lactation at parturition are phenomena dependent on hormone actions, and are quite independent of nerve control, as is now well known. Atropine paralysis occurs in the nerves of the sweat glands. Langley has shown that the sciatic nerves contain secretory fibers for the sweat glands of the foot of the cat and the dog, where he has mapped their distribution. After atropine poisoning these nerves no longer induce secretion. It follows that atropine must be toxic to the nerve endings of the sweat fibers. 5. On the circulatory system. — There is a slight rise of blood- pressure following atropine, together with an increase in the rate of the heart. Experimental investigations of the peripheral circula- tion show that atropine has little effect on the size of the arterioles, except in toxic concentrations. There is a reddening of the skin, with evident vascular dilation just at the beginning of its systemic action, whether due to a paralysis of the vasoconstrictor center or a stimulation of the vasodilator center is not yet determined. In ex- 1 Modrakowski : Pfluger's Archiv, Vol. CXIV., p. 487. ACTION ON THE CIRCULATORY SYSTEM 117 periments on the salivary glands the stimulation of the chorda tympani, which contains vasodilator fibers, produces an increased flow of blood through the glands, though the increase is not associated with a secretion of saliva. This well-known experiment shows that the endings of the vasodilator nerves are not paralyzed, but are active in the presence of an amount of atropine toxic to the secretory endings. On the other hand, the nervous mechanism of the heart is pro- foundly influenced. /Atropine produces an elimination of the in- <%^ajG^<*J«f^. Ct»~MiUU,-2.9«4. SSBBBG Fig. 28. — Stimulation of the chorda tympani after the administration of 10 mg. atropine. The carotid pressure, lower line ; volume of suh-maxillary gland, second line from the top. The volume of the gland increased, showing that atropine does not eliminate the vaso-dilator nerve function. After Bunch. hibitory control of the vagus over the heart. ) When atropine is given systemically the vagus control is lost, and the heart is accelerated in the same way as though the vagus nerves were sectioned in the neck. Whereas stimulation of the peripheral end of the vagus nerve in the normal animal produces more or less inhibition of the heart, after atropine such stimulation of the vagus, and indeed of the region of the sinus, is without influence on the heart, showing a loss of the vagus control at the neuro-muscular unions.) Therapeutic doses of atropine have little accelerator effect on the heart rate of very young animals or of young children, due to the fact that the vagus tone is less developed in the young. The heart muscle itself is very little affected by atropine. In isolated muscle preparations from the terrapin's heart a wide range of concentration of atropine in solution in physiological salines may 118 THE ATROPINE SERIES be applied to the tissue with little or no effect on the rate. There is much irregularity in the results, but the accelerations are about bal- anced by the depressions which occur. Doubtless it is these irregu- larities that have led to the contradictory statements that have Fig. 29. — Diagrammatic representation of the origin and course of the cardiac nerves in the dog, showing the constituent neurones. Dl-5, first to fifth dorsal spinal nerve. Inhibitory fibers in blue, accelerators in red. Modified from Moret. appeared in the literature concerning the effects of atropine on the cardiac muscle. 6. Atropine on the alimentary canal, the stomach. — The peri- stalses of the stomach are under the control of the vagus, which is the motor nerve for this organ. Atropine produces an inhibition of the contractions. Minute doses apparently are not entirely toxic to the local nervous mechanism, but they do * eliminate, at least depress, the THE BLADDER AND UROGENITAL APPARATUS 119 motor control of the vagus endings. The preponderant inhibitory tone of the splanchnic apparatus in the absence of the motor activity of the vagus leads to a cessation of the gastric peristalses, a fact of especial therapeutic interest in the practical use of this drug. The intestine. — The motor apparatus of the intestine is also paralyzed by atropine, though there is some contradiction in the literature in this case. Very small therapeutic doses occasionally increase peristalsis by stimulation of the smooth muscle (Jacobj), or of the ganglion cells like nicotine (Langley and Magnus). In a general way atropine reacts on the intestine in much the same way as on the stomach. Meltzer and Auer 1 say, " Atropine frequently abolished completely the vagus effect upon the stomach and reduced greatly its effect upon the intestines." 7. On the bladder and urogenital apparatus. — The urinary bladder and the uro-genital system are controlled through nerves arising in two different regions of the spinal cord. One set arises from the lumbar region, the fibers passing out in the third to the fifth ventral roots of the lumbar nerves. They run thence through the sympathetic chain and hypogastric nerve. The other nerves arise from the lower sacral cord, the second to the fourth sacral nerves, and run to their distribution by way of the nervi erigentes. Langley and Anderson 2 found variations in the physiological responses of the uterine walls given in different animals when the hypogastric nerves were stimulated. Dale 3 later demonstrated that upon stimulation of the hypogastric in the non-pregnant cat there was generally a relaxation of the muscular walls of the uterus. But in the rabbit sometimes there was relaxation and sometimes contrac- tion of the muscles. If the test was made on a pregnant animal the response was always a contraction of the muscular walls, sometimes followed by peristalsis. In the male the muscular walls of the vasa deferentia and seminal vesicles are set into contraction by the stimulation of the hypogastric nerve. It will be remembered that this nerve contains the vasoconstrictor fibers for the blood-vessels of all these organs. Atropine does not abolish the functional nerve con- trol of the uterus on the one hand or of the seminal vesicles on the other. 1 Meltzer and Auer: American Journal of Physiology, Vol. XVIL, pp. 143-166, 1906. •Langley and Anderson: Jour. Physiol., Vol. XIX., p. 127, 1895. •Dale, H. H.: Jour. Physiol, Vol. XXXIV., p. 189, 1906. See also Cushny: Jour Physiol., Vol. XXXV., p 1. 120 THE ATROPINE SERIES The innervation of the bladder is twofold. Fibers reach it by way of the hypogastrics as mentioned above, and through the nervi erigentes. Stimulation of the hypogastric leads to contraction of the muscular walls of the bladder, chiefly of the sphincter. The sacral nerves, i.e., the nervi erigentes, it will be remembered, are the special paths of vasodilator fibers. They also supply motor fibers to the bladder as well as to the constrictor urethrae. " The sacral nerves cause contraction of all the muscle fibers of the bladder, whether they are circular, oblique, or longitudinal. ' ' Langley and Anderson question the presence of inhibitory fibers in the muscular walls of the bladder, stating that " few, if indeed any, exist." Atropine in large doses acts to reduce the sacral motor control over the bladder, apparently acting in a way compa- rable to its influence on the nervous control of the stomach and intestine. It does not completely eliminate the nerve control, that is, it does not completely poison the endings. The depressing effects produced, even with comparatively large doses, are not very great, not enough to eliminate the nervous control. There is indeed a slight but questionable stimulation of the smooth muscle and possibly of the nerve centers of the cord after mild therapeutic doses of atropine. In the urinary bladder, especially in the hypersensitive conditions, which occasionally occur in children, this atropine quies- cence leads to a better retention of the urine. In the uterus atropine suspends peristaltic contractions. It is not clear just what phase of the nerve-muscular mechanism is primarily influenced by the atropine, but the present tendency is to assume a similarity of action to that which occurs in other better known physiological mechanisms, as, for example, the eye. 8. Atropine excretion. — Atropine is excreted through the kidney. It has been shown by Fleischmann, 1910, and confirmed by Metzner, 1912, that atropine is destroyed by the blood of the rabbit, even in mixtures in the test tube. Atropine breaks down into tropine and tropic acid. This capability probably accounts for the fact that the rabbit is able to resist such large quantities of atropine. However, this animal may have acquired some degree of immunity from eating plants of this series. IV. Condensed Summary of the Pharmacological Action. The changes in physiological reaction in the human body upon the introduction of atropine are relatively complex because of the num- SUMMARY OF PHARMACOLOGICAL ACTION 121 erous secondary disturbances of the physiological balance. In small, i.e., therapeutic doses, there is a dryness of the mouth and throat from a decrease in secretions, a slight increase in physiological reac- tions through the nervous system, excitement followed by a tendency in the toxic stage toward irrational mental reactions, with garru- lousness, unconsciousness, and even convulsions, followed by stupor and paralysis. Respiration is accelerated slightly, then depressed and stopped by central paralysis. Blood-pressure is at first in- creased, through stimulation of the regulative nerve centers, the heart shows initial very slight inhibition, followed by increased rate of beat from terminal paralysis of the vagus. There is little direct effect upon heart muscle. The blood-vessels in the toxic stage are dilated and blood-pressure falls. The general voluntary motor ap- paratus is finally depressed and paralyzed through action on the motor nerve cells. Atropine produces a slight initial stimulation of smooth muscle in various localities, followed by a depression of peri- staltic contractions. This is true for the intestine, urinary bladder, and uterus. Scopolamine or hyoscine has a greater depressor effect upon the various portions of the central nervous system and the autonomic nerve centers. It enjoys a certain amount of prestige in cases of mania, and also as a depressor of hyperexcitable sexual centers. CHAPTER XIII. THE PILOCARPINE, MUSCARINE, PHYSOSTIGMINE GROUP. Under this head may be included a series of active alkaloidal principles which have a strong peripheral stimulating effect. In, the main these drugs produce their action at the point of nerve term- inations in differentiated tissues. I. PILOCARPINE. I. Historical and Chemical. Jowett * has shown that the leaves of Pilocarpus jaborandi and of other species of the genus contain only three alkaloids, pilocarpine, iso-pilocarpine, and pilocarpidine, the last named only in small quantity. Harnack and Meyer 2 have given us the composition of pilocarpine, but the structural formula is quoted from Marshall : C n H 16 N a 2 = C3H5CH-CH.CH2C-N.CH3 CO CH 2 CII-N,/ 011 O Pilocarpine (Marshall) II. Outline of Pharmacological Action. 1. A strong stimulation of glandular structures — the salivary, bronchial, lachrymal, and gastric glands, and the liver. 2. A similar stimulation of the s7nooth muscle of the eye, of the Jowett: Jour. Chem. Soc, 1900, Vol. LXXVIL, pp. 473, 851; 1901, Vol. LXXIX., pp. 580, 1,331; 1903, Vol. LXXXL, p. 438. 2 Harnack and Meyer: Arch. f. Exp. Path. u. Pharm., 1880, Vol. XII., p. 366. 122 DETAILS OF PHARMACOLOGICAL ACTION 123 alimentary tract, the urinary bladder, the spleen, and of the bronchi, but little or no stimulation of the muscles of the blood-vessels. 3. A slight stimulation, followed by marked depression, of the centers of the central nervous axis. III. Details of Pharmacological Action. i. The stimulation of the glands. — In therapeutic dose, 5 to 8 mgr. for man, pilocarpine leads to a marked increase in the secretions. Parotid 3 Fig. 30. — Diagrammatic representation of the neurones in the innervation of the salivary glands. V, VII, and IX, the corresponding cranial nerves. Ch. T., chorda tympani containing secretory and vasodilator fibers, also, according to certain author- ities, gustatory nerve fibers ; Tym. Br. 9th } tympanic branch of the 9th cranial nerve containing secretory and vasodilator fibers for the parotid gland ; Otic O., Otic gan- glion ; Ling., lingual branch of the 5th ; Sup. C. O., superior cervical ganglion of the sympathetic; 8. M. G., submaxillary ganglion. Some of the neurones through this ganglion belong to the sublingual gland. PreganglTonic neurones in red, also the central neurone in the cord. Postganglionic neurones and sensory neurones in black. Diagram based on figures by Sheldon, Brubaker, and Starling. These are most striking in the salivary glands, sweat glands, and the mucous glands of the mouth and throat. The gastric and pancreatic secretions are also increased. The liver produces an increased amount of sugar, leading to glycosuria, which suggests that this organ too is stimulated by the pilocarpine. The amount of saliva and of perspiration produced is enormous, 124 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE amounting to several hundred cubic centimeters more than the normal. Ewing x has made a special study of the quantity and chemical com- position of the saliva in man produced under the stimulus of pilocar- pine. He records an instance in which a normal 15-minute secretion of 37 cc. of saliva was increased to 563 cc. in the third 15-minute period after 10 mgrs. of pilocarpine. He also demonstrated that the Fig. 31. — Influence of 0.2 mg. pilocarpine on the rate of secretion of saliva. The drops of saliva are recorded in the second line from the top. At a injection of pilocar- pine, at b injection of 50 cc. of oxygenated blood. From Jonescu. total amount of solids, both organic and inorganic, keeps pace with the increase in the total secretion. The glands are stimulated through the nervous mechanism. Since the secretion occurs after section of the nerves but is absent when the nerve endings are paralyzed by atropine, it is assumed that the pilocarpine reacts with the substance of the terminations of the nerve fibers, as has been advocated by Langley. 2 However, Langley has more recently arrived at the conclusion that pilocarpine reacts with a differentiated portion of the gland cell, the " receptive sub- stance/ ' which is the linking up substance as between the fibrils and the secreting gland substance. He finds that the sweat glands of the foot produce secretion after sectioning of the sciatic nerve. The kidney and the mammary glands are not particularly influ- 1 Ewing, E. W.: Jour. Pharm. and Exp. Ther., 1912, Vol. III., p. 1. 'Langley, J. N.: Journal of Physiology, 1905, Vol. XXXIII, p. 374. PILOCARPINE ON THE CIRCULATORY SYSTEM 125 enced by pilocarpine. This is due undoubtedly to the fact that these organs do not have a well-developed nervous controlling mechanism. Any influence which is exerted on the two organs is probably due, therefore, to indirect effects through the vascular system. Pilocarpine influences the flow of blood through the glands, and this, together with the increased production of sugar by the liver, would account for the observed increase in sugar in pilocarpine milk. 2. Pilocarpine on the circulatory apparatus. — Pilocarpine in- jected intravenously leads to a marked fall of blood-pressure. The fall is secondary to a marked inhibition of the rate of the heart. / 3. The heart. — Pilocarpine leads to slowing of the heart in both the frog and the mammal. This may reach a complete inhibition Fig. 32. — Showing the increased sensitiveness of the vagus control in the cat after administration of 0.1 milligram of pilocarpine. The right vagus was cut, periph- eral end stimulated, the induction coil at 25 cm. showed no inhibition, at 20 cm. marked inhibition before the drug was applied. A, right vagus stimulated 23 cm. normal ; B, same stimulation after pilocarpine ; C, stimulation at 25 cm., after pilocar- pine. The increased sensitiveness of the vagus gradually wore off. a, pressure base line ; 6, time in seconds ; d, duration of stimulus ; e, Hurthle's manometer record. The top tracing shows the blood-pressure. From Marshall. as the action of the drug proceeds. /The cardiac slowing is due to a stimulation of the vagus terminations, since it occurs after section of the vagi ; in fact, after paralysis of the vagal ganglia) Marshall x has shown that small doses of pilocarpine at once depress, then quickly increase the response of the vagus to stimulation. The reaction is an additive one, since the drug and the electrical stimula- tion produce the same end effect on the cardiac apparatus. Pilocarpine, curiously enough, when taken by the mouth is asso- ciated with an increase in the pulse rate noted quite constantly in 1 Marshall, C. R. : Journal of Physiology, 1904, Vol. XXXI, p. 150. 126 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE man. This has been variously explained. By some it is considered as a direct stimulation of the cardiac accelerator endings. But others, notably Marshall, consider it a secondary effect. This latter is prob- ably the safer explanation. [Pilocarpine and atropine are antagonistic in their cardiac effects, though the former is only about one-twentieth as vigorous in its toxic action. 1 4. The blood-vessels. — Pilocarpine has little effect on the blood- vessel mechanism in comparison with its more profound glandular action. Given intravenously, the marked fall of blood-pressure sug- gests vasomotor paralysis. The pressure change, however, is chiefly due to cardiac slowing at this stage. There is some slight vasomotor action, but not enough to overcome the cardiac slowing. Perfusion of isolated organs (Dixon) shows vasoconstriction. The later and more toxic action leads to paralysis of the vasomotor center. 5. Pilocarpine on the respiratory tract. — In addition to its nerve effects, pilocarpine produces a contraction of the bronchial musculature, which tends to interfere with the free respiratory move- ments, making them more or less labored. In this instance, as in many pharmacological situations, a chain of secondary influences supervenes. The great increase in the secretions of the respiratory passages produces an increase of mucus, etc., that tends to block the smaller tubes interfering profoundly with the respiratory inter- change. Studies indicate that the total respiratory exchange, especially the output of carbon dioxide, is increased under the influence of pilo- carpine. This is to be expected because of the great increase in functional activity of glandular and other motor tissues. 6. On the central nervous system. — At first pilocarpine is slightly stimulative to the nerve centers of the medulla and cord. After larger doses there is a tendency to paralysis and collapse, especially of the medullary centers. The respiratory center is markedly depressed by pilocarpine. The rate is greatly slowed and the amplitude of the respiratory excursions diminished. The slight initial stimulation of the vasomotor center is followed by paralysis. 7. Pilocarpine on the alimentary tract. — Pilocarpine produces a marked, in fact violent, increase in the peristalses of the stomach and intestine. It stimulates at the point of union of the motor nerves and smooth muscle cells, picking out the motor mechanism apparently to the exclusion of the inhibitory mechanism. This action is easily demonstrated by rings of muscle from the stomach of a cold- ACTION OF PILOCARPINE ON THE EYE 127 blooded animal. It is expressed also in the griping muscular con- tractions with pain and by the occasional purging and vomiting noted after the excessive administration of pilocarpine. 8. Action of pilocarpine on the iris and the ciliary mechanism of the eye. — The constriction of the pupil is an obvious and easily Fig. 33. — Influence of pilocarpine on the bronchial muscles, and on the blood- pressure. Trimethylamin hydrochloride produced the opposite result. The further details of the experiment are explained on the figure. From Jackson. noted result associated with the symptoms of pilocarpine action. The accommodating mechanism is also stimulated to contraction. Refer- ence to the discussion of the action of atropine, also of epinephrine, whore a review is given of the normal physiological mechanism of the eye, will show that the contraction of the pupil depends upon a stimulating action of either some portion of the oculo-motor nerve or of the smooth muscle of the iris itself. Anderson * has especially 1 Anderson, H. K.: Journal of Physiology, Vol. XXXIII., p. 414, 1905. 128 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE investigated the problem. By a series of exclusion experiments he has shown that pilocarpine produces an even stronger contraction of the iris after section of the oculo-motor nerve, as it does also after removal of the ciliary ganglia. In this last case the contraction is more prolonged than when the oculo-motor nerves are intact. One hundred and nineteen days after removal of the ganglia, when the short ciliary nerves are presumed to be degenerated, pilocarpine still produces contractions of the constrictor muscles of the iris. He came to the conclusion that pilocarpine can act on the sphincter muscle itself. It is admitted, however, on the basis of greater re- sponse with intact nerves, that pilocarpine acts also at the point of nerve endings. The accommodative spasm is explained in light of these experiments as a peripheral muscle and motor-nerve stimulating effect of pilocarpine. IV. Condensed Summary of the Pharmacological Action of Pilocarpine. Pilocarpine and related alkaloids lead to marked stimulation of the peripheral motor structures. There is a striking increase in the amount of perspiration, saliva and other secretions of the alimentary and respiratory tracts. Pilocarpine has no direct physio- logical action on the mammary gland or on the kidney, but it in- creases the glycogenic functions of the liver. The nervous mus- cular mechanisms of the eye are sharply stimulated through action on the nerve terminations and on the constrictor muscle itself. The heart is slowed by an initial stimulation of the inhibitory mechanism at its terminations, an effect which is followed by final paralysis. In therapeutic doses medullary centers are slightly stimu- lated, in large doses paralyzed. The paralysis is most marked on the respiratory center and on the vasomotor center. In toxic doses heart muscle is weakened and the circulation depressed, the respiration is shallow, and edemic obstruction may take place in the lungs. Pilocarpine is antagonized by atropine, which is an antidote. II. MUSCARINE. I. Historical and Chemical. Muscarine is a very toxic alkaloid present in the poisonous mush- room, Amanita muscarius. Schmiedeberg has produced an artificial OUTLINE OF PHARMACOLOGICAL ACTION 129 muscarine by the oxidation of choline, to which it is closely related, having the formula C 5 H 14 N0 3 . The chemical relationship between choline and muscarine is shown by the following structural formulae : CH 3 CH 3 CH 2 OH CH 3 — N CH 3 CH 2 CH 2 CH 3 — N CIV OH CH 3 ' Choline Muscarine II. Outline of Pharmacological Action. The action of muscarine is very similar to that of pilocarpine, though it is more strongly stimulative of parenchymal tissues. Its general effects are : 1. A marked slowing of the heart by stimulation of vagus terminal endings. 2. Accommodation spasm, with constriction of the pupil of the eye. 3. A marked increase in gastric and intestinal peristalses. III. Details of Pharmacological Action. i. Muscarine on the heart and circulatory system. — The typical action of muscarine is illustrated by its influence on the heart. "When muscarine is perfused through the frog heart or painted over the whole heart a marked slowing leading to complete standstill quickly ensues. The muscarine effect is not due to a paralysis of the contractile substance, since at any time direct stimulation of the ventricle of the heart leads to a contraction. The muscle tissue is irritable and contractile, but held in inhibition. This picture is further emphasized by the immediate recovery of contractions after painting the heart with atropine. The pause disappears and a per- fectly normal rhythm ensues. It is evident that atropine and mus- carine act upon the same structures, namely, the terminal fibers of the vagus in the heart tissue. In certain animals, especially invertebrates which have well-de- veloped cardiac nerves, there is a specific stimulation of the accelerator mechanism, in a way comparable to the stimulation of the inhibitory mechanism in most mammals. Muscarine is without marked effect 130 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE on cardiac tissue as such, hence does not influence the embryonic heart before the nervous connections are established. However, there is a slight direct effect on isolated ventricular muscle of the terrapin, a general increase in the amplitude of the contraction with a some- what slower rate. 2. On blood-pressure. — The administration of muscarine leads to an enormous fall of blood-pressure, but these results are almost exclusively due to the cardiac inhibition as previously described. Upon the intravenous injection of muscarine there is as complete a cessation of heartbeat in the mammal as results from effective vagus stimulation. This action can be controlled by graded doses almost as completely as the vagus itself. This inhibition is removed by counter injection of atropine, under the antagonistic action of which the blood-pressure recovers. 3. Muscarine on the glands and on the alimentary tract. — Muscarine produces an increase in the secretion of salivary and other glands of the mouth and alimentary tract by a stimulation of the terminal secretory fibers at the same point acted upon by pilocarpine and apparently in the same way. In a similar manner there is a marked increase in the peristalses of the stomach ; in fact, of the entire intestinal tract. A 0.5-milligram dose of muscarine per kilo-given to a cat or dog is sufficient to pro- duce violent secretion of the salivary glands, and intense contractions of the stomach and intestine, with vomiting and purging. 4. On the eye. — Muscarine produces a constriction of the pupil and contraction of the muscles of the accommodating mechanism of the eye. These results are accomplished through stimulation of the endings of the oculo-motor nerve on the muscle fibers involved. The stimulation of the terminal fibers of the oculo-motor is more pro- longed and enduring with muscarine than with pilocarpine, the toxic action of the latter tending to paralyze the mechanism. III. PHYSOSTIGMINE, OR ESERINE. I. Historical and Chemical. Physostigmine is derived from the seeds of the Calabar bean, Physostigma venosum, of the western portion of Africa. It has the chemical formula, C 15 H 21 N 3 2 . It was first isolated in 1864 by Jobst and Hesse. OUTLINE OF PHARMACOLOGICAL ACTION 131 II. Outline of Pharmacological Action. Physostigmine, like pilocarpine and muscarine, produces a pro- found stimulation of terminal nerve fibers, but with greater effect on the parenchymal tissue itself. 1. Marked constriction of the pupil and accommodative spasm of the ciliary muscles of the eye. 2. A powerful stimulation of the muscular mechanism of the stomach, intestine, and the muscles of the urino-genital apparatus. 3. A stimulation of the cardiac inhibitory apparatus. 4. Initial slight stimulation, with deep depression of the function of the medullary centers, and to some extent of those of the spinal cord. III. Details of Pharmacological Action. i. Physostigmine on the eye. — The local ocular effects of physo- stigmine are demonstrated by dropping a one per cent, solution over the surface of the eye. After 20 to 30 minutes the pupil becomes constricted and the ciliary muscles sharply contracted, and the eye accommodated for near vision. This accommodative spasm lasts for several hours, three or more. The explanation of the physostigmine action is based on the view that the terminal fibers of the oculo-motor are sharply stimulated. If one stimulates the cervical sympathetic in the neck there occurs the normal complete dilation of the pupil, showing that this apparatus is not involved, i.e., not paralyzed by the action of the alkaloid. That the action is on the terminal fibers is shown by the fact that constriction takes place after operation, cut- ting the short ciliary nerves or removal of the ciliary ganglia. If degeneration of these peripheral fibers is allowed to take place, then the eserine effect is less marked or lost. It was formerly thought that physostigmine produced a direct stimulation of the muscles them- selves. Anderson, who has performed degeneration experiments on nu- merous animals, finds that physostigmine is not active on the iris after the peripheral nerves have degenerated. Acceptance of this observation tends to throw doubt on the current view that physostig- mine stimulates smooth muscle in numerous other organs. He finds that physostigmine contractions return early in the regeneration of 132 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE these fibers, even before they become sensitive to electrical stimulation. All these facts point to localization of the action on the endings of the oculo-motor nerve. Heine has demonstrated by histological methods that the ciliary muscles of the eye and the muscles of the iris are actually contracted in eserine poisoning. Physostigmine also contracts the striated muscles of the bird's eye, differing in this respect from the action of atropine, which does not paralyze striated nerve endings. 2. Physostigmine on the circulatory apparatus. — Intravenous administration of physostigmine produces an immediate fall of blood- pressure. If the dose be toxic the picture is similar to that upon the maximal stimulation of the vagus nerve. In the therapeutic dose there is a marked slowing of the heartbeat associated with inter- mediate periods of more complete cardiac inhibition. This effect is to be explained on the ground of marked vagus stimulation for the whole heart. Atropine removes the depressing action of physostigmine by counteracting its effect on the nerve endings. It would seem that little or no central stimulation occurs on those nervous centers regu- lating the circulatory apparatus. Carlson, however, has shown that the extra-cardiac ganglia of limulus are stimulated by relatively strong solutions of physostigmine. The isolated vertebrate heart or the heart tested in situ always shows a pronounced slowing upon the administration or application of physostigmine. The physiological analysis of the results proves that this action is primarily due to pronounced stimulation of the terminal vagus fibers as in muscarine poisoning. There is this differ- erence, namely, that atropine does not completely eliminate the eserine. Experiments on isolated strips of terrapin heart reveal the reason of this failure of complete atropine antagonism. Strips sub- jected to physostigmine solutions, .01 to .02 per cent, in physiological saline, show a slight slowing with a pronounced increase in the ampli- tude of contraction. The increase of amplitude is interpreted to mean a direct muscular stimulation. The slowing is not so easily ex- plained. One may assume that the terminal inhibitory fibers in this isolated muscle are stimulated somewhat slowing the rate, but the stimulation is not pronounced enough to overcome the direct effect on the amplitude of the contractions. This we have checked on strips from tested atropinized hearts and find that now the increase in amplitude of contractions is greater and that the rate is often, though not always accelerated. 3. Physostigmine on striped muscle. — Physostigmine differs from DETAILS OF PHARMACOLOGICAL ACTION 133 other members of this series in that it stimulates skeletal muscle. The effect of the drug apparently falls both on the motor end plates and on the striated muscle substance. The former deduction is proven by the fact that sub-minimal stimuli for normal motor nerves become effective after the administration of physostigmine. Physostigmine will increase the irritability of the motor end plate sufficiently to overcome or antagonize the less profound paralyses produced by curare. Pal has shown that a curarized animal, in which the voluntary muscles were no longer active to nerve stimulation, will recover the motor control after intravenous injection of physo- stigmine. He considers physostigmine a true antagonist and antidote to curare. Skeletal muscle is set into fibrillar contraction by stronger solutions of physostigmine. 4. Physostigmine on the muscles of the stomach and intestines. — The peristalsis of the stomach is markedly increased by physostig- mine in a manner similar to that of pilocarpine and muscarine. In- testinal peristalsis is also increased. These effects are accomplished through stimulation of the terminations of the vagus nerve, i.e., the terminal neurone in the vagus path. Eserine produces more pro- nounced contraction in these organs because it also directly stimu- lates the unstriped muscle. The gall bladder and its sphincter strongly contract. In fact, all organs possessing the unstriped muscle are set into a greater or less degree of contraction by eserine. The spleen, the urino-genital apparatus, including the uterus, and the muscles of the small arteries are all involved. Atropine is only partially antagonistic to this physostigmine effect. It does not eliminate the direct muscular action, only antagonizing that factor due to the stimulation of the nerve ends, but not counter- acting the blood-vessel effects nor the striated muscle stimulations. 5. On the central nervous system. — The influence of physostig- mine on the medullary centers controlling the circulation is wholly insignificant, but the action of physostigmine on the respiratory center is of special importance. Therapeutic doses have been de- scribed as leading to initial acceleration of respiration, though in laboratory experiments on mammals this acceleration is slight and quickly passes into a slow respiratory rate with diminished amplitude and final complete inhibition. The respiratory pause is not due to the interference with the motor nerve endings, since, as has already been stated, these are stimulated. Section of the vagus nerve does not eliminate the effect, hence we must assume that the toxic influence is on the respiratory center itself. If, in a mammal during physostig- 134 PILOCARPINE, MUSCARINE, PHYSOSTIGMINE mine respiratory pause, atropine be injected intravenously, there is ultimate respiratory recovery. The first influence of the atropine is of course to release the heart from the vagus control, which mechanism is under stimulation by physostigmine. Then, after a variable in- terval, amounting in one published illustration x to 30 seconds, there is a slow, gradual recovery of respiratory rate and amplitude. One must explain this striking antagonism of atropine for physostigmine as due to the fact that atropine is much more profoundly stimulative in its primary action on the respiratory center. The toxic stage of both drugs leads to paralysis of this nervous mechanism. A toxic dose of physostigmine is small and produces cessation of respiratory movements long before elimination of function of the circulatory apparatus. In ordinary toxic doses the cause of death is respiratory failure with asphyxiation. IV. Condensed Summary of Action. Physostigmine has a pronounced stimulating effect on practically all motor nerve terminations — the salivary glands, gastric glands, lachrymal glands ; the muscular apparatus of the eye, of the stomach and intestine, of the bladder and uterus, and of the bronchial tubes. It stimulates the nerve terminations in skeletal motor nerves, antag- onizing curare. Eserine also stimulates practically all the active parenchymatous tissues, such as the glands, the heart muscle, skeletal muscle, and all smooth muscle tissues, with the exception of those of the eye. It has an ultimate paralytic effect on the nerve centers of the medulla the respiratory center being especially sensitive. The action of physostigmine is antagonized by atropine on all nerve struc- tures which are primarily stimulated by physostigmine, but its ter- minal action on the peripheral tissues is not so antagonized. 1 Greene, Chas. W. : Experimental Pharmacology, p. 46, Fig. 2. Philadelphia, 1909. CONDENSED SUMMARY OF ACTION COMPARISON OF THE PILOCARPINE GROUP. 135 Central nervous system Nerve end- ings in glands Nerve end- ings in smooth muscle. Cardiac vagus endings. Skeletal muscle endings. Direct action on terminal tissues. Pilocarpine. Depressing to axial nerve centers. Violently stimulates in all glands ex- cept kidney and mam- mary. Stimulates alimentary, urino- genital system, and eye. Stimulates. No effect. Slight but questionable. Physostigmine. Slight initial stimulation and early and profound pa- ralysisof axial centers. Stimulates. Violently stimulates all structures. Strongly stim- ulates. Stimulates. Stimulates but question- able as to the eye. Muscarine. Sti mulation followed by depression. Stimulates. Vigorous stimulation. Violent stim- ulation. Paralysis. Little or none. Atropine. Vigorous stimulation and toxic pa- ralysis. Simple paral- ysis. Paralysis. Paralysis, ex- cept blood- vessels and inhibitory nerves of ali- mentary ca- nal. No effect. No effect. CHAPTER XIV. THE NICOTINE SEEIES. I. Historical and Chemical. Tobacco, Nicotiana tabaeum, possesses an alkaloid, which has certain characteristic influences on the reactions of the body, to which the widespread use of tobacco is to be attributed. Tobacco was introduced into general use among Europeans following the dis- covery of America. Lord Raleigh, who was impressed by the Indian custom, brought home tobacco and taught the English court the Indian method of smoking it. At the present time the use of tobacco is widespread, and is chiefly limited to smoking and chewing. The latter method results in the swallowing of small quantities of the juices of tobacco with the saliva, while the former results in absorp- tion of nicotine and related chemical derivatives from the smoke inhaled. Chemically nicotine is a pyridine of the following structural formula as given by Schmiedeberg : CH KCH 3 /\ /\ HC C HC CH 2 HC CH H 2 C CH 2 When heated, as in cigar smoking, the nicotine is partially broken down, forming pyridine and pyridine compounds. Lobelia inflata possesses an alkaloid, lobeline, with the chemical formula, C 18 H 23 N0 2 , which has a physiological action similar to that of nicotine. Duboisia Hopwoodii possesses an alkaloid, piturine, C 12 H 16 N 2 . This alkaloid has effects identical with nicotine, according to Langley and Dickinson. The water hemlock, Conium maculatum, contains a series of alka- loids, which have reactions in the body somewhat similar to nicotine. Of these coniine is the most important. 136 OUTLINE OF PHARMACOLOGICAL ACTION 137 II. Outline of Pharmacological Action. 1. Nicotine produces a primary out mild stimulation of the nervous system at all points, followed by a marked depression. 2. It is specific in its action upon the pre-ganglionic synapses of the autonomic system, at first mildly stimulating, but later producing a profound and prolonged paralysis. 3. Cardiac muscular tissue is at first strongly stimulated, then later depressed. Other muscular tissues, the smooth muscle, and skeletal muscle, are similarly though less strongly affected. III. Details of Pharmacological Symptoms. Nicotine is a drug which is strikingly disturbing to the normal functions of the body. When it is used for the first time and in semi-toxic amount the symptoms indicate a profound general stimu- lation of all parts of the body. There is increased respiration, a general rise of blood-pressure, vasomotor constriction, a slow heart in the incipient stage, but a rapid and irregular heart in the advanced stage. There is nausea with vomiting, very often accompanied by increased peristalsis of the alimentary tract and purging. Excessive doses may cause death, which is produced through paralysis of the respiratory muscles and of the central nervous system. i. On the central nervous system. — Nicotine stimulates the en- tire central nervous system, apparently more strongly from above downward. This stimulation is slight and transient, giving way to a depressed or sedative condition. 2. On the cerebral cortex and medulla. — Beneficial action of nicotine on the cortex has not been demonstrated in so far as the ability to do psychic work is concerned. Under conditions of mental disturbance and hyperirritability nicotine is said to contribute to a feeling of comfort and quiet, i.e., is soothing to an overwrought nervous mechanism. This effect is undoubtedly an expression of the second stage in the responses of the body to the alkaloid. On the basal centers of the nervous system, especially of the medulla, the initial stimulating action of nicotine is more pronounced. This is shown partly through the great automatic regulative centers controlling the action of respiration, the circulation, the alimentary, 138 THE NICOTINE SERIES and glandular systems. The respiratory center is stimulated to an increased respiratory rhythm and amplitude. In the more advanced stages this effect gives way to one of depression. The cardiac regula- tive centers, both inhibitory and accelerator, are likewise rendered more sensitive. This leads to a slowing of the heart through the central stimulation, since the inhibitory mechanism is preponderant. After the action of nicotine becomes more intense, the accelerator mechanism is more profoundly stimulated, hence there will be periods of cardiac acceleration approaching palpitation. The vasomotor cen 7 ter is at first sharply stimulated, leading to a marked peripheral con- striction of the arterioles. Later this gives way to vasomotor paraly- sis. The medullary nerve centers controlling the sweat glands of the skin, the salivary glands, also probably the gastric and pancreatic glands, are at first stimulated, then later depressed. 3. The spinal cord. — The nervous mechanisms of the spinal cord are not so profoundly involved as those of the medulla. However, the reflex centers of the cord are rendered more sensitive to the ordinary inflow of stimuli, hence give more profound discharges than normal. This condition is quickly followed by one of obvious depression, which in the toxic stage may result in motor paralysis. 4. Nicotine action on the peripheral ganglia. — The specific ac- tion of nicotine falls not upon the central nervous axis, but upon the peripheral ganglia of the autonomic nervous system. Here, too, nico- tine produces a passing stimulation, but followed by a marked and quick depression, with complete elimination of function. This specific action takes place at the union between the pre- and post-ganglionic neurones. Schmiedeberg was the first to properly locate the characteristic specific action of nicotine, proving the same by its influence on the car- diac inhibitory mechanism. He showed by a skillful series of experi- ments that the elimination of the vagus control over the heart was due to the loss of function in the cardiac ganglia. The stimulation of the vagus nerves in the neck failed to produce an inhibition of the heart at a time when stimulation of the ganglia of the heart at the sinus produced inhibition. It was evident that such an experimental result could only be obtained by a block of the nerve impulse in the cardiac ganglia. This point of specific action of nicotine has been proven through later work to be general for all the autonomic mechanisms. Langley and his pupils have demonstrated this general law, and by turning the fact about and using it as a means of interpretation, have been ON THE CIRCULATORY SYSTEM 139 able to very greatly widen our physiological knowledge of the whole nerve complex of the so-called sympathetic system. The changes of function produced by nicotine on the various special motor organs are largely dependent upon the action of nicotine on the peripheral sympathetic ganglia. The usual delicate and well-balanced normal physiological responses become blunted or impossible when the nerve Fig. 34. — Effects of nicotine on the contractions of the isolated sinus-auricle strip, terrapin. Between the arrows the preparation was bathed in .01 per cent, nicotine. A 70 second interval between the two parts of the record. Note both the tonic and the fundamental contractions are strongly stimulated, the tonic contractions at the begin- ning- of the nicotine action, the fundamental contractions throughout. Time in seconds New tracing by Williams. control is eliminated by the nicotine blocking of nerve paths through the peripheral ganglia. 5. The action of nicotine on the circulatory system. — A physio- logical mechanism so complicated as the circulatory apparatus must of necessity be profoundly influenced by a drug which has widely dis- tributed reactions in the human body. So it is with nicotine. This alkaloid causes marked changes at least at four fundamental points in the circulatory apparatus, namely, on the cardiac muscle itself, the heart's local nervous mechanisms, the medullary centers for the heart, and on the vasomotor nervous complex. The resultant activity of the circulatory complex produced by nicotine shows itself of course in changes in the blood-pressure, and pulse rate and pressure. A very weak dose of nicotine produces a rise of blood-pressure. If the nicotine action becomes stronger, as with a medium dose, this pressure remains up ; in fact, continues to rise. Only in the toxic stage does the pressure fall and finally become nil at death. The components entering into and producing this rise of pressure are discussed more fully below, but the condensed statement is shown in the following table : 140 THE NICOTINE SERIES ACTION OF NICOTINE ON THE CIRCULATION. Blood-pressure Heart rate Heart amplitude . . Vagus control Accelerator control. Vasomotors Dose. Weak. rise slow increased j strongly ) ( increased f increased increased Medium. rapid greater decreased and lost increased decreased Toxic. fall slow and failing less decreased and lost lost 6. The action of nicotine on cardiac muscle. — Cardiac muscle re- sponds very sharply to the presence of nicotine, both by a change of rate and of amplitude, i.e., force of the contraction. Both these factors are increased under the stimulating action of therapeutic quantities of nicotine. The point can be proven readily by studies on isolated strips of cardiac muscle and by the reactions of isolated hearts, both mammalian or warm-blooded and the various cold- blooded hearts. Strips of ventricular muscle, when surrounded by physiological saline containing approximately .001 to .002 per cent, of nicotine show an increase of amplitude amounting to from 10 to 20 per cent, and an acceleration of the rate which is more or less variable. The perfused frog's heart shows comparable re- sults. The most striking illustration of this influence is found when the isolated mammalian heart is perfused with physiological solutions con- taining nicotine, as shown in Figure 35. Often the amplitude of the contractions of the heart is doubled and the rate strongly accele- rated. Undoubtedly a similar cardiac muscular effect is produced on the heart in its normal relations in the body. The late and relatively toxic actions of nicotine are depressant for cardiac muscle. This factor appears in the after effects in those experiments in which there is a maximum of primary stimulation. 7. The local nervous apparatus of the heart. — The peripheral nervous reactions to nicotine are best demonstrated by perfusions either on isolated organs or in blood-pressure studies. If one follows Schmiedeberg's technique, the results of which have already been given, he will note that the heart is at first slightly slowed for a few minutes, probably due to the local stimulation of the nerve THE NERVES OF THE HEART 141 cells of the cardiac ganglia. This stage, however, quickly passes. If now the vagus nerve, or the vago-sympathetic of the frog be stimu- lated in the neck, there is no longer an inhibition of the heart. In the frog, in fact, there is generally an acceleration. Direct stimulation of the sinus still produces inhibition, the observational fact on which Schmiedeberg reached his deduction that the pre-ganglionic nerve endings are blocked in the sinus ganglia. The fact that the ganglionic endings of the accelerator nerves in the frog are located central to Fig. 35 — Nicotine. 0.0002 per cent, in blood-Ringer's solution, on the isolated heart of the cat. Temperature and perfusion fluid constant. A later experiment with .0005 per cent, showed a more pronounced increase in the amplitude followed by a stage of depression from which recovery was very gradual. Rate before profusion 56, imme- diately after, 84. New tracing by Boutwell and Peeler. the point stimulated explains the acceleration observed in that animal. If one would dissect back of the stellate ganglion, in the frog to the white ramus from the third spinal nerve and apply an electrical stimulus, the acceleration observed on stimulation of the vago-sympathetic trunk will not occur. The nicotine has evidently poisoned the pre-ganglionic endings in the accelerator path just as effectively as in the inhibitory path. Emphasis has just been laid on the systemic effects that come from elimination of the coordinative nervous mechanisms. No better organ could be used in presenting the detrimental effects of the toxic alka- loids than this one of the action of nicotine on the cardiac regulative nerves. Certainly the coordinative control of the heart is one of the most fundamental factors in normal physiology. The elimination of this control, therefore, is obviously profoundly injurious. 8. The vasomotor system. — Notwithstanding the cardiac slowing observed, the blood-pressure generally rises when nicotine is injected 142 THE NICOTINE SERIES intravenously. This rise of blood-pressure is in no small part to be attributed to an increased tone of the peripheral blood-vessels. The central effects have already been mentioned, but there are also un- doubtedly peripheral actions, since vasoconstrictions occur in organs isolated from the central nervous system. Occasionally there is some vasodilation, instead of vasoconstriction, suggestive of stimulation of the vasodilator mechanism. When the tonic action from the cardiac inhibitory mechanism is eliminated, the blood-pressure may rise quite decidedly, largely from persistent vascular contractions. The blood-vessels dilate in the toxic stage. 9. On the glandular apparatus. — The peripheral glands show an increased secretion upon the administration of nicotine. This is due to the central action of the drug on the medullary nervous mech- anism. In the larger doses the peripheral ganglia are specifically poisoned and the reflex secretion correspondingly suppressed. It is not clear to what extent nicotine acts on the gland tissue as such. 10. The action of nicotine on the eye. — Nicotine paralyzes the nervous mechanisms of the eye. In fact, one of the simplest methods of demonstrating the specific nerve action of nicotine in laboratory use for many years, thanks to the researches of Langley, is that of bathing the cervical nerve and the superior cervical ganglion with 0.5 per cent, nicotine. Bathing the nerve trunk does not interfere with the passage of a nerve impulse. The function of this ganglion is blocked by the specific nicotine poisoning of the synapses and there is a failure of the usual dilation of the pupil upon cervical stimulation. The oculo-motor nerve has its pre-ganglionic unions in the ciliary ganglion. Nicotine poisons at this point too, hence tends to eliminate the conduction of the nerve whose function is to produce constriction of the pupil and an act of near accommodation, both processes vital to the adaptations of the eye to delicate vision. The diagrammatic relations of the nervous apparatus involved are illustrated in Figure 26, under the chapter on atropine. The resultant general effects of nicotine vary somewhat in different animals, but in man there is usu- ally some degree of contraction of the pupil. 11. Nicotine on the alimentary canal. — The complicated physio- logical control of the alimentary canal has been reviewed in some detail in the chapter on morphine. In order to understand the, action of nicotine one should keep in mind that complex interrelation THE NICOTINE HABIT 143 of neurones involved in coordination of the function of the vagus motor fibers, the sympathetic inhibitory fibers, also the relationships of the plexuses of Meissner and Auerbach. Much of our informa- tion has been obtained by studies on isolated portions of the alimentary tract, especially the contributions of Magnus. Nicotine, in the general circulation, causes as one of its striking symptoms, violent peristalses of the alimentary canal. This symptom is noticed and often spoken of by the social users of tobacco. How- ever, it is a symptom which comes in the more pronounced stage of nicotine intoxication, i.e., upon the smoking of strong cigars. As a matter of fact, the very first and mildest influence of nicotine on the alimentary canal is a quieting or inhibitive phenomenon. This is due to the influence of the alkaloid on the sympathetic or inhibitive fibers, the incipient nerve stimulative stage that has been noted in several previous connections. This stage is soon passed over, being followed by specific toxic elimination of the sympathetic endings in the ganglia of the walls of the stomach and intestine. The elimina- tion of the pre-ganglionic neurones sets the Auerbach 's plexus of the alimentary canal free, which, according to Magnus, controls the local peristalses of the isolated organ. It is open to question, yet the probabilities are that nicotine acts as stimulative to the nerve cells of the plexus of Auerbach. The alternative to this view, however, would explain the increased peristaltic movements of isolated prepara- tions by a direct influence on the muscular tissue. Even large doses of nicotine do not paralyze the contractions of isolated portions of the intestine. Magnus found that if atropine was combined with nicotine, then paralysis occurred, a result which would tend to the view that the nicotine alone acted on the nervous rather than the muscular tissue. 12. Excretion of nicotine. — Nicotine is largely excreted from the body through the kidney. However, there is a slight amount of excre- tion through general glands, such as the sweat glands, salivary glands, etc. Apparently there is some fixation and oxidation of nicotine by the tissues, though this is probably slight. IV. The Nicotine Habit. The social use of tobacco is one of the most widespread, of all drug habits, tobacco at the present time being used in smoking, chew- ing, and taken in powder form as snuff. It has little place in prac- 144 THE NICOTINE SERIES tical therapeutics, yet from the standpoint of experimental phar- macology and of toxicology it is very important. It is very difficult to secure an accurate and scientific estimate of the effects on the body of the constant use of tobacco. A great deal has been written and said, some advocating strongly that no appreciable effects follow the social use of tobacco, others with an equal vehemence attributing extensive and profound disturbances to its presence. The scientific observations depend, for the most part, on acute experi- ments such as have been related in the preceding pages. Obviously a summary of these pages shows that the alkaloid nicotine either directly or indirectly produces variations in the function of prac- tically all parts of the body. Stated generally this variation is a mild incipient acceleration of functional activity followed by a gen- eral depression and toxicity in the more pronounced stages of its in- fluence. The picture is complicated by selective toxicity to the widely distributed autonomic mechanisms. One must assume that repeated use of the drug produces the same cycle of changes, though their relative intensity varies greatly in that the body only slowly regains its normal condition after it has once been subjected to nicotine. All succeeding doses, i.e., smokes, etc., proceed from a very much changed norm. Then, too, a marked tolerance is acquired by the body as an organism. A single use, say the first smoke of tobacco, will leave the body in a condition somewhat depressed below its normal average func- tional alertness. This depression falls upon the nervous system, both central and peripheral, on the heart, blood-vessels, glands, alimentary canal, and muscles. Repeated use is followed by similar, but more accentuated depression. This is just the foundation for that condition of general body sensation which drives an individual to continued use of any agent which runs the cycle of initial stimula- tion and after depression, typical of nicotine. These depressed sensations and general body feelings urge to repetition of the earlier experience. When the use of the drug is mild, what is generally considered as moderate, then the driving sensations are less vigorous. If the indulgence is extreme in any instance the disturbance of mental poise and well-being is correspondingly great. The individual takes tobacco, therefore, in order to produce and maintain that incipient stimulative stage. He is driven to continued repetition by the after depressions which characterize the action of tobacco in every form. Any stimulative agent acts like a whip to the physiological mech- anisms of the body. If those mechanisms be delicately poised and THE NICOTINE HABIT 145 high strung, then the whip leads to nervousness and incoordination in the early phases of its action and to inevitable fatigue and exhaus- tion later. Repetition of the stimulus, in the long run, leads to an average physiological state which is far below the average normal for the individual before the use of the drug. One is led to suspect that herein lies the evil in the case. While there is no vital lesion resulting from the use of tobacco there is a diminution of the delicacy Fig. 36. — Blood-pressure in the decerebrate cat. The effects of the injection of liver extracts, A from a normal rabbit, B, from a nicotine tolerant rabbit. The extracts were made from equal parts of pulverized and dried liver, and each was incubated with 0.01 gram of nicotine for two hours and thirty minutes. Time — 5 seconds. From Dixon and Lee. of sensibility, a reduction of physiological ability, a slight but general lowering of the energy and endurance of the body. Tolerance. — It is a well-known fact that individuals respond less strongly to successive doses of nicotine. "While the first cigar may pro- duce acute symptoms of nicotine poisoning the individual soon ac- quires the ability to smoke, not only one, but several without the extreme symptoms. Dixon and Lee 1 have lately attacked this prob- lem. By the method of repeated doses of nicotine, extending through several weeks' time, they were able to secure animals of marked tolerance. Proceeding on the theory that " nicotine tolerance is due to the destruction of the alkaloid by the tissues " they made liver extracts of tolerant animals with non-tolerants for controls. These extracts were each mixed with a definite quantity of nicotine, allowed to incubate for two and one-half hours, then were estimated for nicotine content by the physiological method of blood-pressure. Dixon and Lee say, ' ' These experiments show that a certain small degree of tolerance can be obtained to nicotine, and that this is brought about by the destruction of the alkaloid. The destruction goes on verjr 1 Dixon, W. E., and Lee, W. E. : Quarterly Jour, of Experimental Physiology, Vol. V., pp. 373-383, 1912. 146 THE NICOTINE SERIES slowly, and it can never be accelerated to such a degree that an in- jection of a poisonous dose of nicotine into the circulation of an animal will lose any large amount of its effect. If the nicotine reaches the circulation slowly and in minute quantities it may be dealt with by the tissues, and this is the condition which we may assume obtains during tobacco smoking. ' ' These observations indicate that such nico- tine tolerance as is acquired depends upon the development of an oxidizing enzyme by the tolerant individual. CHAPTER XV. THE CONIINE, SPARTEINE GROUP. The alkaloids of this group form an intermediate series between nicotine on one hand and curare on the other. The most important members of the series are eoniine, lobeline, gelseminine, and sparteine. The most important member is eoniine, which may be taken as illustrate ing the actions of the other members. The chief difference is that of intensity and relative degree of toxic action. I. CONIINE. I. Historical and Chemical. The poisonous water hemlock, Conium maculatum, yields both from its roots and the stem the alkaloid eoniine, together with methyl eoniine, and conhydrine. Coniine is a piperidine compound and is interesting in that it was the first vegetable compound produced synthetically in the chemical laboratory, Hofmann in 1881. Methyl coniine differs from coniine by the substitution of methyl for the hydrogen attached to the nitrogen. Coniine has the chemical formula, C 8 H 17 N. The chemical relationships are indicated by the following formulae : Ha Ha Ha c c c c /\ /\ /\ /\ HC CH HaC CHa HaC CHa H 3 C CH a HC CH HaC CHa HaC CH-C 3 H 7 H 2 C CH-C 3 H 7 Y V V V H H CH 3 Pyridine Piperidine Coniine Methyl coniine II. Outline of Pharmacological Action. 1. Coniine produces a very mild initial stimulation of the cen- tral nervous system, followed by pronounced depression and paralysis. 147 148 THE CONIINE, SPARTEINE GROUP 2. It is toxic to peripheral nerve ganglia, acting similar to nicotine. 3. Coniine is toxic to motor nerve endings of striated muscle, resembling curare. III. Details of Pharmacological Action. i. On the central nervous system. — Coniine, like nicotine, pro- duces some stimulation of the central nervous system, but this effect is so slight and the depressing action so strong that the stimulating factor becomes insignificant. The symptoms on man are characterized by depression. Following a therapeutic dose there is drowsiness, irregularity of respiration, unsteadiness of gait, slight dilation of the pupil, secretion of saliva with a tendency to nausea, and sometimes vomiting. In toxic dose coniine, especially in the impure form, is char- acterized by the production of a general paralysis, which involves the voluntary muscle system. The paralysis is progressive, ending finally in loss of respiratory movements. Schmiedeberg indicates that the toxic cycle is quickly passed and that death follows in from three to four hours. As an illustration of the toxic action we have Plato 's classical description of the death of Socrates under the administration of the poison cup, which, judging from the symptoms alone, has been attributed to the poison hemlock. 2. On the autonomic nervous system. — Coniine, like nicotine, poisons the peripheral nerve ganglia. It is this which chiefly leads to disturbances of the normal physiological reactions of the peripheral tissue innervated through the autonomic system. There is some indi- cation of an initial stimulation of these ganglia, though this stage is very slight and evanescent. The main picture is that of tissue paralysis. However, it takes a larger dose of coniine to produce this poisonous effect than of nicotine, about in the ratio of 1 to 20. 3. On the voluntary motor nerve endings. — Coniine has a par- alyzing effect on voluntary nerve endings, similar in kind to that of curare. When coniine is administered hypodermically to the frog the ani- mal soon loses its usual erect position, lies flat on the supporting sur- face with the legs more or less extended. It shows, in the toxic stages, some muscular twitching and irregular muscular reactions, which have some superficial resemblance to muscular cramps. However, this effect is primarily due to partial paralysis of the nerve endings CONIINE ON THE CIRCULATORY APPARATUS 149 which eliminates the coordinative nervous control over the voluntary muscles. The presence of the muscular twitchings depends upon some central nervous change of an exciting nature, supposedly in the spinal cord. "When complete paralysis of the motor endings takes place the twitchings cease. Eespiration necessarily ceases, hence asphyxia- tion and death follow. 4. On the circulatory apparatus. — The action of coniine on the circulatory apparatus is primarily due to its interference with the nervous mechanism. A transient rise of blood-pressure has been observed. This is attributable to a peripheral vasoconstriction, which is explained by some as of peripheral origin, possibly an expression Fig. 37. — Coniine on the contractions of ventricular muscle, terrapin. Between the points " on " and " off " the muscle was bathed with .006 per cent, coniine. Time in seconds. of the initial stimulation of peripheral ganglia in the vasomotor nerve mechanism. In the later stages the blood-vessels are dilated and the pressure falls. This is due to paralysis at the same points which receive the initial stimulation, i.e., the peripheral ganglia of the vasomotor nerves. This paralysis eliminates the tonic vasomotor action. The heart is little affected by coniine, in so far as the muscle is concerned, though its nervous mechanism is deranged. At first the heart beats somewhat slower from the initial stimulation of the vagus, but as paralysis of the cardiac ganglia quickly ensues the tonic vagus control is eliminated and acceleration occurs. In those lower animals, which have no vagus tone, this phenomenon is not observed. 5. On the respiratory movements. — While the respiration under the influence of coniine shows some slight acceleration at first, the main picture is that of weakness and irregularity, the respiration becomes slow and the type of respiration shallow and irregular. In the toxic stage respiratory action is the first to disappear and death results from asphyxiation. Some difference of opinion exists in the literature as to whether 150 THE CONIINE, SPARTEINE GROUP respiratory paralysis is primarily central or peripheral. The curare- like poisoning of the motor nerve endings is thought by many to be sufficient to account for the stopping of respiration. 6. The excretion of coniine. — This alkaloid is excreted in the urine in part unchanged. Coniine rather readily breaks down and it is probable that a certain proportion of the drug may be decom- posed in the tissues. The excretion and decomposition is rapid, hence in coniine poisoning artificial respiration may ward off asphyxia- tion until recovery becomes possible. II. PYRIDINE AND PIPERIDINE. The action of pyridine and piperidine is similar to that of coniine, though very much weaker and less toxic. The chief action of the simpler compound, pyridine, is that of depression of the irritability of the nervous system. It shows little peripheral toxicity for the ganglionic cells. III. LOBELINE. Lobelia inflata yields an alkaloid, lobeline, C 18 H 23 N0 2 . Edmunds has described the action of lobeline as very similar, if not identical with that of nicotine. IV. GELSEMININE. Gelsemium sempervirens has yielded the alkaloids, gelsemine and gelseminine. The former alkaloid is described as producing strych- nine-like effects, especially on the frog. Gelseminine produces symp- toms very different from gelsemine and resembling the effects of coniine which have just been described. Gelseminine has a greater depressant action on the responses of the central nervous system than coniine. This influences the centers of the medulla and chiefly the respiratory center, thus leading to respiratory paralysis and death. Gelseminine, or some preparation of gelsemium, is employed rather widely to produce mydriasis. When drops are applied directly to the eye there is dilation of the pupil and loss of the power of ac- commodation. These phenomena are probably due in this case to paralysis of the nerve terminations in the muscles of the eye. On the heart gelseminine produces elimination of the function of the vagus, in this case by an early nicotine-like action on the cardiac SPARTEINE 151 ganglia, Cushny, 1 and by a later atropine-like toxicity to the vagus terminations on the cardiac muscle. V. SPARTEINE. Sparteine is a liquid alkaloid, derived from the broom plant, Cytisus scoparius. Sparteine has a more toxic peripheral action and a less vigorous action on the central nervous system than other members of this series. In this regard it most closely resembles curare. Its fatal effects are due chiefly to the motor paralysis, especially of the nerves of the respiratory apparatus. On blood-pressure sparteine has a somewhat depressing effect. This influence is primarily due to the lowering of the vitality of the heart through toxicity on cardiac muscle, depression which is accen- tuated by a slight initial vagus stimulation. 1 Cushny, Arthur R. : " Die wirksamen Bestandtheile des Gelsemium semper- virens," Arch. f. Path. u. Pharm., Vol. XXXI, pp. 49-68, 1893. CHAPTER XVI. EPINEPHRINE. I. Historical and Chemical. The internal secretion of the epinephros, epinephrine or adrenaline, possesses the formula, according to Aldrich, C 9 H 13 N0 3 . It is chemi- cally an amino alcohol with a pyrocatechin base as follows : HO |/\ CH.OH.CH 2 NH.CH 3 HO I J This active material is elaborated in the animal body by the medulla of the suprarenal gland. That the suprarenal glands contain an active principle was first demonstrated by Oliver and Schaefer x in 1895. They worked with the extracts of the gland itself. Abel 2 was the first to isolate the active principle which he called epinephrine, and assigned the constitutional formula, C 10 H 11 NO 3 -iH 2 O. Takamine also isolated the active principle, calling it adrenaline, and perfected the methods for producing the material on a commercial basis. Folin has perfected a colorimetric chemical test for epinephrine accurate to 1 in 3,000,000 parts. The test rests on a quantitative application of the blue color reaction between adrenaline and phosphotungstic acid, compared in a colorimeter against a standard color solution. Many other glands of the body produce a physiologically active principle, which is given off to the blood or lymph. But the type of reaction of adrenaline is closely approximated to that of certain of the plant alka- loids that have previously been described, in that its action is specifi- cally on the peripheral nerve endings. II. Outline of Pharmacological Action. 1. Marked stimulation of sympathetic nerve endings of all types. The most striking of these groups are: 1 Oliver and Schaefer: Journal of Physiology, Vol. XVIII., pp. 230-277, 1895. 2 Abel, J. J.: Johns Hopkins Hosp. Bull., Vol. IX., p. 215, 1898; Vol. XII., p. 240, 1901. 152 DETAILS OF PHARMACOLOGICAL ACTION 153 2. Vasoconstriction in most organs of the body, especially in the visceral regions. 3. Acceleration of the heart and stimulation of accelerator end- ings, complicated by 4. A secondary medullary stimulation of the vagus center. 5. Stimulation of the sympathetic nerve endings of the salivary and lachrymal glands. 6. Inhibition of physiological activities where the sympathetic furnishes inhibitory fibers, most pronounced in the gastric, intestinal, and uro-genital tracts. 7. Dilation of the pupil. 8. Glycosuria. III. Details of Pharmacological Action. 1. Action on the nervous system. — Epinephrine is specific in its stimulative action on the terminal fibers of mechanisms of the sym- pathetic system in the various tissues. Hence the chief changes in the function of the body which are accomplished by this drug are those which involve reactions of the tissues controlled by the sympathetic nerves. There is some slight acceleration of reaction of the basic centers of the central nervous system, particularly of the centers of the medulla. Of these, the only ones of special importance are the respiratory and the cardiac inhibitory centers. The slowing of the heart observed on adrenaline injection is generally attributed to stimulation of the medullary inhibitory center. However, in experi- mental procedures in which the blood-pressure is prevented from rising above the normal, this slowing is slight or absent. This fact bears the interpretation that the slowing of the heart is a sec- ondary effect, produced by the increase in vagus tone, because of the marked general rise of blood-pressure. 2. Epinephrine on blood-pressure — vasoconstriction. — The in- travenous injection of adrenaline into the circulation produces an enormous rise of blood-pressure, an effect first described by Oliver and Schaefer, who experimented with extracts of the gland itself several years prior to the chemical isolation of the active principle. "With maximal doses the blood-pressure may rise from 100 to 150 per cent. The blood-pressure remains high for a few moments, then slowly declines to approximately the original pressure. A characteristic of the picture is its short duration, Figure 42. 154 EPINEPHRINE The tremendous rise of pressure is due to a marked arterial con- striction, which takes place, especially, in the visceral organs, such as the alimentary canal, spleen, kidney, also in the general systemic vessels. "When, for example, either the kidney or the intestine is placed in an oncometer and adrenaline injected into the circulation, the volume sharply decreases and the organ remains under its normal size, even at a time when the blood-pressure is at its maximum. Pig. 38. — Intravenous injection of 0.1 gram of suprarenal of the calf. Dog with the vagi cut ; the brachial plexus cut on the right side only. A, kidney volume ; B, volume of the right arm ; C, volume of the left arm ; D, carotid blood-pressure ; E, blood- pressure. The time of the injection as marked. From Oliver and Schaefer Meltzer 1 has shown that the duration of the vasoconstriction is dependent upon the maintenance of the normal relations of the sym- pathetic nerves. For example, if the cervical nerve of the rabbit is previously cut, then adrenaline produces a slower, longer, and stronger constriction in the blood-vessels than in the normal. This change takes place also after removal of the superior cervical s} T m- pathetic ganglion. The plethysmogram of the limbs (Oliver and Schaefer) may show a passive dilation, following the rise of the blood-pressure curve. However, when artificial means are taken to keep the general blood- pressure constant it is shown that the constrictions take place in the arterioles of the limbs also. This active constriction may be mechanically overcome, in ordinary experiments, as in Oliver and Schaefer 's tests, by the enormous general rise of blood-pressure. Studies on isolated organs show that perfusions of adrenaline solution produce vascular constriction. This, of course, indicates that the adrenaline effect is on the peripheral structures, but whether the 1 Meltzer, S. J., and Meltzer, Clara: American Journal of Pht/siolog;/, Vol. IX., p. 147, 1903. DETAILS OF PHARMACOLOGICAL ACTION 155 stimulation is due to a reaction on the vasomotor terminal fibers or a direct stimulation of the smooth muscle has been far more diffi- cult to determine. The classic work of Elliott, 1 and the later work of Dale, 2 have finally determined that adrenaline reacts >at the myo-neural junction leading to stimulative or inhibitive end reactions according to the particular autonomic nerve mechanism considered. Sollmann noted that isolated organs perfused, with adrenaline p IG< 39. — Shows the fall in hlood-pressure and the increase in the volume of the intestine upon injection of successive doses of 0.1 mgr. adrenaline. The vasoconstrictor nerve-endings have previously hern paralyzed hy 100 mgrs. chrysotoxin. Dale. solutions exhibited a constrictor effect followed by a late dilation. It is well known that certain visceral organs are doubly innervated, i.e., by antagonistic acting nerves. The above phenomenon is ex- plained on the ground that the adrenaline, not only stimulates the nerve endings of the constrictor mechanism, but at the same time the ends of the dilator fibers. Since vasoconstriction is the dominant nerve influence, the dilator effects come on only after the former 1 Elliott, T. Pv.: Journal of /'////.s/o/o.r/.'/. Vol. XXXII., p. 401, W05. 2 Dale, H. H.: Journal of Physiology, Vol. XXXIV., p. 163, 1006. 156 EPINEPHRINE have passed away. This phenomenon is rendered more intelligible when considered in connection with the well-known fact demonstrated by Bowditch and Warren that the vasodilator nerve mechanism retains its physiological properties longer after isolation from the central nervous system. Dixon x showed that adrenaline was inactive after the sympathetic endings were poisoned with apocodeine. Dale has given us the cleaner cut analysis by demonstrating that ergotoxine in larger doses Pig. 40.— Epinephrine 0.0012 per cent, in Ringer's solution perfused through the frog's heart. Normal rate, 30 ; maximum rate, 35. The amplitude was increased more than 100 per cent. New tracing by Summers. N produces a selective paralysis of the sympathetic stimulative mechan- isms without at the same time suppressing the function of the inhibi- tory mechanism. In his hands, adrenaline injected into the circu- latory system, after the poisoning of the vasomotor nerve endings by ergotoxine, produced a sharp stimulation of the vasodilator nerves. In fact, this was true of the inhibitory nerves of all organs, i.e., not only of blood-vessels but of the inhibitory nerves of the viscero-motor mechanism and of the uro-genital system, see table, page 159. In this clean-cut technique we have a means for the physiological separation of stimulative and inhibitory mechanisms, not only of the vascular system, but of other portions of the body as well. By the applica- tion of ergotoxine, it has been possible to demonstrate the fact that 1 Dixon, W. E. : Journal of Physiology, Vol. XXX., p. 97, 1903. DETAILS OF PHARMACOLOGICAL ACTION 157 adrenaline stimulates both inhibitory and motor mechanisms, when they arise by sympathetic nerve channels. 3. On the heart. — In the study of the action of epinephrine on the isolated heart, it is abundantly shown that it produces an increase in the rhythm and also in the amplitude of the contractions. This effect is true for both the frog heart and for the mammalian heart. <2r@Eye Submaxillar?/ Parotid Visceral blood vessels Stomach Liver Pancreas Intestine Kidney Colon-rectum Urinary bladder Genital organs Fig. 41. — Diagrammatic representation of the paths of the autonomic nervous dis- tribution. Modified from Meyer and Gottlieb. A perfusion through the frog heart isolated from the central nervous system shows this acceleration accompanied by an increase in ampli- tude. In the perfused isolated mammalian heart the amplitude x>f the contractions will often be doubled or even trebled. The rate may follow the increase in amplitude or may remain constant. There is great variation in individual experiments. If the heart is studied in the intact mammal, then the picture is somewhat different. At the stage of maximal blood-pressure, in- stead of an increase in heart rate there is a decrease, a fact attributed to the increase in tonic activity of the vagus center. The rise of 158 EPINEPHRINE blood-pressure is itself sufficient to stimulate the vagus center — a fact that has long since been known. Hence many authors consider this vagus slowing under adrenaline as purely a secondary effect. The matter cannot be said to be fully settled, for it seems that there is a questionable factor of direct medullary stimulation involved. In any case, the stimulating effect on the accelerator mechanism is far more powerful and the quickest to take effect as shown by the accelerated heart rate during the rapid. rise of blood-pressure. It is the pre- dominant factor in determining the major change in heart function under adrenaline in the intact animal. Cardiac muscle is itself directly stimulated by adrenaline. This is proved by experiments on isolated heart muscle. Strips of the terra- pin 's ventricle increase in amplitude and also in rate, under the influ- ence of solutions of adrenaline. The accelerator cardiac mechanism is absent or at most poorly developed in this animal, hence the favorable muscular effects cannot be explained by assuming a stimulation of the accelerator endings. 4. Salivary glands. — The injection of adrenaline in mammals leads to an increased secretion of the salivary glands and of the lachrymal glands. The glands of the respiratory tract, in general, show acceleration in function, though there is apparently no stimula- tion of the sweat glands. Adrenaline stimulates the sympathetic secretion. This action of the drug is relatively unimportant. 5. On gastric and intestinal movements. — Brodie and Dixon 1 present a table showing that adrenaline influences all those organs that respond to sympathetic stimulation. The important function in the sympathetic control of the gastric and intestinal movements is through inhibitory nerves. These are primarily stimulated by adrena- line. Dale, 2 in the comparative table presented below, finds that adrenaline produces the same inhibitive action on the alimentary tract after ergotoxine as before poisoning by the drug. The ileo-cecal sphincter (Elliott) is strongly contracted by adrena- line, though adjacent muscles on either side are inhibited by the drug, a result in complete accord with sympathetic stimulation. 6. Adrenaline on the uro-genital apparatus. — Adrenaline pro- duces on the bladder and the uterus of the mammal the same general effects as are produced by stimulation of the sympathetic nerves. This Dale has shown to be both stimulative and inhibitive for the uterus, owing to the twofold sympathetic innervation. 1 Brodie and Dixon: Journal of Physiology, Vol. XXX., p. 476, 1904. 2 Dale, II. II.: Journal of Physiology, Vol. XXXIV., p. 163, 1906. ACTIOX OF EPINEPHRINE ON THE EYE 159 The Action of Adrenaline on Different Organs of the Mammalian Body in the Normal Animal, and after Ergot Poisoning. From Dale. Organ. Effects of stimulating the sympathetic nerve supply, or injecting adrenaline intravenously. Before ergot. After ergot. Arteries (cat, dog, ferret) (rabbit) Cardiac muscle Spleen (cat) Stomach (cat) • Small intestine (cat, dog, monkey). Large intestine (cat) Ileo-colic sphincter (cat) Internal anal sphincter (cat) Gall bladder Fundus of urinary bladder (cat). . . Fundus of urinary bladder (ferret) Base of bladder and urethra (cat). . Pilo-motor muscles Dilator iridis Uterus (cat, non-pregnant) Uterus (cat, pregnant) Uterus (rabbit), Uterus (monkey) Retractor penis (dog) M M 31 M I I I M M I I M M M M I or M and I M M M M I Nil or weak M Nil or weak M I I I I Nil I I I I Nil Nil Nil with adrenal- ine. Weak M with cervical sympa- thetic stimulation I I I (slight) I Nil M.— Motor effects. I.— Inhibitory effects. If the uterine motor nerves, which are dominant under certain conditions, are first paralyzed by ergotoxine, then injections of adren- aline stimulate the inhibitory nerves just as in the doubly innervated vascular regions. The uterus and vagina react together. 7. On the eye. — The intravenous injection of adrenaline produces a marked dilation of the pupil of the eye together with the usual vascular constrictions. On the other hand, local instillation of adrenaline in the normal eye produces no pupillary effect (Radzwei- sky, 1898), a failure that has been difficult to explain. Meltzer and Auer, 1904, in studying rabbits found that if the cervical sympathetic nerves were cut then adrenaline produced vasoconstrictions in the ear, both when given intravenously and when introduced hypodermic- ally. The contractions of the vessels, under these conditions, came on later, were stronger, and lasted very much longer. The eye still responded as in the normal animal. After excision of the superior cervical ganglion the pupil of the eye was markedly dilated, not only by intravenous, but also by hypodermic and by local injections of 160 EPINEPHRINE adrenaline. This dilation did not occur immediately after excision of the ganglion, but only after an interval of 24 hours or more, and it occurred as late as three and one-half months. Undoubtedly the cervical sympathetic exerts a tonic mydriatic effect on the iris. Section of the nerve in the neck leads to a loss of Fig. 42. — The action of 0.1 mgr. adrenaline injected into the circulation of the cat. B. P. arterial hlood-pressure, lower tracing. The upper tracing represents the contrac- tion of the pregnant uterus. Note from the tahle, page 159 that adrenaline causes relaxation of the non-pregnant uterus. Time in seconds. From Dale. tone, hence to slight constriction of the pupil. Following excision of the ganglion the peripheral nerves will in time degenerate. Hence the mydriasis produced by injections or instillations of adrenaline at long intervals after the ganglion has been removed would seem to be dependent upon the local stimulation of the radial muscles. In what way the presence of the ganglion prevents this " paradoxical " action in the normal animal is not clear. The oculo-motor nerve is not influenced by adrenaline. ACTION OF EPINEPHRINE 161 8. Glycosuria. — When adrenaline is administered to a mammal in stimulative quantity sugar appears in the urine. This is attributed to an increase in the glycogenolysis of the liver. The studies of Paton show that the glycosuria does not have its origin in the kidney. By operations on the rat which is a favorable animal for this purpose, it has been shown that extirpation of the suprarenal glands leads to the elimination of the stored glycogen from the liver. Schwarz 1 found from 2.44 per cent, to 5.07 per cent, glycogen in the livers of normal rats. After complete epinephrectomy, the two adrenals being removed in successive operations, the liver was never found to con- tain more than a trace of glycogen — in seven epinephrectomized livers, two only showed traces of glycogen. IV. General Discussion of the Action of Epinephrine. Epinephrine, like the members of the pilocarpine group, produces its action chiefly at the terminal fibers of a special group of nerves, in this case the strictly sympathetic nerves, such as the accelerators of the heart, the inhibitory nerves of the stomach and intestine, etc. Fig. 43. — Intestinal strip beating in inactive blood which was removed at o. Blood from adrenal veins substituted at b, and removed at c. Contractions restored in inact- ive blood, blood removed at d; then blood from renal vein (same animal) added at e. Time in half minutes. From Cannon and de la Paz. But of all the reactions the most specific and characteristic is the profound general stimulation of the vasomotor nerves. Here again we have a marked specificity of action and one which has a profound influence on the normal function of the body. 1 Schwarz, Oswald: Pfliiger's Archiv, Vol. CXXXIV., p. 259, 1910. 162 EPINEPHRINE Cannon and de la Paz, 1 1911. advanced the interesting view that the suprarenal gland is of specific physiological importance in connec- tion with the function of the sympathetic system, particularly in times of stress. They observed that cats, dogs, and other animals when in fright show dilation of the pupils, erection of the hairs, inhibition of alimentary movements, etc. — typical sympathetic reactions. Under these conditions they say there is a strong stimulation of the supra- renal glands, whereby the secretion of epinephrine into the blood- stream is increased. This increase in turn reacts on the terminal structures of the sympathetic system in general to render physio- logical responses of the organs more effective. That the suprarenals markedly influence metabolism is indicated by the disturbances of the glycogenic function upon their removal, or upon the injection of epinephrine. The same significance at- taches to the disturbances of function that occur in disease of the glands, as, for example, in Addison's disease. Normal suprarenal glands contain from 2.5 to 3 per cent, adrenaline, whereas diseased glands may have little or none of this active principle. The transient effect of epinephrine has been difficult to explain. As a matter of fact, the direct effect of epinephrine on cardiac mus- cular tissue is more persistent. The observations of Meltzer and Auer, already referred to, on the blood vascular constrictions and the mydriasis after excision of the superior cervical ganglion show that after this operation the action of adrenaline is very persistent, lasting one hour and often more. It would seem, therefore, that the transient effect is dependent in some way not fully explained upon the reactions through the sympathetic system. Of course, in paralysis or other loss of function of the nervous system the more enduring effect may be expected, and is to be kept sharply in mind by the clinician. The disappearance of the vasoconstriction was at first thought to be due to oxidation of the adrenaline, either directly by the tissues or through the influence of the alkalinity of the blood and tissues. But it has been shown that the blood of an animal that has received a large dose of epinephrine and has apparently recovered from the effects still is capable of producing the adrenaline reaction in a second animal. Adrenaline injected into the leg of a rabbit, in which the circulation is obstructed by a ligature, will produce the typical reactions in the body when the ligature is removed. Contact with 1 Cannon, W. B., and do la Paz: American Journal of Physiology, Vol. XXVIII, p. 64, 1911. SUMMARY OF ACTION 163 the tissues for one hour or more ought to suffice to oxidize the epinephrine if that accounted for its short reaction in the body. The evanescent effect of epinephrine has been against its use as an ideal blood vascular stimulating agent for therapeutic purposes. But many conditions arise, disturbing the efficiency of the sympathetic nervous mechanism, such as a general vasomotor depression with atony of the blood-vessels. Here intravenous perfusions of warm saline containing not more than one drop of standard solution of adrenaline hydrochloride per 100 cubic centimeters, has proven extremely bene- ficial in overcoming the splanchnic vascular dilation in vasomotor shock. The peripheral action of epinephrine is beneficial even when the splanchnic dilation takes place from central shock. This would seem to indicate that epinephrine is a valuable agent in the trans- fusion of saline in this type of depressed sympathetic nerve function. Summary of Action. Epinephrine intravenously injected produces a tremendous rise of blood-pressure. When given hypodermically the effect is slight unless the dose be very large — one hundred times as great as the intravenous dose. But it is effective and prolonged, especially in operative or degenerative removal of the peripheral sympathetic ganglia. The rise of blood-pressure is produced by strong stimula- tion of the arterioles primarily through the endings of the vasomotor nerves, or in cases of paralysis of the post-ganglionic nervous mechan- ism through direct stimulation of the muscular tissue. Arterial constriction occurs through the body, but is greatest in the splanchnic area. The heart itself is stimulated through the ac- celerator nerves and by an increase in contractile power of the heart muscle. This effect is somewhat counteracted by the increase in tone of the cardiac inhibitory center, which effect is at its maximum at the time of maximal blood-pressure. Other organs respond to epinephrine by an increase of function of the type produced by the stimulation of the sympathetic nervous mechanism. The organs of chief importance are the eye, in which dilation of the pupil occurs on intravenous injection of epinephrine, or in local application or sub- cutaneous injection after removal of the superior cervical ganglion; the stomach and intestine, in which there is an inhibition of peristalsis accomplished through stimulation of the sympathetic inhibitory nerves; and on the bladder, uterus, and spleen, where similar effects 164 EPINEPHRINE are produced. Metabolism is sharply influenced by adrenaline, shown primarily by the increase in the glycogenolysis of the liver. This active principle is produced by the suprarenal gland under the nervous control of the sympathetic nervous system. The alkaloid is discharged into the blood-stream and distributed especially to the nerve endings of the sympathetic fibers throughout the body which it specifically stimulates, and to the muscular and glandular tissues controlled by these fibers. Epinephrine is largely consumed in the body, though when excessive quantities are present, small amounts are excreted through the urine. CHAPTER XVII. THE ERGOT SERIES. I. Historical and Chemical. The fungus, Claviceps purpurea, which grows chiefly on rye, con- tains a series of pharmacologically active principles more or less toxic. Preparations of ergot have been used in medicine since the sixteenth century. The active principles have been difficult to isolate but have been the subject of numerous careful studies. The first important investigation which should be mentioned is that of Kobert * in 1884. Kobert isolated three substances, to which he gave the names ergotinic acid, sphacelinic acid, and cornutine. Kobert 's ac- tive principles have been proven to be in all probability impurities. However, he showed that ergot contained two types of toxic sub- stances, one of which leads to chronic disintegration and sloughing of the tissues, the other to more acute conditions associated with high blood-pressure and accompanying nerve symptoms. In chronic ergotism, resulting during severe epidemics which have occurred in certain parts of Europe following the use of infected rye bread, these two types of intoxication have occurred. Through the mutually supporting chemical and pharmacological work of Barger and Dale, 2 in combination with various associates, we now know that the activity of ergot is due primarily to three chemical substances. These chemicals are ergotoxine, isoamylamine, and the more strongly toxic parahydroxyphenylethylamine. The latter approaches adrenaline in the character of its action. Ergotoxine, CsbH^ObNb Isoamylamine, £^f)CH.CH a .CH,.NH 9 1 Kobert, R.: Arch. f. Path. u. Pharm., Vol. XVIII., pp. 316-380, 1884. "Barger, G v and Dale, H. H.: Bio-chemical Journal, Vol. II., pp. 240-299, 1907; Journal of Physiology, Vol. XLL, p. 19, 1910. 165 166 THE ERGOT SERIES Parahydroxyphenylethylamine, HO^ \CH 2 .CH,.NH 2 HO Adrenaline, Ho/ \cH(OH).CH 3 .NH.CH 3 . Isoamylamine and parahydroxyphenylethylamine, the latter known under the trade name of tyramine, were isolated from ergot by the methods used in isolating the same substances from putrid meats, 1 and it is interesting to note that the probable origin is similar in the two cases, namely, from leucine in the first instance and from tyrosine in the second. The pharmacological reactions are identical in kind. The complex content of ergot preparations readily decomposes, hence such preparations rapidly change in the intensity of their physiological actions, a factor that should be taken into account in the therapeutic application of the drug. II. Outline of Pharmacological Action. The pharmacological action of individual ergot preparations varies, but when preparations of the crude drug are used the following primary effects occur: 1. Stimulant effects on plain muscle organs, prominent among which are the circulatory system, the alimentary canal, and the uro- genital system. 2. Specific toxicity to the motor types of myo-neural junction (ergot oxine) . 3. Toxicity to protoplasmic structures in general. 4. Parahydroxyphenylethylamine produces a sympathomimetic activity comparable to epinephrine. 5. Ergotine produces primary stimulation followed by paralysis of the myo-neural junction. III. Details of Pharmacological Action. i. The action of chemically pure principles. — The exact action of the ultimate principles in ergot is still under some discussion in the 1 Barger, G., and Walpole, G. S.: Journal of Physiology, Vol. XXXIX., p. 343, 1909. ERGOTOXINE 167 literature, but accepting the work of Barger and Dale, as indicated above, we may attribute the characteristic ergot symptoms, first, to ergotoxine, which is responsible for the gangrenous degenerations at- tributed to ergot, and second, to the parahydroxyplienifletJiylamine, the blood-pressor and other involuntary motor effects. 2. Ergotoxine. — Ergotine produces " ataxia, dyspnea, saliva- tion, gastro-intestinal irritation, and gangrene." It also produces stimulation of those organs containing smooth muscle, especially the Fig. 44. — The action of ergotoxine perfused through the frog's heart. The rate la little changed though the amplitude is slightly increased and remains high after the normal Ringer's solution is returned. New tracing by Summers. uterus and the arteries. In these latter paralysis follows at a later stage of its action. It is an interesting fact that the extreme toxicity of ergotoxine is lost by its dehydration, in the crystalline ergotinine C 85 H 89 O s N 5 . It is the ready transformation between these two sub- stances to which is ascribed much of the variability in current prepara- tions of ergot. Barger and Dale believe that the active ergotoxine has been present as an impurity and accounts for the action ascribed to many of the specific substances that were prepared earlier in the history of the study of ergot. 3. Isoamylamine. — This active principle has been tested out by Dale and Dixon, who found that it was a positive blood-pressure producing substance. Its reaction is not so vigorous as the other active ergot principles, and its quantity is relatively small in ergot, hence it may be passed without special emphasis. 4. Parahydroxyphenylethylamine. — This substance was isolated from ergot by Barger and Dale in 1909, and was carefully studied 168 THE ERGOT SERIES pharmacologically by Dale and Dixon. They found it to be a very strong pressor principle. It caused a vigorous rise of blood-pressure when injected intravenously in as low as two-milligram doses. It also sharply stimulated the amplitude and rhythm of the heart, the con- tractions of the spleen, the uterus, and of muscular portions of the urinary apparatus. The action is indeed very similar to that of Fig. 45. — The influence of isoamylamine on strips of muscle from the terrapin heart. The upper tracing is a ventricular, the lower a sinus-auricular strip. The strength of solution 15 per cent, in physiological saline. The most striking change is the marked increase in tone and suppression of the rhythm in the ventricle. Both strips exhibit a strong rhythm in the late after-period. New tracing by Stone. adrenaline, producing both the motor and inhibitory effects charac- teristic of nerves of the sympathetic system. The motor effects are more powerful than the inhibitory. However, the stimulating action of the drug is many times less intense than that of adrenaline. 5. The action of extracts of ergot. — The pure principles of ergot have not yet been fully accepted for general use. Therapeutists still find the principal available preparations to be the older Galenic ex- tracts, or the more or less purified extracts. The extracts of ergot contain beside the pure principles mentioned above traces of a num- ACTION OF ERGOT ON THE UTERUS 169 ber of more or less toxic substances, some of which have deleterious effects, particularly on the heart. As these principles vary in quantity in different preparations the extracts should, like digitalis, always be physiologically standardized and should be used within a reasonable time after this standardization. Fig. 46. — The effect of 2 mgrs. p-hydroxyphenylethylamine given intravenously. Spleen volume upper, and blood-pressure lower curve. Time in 10 seconds. Pithed cat. From Dale and Dixon. The most typical and characteristic influence of ergot is the pro- duction of an increased action of smooth muscle tissue. The thera- peutic value of the drug depends especially on this reaction as regards, first, the function of the uterus, and second, the reactions of the blood vascular system. 6. The action of ergot on the uterus. — For many years ergot has been used for its beneficial effect upon the contractions of the uterus during parturition. When given in therapeutic quantity it leads to an increase in the expulsive uterine contractions during child- birth, especially when the uterine wall is reacting weakly. In ex- cessive or toxic doses the normal peristaltic contractions may become 170 THE ERGOT SERIES tetanic in character, which, of course, is detrimental to the normal function at this time. Over-violent contractions against the volume of the fetus may in fact lead to laceration and rupture of the uterus, as well as asphyxiation of the fetus itself. A second obstetric use of ergot is to aid in the post-partum con- tractions of the uterine wall in order that the open and bleeding Fig. 47. — The effect of 2 mgrs. of parahydroxyphenylethylamine on the isolated apex of the pregnant uterus of the cat. The drug was added at the ! and changed to pure Ringer's solution at the J . Contractions, down strokes. Time in 10 seconds. From Dale and Dixon. uterine sinuses may be somewhat closed during the critical time that these lacerated surfaces are being occluded through blood coagula- tion, etc. There is no doubt that a favorable exhibition of the drug is of value in this connection, though its excessive use may lead to an after-paralysis and relaxation with post-partum bleeding. In following the reactions of the uterus to ergot it must be kept in mind that the organ has a double innervation, stimulative motor nerves, chiefly through the hypogastric and the inhibitive nerves, in part from the sacral region. The relative physiological control of these nerves over the organ varies according to the state of the uterus. Numerous experiments have shown that the pregnant uterus is much ACTION OF ERGOT ON THE CIRCULATORY SYSTEM 171 more amenable to the motor nervous control than the non-pregnant. Ergot, for example, often causes relaxation of the virgin uterus, whereas it produces strong contraction of the pregnant uterus. The ergotoxine first stimulates, then paralyzes the utero-motor apparatus, apparently paralyzing at the myo-neural junction. After this paral- ysis epinephrine, which stimulates both motor and inhibitory uterine nerves, now produces only inhibition. 1 The ergotoxine constituent of extracts of ergot may through this latter effect modify the pressor in- fluence of the parahydroxyphenylethylamine. 7. The action of ergot on the circulatory system. — Sollmann and Brown 2 have exhaustively studied the influence of ergot on the circulatory system, showing the remarkable variation in the intra- venous effects of these preparations. They more often found a fall of blood-pressure on intravenous injection of ergot than the contrary. This, in view of the well-established blood pressor action of both ergotoxine and of parahydroxyphenylethylamine, shows the inherent danger of reliance on extracts of ergot. The logic of the case would indicate the greater reliability of the chemically pure preparations. The therapeutically valuable principles of ergot produce a tremendous rise of blood-pressure by a stimulation of the vasoconstrictor nerve endings. The vascular contraction is similar in character, but smaller in amount and more prolonged than that produced by epinephrine. The gangrene that follows the use of certain ergot preparations has been explained on the ground that the vascular spasm of such vascular peripheral organs as the ear and the cockscomb is due to the fact that the prolonged contraction shuts off the blood-supply to such an extent as to cause asphyxiation and degeneration of the tissues. Histological studies have shown obliteration of the cavity of the blood-vessels accompanied by hyaline degeneration. However, this explanation may account only in part for the gangrene effects, since many preparations of ergot contain considerable quantities of saponine-like bodies. 8. On the heart. — The cardiac action is decidedly strengthened by ergot, especially is the amplitude of the contraction of the ventricles increased. This is shown not only on the heart in place, but on the isolated heart (Sollmann and Brown), and is therefore to be ascribed to peripheral action, and is due to stimulating effects on the accelerator nerve endings. In contrast with the cardiac stimulation of alkaloids 1 Dale, H. H.: Journal of Physiology, Vol. XXXIV., p. 163, 1906. 2 Sollmann, Torald, and Brown, E. D. : Journal of the American Medical As- sociation, Vol. XLV., p. 229, 1905. 172 THE ERGOT SERIES such as epinephrine, it is noted that the ergot stimulation is much more persistent and prolonged. Epinephrine stimulates the accelerator nerve endings in cardiac muscle, and the resulting physiological changes are quickly developed and profound in volume though rel- Fig. 48. — The effect of 0.2 mgr. of parahydroxyphenylethylamine on the isolated heart of the rabbit. Time in 1-4 seconds. From Dale and Dixon. atively short in duration. The cardiac action of the active prin- ciples of ergot is somewhat more prolonged, though otherwise similar to epinephrine, a fact which undoubtedly is to be ascribed as chiefly due to the parahydroxyphenylethylamine constituent. However, the Fig. 49. — The effect of 0.2 cc. — solution of isoamylamine hydrochloride on the isolated heart of the rabbit. Time in 2 seconds. From Dale and Dixon. isoamylamine constituent also stimulates after a very brief muscular depression, as shown in the figure. Augmentative influence on the heart produces a strong percentage of the rise in blood-pressure. It is the combination of the two factors, increase in peripheral resist- ance and cardiac augmentation, that accounts for the firm, hard pulse in ergot poisoning. In those preparations of ergot which have cardiac depressing principles the stimulating effect may be counter- acted by the direct cardiac muscular depression. 9. Action on the alimentary canal. — Ergot leads to a marked increase of the peristalsis of the alimentary tract. Not only does this systemic effect result, but local irritations may lead to pro- ACTION ON OTHER PHYSIOLOGICAL MECHANISMS 173 nounced insalivation, vomiting, and purging. The peristaltic action is ascribed largely to the effect of ergot on the nervous mechanism controlling alimentary peristalsis, though a direct stimulation of the smooth muscle has been described. Gangrenous foci are also found in the mucous membrane and walls of the alimentary canal. These are due to the vascular stagnation and resulting local degenerations from the action of ergotoxine. 10. Effect of ergot on other physiological mechanisms. — The nerve centers in the medulla are stimulated to some slight extent by ergot, though it has not always been clear whether or not these stimulations are the indirect effects of the change in vascular supply. The secreting glands are influenced to a greater output, the eye exhibits a marked contraction of the pupil, and the urinary bladder is thrown into motor activity, all by intravenous injections of ergot. These effects are doubtless due primarily to the two most active con- stituents, ergotoxine and hydroxyphenylethylamine. D. Drugs With Primary Activity On Smooth Muscle. CHAPTER XVIII. BARIUM CHLORIDE. Barium chloride, one of the inorganic salts, has a very pro- nounced influence on the circulatory system, an action in a way inter- mediate between that of digitalis and ergot. II. Outline of Pharmacological Action. Barium chloride is a very toxic substance and produces toxic change in the physiological reactions in most parts of the body, sum- marized as follows : 1. A pronounced stimulation, followed by a toxic paralysis of the central nervous axis, especially of the medulla and cord. 2. Vascular constriction by direct stimulation of the muscles of the arterioles. 3. Increase in the heart rate, with fibrillation in the toxic stage. 4. Respiratory acceleration from medullary stimulation. 5. A toxic contraction of skeletal muscles, with delay in the re- laxation phase. 6. Cathartic and diuretic action. 7. Local irritation and toxic necrosis of tissue. III. Details of Pharmacological Action. i. Barium chloride on the circulatory system. — On the heart: The most striking influence of barium chloride is that on the circula- tory system. The function of the heart is decidedly influenced. In therapeutic quantity introduced into the general circulation, the heart beats stronger but slower, but a greater quantity (30 mgr. 174 ACTION ON THE HEART 175 intravenous in a dog) leads to a tremendous increase in the heart rate. On the isolated perfused heart the contractions are more vigorous and far more rapid than under normal conditions. The peripheral action of barium chloride is directly on cardiac muscle. Isolated strips of ventricle contract with greater amplitude and with increased rhythm. There is a tendency to great increase in tone, so that the muscle enters a strong systolic contracture. If the concentration of the salt be too great or it act too long, the contrac- d'»ltliimil> %m WMWw Fig. 50. — The effect of 5 mgrs. of barium chloride on the blood-pressure after paral- ysis of the vasomotor nerve endings by 150 mgrs. of chrysotoxin. This demonstrates that the barium chloride acts directly on the smooth muscular tissues of the arterioles. From Dale. tions cease to be coordinated. Independent rhythmic centers are set up over the heart, leading to fibrillation. This effect of barium chloride is produced by 0.01 per cent. (1 in 10,000) in physiological saline. Perfusions of barium chloride solutions through the isolated mammalian heart produce changes that are quite comparable to the muscular actions just described. The rhythm is increased, the volume of the contractions is greater, and there is a marked tendency toward fibrillation. When the heart is studied in its normal relations it shows a de- cided slowing, due to the preponderant influence of barium chloride on the cardiac inhibitory center. But if the vagus nerves are first cut, then there is a primary acceleration of rhythm. 2. On the peripheral arterioles. — Barium chloride solutions in- crease the peripheral resistance of the circulatory bed by contractions of the arterioles. The reaction is due in part to stimulation of the vasomoter center, but in larger part to peripheral muscular action, as shown by the great decrease in volume observed in the plethysmo- 176 BARIUM CHLORIDE graphic measurements of isolated organs. The contractions occur also after drugs which poison the nerve endings and are therefore to be ascribed to a direct stimulation of the smooth muscle in the walls of the arterioles. 3. Barium chloride on the alimentary and uro-genital muscle. — The alimentary canal is actively stimulated to increased peristalsis. In both the gastric and the intestinal regions the changes are very pro- nounced. This influence is in large measure a direct action of the barium chloride on the smooth muscle walls. For the same reason the walls of the uterus and urinary bladder have their typical mus- cular movements decidedly increased. 4. On skeletal muscle.- — Skeletal muscle is rendered more un- stable and irritable by barium chloride. "When a test is made by a series of contractions of an isolated muscle it is found that the amplitude of the contractions is sharply increased in the earlier numbers of the series, while contracture from delayed relaxation makes its appearance later in the series, but long before the muscle is exhausted. 5. On the central nervous system. — Barium chloride is a toxic substance for the nervous tissue. Its influence is characterized by prolonged and violent stimulation with paralysis in the later stages. Practically all the basic nerve centers have their irritability sharply increased. The spinal cord, for example, is far more sensitive to reflex stimulation and shows a tendency to the discharge of reflex spasms that approach the character of tetani. Most typical nerve changes are shown by the disturbance of func- tion of the reflex centers of the medulla. The vasomotor center is increased in tone and stimulated, the cardiac inhibitory center stimu- lated, and the influence on the respiratory center leads to a great acceleration of respiratory rhythm and amplitude. Intravenous in- jections of non-toxic quantities of barium chloride produce on the respiratory center at first a great acceleration in rhythm, which may amount to as much as 100 to 150 per cent, of the preceding normal. This enormous increase of rhythm is associated with a great increase in respiratory amplitude. This stage is followed by a marked diminu- tion in amplitude, usually with the prolonged maintenance of the supra-normal rate. Recovery is slow and characterized by irregularity of respiratory rhythm. 6. The local action of barium salts. — Barium salts are extremely toxic. "When brought into contact with mucous membranes or in- jected hypodermically they tend to produce disintegration and necrosis THERAPEUTIC INDICATIONS 177 of the local area. This is due to a toxic action on protoplasm in general. 7. Therapeutic indications. — Pharmacologically the reactions of barium in the body strongly suggest a comparison with the digitalis series. Various attempts have been made to introduce it into thera- peutics with indifferent success, chiefly from its dangerous toxic after- effects. It has been cautiously exhibited in conditions of extreme atony, especially of the circulatory system. Barium chloride was recognized in 1910 and 1911 only by insertion into New and Non- official Remedies, with the following description under the caption, * l Actions and uses ' ' : ' ' Barium chloride is a toxic substance, its most striking effects being exerted upon muscle tissue, especially unstriped and heart muscle. In large doses it affects the spinal cord and me- dulla. By actively stimulating peristalsis, through action on the mus- cle wall, and by its direct irritant action, it readily produces vomiting and purging. It strengthens the cardiac contraction by direct action of the heart muscle, and by this means and still more by direct action on the vessel walls it greatly increases blood-pressure, acting like digitalis. It acts on the muscles like veratrine. It first greatly excites and then paralyzes the spinal cord and medulla. Given in very dilute solution, absorption is small and the barium is deposited in the bones. Injected intravenously it causes tonic and clonic spasms, because of stimulation of the spinal cord and medulla. " In fatal doses it causes hemorrhages into the stomach, intes- tines, and kidneys. " Its clinical use has been attended with little success, chiefly because of the gastro-intestinal irritation and high toxicity. It has, however, been used in cardiac disease with insufficient blood-pres- sure, as a general tonic, and with less reason in tremors, in scleroses of the central nervous system, internally and locally in varicose veins, etc. Its use is attended with considerable danger." CHAPTER XIX. • THE NITEITES AND THE NITROGLYCERINES. I. Chemical. As illustrations of a group of drugs acting particularly on the circulatory system, but to produce effects of depression of function just the opposite of ergot, barium chloride, etc., the nitrites form the most important example. Sodium nitrite, NaN0 2 , is a soluble salt. Amyl nitrite is a highly volatile, amber-colored liquid, which can be taken as a representative of the derivatives of the methane series, in which the alkyl is attached by an atom of oxygen, as shown in the formula, CH 3 O.NO, etc. The tri-nitrate of glycerine, or nitro-glycerine, C 3 H 5 (N0 3 ) s . This sub- stance is readily decomposed in the alkaline fluids of the body, giv- ing off nitrites and nitrates, the latter being inactive in small quantities, while the former give rise to the usual nitrite functional reactions. II. Outline of Pharmacological Action. 1. Marked depression of blood-pressure produced through (a) a decrease in the functional activity of the smooth muscle, and (b) depression of the cardiac nervous mechanism. 2. The formation of methemoglobin. III. Details of Pharmacological Action. i. On the circulatory system. — The most characteristic physio- logical change produced by the nitrites is that of relaxation of mus cular tissue, and particularly in the circulatory and respiratory mechanisms. When sodium nitrite is given intravenously, or amyl nitrite given either intravenously or by inhalation, there is a marked and prolonged fall of blood-pressure. This circulatory effect is pri- 178 DETAILS OF PHARMACOLOGICAL ACTION 179 marily due to dilation of the arterioles. The skin is flushed and the great vascular beds in the abdominal viscera are congested. The perfusion of isolated organs is accompanied by a similar evidence of peripheral dilation. There is a more rapid outflow of the perfusion fluid, and if the organ be inclosed in a plethysmo- Fig. 51. — Showing tho action of nitrites on the form of the human pulse. A, normal pulse ; B, immediately after amyl nitrite vapor ; C and D, successive later stages in the return to the normal. graph, increase in volume occurs. If the organs be studied in their normal relations, as, for example, portions of the abdominal viscera, it can be shown that the nervous mechanisms are still functional, though less actively so. Stimulation of the splanchnic nerve produces a slight constriction of its terminal visceral bed. This contriction is less pronounced than in the normal, a fact, which, together with those related above, leads to the conclusion that the action of the nitrites is on the smooth muscle itself. 2. On the heart. — Dilation of the blood-vessels, associated with fall of blood-pressure produces a physiological condition, which acts as a stimulus to increase the heart rate. Increase of heart rate is also brought about by any condition which diminishes the tone of 180 NITRITES AND NITRO-GLYCERINES the vagus center, or, on the other hand, increases the contractile power of the cardiac muscle, as by barium chloride. When the nitrites are given the heart rate is sharply increased, but the amplitude of the contractions is practically unchanged. In studies of the isolated hearts of both the frog and the mammal, the increase of rate is less marked, but enough to indicate that the nitrites do slightly add to the irritability of cardiac muscle, though this effect is accomplished only by very minute doses. The stronger action of the nitrites is to depress cardiac muscle, much in the same way as it depresses smooth muscle. 3. On the respiratory apparatus. — Nitrites have proven to be active depressants of muscular contractions in the respiratory ap- paratus. The drug acts directly on the smooth muscle of the bron- chioles, producing a relaxation of these muscles and dilation of the bronchioles. This effect is of value in clinical conditions, such as in asthma. Respiratory acceleration is generally noted, an effect which is due in mild extent to stimulation of the respiratory center. The depressed circulation through the respiratory center has a secondary effect, which must not be forgotten in this relation, an effect which is thought by some to be adequate to explain the acceleration noted. 4. The formation of methemoglobin. — The nitrites are methe- moglobin formers. There is not the disintegration of the corpuscles to the extent noted in pyrogallol poisoning. IV. Condensed Summary of Action. The nitrites and the nitrite liberators are of peculiar value in that they produce relaxation of structures depending for their action upon smooth muscle. For example, the blood-pressure falls from arteriole dilation, and the effect is accompanied by a direct depres- sion of the function of the smooth muscles of the arteriole walls. The heart is accelerated, largely from depression of the inhibitory mechanism, but in part through an initial though slight increase of irritability of cardiac muscle. Respiratory spasms of the bronchioles are relieved by relaxation of their smooth muscle. There is some toxic formation of methemoglobin accompanied by the secondary symptoms, which result from a lack of sufficient oxygen carried by the blood. Nitrites in therapeutic quantity are peculiarly valuable to relieve smooth muscle spasms wherever they occur throughout the body, as, for example, in asthma, angina pectoris, lead poisoning, etc. E Glucosides of the Digitalis Series. CHAPTER XX. THE DIGITALIS GROUP. Historical and Chemical. Under the digitalis group one may classify a series of plant and animal substances, which have a rather extreme toxicity to animal Fig. 52. — Digitalis purpurea?, Foxglove, the plant in full bloom, a flower about two- thirds size, and a section natural size. Baillon. tissues in general, and are particularly stimulative and toxic to the heart and circulatory system. 181 182 THE DIGITALIS GROUP The substances of this series are derived from a rather wide range of plants, of which the most important are members of the genera Digitalis, Strophanthus, and Scilla. Of a long series of genera yield- ing active principles, but of more or less secondary importance, may be especially mentioned Apocynum, Helleborus, Convallaria, Antiaris, and Erythrophloeum. For the most part these plants yield non-nitrogenous glucosides and resinous principles. The active substances of the digitalis species were first separated by Schmiedeberg x and have later been studied by several authors. The active principle of Strophanthus, strophanthin, has also been separated, and has a therapeutic value similar to that of digitalis. Of these substances the most important are: Digitalin. Digitalein. Digitophylline. Digitoxin. Strophanthin. Preparations of the glucosides readily decompose, giving rise to toxiresins, in which their physiological reactions are markedly changed in the general direction of increased toxicity. II. Outline of Pharmacological Action. The different active principles have somewhat varying effects in the body, but in general they all produce : 1. In therapeutic quantity an increase in the function, and in toxic quantity paralysis of practically all the tissues in the body. 2. Specific stimidation of the heart muscle. 3. Stimulation of the cardiac inhibitory nervous meclvanism. 4. Specific stimidation of peripheral arterioles, particularly strong on the splanchnic region. 5. Stimulation of the vasomotor center of the medulla. 6. A marked diuretic action. 7. A tonic action on the central nervous system, and on endothelial and lymphatic tissues. 1 Schmiedeberg: Arch. f. Exp. Path. u. Pharm., Bd. 3, S. 16, 1875. DETAILS OF PHARMACOLOGICAL ACTION 183 8. Local irritation and inflammation when applied hypodermically, or to mucous surfaces. III. Details of Pharmacological Action. In the study of the details of the change in physiological function induced by the different members of this series we will take as a standard for comparison the action of soluble digitalis and of stro- phanthin. i. Action on the circulatory system. — Digitalis produces its pri- mary, one might almost say specific, action on the circulatory system. The therapeutic effects are (1) stronger and slower heartbeat, (2) general vascular constriction, and (3) a pronounced increase in blood- pressure. The details of these changes must be given before general discussion of their inter-relations. 2. The heart. — Digitalis given to a living mammal by the mouth usually produces a stronger, slower, and more efficient beat of the heart. Keeping in mind the complicated nervous and muscular arrangements of this organ, we may summarize by saying that the direct cardiac effects of the digitalis series are : 1. Stimulation of the cardiac muscle, producing increased ampli- tude and usually an increase of the rhythm of contraction, and a greater irritability of the tissue. 2. Stimulation of the cardiac inhibitory nervous mechanism by strong direct action on the vagus center, together with weaker local action in the heart ganglia. This produces slowing and greater re- laxation of the heart. These two factors, i.e., the direct muscular effects and the vagus nerve effects, are diametrically opposed to each other, hence many of the characteristics of the heartbeat under digitalis in the body are to be interpreted through their algebraic addition. Secondary effects on the heart are produced because of the tre- mendous rise 4 of blood-pressure following the peripheral vasoconstric- tion. This rise of pressure in itself increases the irritability of the medullary centers, therefore the vagus tone, and produces a mechanical stimulation of the sensory end organs of the depressor nervous meehanism, which Eyster and Hooker have shown to be located in the walls of the aorta. An experimental analysis of the heart effects of digitalis can be made by studying -. 184 THE DIGITALIS GROUP 1. Isolated heart muscle. 2. The isolated heart. 3. The heart in situ. Isolated pieces of cardiac muscle, of the terrapin or of the cat, have their irritability sharply increased by members of the digitalis series — digitalin, strophanthin, etc. True, it requires a rather Fig. 53. — Action of digitalis on the cardio-inhibitory center. During the time marked 0.01 per cent, digitalin was perfused through the isolated brain of the terrapin, vagus nerves intact, general circulation isolated from the brain. At the point marked the right vagus was cut, the heart immediately escaped. Cutting the left vagus dur- ing this experiment induces no change in rate. Time in 5 seconds. New tracing by Peeler. stronger dose, but both the amplitude and the rate of the heart muscle contractions are favorably influenced. With a relatively strong dose the terrapin ventricular muscle has its systolic phase increased and its relaxation hindered so that a state of tonic contracture super- venes. 3. The isolated frog's heart. — Perfusions of the isolated frog's heart show phenomena similar to those obtained from the muscle alone. The rhythm is slightly accelerated, but the greatest change consists in the increase in the systolic and decrease in the diastolic phase of the contraction. The net result is a tendency of the heart to remain in systole. In the tonic stage this condition becomes dominant. The contractions of the auricles of the perfused frog's heart arq much more complete, and the relaxations relatively more incomplete than is the case with the ventricle. However, in experiments a slight excess of mechanical pressure may obliterate this effect and the auricles will remain dilated. 4. On the isolated mammalian heart. — The isolated mammalian heart studied by the coronary perfusion method is most instructive. Here very dilute solutions of soluble digitalin, 11 parts to 1,000,000 of ACTION ON THE ISOLATED MAMMALIAN HEART 185 perfusing solution, produce a sharp increase in the amplitude with only slight, if any, variation in the rate. If the dosage be increased, then both amplitude and rate are strongly increased. These effects are interpreted as primarily muscular. With perfusion of a toxic concentration the heart becomes irregular in its rhythm. Independent rhythmic centers are set up in the ventricular muscle, together with arrhythmia of the auricles and ventricles. This condition comes on rapidly and ends in fibrillation and death in the systolic stage. Fig. 54. — Digitalis on the isolated mammalian heart, dog. The heart was kept contracting rhythmically hy coronary perfusion with oxygenated Ringer-blood, 1 to 3. During the time indicated by the signal marker 0.0005 per cent, of digitalis in Ringer- blood solution was perfused. The rhythm of the heart remained absolutely constant during the experiment. The increase in amplitude amounted to 14 per cent, just before perfusion of digitalis was stopped, but increased to 19 per cent, in a few seconds after the normal was re-established. Time in five seconds. New tracing by Kruse, Heldt, and Stewart. Strophanthin perfused through the isolated heart by the method of Bock produces little or no change in rate, but the volume of the beat is increased sufficiently to slightly raise the pressure. The toxic margin is very slight in this case, and in the toxic stage the heart becomes arrhythmic, the muscles fibrillating, and death follows with the heart in the fibrillation stage. 5. The mammalian heart in situ. — We owe largely to Cushny * the details of the influence of strophanthin on the mammalian heart- studied in its normal position. The therapeutic action of digitalin or of strophanthin produces in the mammalian heart an increase in the systolic phase of the contractions of both the auricles and the ventricles. As a rule, with the change in amplitude there is a slowing of the heart rate. The individual contractions are more complete, that is, have both a greater amplitude and a greater relaxation, hence the filling and emptying of the heart is more efficient. This efficiency 1 Cushny, Arthur R.: Heart, Vol. IV., p. 33, 1912. 186 THE DIGITALIS GROUP is twofold, i.e., increased diastole, therefore greater filling, and in- creased systole, therefore more effective discharge. This effect is accomplished by the twofold action of digitalis. (1) The direct mus- cular action increases the muscular contractions when they occur, and (2) the action of the vagus center holds in check the muscular effects and in the face of the muscular stimulus produces a greater dilation and more efficient filling of the cavities of the heart. TABLE I Experiment 1 of Cashny on a dog narcotized by morphine and curare, Myocardiograph attached to the left ventricle. Time. Number of contractions in 10 seconds. Height of syntole from base line. Height of diastole from base line. Length of excursion of lever. Normal After 20 seconds 35 1 mg. strop 35 33 28 244 22 26 mm. hanthin injec 27 mm. 264 '• 25 •« 23 " 20 " 384 mm. ted into the j 39 mm. 43 - 45 " 44 " 43* " 124 mm ugular vein. 12 mm. " 50 " 164 " 20 " "70 " 90 " 21 " " 110 " 234 " The experiment shows slowing of the heart rhythm, with a more complete systole. There is much greater diastolic relaxation, there- fore a corresponding increase in the total excursion of the ventricular contractions. TABLE II Experiment 9 of Cashny, cat narcotized with morphine and acetone chloroform, atropine to poison the vagus. Rate in 10 seconds. Contraction volume. Percentage increase in contraction volume. Output in 10 seconds. Percentage increase in output per 10 seconds. Before strophanthin After strophanthin Later Still later 18 18 18 18 23 27 29 30| 174 26 33 414 486 522 549 m 26" 33 This experiment shows no slowing of the heart; in fact, no change in heart rate, but an increase in the amplitude of the con- tractions. Therefore the efficiency of the heart is markedly increased by direct action of strophanthin on the muscle walls. DIGITALIS ON THE PERIPHERAL ARTERIOLES 187 As the therapeutic stage passes toward the toxic stage an interest- ing intermediate condition supervenes in the heart. The increase in the irritability of the muscle tends to break down the sequence and the rhythm within the heart, while the hyperirritable condition of the vagus center tends to hold the heart in inhibition. There will come at this time periods of quite rapid contractions interspersed with periods of very slow beats or even complete inhibition. The medullary and local nervous centers pass into the paralytic stage somewhat earlier than does the muscle, hence the direct cardiac muscle stimulation presently becomes dominant. More frequent series of rapid beats now occur, with an increase in efficiency of the heart as a pump. However, this condition does not last long, since arrhythmia soon sets in because of the increasing hyperirritability of the muscle. The contractions of the auricle at this stage are not always followed by contractions of the ventricle, nor are these two events in proper sequence. In addition to the change in irritability of the muscle substance, there is an influence of digitalis on the conducting substances of the bundle of His. There is evidence, chiefly therapeutic, to indicate that digitalis diminishes the rate of conduction through this special mechanism of the mammalian heart. In other words, digitalis in its tendency to produce slowing of the auriculo-ventricular interval ac- complishes an effect of more or less complete heart block. The me- chanical effect of the combined change in the muscular irritability and the depression of conduction in the bundle of His is a great irregu- larity in the blood-pressure. When, during the arrhythmia, the au- ricular and ventricular contractions happen to fall in sequence, there is a sharp rise of blood-pressure; when they are in opposite phase, a similar fall. The ultimate toxic result is increasing arrhythmia, inefficient contractions, fall of blood-pressure, and final paralysis and cardiac death. 6. Digitalis on the peripheral arterioles. — Members of the digi- talis series produce a marked contraction of the arterioles throughout the body. This peripheral vascular contraction produces a tremendous increase in the peripheral resistance to the blood flow and a resulting great rise in blood-pressure, which may amount to from 50 to 100 per cent. The vascular constriction is most pronounced in the visceral organs of the abdominal region. This was especially investigated by Gottlieb ami Magnus x in 1902. These authors compared the action of the 1 Gottlieb and Magnus: Arch. f. Exper. Path. u. Pharm., Vol. XLVIL, p. 135, 1902. 188 THE DIGITALIS GROUP P^B «m S? a> * o — fl 5 .fl fc£t-< S2-8 °fl„, ^a-S^St* be" gg gt^-fl a * eh.2 S S ° "t; a> Si a> fl »c— « S-SSa-asssH . a > as . o i2 w C S 5 o«*°Stl5 1=3 fl 3,0 25 cj- 1- ' aa S o 3 c o °„o "2*^ m <" O 5f - fl <*> flS^S.^ *•£>> «a^ s c w "So- >5 ° £*§ «"K •^fl.C^fl.E.flO CO DIGITALIS ON THE PERIPHERAL ARTERIOLES 189 different members of the digitalis series on the visceral organs — the spleen, the intestine, and the kidney, and on the peripheral regions, using the volume of the leg as an index. It was shown that the con- striction in the volume of the extremities produced by digitalin, strophanthin, convallaria, etc., produced a tremendous rise of blood- pressure, with vascular spasm of the spleen, kidney, and intestine. With the weaker members of the digitalis series the influence on the Fig. 56. — The effect of 12 mgr. strophanthin, intravenous, dog. From Gottlieb and Magnus. blood-vessels of the limbs is very much less than on the visceral organs. A quantity of strophanthin, therapeutically active for the viscera, has practically no direct influence on the blood-vessels of the leg. Gott- lieb and Magnus found that the volume of the limb even followed the rise of blood-pressure very closely, a result which they explained as the physiological reflex associated with a condition of increased pressure in the viscera. With digitoxin, on the other hand, the vascular spasm was marked in the vessels of the limb as well as in the visceral organs. When they excluded the abdominal circulation the peripheral arterioles contracted in the face of a rise of blood-pressure. It may be reiterated, therefore, that the digitalis substances pro- duce marked general arterial constriction, though this effect is less strong in the periphery than it is in the viscera. It is less vigorous with certain members, strophanthin, than with others, for example, 190 THE DIGITALIS GROUP digitoxin. In this connection it must be recalled that these two great vascular regions normally act in physiological opposition under many physiological conditions. Therapeutic quantities of digitalin, stro- phanthine etc., which just call forth visceral constriction are apt to be associated with dilation of the blood-vessels of the periphery, a secondary effect called forth through the interactions of the ordinary physiological mechanisms. The analysis of the vasoconstrictor effects of digitalis was made in part by Gottlieb and Magnus. They isolated the organs studied by them from the central nervous system, and found that the vasocon- striction occurred in practically the same degree as before. Others have shown that after sectioning of the splanchnic nerves a marked diminution in the rise of blood-pressure results. It would seem, therefore, that there is some stimulation of the medullary vasomotor centers, though it may be relatively slight and at times insignificant. Gottlieb and Magnus did not determine on what part of the periph- eral mechanism the digitalis acted. Cushny x stated in 1897 : " I think the evidence is overwhelming that the rise in pressure in the arteries is to a considerable extent due to action on the muscular walls of the arterioles." This point was finally cleared by Dixon, 2 who poisoned the terminal vasoconstrictor fibers with apocodeine. Digitalis following this drug still produced vasoconstriction, proving that there was a stimulating action on the smooth muscle in the walls of the blood-vessels. Very slight, if any, change in the resistance of the pulmonary cir- culation has been noted with digitalis. There is always a marked diminution in the output of blood flowing from the isolated heart, fed by coronary perfusion. This decrease is attributable to coronary con- striction. 7. The action of digitalis on the central nervous axis. — It has already been stated that digitalis produces a sharp rise in the tonic action of the cardiac inhibitory center, the details of which have been presented. The vasomotor center also is stimulated, though apparently in less degree. Other medullary centers show some slight increase in tonic activity, especially the respiratory, as indicated by the change in respiratory rate and depth. Mackenzie states that in clinical treat- ment " the most frequent nervous symptom was headache," some- times so severe as to stop the use of the drug. Perfusions of digitalis in experiments on the circulatory system of lower animals with intact 1 Cushny, A. R.: Jour, of Exper. Medicine, Vol. II, pp. 233-313. 1897. 2 Dixon: Jour, of Physiology, Vol. XXX., p. 97, 1903. DIGITALIS AS A DIURETIC 191 spinal cords are very often accompanied by a marked increase in reflex movements. The same may be observed also on mammals, all showing an increase of the reactions of nerve centers under the in- fluence of the digitalis. Toxic doses of digitalis lead to convulsions which are undoubtedly of central origin. The direct therapeutic effect of digitalis on the cord and medullary portions of the nervous system is that of a general nerve tonic, especially on the vagus nucleus. 8. Digitalis as a diuretic. — Any drug which produces so profound an influence on the circulatory system as digitalis may be expected Fig. 57. — The influence of digitalis on the irritability and muscle work of the gas- trocnemius of the frog. Tracing No. 1 is from 20 gram, frog, dose 8 minims of 0.1 per rent, solution, allowing 20 minutes for absorption. There is little change in Irritability, but the amount of muscle work obtained is markedly diminished. Top tracing No. 2 shows the action of 6 minims of .0.1 per cent, solution on an 18-gram. frog after 15 minutes of absorption. The normal tracing is not shown, but it is very similar to the normal represented. Minute doses of digitalis slightly increase the amount of work given by the gastrocnemius. New tracing by La Force. to change the functional activity of the kidney. If for no other reason, this effect would occur indirectly from the action of the drug on the circulation. The volume of the circulation through the kidney is often decreased by profound vasoconstriction in the acute stage, but in the general administration of digitalis the total efficiency of renal circulation is raised. Digitalis produces diuresis. This can be demonstrated on the normal animal, where diuresis is distinct though relatively slight. In pathological conditions, especially when involving the circulatory ap- 192 THE DIGITALIS GROUP paratus associated with dropsy and edema, this diuretic action is very greatly increased. The mechanism of diuresis by digitalis has been variously ex- plained, by some authors as wholly vascular, by others as due to a direct influence of the drug on the renal epithelium. While one must admit the favorable vascular effects it seems that one cannot deny the direct renal stimulation. In relation to the clinical dropsical condition there is a disturbance of function of the vascular endothe- lium over the body which varies the regulative control as between the fluids inside the blood-vessels and the fluids in the lymph spaces and in the tissues. Digitalis produces some stimulation of this endothelial tissue, increasing its efficiency of action. It thereby favors the taking up and elimination of the excess of tissue fluids. Similar action also falls on the lining cells of the renal blood-vessels as well as on the renal Epithelium. 9. The local irritating effect of digitalis. — Digitalis applied locally to mucous membranes or hypodermically injected into the cutaneous or muscular tissues, produces considerable local irritation. This irritation may lead to the usual cycle of inflammatory changes, even to the formation of local abscess. There is a sharp stimulation of the sensory nerve endings, accompanied by acute pains. These facts make it undesirable to administer members of this series hypo- dermically. Digitalis, by way of the mouth, when its administration is oft repeated, has a tendency to produce gastric irritation and even inflammation. The nausea and vomiting that occasionally occur after digitalis, or more often after squills, are due to reflexes set up by gastric irritation. IV. The Cumulative Action of the Digitalis Series. The effects of digitalis are very persistent in the body. Absorption of the drug is indeed relatively slow, but its elimination is extremely slow, complete elimination taking place only after many days. The result is that in repeated dosage the effects are additive, i.e., cumu- lative. Cases of poisoning by digitalis have occurred from the too rapid administration of otherwise therapeutic doses. Digitoxin especially, which is the most toxic of the series, a dose of 2 mg. being dangerous for a grown man, is particularly slow in its elimination, hence cumulative in its action. SUMMARY OF PHARMACOLOGICAL ACTION 193 The great variation in the strength of digitalis leaves and the preparations made therefrom, together with the fact that the active principles tend to decompose, all require standardization of these drugs by measurement of the reactions on mammals. At the present time most firms are issuing physiologically standardized preparations. The clinician should be particularly careful to use recently stand- ardized preparations, a caution that applies no less to the experi- mentalist. V. Summary of Pharmacological Action. The members of the digitalis series are extremely toxic, yet because of their almost specific action on the circulatory apparatus they have proven invaluable as therapeutic agencies. Members of the series vary somewhat in their relative intensity of action at different points of the body. In therapeutic quantity the chief changes produced in the body are: Strengthening of the heartbeat and slowing of its rate — strengthening through direct muscular action and slowing through stimulation of the inhibitory nerves, primarily through the inhibitory center in the medulla. There is a sharp and general rise of blood-pressure from arterial constriction, the effect being produced primarily by direct stimulation of the muscles of the arteries, but in some degree by similar stimulation of the vasomotor center. The arterial constriction is greatest in the splanchnic region, in mild doses being almost limited to this area. However, vasocon- striction is produced in all parts of the body, especially by the very toxic digitoxin. In toxic dose the inhibitory stimulation of the heart is profound, while the direct increase in muscular irritability tends to produce arrhythmia and delirium cordis. The algebraic sum of these two factors results in great irregularity of blood-pressure in this stage. The change in the circulation to some extent accounts for the diuretic value of digitalis, though a favorable stimulating effect upon the renal epithelium is to be assumed. Digitalis produces local irritation of the mucous membranes. Acute sensory stimulations, also inflammatory changes, occur in the local area when digitalis is given hypodermically. The inflammation is accompanied by the usual vascular congestion, edema, and sometimes degeneration of the tissue with pus formation. The sensory stimulations lead to im- portant reflex effects, also to acute pain. Local irritation in the 194 THE DIGITALIS GROUP stomach produces nausea and vomiting. Toxic doses induce central nervous spasms ending in paralysis. The digitalis substances act cumulatively, due to their extremely slow elimination from the body. Excretion occurs chiefly through the kidney. In the present state of our knowledge of the chemistry of the active principles of this group clinicians must rely upon physiological standardization of these products. BUFONINB AND BUFOTALINE. I. Historical and Chemical. Faust 1 (1902) isolated and identified two digitalis-like principles from the skin of the common toad. It was known in ancient times that the dried skin of the toad possessed certain toxic properties and this material entered into the list of medicinal substances. Bufonine possesses the formula C 35 H540 2 , and bufotaline, C34H46O103. They are not glucosides but are chemically related to cholesterol. These substances are of peculiar interest because of their animal origin. II. Pharmacological Action. When injected subcutaneously or given by way of the mouth they produce digitalis-like changes in the functions of the animal tested. 1. On the frog's heart. — Bufotaline produces on the frog's heart a marked slowing of the rate and an increase of the pulse volume. 2. On the mammal. — Subcutaneously a 2.6 mgr. dose produced in the dog increased secretions and evidences of nausea followed by vomiting. There is a decrease in the rate and amplitude of respiration with Cheyne Stokes breathing. The heart is very irregular, the pulse small and strong. Similar phenomena occur in rabbits, but as the experiment proceeds there is a distinct dyspnea as with digitoxin. In the toxic stage convulsions occur. 3. On blood-pressure and the pulse. — On mammals bufotaline produces a decrease in the pulse frequency with an increase in the pulse volume. Bufonine produces the same qualitative physiological effects as bufotaline, but is much weaker in its action. 1 Faust, Edwin S.: Archiv f. Path. u. Pharm., Vol. XLVIL, p. 278. 1902. CHAPTER XXI. THE SAPONIN AND SAPOTOXIN GROUP. I. Historical and Chemical. Saponin and sapotoxin are widely distributed and highly toxic glucosidal principles. They are pharmacologically classified with the protoplasmic poisons, but are inserted here because chemically they are non-nitrogenous and in decom- position yield glucose. They are of the general chemical composition C n Han = eOio (Robert). Of the plants yielding members of the group may be mentioned as most important The Soapbark, Quillaja saponaria The Soapwort, Saponaria officinalis Sarsaparilla, Smilax The Corncockle, Agrostemma githago Closely related to the Saponins are the Solanins, which are glucosidal alka- loids yielded by the black nightshade, bitter sweet, potato, etc., members of the species Solanum. Solanin is decomposed into a glucose and a poisonous base, solanidin. Solanin is present in the green and growing parts of the potato, some- times in quantities sufficient to produce distinct poisonous symptoms. Saponin is very much less toxic than sapotoxin. II. Details of Pharmacological Action. Members of the saponin series are chiefly of toxicological interest. They are toxic to practically all the tissues. Their property of forming emulsions adapts them to commercial use to cleanse substances that are injured with the alkalies. For example, soapbark enjoys a well-merited popularity as a hair wash. i. Sapotoxin as an irritant. — Sapotoxin is a violent local irritant. When inhaled this action on the nasal epithelium leads to uncontrollable reflex sneezing. The local inflammation thus produced may under certain conditions prove decidedly injurious. Hypodermic injections also lead to inflammation at the point of injection. When introduced into the stomach sapotoxin produces the usual cycle of events following gastric irritation, namely, pain, nausea, and vomiting. As absorption does not readily occur systemic effects may not follow these local gastric changes. 2. Toxic systemic effects. — The toxic symptoms produced by the sapo- toxins are in large part due to the irritant nature of the drug. There is in 195 196 SAPONIN AND SAPOTOXIN GROUP the mild stages general malaise, loss of appetite, often with vomiting and diarrhea, feeble pulse, and respiration, leading in the stronger action to con- vulsions and respiratory failure. The tissues throughout the body show more or less evidence of inflammation and disintegration, especially the capillaries whose walls are often permeated, showing hemorrhagic extravasation. The hemoglobin is discharged from the blood by the hemolytic action of the saponins, a reaction which also takes place in the test tube. The explanation of the hemolysis is that the saponins dissolve the fat-like material in the wall of the corpuscle. 3. Saponin. — Loeb and Wasteneys * have reported experiments showing that the cytolytic action of saponin on the cortical layer of the eggs of the sea urchin tends to increase the rate of oxidation under certain conditions. They give the following table as an example: TABLE I Eggs of S. Purpuratus, Temp. 15°C. Oxygen consumed per hour Coefficient of rate of oxidations. Unfertilized eggs The same eggs after cytolysis with saponin Unfertilized eggs The same eggs after cytolysis with saponin Mgr. 0.15 1.07 0.22 0.80 1.00 7.10 1.00 3.60 " The variation in the effects of cytolysis in the two experiments may be due to the fact that in the second experiment an excessive amount of saponin was used. " This experiment proves that the increase in the rate of oxidations due to fertilization or artificial membrane formation is merely caused by the cytolysis of the cortical layer." 4. Solanin. — The potato poison, solanin, has the same general toxic action as saponin and requires no special discussion. 1 Loeb, J., and Wasteneys, H. : The Journal of Biological Chemistry, Vol. XIV., p. 479, 1913. F. Drugs, Chiefly Alkaloids That Primarily Influence General Metabolism. CHAPTER XXII. HYDROCYANIC ACID. I. Chemical. Hydrocyanic acid and the cyanides are very toxic substances which owe their physiological action to the CN group, cyanogen. This group is represented in nature in certain animal secretions and in certain plant products. It is present in the seed of the bitter almond in the compound known as amygdalin. When amygdalin is decomposed by the natural ferments it sets free hydrocyanic acid or prussic acid. The bitter almond kernel yields about one-fourth of one per cent, of hydrocyanic acid, according to the reaction: C 20 H 27 NO„ + 2H 2 = 2C 6 H 12 6 + HCN -f C 6 H 5 COH Amygdalin Dextrose Prussic Benzaldehyde acid The inorganic salts, the cyanides, in solution, yield the active cyanogen ions. The most common of the salts used in experimenta- tion and in medicine are sodium cyanide and potassium cyanide. II. Outline of Pharmacological Action. 1. Toxic to protoplasm, especially to nervous tissue, which it paralyzes after an initial stimulation, the respiratory center being the vulnerable point. 2. Destructive to enzyme action. III. Details of Pharmacological Action. i. On the central nervous system. — Prussic acid is especially toxic to animal tissues and particularly to the delicately sensitive 197 198 HYDROCYANIC ACID nerve tissues. Its toxicity is undoubtedly due to interference with oxidations, a deduction that is strengthened by the experiments of Loeb on general protoplasm. Loeb x has found that potassium cyanide inhibits the oxidation processes in the protoplasm of the ova of certain invertebrates. On nerve tissues of all kinds the cyanides at first increase the irritability, then depress and paralyze. Particularly on the centers of the medulla does this change show itself. These centers have their reflex irritability greatly increased at first, then rather quickly follows a marked depression to the point of complete loss of irritability. The cycle of changes is not unlike that of asphyxiation, a phenomenon that is indeed involved. The nervous centers controlling respiration, the glands, the eye, and the vascular mechanisms, are all at first stimulated then rapidly depressed, all in a few seconds in the presence of toxic doses. These changes are of themselves largely sufficient to explain the cycle of symptoms which occur on the administration of prussic acid and the cyanogen compounds. 2. On respiration. — The action of the cyanides on the respiratory center is so striking and so important that it calls for special men- tion. Under the cyanide influence the discharges from the respiratory center are greatly strengthened and markedly accelerated. These changes are followed by respiratory depression to the point of com- plete standstill. The ganglion cells of the respiratory center are directly altered by the cyanides in such manner as to prevent the utilization of oxygen. In therapeutic quantity hydrocyanic acid is therefore a respiratory stimulant. Dresser 2 showed that 0.6 mgr. potassium cyanide produced in the rabbit both an acceleration of respiratory rate and an increase in the expiratory volume. His ex- periment is as follows: Rabbit (weight 2170 grs., under 1.6 grms. urethan, vagi sectioned). Expiratory volume. Frequency per minute. Normal 156 cc. 175 cc. 30 After 0006 grm. KCN 32 In toxic quantity, and cyanogen is very toxic, it quickly leads to loss of medullary respiratory control, and death follows from x Loeb, Jacques: Biochemische Zeitschrift, Vol. XXVI., p. 279, 1910. 2 Dresser, H.: Archiv f. Exper. Pathol, u. Pharmakol, Vol. XXVI., p. 237, 1890. ACTION ON THE CIRCULATORY SYSTEM 199 asphyxiation of the tissue. The stage of depression can be greatly alleviated and sometimes recovered from by artificial respiration, since the tissues are not directly so strongly influenced toxicologically as are the nervous reflexes involved. 3. On the circulatory system. — Changes occur in the circulation at three points, i.e., the peripheral blood-vessels, in. the heart, and in the controlling nerve centers. Using isolated organs (the kidney) Sollmann has shown a vascular dilation when solutions of hydrocyanic acid gas were perfused. When the normal solutions were substituted there was a disappearance of the dilation of the blood-vessels. The heart is directly influenced by this drug. Loewi 1 has shown that .00013 per cent, hydrocyanic acid is sufficient to partially depress the pulse frequency, while .00025 per cent, rapidly lowers the amplitude of contraction. Prolonged contact of the cyanides is espe- cially depressing to the heart function, presumably by interference with the oxidation processes. The chief cardiac change, however, is due to the influence of the cyanides on the central nervous system. The vagus center is at first stimulated, leading to cardiac slowing by vagus inhibition. In a similar manner the vasomotor center shows an initial stage of in- creased tone, followed by depression of function as toxicity appears. When perfused through the isolated frog's heart hydrocyanic acid or its compounds quickly produces a cessation of the rhythm, the heart stopping in diastole. The irritability of heart muscle, al- though depressed, is not completely lost for a time, as can be proven by applying stimulating electrodes directly to the muscle. Recovery with the perfusion of normal fluids is relatively rapid. 4. On metabolism. — It is evident that a substance so toxic as a cyanide will influence the metabolism of protoplasm in general. This is true in this case. The CN group, by interfering with oxida- tions, depresses metabolism. This is proven by experiments on both animals and plants. Animals show a decrease in the percentage of oxygen consumed and carbon dioxide liberated, further proof indicat- ing a decrease in the oxidative processes (Geppert). There is some evidence that the cyanides take part in the reactions occurring in certain normal functions of the tissue. One such evi- dence is found in the presence of sulpho-cyanides in the saliva. Then, too, prussic acid is eliminated from the body in the form of sulpho- cyanides. Prussic acid produces cyan-methemoglobin in the body, a reac- 1 Loewi, Otto: Archiv f. Pathol, u. Pharm., Vol. XXXVIIL, p. 126, 1897. 200 HYDROCYANIC ACID tion that is especially characteristic when the reagent is mixed with blood in the test tube. This compound is a combination between the hematin and the hydrocyanic acid. In cases of poisoning from this drug the blood of the animal possesses a bright red color, which is characteristic. The reaction between methemoglobin and hydrocyanic acid is characteristic and extremely sensitive. If a sample of blood have added potassium chlorate to produce methemoglobin, and a drop of this fluid be allowed to spread on a filter paper, then the merest trace of hydrocyanic acid in a suspected solution when added to this methemoglobin paper will produce a change in color from the dark brown-red to a brilliant scarlet-red. CHAPTER XXIII. ACONITE. I. Historical and Chemical. Aconite, from the roots of monkshood, Aconitum napellus, is one of the most toxic, and at the same time one of the oldest known poisons. The active alkaloid, aconitine, presents some difficulties in its isolation because of the readiness with which it decomposes. The related alkaloids of this group are found in species of the genus Aconitum, from which are derived aconitine, with the chemical formula, Cs^^NO^ ; pseudoaconitine, C 36 H 49 N0 12 ; delphinine, CgjH^NO,.. 1 The last named drug is less toxic than the first. On hydration aconitine and its relatives break down into acetic acid and benzaconine. The latter further decomposes into aconine and benzoic acid. Because of the ease of cleavage of aconitine there is in its commercial preparations great variation in the propor- tion of the different cleavage products. This presents an element of danger, as is obvious, considering the toxicity of the alkaloid, the fatal dose for man being 3 mgr. II. Outline of Pharmacological Action. 1. Aconite is a general protoplasmic poison of extreme toxicity. 2. Like many poisons, it at first stimulates, then paralyzes the tissue. Aconite is particularly poisonous to the basic centers of the central nervous system. 3. It produces primary sensory stimulation followed by paralysis. 4. The blood-pressure is depressed by vasodilation and by slowing of the heart through primary stimulation of the vagus center. 5. Heart muscle, as such, is stimulated, and is finally set into fibrillation by toxic doses. 1 These formulae are those presented by Schmiedeberg's Pharmakologie, 6th edition. 201 202 ACONITE III. Details of Pharmacological Action. i. Systemic action. — Aconite in toxic quantity, 2 or 3 mgr. for man, produces almost immediate paralysis of the medullary centers, with respiratory and cardiac failure. In therapeutic quantities there is a primary medullary stimulation of the cardiac inhibitory center (questioned by Mackenzie recently), but with depression of the respiratory mechanism. The sensory symptoms are also most characteristic. After absorption there is a stinging, prickling, or tingling sensation of the skin. If the drug is taken by the mouth, this local effect appears first in the mouth, tongue, and throat. If these first symptoms are rather severe they are apt to be followed by a feeling of numbness from incipient local sensory paralysis. Aconite is rather readily absorbed, and when applied locally to the skin or to mucous surfaces it leads to the same local sensory symptoms as when taken internally. Stimulation by local action produces marked reflexes which influence the different fundamental tissues accord- ing to the point at which the local stimulation is produced, i.e., in- salivation, gastric irritation, with nausea and ofttimes vomiting. The fact that the peripheral sensory effects are produced by aconite after absorption, is generally explained on the ground that the stimu- lation and paralysis occur in the peripheral structures. Aconite apparently produces a somewhat selective paralysis of cutaneous sensory mechanisms. 2. Aconite on the central nervous system. — The primary action of aconite on the central nervous system is that of mild initial stimu- lation, followed by depression and paralysis. This is true especially for the medullary and spinal centers. Slight, if any, effect is noted on the cortical region, since consciousness remains intact until death. Of the medullary centers the chief symptoms of stimulation are noted in connection with the cardiac inhibitory center and the vaso- motor center. The cardiac inhibitory center is primarily stimulated, as shown by slowing of the heartbeat. In the same way the vaso- motor stimulation is indicated by peripheral vascular constriction. The respiratory center is mildly stimulated, then the amplitude is de- pressed and the movements slowed, a condition which is succeeded by ultimate paralysis and death by asphyxiation. 3. Aconite on the circulatory system. — The circulatory influences of aconite are twofold, i.e., cardiac and vasomotor. "When the drug ACONITE ON THE CIRCULATORY SYSTEM 203 is injected intravenously into the circulatory apparatus of a normal animal, for example, a frog or a mammal, the heart is at first ac- celerated, then greatly slowed, often stopped. Still later this is fol- lowed by a series of weak beats or sometimes by complete quiet. This contradictory picture is explained by the successive stimulations, which occur on different parts of the cardiac mechanism. The stimu- FiG. 58. — The stimulating action of .001 per cent, aconite on the contractions of the frog's heart. This concentration ultimately leads to arrhythmia, but the imme- diate effect is a great increase in the contraction. A, first perfusion ; B, second perfu- jion after several minutes' interval. Time in seconds. lating effects of the aconite fall on the medullary centers, the nerve endings in the muscle, and on the muscle itself. In the first or ac- celeration stage the accelerator nerve endings are dominant; in the stage of slowing and inhibition the inhibitory nervous apparatus is dominant. After the regulative nerves are finally paralyzed the fundamental rhythmic property of the muscle is free to act, and the heart is able to carry on beats for a time. The automatic rhythm finally ceases. However, the muscle can still be made to contract by direct electrical stimulation, though this power does not last long. The direct action of aconite on isolated cardiac muscle is primarily stimulating, producing an increase in the rhythm, followed by in- coordination and later by paralysis. When the rhythm has disap- peared, the muscle can be made to contract by the direct application of a strong electrical stimulus. Cushny x has recently examined the 1 Cushny, Arthur R. : "The Irregularities of the Mammalian Heart Observed under Aconitine and on Electrical Stimulation," Heart, Vol. I., pp. 1-22, 1909. 204 ACONITE reactions of the mammalian heart and finds that there is marked interference, both with the conduction of the contraction wave and with the rhythm. The mammalian heart in an early toxic stage shows in a large percentage of the cases reversal of sequence, i.e., to the ventricle-auricle rhythm, in which the impulse is " generated in the ventricle and spreads upward to the auricle." He finds an im- paired conduction, which may at times lead to partial or complete block. There is also a tendency to " sudden changes in the rhythm of the whole heart. It is evident that aconite produces a profound change, not only in contractility, but in rhythm and conductivity in the mammalian heart.' ' 4. Aconite on the blood-vessels. — The exhibition of aconite causes an initial contraction of the blood-vessels, from the stimulating action of the drug on the vasomotor center. This stage of stimulation, however, is very brief, and later, as the nerve center becomes depressed vasodilations occur, as shown by slight flushing of the skin. In the therapeutic action of aconite on the circulatory system, therefore, the great inhibitory slowing of the heart, together with the tendency to vascular dilation, leads to a general fall of blood-pressure, with depression of the circulation as a whole, a condition which undoubt- edly enters into the antipyretic action of the drug. 5. On the glands. — An increase in the secretion of the glands of the mouth and especially of the skin is noted after aconite. But the increased flow of saliva is primarily reflex, due to stimulation of sensory endings in the mouth. However, some stimulation of the secretory center in the medulla may also occur. 6. Aconite as an antipyretic. — Aconite because of its great toxic- ity to protoplasm tends to lower the metabolic processes of the body. In fevers, which result from increased central stimulation, aconite is particularly effective, and lowers the temperature by depressing metabolism. The lowering of heat production is added to the in^ creased heat loss from the dilation of the cutaneous blood-vessels and the increased secretion of perspiration mentioned above, hence the general body temperature is brought down. To what extent this action falls on the heat regulating centers of the brain is not fully explained. SUMMARY OF PHARMACOLOGICAL ACTION 205 IV. Summary of Pharmacological Action. Aconite is the most toxic of alkaloids and is poisonous to all the tissues of the body. Its action is characterized by an initial irrita- tive or stimulative process, followed by loss of function or by paraly- sis. In the central nervous system the cortex is not particularly affected, but the vital centers of the brain-stem and cord are es- pecially poisoned. The cardiac inhibitory, the vasomotor, and the secretory centers of the medulla are initially stimulated, then with the respiratory center, depressed and paralyzed. Of these influences the stimulation of the respiration is practically negligible, while that of the inhibitory center is strong. Death follows from the cessation of respiration and by paralysis of the heart. The most characteristic, one might almost say specific, influence of aconite is on the sensory receptive organs. Cutaneous sense organs are stimulated by the smaller doses, which may reach them either locally or through the circulation. Here, too, stimulation is followed by depression and paralysis. On peripheral tissues, the glands, skeletal muscles, heart muscle, and smooth muscle, aconite exerts a rather strong initial stimulation, though in each tissue ultimate paralysis follows. The general effect on metabolism is to lower heat production. Dilation of the blood-vessels of the skin and the greater evaporation of sweat increase heat dissipation, hence contribute to the general lowering of temperature. The former use of aconite as an antifebric is falling into disrepute because of the danger from its depressant cardiac action. Aconite is being displaced by safer antipyretics which are now available. CHAPTER XXIV. VEEATRINE. I. Historical and Chemical. Veratrine is representative of a series of very toxic alkaloids closely related to aconite and derived from different species of Lilaceae. The most important is veratrine, C 32 H 49 N0 9 , from Veratrum sabadilla and Veratrum viride, and protoveratrine, C 32 H 51 N0 11 , from Veratrum album. Aside from these there are some eight or ten related alkaloids which have been isolated and most of them tested pharmacologically. The name Hellebore, sometimes used, confuses the above plants with Helleborus niger. Helleborine, the active principle of the latter plant, is classified in the digitalis series, to which it is most closely related. The alkaloid of the death Camas, the poisonous lily of the valleys of the Cascade Mountains, contains members of this series, as demonstrated by Slade 1 in 1905. II. Outline of Pharmacological Action. 1. The chief action of the veratrine alkaloids is due to their ex- treme general toxicity, but they possess a degree of selective activity on sense organs and sensory nerves cmd on muscle substance. 2. A peculiar and typical stimulation of muscular contraction leads to persistence of the muscular tone and delayed relaxation. III. Details of Pharmacological Action. i. Veratrine on sensory and nervous mechanisms. — Like aco- nite, veratrine causes a pronounced stimulation of sensory organs, especially the cutaneous sense organs. This occurs whether the drug be taken systemically or brought into contact with the tissues locally. The symptoms are smarting and tingling, and peculiar temperature- 1 Slade: American Journal of Pharmacy, Vol. LXXVIL, p. 262, 1905. VERATRINE ON SKELETAL MUSCLE 207 like sensations, followed by anesthesia of the skin. On the nasal mucous membrane it leads to irritation, with reflex stimulation, sneez- ing, coughing, etc. In the mouth the sensations are those of burning and stinging pain, with slight involvement of taste sensations. All of these symptoms are followed by anesthesia in the later stage of action. Yeratrine is extremely toxic to nerve tissues. Yet under certain conditions of hyperirritability of these systems veratrine is truly antidotal. 2. Veratrine on skeletal muscle. — Pharmacologically the action of veratrine on skeletal muscle is most interesting. All kinds of muscular tissues are affected by the alkaloid, and in much the same way in the various species of animals. Isolated skeletal muscle contracts in the normal way after verat- rine, but relaxation is extraordinarily prolonged, many times that of the normal relaxation. This effect is characteristic. When the poison is given systemically the inability of the skeletal muscles to quickly relax leads to a peculiar type of general muscular movement in the poisoned animal. Such animals can make quick enough mus- cular contractions, as in the limb extensions in leaping, but the return to the normal relaxed position is hindered. This leads to very irregular and seemingly incoordinated movements, and to the fixing of the body in the position of contraction of the stronger sets of muscles. The explanation offered of this veratrine effect, which has re- ceived most general consideration, is that of Bottazzi. 1 This author, in 1901, called attention to the double nature of skeletal muscle sub- stance, namely, that it possesses highly differentiated fibrillae sur- rounded by a certain amount of less differentiated sarcoplasm. The fibrillae are responsible for the characteristic quick contractions of skeletal muscle, in which the part taken by the sarcoplasm is slight and thrown into the background. Under the influence of veratrine (and the effect is produced by other muscle poisons, such as muscarine, helleborine, etc.), the irritability of the sarcoplasm is sharply raised. When a muscle receives a single stimulus, such as calls forth a typical simple contraction, the fibrillae respond with the usual rapidity, and the contraction phase is as short and abrupt as in the normal. Ke- laxation begins in the usual way, but before it proceeds far is arrested by the slowly developed second contraction, and is followed by a very prolonged relaxation. The delayed relaxation is by this view 1 Bottazzi: Arch. f. Physiologie, p. 377, 1901. 208 VERATRINE due to the stronger contraction of the slower reacting sarcoplasm, which develops under the influence of veratrine. The recorded trac- ing is the algebraic sum of the contractions of the two substances, i.e., the quick contraction of the fibrillar and the slower but hyper- stimulated contraction of the sarcoplasm. By the above theory it is obvious that the prolongation effect will be greater in those tissues which have relatively greater amounts oi; sarcoplasm. This is found to be the case. The effect is more pro- nounced in the order — smooth, cardiac, skeletal muscle. Certain ani- mals whose muscles of a given type are known to possess a relatively Fig. 59. — The influence of veratrine, 0.0002 per cent, in Ringer-blood perfused through the coronary vessels of the cat heart, between the two arrows. There is a Blight delay in the effect represented by the time the fluid is flowing through the cannula. Just before the second arrow, the lever misses at the top an amount indicated by the dotted line. New tracing by Bullard and Stine. greater amount of sarcoplasm respond even more characteristically, as, for example, in the muscular tissues of the toad. 3. Veratrine on the heart muscle. — Heart muscle, as has already been stated, is influenced by .veratrine in that the contractions are also prolonged and the relaxations delayed, a phenomenon shown most typically in the cold-blooded animals. The heart muscle tends to persist in a continuous contraction in the systolic phase. The heart of the mammal is similarly influenced, though the picture is compli- cated by a primary stimulation of the nerve fibers of the inhibitory apparatus. Even in the isolated mammalian heart this later stimula- tion produces a slowing at the beginning of the veratrine action. ACTION ON SMOOTH MUSCLE 209 4. On smooth muscle. — Smooth muscle is strongly stimulated by veratrine, leading to increase in tone, with persistent contractions in organs where this type of muscle is dominant, i.e., the alimentary canal, the uro-genital system, the peripheral blood-vessels, etc. Yeratrine, like aconite, is a dangerously toxic drug. The thera- peutic effects, for which it was formerly used, are now produced more safely by other less toxic substances, hence the practical use of verat- rine has declined. It serves, however, through its muscular effects as one of our best pharmacological illustrations of characteristic and specific acting drugs. CHAPTER XXV. COLCHICINE. I. Historical and Chemical. Preparations of Colchicum autumnale have enjoyed a certain amount of popularity in the treatment of gout, though such treat- ment has not been based on any pharmacologically demonstrated ac- tivities. This plant yields two alkaloids, colchicine, C 22 H 25 N0 6 , and colchicein, C 21 H 25 N0 6 . II. Details of Pharmacological Action. i. General systemic and toxic effects. — Colchicine when given in therapeutic quantity produces little or no acute effects, but in stronger dose symptoms follow similar to those of aconite, and to some extent of pilocarpine. There is a slight increase in glandular and muscular activity, with evidences of sense-organ stimulation. These reactions are followed rather late by marked disturbances of the alimentary tract associated with violent pains, vomiting, and diarrhea. Continued therapeutic use leads to gastro-intestinal dis- turbance. Death is due to collapse of the respiratory system. The delay in the reaction of the body to colchicine is due to the fact that the real poisonous effects come only after oxidation of the alkaloid into an oxy-produce. 2. Colchicine on the white blood corpuscles. — An action which should be mentioned and which can readily be experimentally dem- onstrated is the production by colchicine of a marked leucocytosis. The immediate effect is a decrease in the number of leucocytes, chiefly polymorphs in the blood stream. This acute effect is followed later by a marked increase. It would seem as though the alkaloid w* sharply stimulative to this more undifferentiated cellular type. Ii leucocytes are stimulated then in all probability the endothelial 210 ACTION ON WHITE BLOOD CORPUSCLES 211 lymphoid, and synovial tissues, and the relatively undifferentiated connective tissues are also similarly stimulated. The stimulation of such tissues finds expression in cell growth and cell multiplication. However, and probably more important clinically, all such tissues as the endothelial tissues of the blood-vessels in reacting to stimula- tive agencies display first of all an increase in tonic resistance, a strengthening of the factors of control as displayed in their influence on osmotic and exudative processes. One must remember that such tissues form the boundary walls of cavities filled with fluids. It is suggested that this may be the explanation of the beneficial effect observed in the clinical use of colchicum in rheumatism, gout, etc. CHAPTER XXVI. EMETINE. I. Historical and Chemical. Emetine, C 14 H 18 CH 3 N0 2 , derived from the root of Cephaelis Ipecacuanha, is noted for its action as an expectorant and emetic. This alkaloid, too, is a general protoplasmic toxic substance and is to be classed with the aconite group. II. Details of Pharmacological Action. i. Systemic actions. — Emetine differs slightly from the other members of the group in its excessive toxic and local irritation. It is this property which, upon its administration, leads to marked irritation and stimulation of the mucous membrane of the mouth, throat, and stomach. In this way it quickly produces reflex nausea, with vomiting, and the train of associated symptoms. Ipecacuanha, as an expectorant and emetic, possesses the same dangers as have already been strongly emphasized in association with the other members of this series. 212 G. Drugs Poisonous to General Protoplasm. CHAPTER XXVII. COCAINE. I. Historical and Chemical. The tree Erythroxylon coca is native to the Andes of the west- ern coast of South America. The natives conducting the pack trains going through the mountain passes, chew the leaves of this species, in lieu of food, on their long mountain marches. They are said to go for extra long periods without rest or food under these conditions, endurance being greatly increased by the action of the active prin- ciple of the Coca leaves, cocaine. Cocaine was made known by Niemann, but its present popularity arose only after its introduction into use as a general local anesthetic in 1884 by Koller. Chemically cocaine is an alkaloid with the composition C 17 H 21 N0 4 . It is a methyl-benzo-ecgonine compound decomposing into ecgonine, pyri- dine, and benzoic acid. H 9 C- H 2 C- -CH CH 2 I I N.CH 3 CH.OH I I -CH CH 2 Tropine H 2 C CH CH.COOH I I N.CH, CH.OH H Q C CH CH 2 Ecgonine H 2 C CH CH.COO.CH3 I I N.CH3 CH.O.CO.CeH; I I H 2 C CH CH 2 Cocaine Ecgonine has a close relationship to tropine which is a hydro- lytic cleavage product of atropine. The anesthetic action of cocaine is lost by the removal of the methyl group or of the acid radicle. Other alkaloids are present in small quantities in the species of this genus. These alkaloids owe their toxicity and action to the same base, ecgonine, but differ somewhat in the attached acid radicles. 213 214 COCAINE The most important of these alkaloids is tropacocaine, extracted from the Java Coca. II. Outline of Pharmacological Action. Cocaine is described as a general protoplasmic poison. Its action may be summarized as follows: 1. Initial stimulation with later anesthesia of nerve tissues. Sen- sory nerves and sensory nerve endings are peculiarly susceptible. 2. Local applications lead to local anesthesia, an effect which readily passes away when the concentration of the drug is suffi- ciently reduced by diffusion or absorption. 3. The central nervous system is at first stimulated, then para- lyzed, chiefly in the descending direction. 4. Stimulation followed by paralysis of the heart muscle. 5. Marked vasoconstriction by central vasomotor stimulation and by peripheral stimtdation of the muscles of the blood-vessels. 6. Increase in the muscular power and endurance of the skeletal muscle by direct action on the muscle fibers. 7 . Marked mydriasis. III. Details of Pharmacological Action. i. On the central nervous system. — Cocaine is a recognized ex- citant of the cerebral cortex and the central nervous system. The excitement stage is associated with increased excitability of the cortex accompanied by restlessness, often passing into convulsions in the toxic stage, and ultimately ending in paralysis. The medullary cen- ters are excited, then depressed, shown in the quicker respiration, the slower heartbeat due to central vagus stimulation, and an increase in tone of the vasomotor center. All these stages pass rapidly into depression and paralysis. The spinal cord, after cocaine, likewise exhibits an increase in the irritability of the motor side of that apparatus. Reflexes are therefore increased, and this is true, not only for the cord reflexes, but for those reflexes which take place through the brain-stem, and even through the cortex itself. The change in function is due to an increase in the sensitiveness of the nervous elements. Dixon has determined that the amount of cocaine necessary to produce convulsions in the different species of animals COCAINE ON THE CIRCULATORY SYSTEM 215 closely corresponds to the proportional amount of brain matter per kilo, as indicated in the following table : Grams of brain per kilo of ani- mal. Rabbit. . . . Guinea-pig Pigeon Dog Ape Dose of cocaine per kilo neces- sary to produce convulsion. 0.18 0.07 0.06 0.02 0.012 Ott found also a strongly toxic influence on the posterior columns of the cord, indicating a slight degree of differential action within the cordu 2. Cocaine on the circulatory system. — The initial effect of cocaine when injected into the circulation is a rise of blood-pressure. Fig. 60. — The recovery phase of the frog's heart from the depressing action of cocaine. New tracing by Kruse. This rise is due primarily to great vasomotor constriction, but in part to direct heart effects. The initial rise of pressure is generally followed by a rather sudden fall with a second rise as toxicity ap- proaches. In the toxic stages blood-pressure falls and the animal becomes markedly cyanotic. The variations in blood-pressure may be analyzed by considering the action of the drug on the different parts of the mechanism. 3. The peripheral blood-vessels. — The most striking influence of cocaine is expressed in vasoconstriction. This is sharp, vigorous, and prolonged. The primary rise of blood-pressure is undoubtedly due to the stimulation of the vasomotor center in the medulla. There 216 COCAINE is, however, a marked vasoconstriction both in the spinal animal, and in organs for which the vasoconstrictor nerves are severed. Hence the cocaine effect is peripheral as well as central. The peripheral effects are due in part only to stimulation of the nerve endings. Evidence in this direction is the fact that when there is a sharp rise of blood-pressure under the influence of cocaine injection, cutting the splanchnic nerves leads to a decrease of the pressure. The stronger solutions certainly stimulate the muscles of the blood-vessel walls directly, as observed in the blanching of the gums when cocaine is injected for dental purposes. 4. Cocaine on the heart. — The intravenous injection of mild doses of cocaine leads to a marked slowing of the heart, occasionally after a short initial acceleration. This slowing is produced by the stimulation of the inhibitory center in the medulla. Cocaine per- fused through the isolated heart of the frog produces little change in rate, but a marked increase in the amplitude of contractions. This indicates a direct stimulation of the contraction amplitude of the cardiac muscle substance. This fact is further confirmed by the influence of cocaine on isolated terrapin heart strips in which also there is a marked increase in amplitude. The isolated mammalian heart gives evidence of direct stimulation of the heart by cocaine in therapeutic concentration, i.e., under 0.0002 per cent, concentration in perfusion fluids. In all heart work, whether it be muscle or nerve involved, the toxic end effect of cocaine is paralysis and loss of function. 5. Cocaine on skeletal muscle. — As is shown by the practice of the South American natives, cocaine increases the efficiency of the neuro-muscular apparatus in the production of voluntary muscular work. Especially does this effect follow under conditions of fatigue and partial exhaustion. An analysis of this effect would lead one to suspect that it was due, primarily, to the heightened irritability of the motor nervous mechanism. Experiments on the irritability of the spinal cord indi- cate that this is a factor. When the isolated gastrocnemius muscle contracting under repeated electrical stimulation is under the influ- ence of cocaine the amount of energy expended is much greater and the onset of muscular fatigue is strikingly delayed. Both these effects in this experiment are to be attributed to the direct action of cocaine on skeletal muscle substance. The functional influence is indeed quite similar to that on cardiac muscle. It is this double favorable therapeutic influence of cocaine on the nerve and on the muscle which COCAINE ON THE EYE 217 leads to the feeling of freshness and strength under its influence. It is a strong factor in the formation of the cocaine habit. 6. Cocaine on the eye. — One of the toxic symptoms of the in- fluence of cocaine is the dilation of the pupil of the eye. This effect is best studied by the direct application of cocaine into the eye. This leads to dilation of the pupil and a partial loss of accommodation. The dilation of the pupil is not associated with the loss of the light reflex. In other words the oculo-motor nerve is still reflexly active Fig. 61. — Showing the action of cocaine on the amplitude of contraction and the amount of work done by skeletal muscle. The lower tracing represents the work of the normal gastrocnemius of the frog ; the upper tracing, the cocainized muscle. Direct muscle irritability tested in the beginning of the experiment, the cocainized muscle showing very slightly greater irritability. Four minims of 0.5 per cent, cocaine was injected into the lymph sack 10 minutes before the experiment. Parallel experiments In which the cocaine acts for a longer time show depression on muscle contractility. New tracing by La Force. in the presence of the local mydriasis. Direct stimulation of this nerve produces active constriction of the pupil. When the superior cervical ganglion is removed cocaine still produces dilation. If, however, the post-ganglionic fibers, Figure 27, page 114, first be allowed to degenerate then the dilation is slight or absent. The whole effect is like that produced normally by stimulation of the cervical sym- pathetic and is to be attributed chiefly to stimulation of the endings of the post-ganglionic fibers on the radial muscles of the iris. 7. The elimination of cocaine. — Cocaine, like alcohol, is prac- tically all consumed in the body. Not only is it oxidized, but the cleavage products, ecgonine, benzoic acid, etc., are oxidized. 8. Local and anesthetic action of cocaine. — Cocaine owes its present therapeutic position primarily to the fact which was first emphasized by Koller in 1884. This action is dependent upon the fact that when cocaine is brought in contact with the tissues in sufficient concentration it leads to a temporary narcosis of all nerve 218 COCAINE structures, especially of sensory nerve endings. This analgesic effect comes on after five or ten minutes, lasts for a variable time, accord- ing to the rapidity with which absorption takes place from the local area, and gradually and completely disappears. Cocaine is, therefore, admirably adapted to local and minor operations. When injected into the tissues by hypodermic syringe or applied locally as in the case of mucous membranes, the eye, etc., it produces a local anemia from its stimulation of the small blood- vessel walls, also a local analgesia. Solutions of from 0.5 (or weaker) to 2 per cent, are used for this purpose. In every case rapidity of absorption is hindered as far as possible and care must be taken never to allow a maximum dose of more than 50 mg. to be absorbed into the general circulation. Susceptibility varies extremely with different individuals, many are more tolerant, but one grain (66 mg.) is often a toxic dose. With deep analgesia not only are the local sensory endings narcotized but nerve trunks can be cut without pain. For larger nerve trunks it is necessary, however, to inject the cocaine directly into the nerve sheath. Cocaine is also used for major operations by the method of spinal analgesia. For this purpose cocaine is injected directly into the meninges around the spinal cord, the puncture being made between the laminae of the lumbar vertebrae. As the drug diffuses around the meninges of the spinal cord it produces a temporary spinal paralysis and this persists long enough for elaborate and extensive surgical operations. The first major operation of this type was executed by Bier in 1898, the operation being the resection of a tubercular foot under spinal analgesia produced by 3 cubic centimeters of a 0.5 per cent, solution of cocaine. 1 The limit of the spinal use of cocaine is set by the presence of the nerves of vital function having their origin from the cervical cord. Of course spinal analgesia cannot safely be carried to the cervical region, since the loss of function of the phrenic nerves, arising from the third and fourth spinal nerves, will lead to respiratory paralysis. 9. The cocaine habit. — The use of cocaine, like alcohol, mor- phine, etc., leads to the formation of the habit. Under the cocaine habit the individual has an irresistible craving for the drug. The body becomes more and more tolerant, therefore correspondingly stronger doses are required to produce the desired stimulations. 1 Murphy, John B.: "Analgesia from Spinal Subarachnoidean Cocainization," Jour, of Am. Med. Association, Vol. XXXVI., p. 359, 1901. SUBSTANCES SIMILAR TO COCAINE 219 Cocaine is very much abused, especially in America, where it is said to have reached a widespread use among the negro population, as well as among the whites. IV. Substances Which Produce Anesthesia Similar to Cocaine. The cocaine nucleus permits chemically of a number of substitu- tion products, and a knowledge of the factor which contributes to the anesthetic properties has led to the development of a long series of compounds of this group. In the development of these compounds the attempt has been made to produce drugs which increased the anesthetic effects and as far as possible diminish the undesirable and toxic effects of cocaine. Of these synthetic and substitution products the most important, together with their variations from the cocaine reaction, are as follows : Tropacocaine. This synthetic alkaloid produces effects very similar to cocaine. The main differences are that it acts more rapidly, pro- duces little or no dilation of the pupil and less vasoconstriction. Its anesthetic power is slightly greater than cocaine, and it is somewhat less poisonous. Eucaine. Two synthetic eucaines with an ecgonine foundation have been produced, a Eucaine (C 19 H 27 N0 4 ) was the first produced and used, but it has been abandoned because of its marked irritant action. /? Eucaine (C 15 H 21 N0 2 ) enjoys a certain amount of popu- larity because of its lessened toxicity, one-fifth as toxic as cocaine. It produces neither vasoconstriction nor mydriasis. It is slightly less stimulating to the central nervous system and has a less tendency to produce convulsions than does cocaine. It does not decompose on prolonged boiling as does cocaine. Stovaine produces a similar local anesthesia to cocaine. It has the advantage in that it is more soluble and less toxic. For hypodermic and intramuscular injections it has the very great advantage in that it can be sterilized without decomposition. It leads to vasodilation rather than to the constrictor spasms which characterize cocaine. Holocaine is a coal tar product, produced by the interaction of phenacetine and paraphenetidine. It is more poisonous than cocaine, produces quicker anesthesia without vasoconstriction, has some anti- 220 COCAINE septic action, and the effect passes away in a shorter time than with cocaine. Novocaine is p-aminobenzoyldiethylaminoethane hydrochloride, with the formula CH 2 (C 6 H 4 NH 2 .COO).CH 2 [N(C 2 H 5 ) 2 ].HCl. Chiefly through its extensive use by Crile and by Bloodgood as a reliable local anesthetic to be depended upon in major surgical work, this drug has come into prominence in the last two or three years. It is said to be less toxic than other cocaine substitutes, and is a " prompt and powerful anesthetic." Novocaine is not strongly irri- tant. In practice it is often combined with some vasoconstricting drug like epinephrine. Other substances produce a degree of sensory anesthesia, as for example the coal tar phenol, creosol, etc. ; aconite, veratrine, etc. ; and the alkaloid yohimbine. V. Condensed Summary of Action. Cocaine is an alkaloid which has an initial general stimulating effect followed by narcosis and final paralysis as toxicity proceeds. Its peculiar interest is associated with its ability to produce local and temporary anesthesia which comes on about five minutes after application, and disappears in fifteen to thirty minutes with recovery of function. In local application it is peculiarly selective of sensory mechanisms but acts on all tissues. In spinal analgesia there is a local narcosis of the spinal cord and nerves originating therefrom, leading to loss of pain in that portion of the body the innervation of which passes through the local segment of the cord. In therapeutic quantity the central nervous system is at first stimulated, the effect passing over into depression and narcosis to a degree depending upon the concentration of the cocaine. The nerve structures readily re- cover from cocaine provided vital functions are maintained until the alkaloid is sufficiently oxidized or eliminated. Hence its toxicity is in large degree due to a true narcosis. The vital centers of the medulla are sharply stimulated by the therapeutic dose; respiration being accelerated, the tone of the vagus center increased, and the vasomotor center stimulated. The spinal cord is less vigorously influenced, but reflexes are at first accelerated, then depressed, the action being more acute on the sensory connections in the cord. The circulatory system is strongly stimulated. There is peripheral vaso- constriction chiefly from stimulation of the vasomotor center, but CONDENSED SUMMARY OF ACTION 221 partially by local nerve-end stimulation. In local anesthesia the blood-vessels are characteristically contracted, leading to a blanching of mucous membranes, etc. The heart is influenced in opposite direc- tions by the simultaneous stimulation of the inhibitory nervous mech- anism and of the cardiac muscle. The nerve influence is more acute and briefer, hence is dominant in the earlier stage, while the muscular influence is dominant in the later stage. The amount of muscular work is increased, primarily through the action of cocaine on the voluntary motor nerves, but secondarily through a direct favorable influence on the striated muscle. However, consecutive tests on sol- diers and athletes indicate that the drug is of little or no permanent value. Locally applied to the eye, cocaine produces dilation of the pupil and partial loss of accommodation. The light reflex persists, hence the iris reflex mechanism is not affected. The dilation is due to stimulation of the nerve endings of the radial muscles. Cocaine is fully oxidized in the body, but sometimes a little is excreted through the kidney. There is a tendency to habit formation with a great increase in tolerance in the body. CHAPTER XXVIII. QUININE. I. Historical and Chemical. The bark of different species of the Cinchona tree, Cinchona succirubra, etc., yields a series of over twenty alkaloids of varying composition. Of these the quinine, quinidine, cinchonine, and cin- chonadine are of special importance. These alkaloids are quinoline derivatives as illustrated by the following formulae: HC I HC CH CH CH CH 2 C 9 H„NO CH CH 2 C y H 14 NO CH CH 3 G I I CH HC CH HC CH I I I CH HC CH n/v \/\y \x\/ CH N CH N CH N Quinoline Quinine Cinchonine II. Outline of Pharmacological Action. Quinine produces its results in the body because of its toxicity to protoplasm of all kinds, the action being strongest on undiffer- entiated protoplasm. It produces a very mild initial stimulative increase in function, followed by marked depression and loss of function, hence: 1. Toxicity to protoplasm of all kinds. 2. Specific, i.e., selective toxicity to undifferentiated protoplasm such as white blood corpuscles, malarial Plasmodia, etc. 3. Antipyretic action by the primary decrease of heat production with secondary increase of heat loss. III. Details of Pharmacological Action. i. Systemic action. — The pharmacological effects of quinine are directly traceable to its great toxicity for all kinds of protoplasm. In 222 ACTION ON UNDIFFERENTIATED PROTOPLASM 223 this regard it differs, however, from members of the aconite group in that the irritant and antecedent effects are very much lower and its depressing effects before the final intoxication occurs more pro- found. The general symptoms in the mammalian body are those de- pendent upon the general toxic activity throughout the organism. They will be better understood upon examining the behavior of dif- ferent tissues after subjection to quinine. 2. Action on undifferentiated protoplasm. — The greater in- tensity of action of quinine on undifferentiated protoplasm accounts for its most important use, i.e., to destroy the malarial parasites when they infect the body. This therapeutic quality was discovered em- pirically early in the seventeenth century, long before the scientific reason was understood, either as regards the active alkaloid or the identity of the invading parasite. Binz x in 1867 determined that quinine was poisonous to certain one-celled animal forms, also to the white blood corpuscles. Vorti- eellae became inactive in 0.2 per cent, solution and actinophrys in 0.1 per cent, withdrew its pseudopodia, its protoplasm became more gran- ular and darker. He showed that fresh water amebae are very sensitive to quinine, though, strange to say, the salt water forms are much more resistant. White blood cells kept at a temperature of 35° C. in a moist chamber are actively motile. "When mounted in serum containing 0.05 per cent, quinine this motility fails to develop and the white corpuscles remain round and darkly granular. Parasitic ameboid forms, such as the dysentery ameba and the malarial parasites, are also particularly susceptible to the influence of quinine. Quite recently its use has been advocated in rabies on the view that the Negri bodies are ameboid in nature. The malarial parasite runs a cycle of change in the body. It develops in the red blood corpuscles to a certain stage, then passes out into the blood plasma in an active free swimming form. This critical period in the life cycle of the malarial parasite is the one at which toxic substances are liberated into the body, and at this time the character- istic malarial symptom of paroxysms followed by fever occur. The motile malarial organism is peculiarly susceptible to quinine, hence, if it is present in the blood plasma in sufficient strength at this time the germs will be destroyed and their regeneration in a new cycle prevented. An influence in the body depending upon this general toxicity is felt on the white blood corpuscles, as can be demonstrated on the frog 1 Binz, C: Archiv f. Mikroskopische Anatomie, Vol. III., p. 383, 1897. 224 QUININE or the mammalian leucocytes. A prolonged and profound applica- tion of quinine may lead, therefore, to a reduction of the number of leucocytes, a fact which secondarily influences other conditions in the mammalian body. 3. Quinine as an antipyretic. — The normal and constant tem- perature of warm-blooded animals depends upon regulating the heat through the interaction of two complex sets of factors: (1) the fac- tors that contribute to the regulation of heat production, and (2) the factors interacting for the regulation of heat loss or heat dissipa- tion. The production of the heat of the body is a direct result of the oxidations taking place during the metabolism of the tissues. Any and all factors which vary the intensity and amount of tissue oxida- tive changes will, of necessity, cause a variation in the amount of, heat produced. The most active tissues of the body are the muscles and glands, both of which are under nervous regulation and coordi- nation. But of all the heat producing tissues the greatest in mass and the greatest in intensity of oxidative process are the voluntary muscles. These are, therefore, the chief source of the body heat. Heat production takes place through oxidative changes in the skeletal muscles more or less independent of the liberation of active motion during the phenomenon of contraction (Pfluger's chemical tonus). The glands also produce considerable quantities of heat in pro- portion to their mass metabolism. Both these sets of organs vary in their oxidative activity under the influence of an elaborate nervous mechanism over which certain centers in the brain-stem have primary regulative influence. The chief center or centers that con- cern us in this relation are the thermogenic centers of the corpus striatum, the heat centers. Subsidiary centers are present in the mid-brain and the medulla, but the spinal animal does not possess regulative control of heat production. Heat production, therefore, may be varied by varying the activity of the thermogenic center. This center, like other nervous regulative mechanisms, is acting in response to the inflow of sensory stimulation and gives rise to nerve impulses in proportion to the sum of the algebraic factors, (1) volume of inflowing stimulation, and (2) the relative irritability of the center itself. As a matter of fact there are three instead of two links in the regulative chain controlling heat production. Be- side the two just given there is, (3) the condition which varies the ability of the terminal motor tissues to respond to a given nerve stimulus. There is a rise or fall of motor tissue stability under the ACTION AS AN ANTIPYRETIC 225 influence of normal variations in the nutritive condition, or of patho- logical factors in the environment, both very prone to react through this third factor. Heat loss or heat dissipation is measured by the output of heat from the surface of the body through the three physical processes, a, heat radiation; b, heat convection, and c, heat loss through evapo- ration of moisture. Heat radiation and heat convection occur in proportion to the relative temperature of the surface of the body and its immediate environment. Loss of heat through evaporation of moisture bears a similar relation to environment, but is primarily dependent upon the amount of moisture thrown on the surface by the sweat glands. The surface temperature of the skin during the times when heat is being rapidly lost from that region bears a close relation to the volume of blood flowing through the skin per unit of time. Whenever the cutaneous blood-vessels are markedly dilated and there is an increase in the circulation of blood through the skin, there is a rise in surface temperature and heat loss through conduc- tion and radiation is greatly increased, unless perchance the external temperature is actually greater than that of the skin. Incidentally, the better cutaneous circulation is also favorable to increased activity of the sweat glands. Heat loss, therefore, is also regulated, i.e., coordinated by nervous mechanisms, in this case primarily two mechanisms, (1) the sweat secretory apparatus, and (2) the nervous factors which control the circulation, both general and local. When the sweat glands are stimu- lated by the secretory nerves there is a corresponding increase in the formation of sweat with its accompanying increased evaporation from the surface and resultant greater loss of heat. This stimulation of the sweat-producing apparatus is almost invariably associated with a corresponding stimulation of the vasodilator mechanism form the skin. It will be seen, therefore, that the constant temperature of the body involves the coordination of several nervous mechanisms, one group, the regulators of heat production, the other, the regulators of heat dissipation. These factors are maintained in balance at various levels in the different species of animals. Normal Temperature. Man 37°C. Dog 38°C. Rabbit 38.6°C. Guinea-pig 37.6°C. Chicken 41°C. 226 QUININE These heat levels in the given species are remarkably constant under the widely varying conditions of external temperature. Yet a slight disturbance of the relative irritability of any one of the various coordinative nerve centers may decidedly change the average temperature level at any time. This is illustrated by the results of puncture of the corpus striatum, also by fever resulting from the toxins of bacterial infection, or by other pathological conditions. Following brain puncture there is a gradual rise of level of heat equilibrium in an animal of from 1 to 3 degrees. Numerous studies of brain puncture, 1 have shown that there is an increase of heat production during the rise of temperature, rather than a decrease of heat loss. In other words, the puncture serves as a mechanical stimulus of the thermogenic center and this leads to a rise of heat production without a corresponding increase of heat dissipation suffi- cient to maintain the temperature of the body at the normal level. The result is that the temperature is raised. Two Experiments showing the effects of Heat Puncture in the Rabbit on heat pro- duction, heat loss and body temperature (from Schultze). Animal. Stage. Temperature Centigrade. Heat loss per hour. Heat produced per hour. Calories. Per cent, of normal. Calories. Pit cent, of normal. J Normal During rise 38.5-38.6 38.6-39.6 39.6-39.5 6.46 6.87 7.71 100 106 120 6.49 7.67 7.64 100 118 | Climax 118 Normal 38.7-38 9 38.2-41.0 41.0-41.2 40.8-40.8 7.22 7.97 8.70 8.40 100 110 120 123 7.28 9.63 8.88 8.42 100 ( During rise 132 n Climax 122 ( Second day 121 At this new level, heat regulation can still be maintained. In other words, a shift in the point of heat equilibrium does not neces- sarily destroy the reflex responsiveness of either the thermogenic centers or of the blood vascular and sweat centers, the reactions of which control heat loss. In fevers, likewise, the disturbance of the balance between heat loss and heat production leads to a rise of temperature of the body but without loss of the temperature reflexes. In other words, there is a degree of heat regulation still shown under the fever condition, though the ability to maintain the temperature at the normal level 1 Schultze, Otto: Archiv f. Path. u. Pharm., Vol. XLIIL, p. 193, 1900. ACTIOX AS AN ANTIPYRETIC 227 is lost. Here, again, certain fevers depend upon a rise of heat production and the picture can readily be explained as a heightened irritability of the thermogenic center. Light is thrown upon the situation by considering what occurs under normal conditions during excessive physical activity. An enormous increase in heat production takes place with a rise of the temperature of the blood of the body. The increased temperature of the blood reacts through stimulation of the peripheral sensory mech- anisms, i.e., sense organs of heat, leading to reflexes that react through the centers concerned in both heat production and heat dissipation. The warmer blood flowing through these brain centers also acts directly on the nerve cells, especially those of the great medullary centers. The rise of blood-pressure within physiological limits also reacts on the nerve centers, contributing to an increase in their irritability. In the normal animal, under these conditions, the in- crease in irritability of the sweat and vascular centers is great enough to increase heat dissipation to a point that will quickly bring the temperature down to the normal, and in prolonged activity hold it there. In an animal in fever, in the case of puncture fever particularly, the stimulus falls directly on the thermogenic center. The mechanical stimulus of the puncture keeps this center in a state of hyperirritability which cannot be entirely overcome by the action of the heat dissipating centers. In fever from toxemia the phe- nomena are so similar that one may believe that there is a degree of toxic action (possibly selective) on the thermogenic center which increases its activity in a way comparable to the puncture fever. When quinine is given it leads to a fall of temperature, a change that is most pronounced if the body is already in the condition of fever. This fall of temperature takes place before there is a cor- responding increase in loss of heat, a complex that has been investi- gated by Gottlieb. This observation shows that the lowering of the temperature is in reality a primary lowering of heat production. Now quinine does not interfere with the output of carbon dioxide in normal animals, but it does result in a marked diminution in the excretable nitrogen. Tissue metabolism is therefore reduced, and since this reduction takes place when the brain and medulla are separated from the cord (Binz), it is evident that the primary in- fluence of quinine is directly on the tissues in which the heat is evolved rather than in the lowering of the irritability of the thermo- genic center itself or on the sensory side of this reflex arc. In fact the center is still reflexly responsive. However, in explanation of the 228 QUININE favorable action of quinine in fevers dependent upon hyperirritability of the thermogenic center one can scarcely exclude a degree of narcotic action on this group of nerve t cells. Gottlieb 's experiments * show that the lowering of temperature will take place independent of change in heat dissipation. However, he observed that under certain conditions there was an actual lower- ing of the heat output. Quinine often produces a vasodilation in the blood-vessels of the skin and a corresponding increase in heat loss, a result that is readily explained by consideration of the toxic influence on the blood vascular system. If the toxicity leads to that degree of vascular paralysis in which the cutaneous vasomotor tone is lost, then this factor of heat dissipation assumes a more important role. The antipyretic action of quinine, therefore, is twofold: (1), chiefly a toxic lowering of tissue metabolism and therefore heat production, accompanied by a certain but slight degree of diminution of irritability of the thermogenic center; and (2), a secondary cutaneous dilation, especially in the rather toxic stage, with corre- sponding increase of heat loss. The absolute loss of course diminishes in the later stages of the reaction. The greatest antipyretic action of quinine is noted under pathological conditions or in brain punc- ture where the fever is due to hyperirritability of the tissues. But in normal animals there is also a lowering of temperature by quinine, showing that its peculiar influence is not limited to the special patho- logical case, but is general. 4. Action of quinine on muscle. — Quinine is very toxic to skeletal muscle, producing a marked decrease in the power to do work. Even solutions of 1 in 50,000 are depressant to this tissue. The onset of the depressant action in the toxic concentrations is introduced by a brief and transient period of heightened irritability. The depressing ac- tion is proven to be directly on the muscle substance since it occurs when the nerve endings have been eliminated. Certain organs, such as the spleen, undergo a degree of contraction under the influence of quinine, which suggests that smooth muscle tissue has a somewhat greater initial stimulative reaction to quinine than most parts of the body. Larger doses produce depression of function. 5. On the digestive tract and on digestion. — Quinine possesses a very bitter taste, hence reacts locally on the reflex mechanism of the mouth. The bitter taste leads to a strong reflex which givea 1 Gottlieb, R: Schmiedeberg's Archiv, Vol. XXVI., p. 419, 1890. Also Vol. XVIII., p. 167, 1891. DETAILS OF PHARMACOLOGICAL ACTION 229 quinine the indirect influence of a tonic. The character of the reaction of this class of drug is discussed more fully under the sub- ject of bitter tonics. Larger quantities of the more soluble hydro- chloride occasionally produce some local effects on the stomach leading to nausea, in some cases diarrhea. The digestive processes are lowered by a mixture of the enzymes with the quinine, presumably by direct destruction of the enzyme itself. 6. On the liver. — Quinine leads to a depression of the glycogenic function of the liver. This reaction is explained as a result of the toxic lowering of the amount of glycogenic ferment due to the depres- sion of function of the liver parenchyma. 7. On the central nervous system. — Beside the effect on the heat regulative center the general nerve structures undergo a depression of function ending in paralysis. This is demonstrated through the influence of the drug on the sensitiveness of the responses of the cere- bral cortex. There is often noted after relatively large quantities of quinine a distinct interference with the special sense organs, especially of the ear and eye, partial deafness being a peculiarly characteristic after result of the continued display of the drug. 8. The elimination of quinine. — The alkaloid quinine is relatively insoluble and its absorption takes place only slowly from the alimen- tary tract. The hydrochloride is rather more readily absorbed be^ cause of its greater solubility. In the body a large quantity, 70 to 75 per cent., is oxidized and disappears. The remainder is excreted unchanged by the kidney. Only traces of quinine are excreted in the feces. Schmitz 1 has carefully investigated this question. His results show that of the quinine administered by the mouth about one-fourth to one-third is slowly regained from the urine. The following figures, quoted from him, illustrate this point. Experiment I., 0.817 gr. quinine given, .217 gr. recovered = 26.6 per cent. II., 0.817 gr. " " .244 gr. " =29.9 III., 1.226 gr. " " .346 gr. " =29.7 When the quinine was introduced subcutaneously it was excreted more slowly, as shown in the following table, also from Schmitz: 3 Schmitz. Richard: Schmiedeberg's Archiv, Vol. LVL, p. 301, 1907. 230 QUININE Day. Quinine given daily. 24 hour urine in cc. Quinine recovered. Per cent. Second ] r i i Y 0.605 ■{ l J I 1400 1700 1400 1450 1600 1500 0.108 0.120 0.083 0.128 0.076 0.071 17.9 Third 19 8 Fourth ' 13.7 Fifth Sixth 21.1 12.6 Seventh 11.7 This shows an average daily recovery of 16.1 per cent, of the amount of quinine given. The human body does not acquire any marked tolerance, as shown by the usual method of determination by the increased power of oxida- tion. This Schmitz determined on an individual who excreted an average of 25.3 per cent, of the quinine given during the first seven days, while five weeks later he excreted 26.9 per cent. IV. Condensed Summary of Action. Quinine and its closely related alkaloids are protoplasmic poisons which show a minimum initial stimulation and a prolonged paralytic after effect. Undifferentiated tissues, such as the white blood cor- puscles, the general type of tissue cells, as connective tissue, etc., and micro-organisms, such as amebae and the malarial parasites, present the greatest susceptibility, approaching that of specific reaction. As might be expected, quinine is an antipyretic of value. There is a decrease in body temperature in the normal body, but a more conspicuous decrease occurs in fevers. The reduction is primarily through depression of the function of the thermogenic tissues. The muscular tissues show an initial slight stimulation chiefly in con- tractility, followed by a marked depression of ability to do muscular work. This effect is true for skeletal muscle, cardiac muscle, and smooth muscle. The nervous system is depressed by the lowering of the irritability of the nerve cells of whatever type. The effect shows itself through interference with the action of the cortex in interpreting visual and auditory sensations and with other coordina- tive centers of the central nervous axis. There is a slight bitter tonic effect on the digestive tract, but this is more than counter- balanced by the lowering of the efficiency of the digestive enzymes. Quinine is very readily absorbed from the alimentary tract, is slowly oxidized by the tissues and excreted unchanged to the extent of 25 to 30 per cent, by the kidney. H. The Coal Tar Series CHAPTER XXIX. THE COAL TAK ANTIPYRETICS. I. Historical and Chemical. The chemical separation of the coal and wood tar products lias yielded a long series of carbon compounds, many of which have im- portant influences on the functions of the body. The most important of these compounds pharmacologically are those that have as their base the benzine nucleus, often, it is true, fundamentally modified. The distillation of many woods and wood tars also, especially of the pines, beeches, etc., yields compounds of this series, of which the creosotes are an illustration. The coal tar products are characterized by their toxic influence on living protoplasm, a toxicity that varies widely with the exact com- pound. But for convenience in presenting their pharmacological actions the numerous members of the series will be treated in two sub-groups : the Antipyretics and the Antiseptics. The older antipyretics are such drugs as aconite and quinine. These, in recent times, have been very largely superseded by the antipyretics of the coal tar series. The introduction of phenol as an antiseptic by Lister x in 1867, which so profoundly revolutionized our surgical technique, was soon followed by the important discovery that its carboxyl derivative, salicylic acid, produced a marked fall of body temperature. This antipyretic action of salicylic acid was soon extended to phenol itself and to others of the simpler phenol series. The almost limitless possibility of variation in structure of both nucleus and side chain among the ring compounds has led to the iso- lation, and, in many cases, synthetic production of numerous com- pounds, which are theoretically possible, according to the laws of chemical substitution. 1 Lister, Sir Joseph: British Medical Journal, Sept. 21, 1867. 231 232 THE COAL TAR ANTIPYRETICS Phenol is sharply toxic to protoplasm and its antipyretic action is secured with danger. The attempt has been to reduce toxicity and if possible retain or strengthen the antipyretic action. Many of these preparations have been manufactured and thrown on the market, often under trade names, and without adequate therapeutic testing. Of the series that have proven of distinctive antipyretic value and which have now been used and tested through a number of years until their pharmacological actions are well proven may be mentioned : (1) Acetanilide, an analine derivative with the formula: CH HC CH C 6 H 6 NH.CO.CH 3 = || | HC CH \^ CNH.CO.CH 2 (2) Antipyrene, which is a phenyl-dimethyl-isopyrazolon, with the formula : CH 3 C = CH I I C 6 H 6 N.N(CH 3 ).C(CH 3 ).CO.CH = CH 3 N CO N.C B H e (3) Acetphenetidine (phenacetine), with the formula: CNH.CO.CHs /^ HC CH C 6 H 4 OCHaCHs.NH.CHsCO = II | HC CH \^ CO.CH 2 .CH 3 To this series one might add members of the group of salicylates, which have considerable antipyretic action. Especially to be men- tioned are ethyl salicylate (oil of wintergreen) and acetyl salicylic acid (aspirin). OUTLINE OF PHARMACOLOGICAL ACTION 233 II. Outline of Pharmacological Action of the Coal Tar Antipyretics. The chief activity of the subgroup is expressed by the name, and is therefore : 1. Antipyretic. 2. A tendency to reduce oxy -hemoglobin to methemoglobin. 3. General toxicity. 4. Analgesic action. 5. Initial slight stimulation, followed by prolonged depression and paralysis of differentiated tissues, intensity of action greatest for nervous tissue. III. Details of Pharmacological Action. i. The general antipyretic action. — Under the chapter on quinine a review of the normal mechanism for the regulation of heat in the body for those animals that have a constant temperature is given. Attention is called there to the two regulative factors, heat production and heat dissipation, both of which are under nervous control. It is there explained that heat production which takes place in the tissues is regulated through definite nervous cen- ters in the brain-stem. Heat loss, on the other hand, is a factor of heat dissipation from the surface of the body. So far as the body is concerned, the rate of loss of heat and its regulation will depend chiefly on variations in the two factors, i.e., the circulation through the skin and the activity of the sweat glands. The coal tar antipyretics depress the vasomotor tone, hence lead to marked vasodilation, particularly in the skin. This physiological change produces an immediate increase in the relative warmth of the skin, a factor which is favorable to the loss of heat. The change in the circulation in the skin favors an increase in sweat production, adding still a third factor favorable to heat loss. In the therapeutic intensity of action the thermogenic center is still responsive to stimuli, hence at this stage there will be an associated actual increase in heat production. Under the more pronounced influence of the coal tar antipyretics the activity of the thermogenic center itself is de- pressed, hence there is a decrease in heat production. These factors 234 THE COAL TAR ANTIPYRETICS were determined on rabbits by Gottlieb. 1 He contrasted the anti- pyretic action of quinine and the coal tar products, showing that whereas quinine primarily depresses thermogenesis with little or no change in heat loss, antipyrine greatly increases the heat dissipation, which is the primary source of its ability to depress the body tempera- ture. In the more intense action it also decreases heat production, a factor that is relatively secondary in this group. 2. Narcotic action of the antipyretics on the central nervous system. — The antipyretics as one characteristic of their action pro- duce a decrease in the sensitiveness of the nerve centers to reflex stimulation, therefore are analgesic. This narcotic factor has led to their use (and abuse) in cases of severe migraine. Acetanilide, which is the most widely used in this connection, is decidedly, in fact dan- gerously, toxic. Even with mild dosage there is some depression of reflex irritability, indicated by a greater drowsiness and sluggish- ness than normal. In toxic quantity acetanilide produces cyanosis and convulsions in both man and mammals. These latter effects have been ascribed to lack of coordination of the nerve reactions through the spinal cord to a degree approximating to strychnine poisoning. The convulsions are to some extent, but by no means wholly, traceable to the cyanosis and asphyxiation, which occur at the same time. 3. On the circulation. — The effects of the coal tar antipyretics on the circulatory system are threefold : First, cardiac ; second, vaso- motor; third, on the blood. Studies on the frog's heart show that the initial rhythm is ac- celerated, but that this is followed by decided cardiac slowing. The cause of the behavior of the heart is best shown by studies on isolated heart muscle. The toxic action can readily be shown on isolated strips of terrapin heart. This line of experimentation shows that it takes careful gradation of dosage to develop the stimulating action of the antipyretics, for example, acetanilide. Solutions of from 0.02 to 0.04 per cent, of acetanilide in weak Ringer's solution or in physio- logical saline lead to acceleration in the rhythm of heart strips, occa- sionally accompanied by increased amplitude. But a very slightly stronger solution, while it may produce one or two beats with ac- celerated rhythm, invariably leads to slowing and sometimes complete, cessation of the rhythm. Toxic solutions (up to saturation, i.e., 0.5 per cent.) produce a slow and weak rhythm followed by a pause. The initial contractions may be more or less incoordinated and show a tendency to fibrillation. 1 Gottlieb, R.: Archiu f. Exper. Path. u. Pharm., Vol. XXVI., p. 419, 1890. ACTION ON THE CIRCULATION 235 Even these solutions are not immediately toxic, since after strips are returned to normal solutions they finally recover fully. It is evident, therefore, that acetanilide produces its effect in the frog's heart too by a narcotic depression of cardiac muscle. The blood-vessels are dilated under the antipyretics, a condition which may be preceded by a slight but insignificant vascular constric- tion, with associated higher blood-pressure. Certainly in the toxic stage the blood-pressure is low, the blood stream stagnated with pro- nounced cyanosis. These effects are due to the general paralysis of the vasomotor nervous mechanism, leading to a reduction in the resistance to peripheral blood flow. However, the cardiac depression will also account for some percentage of the decrease in blood-pressure. The Mood is affected through the formation of methemoglobin, es- pecially marked with acetanilide, though with antipyrine the action does not take place to so profound a degree. As the dose is increased and the toxic action comes on the disintegrating red blood cells set methemoglobin free in the blood stream. It is finally excreted by the kidney and makes its appearance in the urine. The methemoglobin action is produced largely by the decomposition product, para-amido- phenol, which occurs on oxidation of acetanilide in the body. The fact that antipyrine is not so readily oxidized and does not so rapidly give rise to this compound explains its failure to produce oxy-hemo- globin. Of the three representatives of the series chosen, acetanilide is the most toxic to the blood and phenacetine the least. 4. Variations in susceptibility. — There is unusual variation in individual susceptibility to the members of the coal tar antipyretic series. The general literature notes numerous cases of recovery after enormous doses, and at the same time of deaths that have occurred from relatively small doses. Children are particularly susceptible, and a greater reduction in dosage allowance for them than is called for by the rule must be made. In children the tissues are in an active stage of growth. Their protoplasm is relatively undifferen- tiated, and, as is true for most substances toxic for general proto- plasm, their tissues are particularly susceptible to chemicals of this series. The narcotic action of the coal tar antipyretics has led to their extensive use in the so-called headache remedies, a use fostered to an undesirable degree by chemical manufacturers and of course by the medical charlatans. The methods contributing to the extensive use of these drugs as home remedies are responsible for a large percentage of the fatalities that have occurred therefrom. The toxicity of the 236 THE COAL TAR ANTIPYRETICS series is entirely too great to justify use except under the direction of a physician. The abuse of this principle has resulted in numerous cases of collapse and an occasional death that might otherwise have been prevented. 5. Comparison of acetanilide, antipyrine, and acetphenetidine. — Of the three drugs the least toxic, possibly because it is least soluble, Acetanilide NaHCO s . Acetanilide. Acetanilide Caffeine jVaffC0 3 . Acetanilide Caffeine. Fig. 62. — The relative toxicity of acetanilide in combination with sodium bicar- bonate and caffeine. From Worth Hale. is acetphenetidine ; the most toxic, antipyrine. Acetanilide particu- larly is oxidized in the body to para-amido-phenol, to which form its general effects are often ascribed. The phenol acts on the red blood corpuscles, producing methemoglobin. The antipyrine also pro- duces methemoglobin. It is oxidized to the para-amido-phenol more slowly, hence the substance can be taken care of by the body without so intense a reaction with the hemoglobin. Worth Hale has demon- strated that caffeine added to acetanilide greatly increases its toxicity. Sodium bicarbonate tends to reduce the toxicity of acetanilide, also the toxic action of acetanilide and caffeine. CHAPTER XXX. THE COAL TAR ANTISEPTICS. I. Historical and Chemical. The coal tars yield a long series of antiseptics, i.e., drugs which are particularly toxic to generalized protoplasm, and therefore to bacteria and other lower organisms. An ideal antiseptic for the human body is one that is toxic to any foreign invading organism, bacterial or otherwise, and at the same time non-toxic for the tissues of the body itself. It is expecting too much to suppose that we can with our present state of chemical knowledge attain this ideal, but the goal is worth striving for, and the works of such men as Ehrlich give promise that we may reach it at a day not so very far distant in the future. That the protoplasm of bacterial organisms is similar to that of the human organism in its fundamental composition cannot be denied. That there is a differ- entiated structure for bacterial protoplasm also goes without saying. The point to be desired in the antiseptic is that it may so chemically combine with some characteristic structure of the organism as to become toxic without at the same time forming disadvantageous combinations with the protoplasm of the tissues of the host. The suc- cess of Ehrlich in synthetically developing the organic arsenic com- pound, arsenobenzol, stands to-day as our best illustration of the modern tendency of research in this field. Benzene, C 6 H 6 , the base or nucleus on which are built nu- merous series of coal tar preparations, is practically incapable of chemically combining with protoplasm. But this nucleus is chemically wonderfully labile, since it permits of innumerable substitutions for the hydrogen atoms of the ring, and, as we have already seen in the antipyretics, for the carbon as well. The substitution products carry the ability to attach the ring to the chemical substances entering into the composition of protoplasm. As an example, when one hydro- gen is substituted by one oxy-hydrogen, phenol is formed. 237 238 THE COAL TAR ANTISEPTICS OH Phenol - ! Phenol is wonderfully toxic to protoplasm, therefore antiseptic. The toxic and antiseptic properties of the benzene nucleus increases with the number of attached OH groups in the order illustrated by the following: Toxicity increases from Phenol to Pyrogallol OH OH OH OH OH OH V \s \/ Phenol Resorcin Pyrogallol The toxicity is due to two factors, (1) the greater combining ability, and (2) the property of the hydroxyl grouping. The toxic and antiseptic action of the phenol compounds is changed somewhat with the introduction of other nuclei in the side chain, as, for example, in salicylic acid or in methyl salicylate. OH OH I I COOH I I COO.CH< V Salicylic acid Oil of wintergreen Salicylic acid is much less toxic to the human body than phenol. This property makes it less irritant to mucous surfaces. Its some- what lesser degree of solubility in the tissue fluids also reduces its toxicity. The introduction of other radicles, such as methyl, CH 8 , etc., adds the pharmacological action of the new group, which may cause variation either in the stimulative phase or in the toxic phase of the action of the original product. The antiseptics of the coal tar series also owe their toxicity in some degree to the decomposition products, as is illustrated very well by the explanation of the methemoglobin formation in the case of acetanilide. In the body these decompositions may set free active antiseptic compounds, as illustrated by salol. Salol Decomposition products OH OH OH I I COO II || Phenol Salicylic acid PHARMACOLOGICAL ACTION OF COAL TAR ANTISEPTICS 239 In like manner the body protects itself by the formation of inert compounds. The phenols and phenol derivatives are largely oxidized to phenol sulphate and other relatively inactive compounds, in which form they are rapidly excreted by the kidney. OH I I O.S0 2 .OH \/ \/ Phenol Phenol sulphuric acid It would be out of place to treat specifically every member of this enormous group of compounds. For our purpose it will be better to illustrate the group by specific treatment of the most important types. For this purpose we will take (1) the phenols, (2) the sal- icylates, and (3) the creosotes. II. Outline of Pharmacological Action of the Coal Tar Antiseptics. 1. General toxicity for all kinds of living protoplasm. 2. This toxicity manifests itself in an initial but slight stimulation pliase, followed by a narcosis and paralysis. 3. Peculiarly toxic to the nerve centers of the central nervous system. 4. A certain degree of anesthesia to local sensory mechanisms. 5. Toxic to the blood with the formation of methemoglobin. I. THE PHENOLS. Phenol, or carbolic acid, is the oldest and best known of the coal tar antiseptics. It is derived from benzol by the substitution of one hydroxyl, thus, C 6 H 5 OH. It was phenol which Lister first introduced into antiseptic surgery in 1867. 1 III. Details of Pharmacological Action. i. Toxicity to protoplasm. — Phenol owes its antiseptic quality to its solubility in, and toxic chemical avidity for, protoplasm. It 1 Lister, Sir Joseph: "On the Antiseptic Principle of the Practice of Surgery," British Medical Journal, Sept. 21, 18C7. 240 THE COAL TAR ANTISEPTICS acts somewhat more strongly on undifferentiated protoplasm, such as bacteria, protozoa, etc., but it is relatively toxic for all kinds of differentiated tissue. As an antiseptic to be used in surgical sterili- zation and dressings, it is customary to use solutions of from 3 to 5 per cent. The latter solution is not only germicidal, but quite toxic for exposed tissues, hence when kept in long contact leads to de- generation and disintegration. More dilute solutions of phenol will destroy active bacteria if kept in contact for a sufficient length of time, in the course of a few minutes with certain forms, while others resist for hours or even days. Bacterial spores are the most resistant forms of living matter to the action of chemical poisons. The spores of anthrax are particu- larly resistant in this regard. They withstand the toxic action of the stronger solutions of phenol for many hours. The typical action of phenol on general protoplasm is the pro- duction of a degree of local irritation. This is especially the type of action when phenol is applied to mucous membranes. "When car- bolic acid is swallowed the local corrosive action on the mouth and stomach leads to irritation accompanied by the reflexes expressed in nausea and vomiting. This is particularly true of gastric irritation from this source. Such reflexes may and often do follow non-toxic amounts of the drug. Phenol is easily soluble and readily absorbed, therefore, in addition to the local reflexes from gastric irritation, the substance quickly produces its systemic effects, especially when there is a possibility of being absorbed through abraded surfaces. 2. On the central nervous system. — Carbolic acid produces a slight and transient stimulation of the cells of the central nervous system, but the main picture is one of toxic depression and collapse. The collapse appears early and after a relatively slight amount of absorption. It is due to the action of phenol on the basic nuclei of the brain-stem and cord. The initial stimulating effect on the great regulative centers is slight, but shows itself through rapid respira- tion, accelerated pulse, and other vascular disturbances. The stage of toxic collapse quickly follows through a depression of, (1) the ir- ritability of the thermogenic center, which leads to a lowering of heat production, (2) through a paralysis of the vasomotor and cardiac centers of the medulla, deranging the efficiency of the circulation, and (3) by paralysis of the respiratory center leading to shallow respira- tion, asphyxia, and death. The spinal cord is affected in such a way as to interfere with the coordinative control of voluntary nerve im- pulses. It is apparently this which leads to the irregular contrac- ACTION ON THE CIRCULATORY SYSTEM 241 tions and muscular twitchings, both in the frog and in the mammal, resulting in response to sensory stimulation. The absorption of phenol is so rapid after the swallowing of toxic quantities that this chain of nervous symptoms follows in rapid succession, a fact only too well known from the numerous cases of suicidal poisoning. 3. On the circulatory system. — The toxic action on the medullary centers mentioned above of course includes those centers controlling the circulatory apparatus. In therapeutic limits the first influence on the circulatory centers is slightly stimulative. This limit is quickly passed, and there is a marked depression, which shows itself most strikingly on the vasomotor center. "With the decrease of response of this center there is dilation of the peripheral blood-vessels and fall of blood-pressure, all contributing to the well-known condition of collapse. The cardiac muscular tissue is also affected by phenol. Perfusions of the heart, as, for example, in the frog, with very dilute phenol solutions (.005 per cent.) lead to an increase in both ampli- tude and rate. With stronger solutions of phenol this favorable picture is changed to one of marked depression, showing an evident direct muscular toxicity. The circulatory system, therefore, contrib- utes sharply to the total picture of collapse under the influence of phenol. 4. The excretion of carbolic acid. — Small amounts of phenol are adequately taken care of by the body of man and eliminated in more or less oxidized form, the oxidation taking place through the hydroxyl bond. Phenol is oxidized into phenol-sulphuric and glycu- ronic acids, which leave the body by way of the urinary system. In the oxidation and excretion of phenol, the toxic drug is brought into intimate contact with the renal cells and may produce there local intensity of action sufficient to produce nephritis. As a result the cells of the renal tubules, both of the capsule and the secreting tubules, may undergo toxic degeneration and necrosis, if excretion is rapid enough to produce a sufficient concentration of the drug about the tissues. This is one of the great dangers from the use of benzol compounds as physiological antiseptics. On the other hand, a certain mild degree of local antisepsis may be produced in the excreting organs because of the interaction of the factors just mentioned. 5. Toxicology. — The toxicology of phenol is assuming wide prac- tical importance because of its ever increasing use with suicidal purpose. The extensive use of the antiseptic in the arts and for practical disinfection makes it a substance easy for the layman to obtain. Its terrific corrosive action is enough to deter any one from 242 THE COAL TAR ANTISEPTICS so unfortunate a choice of suicidal drugs as phenol, but this factor is, probably because of ignorance of the fact, given little weight by our numerous despondents. One gram or less may be a fatal dose, though two or three times this amount may be safely eliminated by the body if introduced through sufficient time. For example, in the days of the use of the Lister carbolic acid spray in surgical work it often happened that large enough quantities were inhaled by the surgeon to produce distinct depression, though no acute toxic effects. Both the absorption and excretion of phenol are rapid, hence the toxic dose will depend largely upon the concentration as well as on the rapidity of introduction. A quantity toxic when suddenly intro- duced into the stomach may not be so if taken in a series of smaller doses. The stage of collapse and death may come on in 20 to 30 minutes, while death may be delayed for 12 to 24 hours. In case of poisoning the remedies should be directed toward quick and decisive removal of the non-absorbed phenol, and be followed by symptomatic treatment. Externally phenol is best removed by wash- ing with alcohol or the stronger alcoholic liquors, which dissolve and thus eliminate the drug. When these solvents are not available, then olive oil, sweet oil, or vaseline may be used, as the oils are phenol solvents. Internally phenol may in some cases be dissolved in weak liquors and at once removed by the stomach pump, or it may be par- tially neutralized by the use of lime water, permanganates, or sulphates. The sulphates do not react with phenol externally, but are an aid to the body in the formation of phenol sulphates during systemic poisoning. Sollmann has shown that too much reliance should not be placed on the sulphates in the case of acute poisoning, although the sulphates are somewhat counteract- ing in their systemic effects, because they also stimulate where phenol depresses. Salol is itself not strongly active, but after it passes out of the stomach and is brought into contact with the alkaline contents of the intestine it is broken down into phenol and a salicylic acid com- ponent. The released phenol now becomes actively antiseptic, while the salicylic acid produces its typical antipyretic and antiseptic action. Resorcin, di-hydroxy-phenol, and pyrogallol, tri-hydroxy-phenol, are very much more toxic than phenol, the toxicity increasing with the number of OH ions attached. These compounds are still more highly irritant to the tissues. The latter especially is peculiarly toxic to the blood, breaking down the red blood corpuscles with the formation CONDENSED SUMMARY OF THE ACTION OF PHENOL 243 of methemoglobin. These chemicals are now primarily of interest because of their toxicology. IV. Condensed Summary of the Action of Phenol. Phenol, or carbolic acid, is an irritant toxic mono-hydroxy-benzol, which is toxic to all living protoplasm. The di-hydroxy resorcinol and tri-hydroxy-pyrogallol produce the same type of changes, though they are more intense in action and more toxic. When applied locally phenol produces a degree of irritation, and, if concentrated, corrosion and death of the tissue, whether this be epidermal or mucous mem- brane. It is rapidly absorbed into the general circulation. The systemic effects are slight and transient stimulation, followed by rapidly developed depression and paralysis. This effect shows most strongly on the central nervous, system, particularly the basic nuclei, in which the paralysis leads to depression of the heat regulative center, as well as of the vasomotor and respiratory centers. The general toxic action on the nervous system quickly leads to uncon- sciousness and systemic collapse, from which the individual does not recover. The motor tissues, the glands, skeletal muscle, smooth muscle, and heart are all sharply depressed, showing a lowering of general metabolism and of specific functional activity. The heart itself is at first accelerated, then weakened and paralyzed by direct action on the cardiac muscle. Phenol is rapidly excreted from the body, chiefly after oxidation to sulphates, in which form the substance is less toxic. In the process of elimination through the kidney a degree of local irritation is produced, leading to nephritis with necrosis, conditions that develop particularly in prolonged or chronic poisoning. On account of the toxic action of phenol it is of peculiar value as an antiseptic and disinfectant. For surgical antisepsis from 3 to 5 per cent, solutions are used, though the stronger solutions must be guarded from too prolonged contact and too excessive absorption. Most bacteria readily succumb to these strengths of carbolic acid, but some species, especially anthrax, in particular the spores, are pecul- iarly resistant. For local cutaneous antisepsis it is now the practice to use concentrated phenol for a few moments of contact, then wash off the phenol with 95 per cent, alcohol. As a disinfectant for sputum, excreta, etc., 10 per cent, phenol is used, leaving the material to be disinfected in contact for several 244 THE COAL TAR ANTISEPTICS hours. This will kill all but the most resistant spore-forming bacteria, and these can be killed by prolonging the contact with phenol. II. SALICYLIC ACID AND THE SALICYLATES. I. Details of Pharmacological Action. i. Toxicity to general protoplasm. — The salicylic acid group is relatively very much less toxic than phenol. The substitution of a carboxyl radicle leads to a great decrease, but far from a loss in irritant properties of the compound. Therefore these compounds are much more mildly toxic to animal tissues than the phenol, from which they are derived, but are none the less valuable as antiseptics. Solutions of 0.1 to 0.2 per cent, are ordinarily sufficient to prevent the growth of bacteria. The more undifferentiated types of proto- plasm are also more strongly influenced by salicylic acid and the salicylates. Salicylates in the body, presumably due to their initial stimulat- ing effects, lead to an increase in the number of leucocytes, a factor that is by some thought to be the explanation of the favorable activity of these compounds in the clinical treatment of rheumatism. 2. On the central nervous system. — Salicylic acid in contrast with phenol is more stimulating and less depressant to the centers of the brain and cord, hence its action is more in line with that of the antipyretics than is phenol. In fact the salicylates formerly enjoyed a popularity as antipyretics, a position dependent upon the depres- sion of the thermogenic center and their toxic influence on tissue metabolism in general. Hanzlik, 1 who has studied the toxicity of the salicylates, states that when salicylate is given in doses of from 10 to 20 grains per hour signs of toxicity appear after from 180 to 200 grains. ' ' Toxicity is indicated by the appearance of headache, nausea, vomiting, ringing in the ears or deafness, rarely delirium and hallucinations, and some- times diarrhea.' ' The toxicity is somewhat greater with other salicy- lates, as indicated by the table below. 1 Hanzlik, Paul J.: Jour. American Medical Ass'n, Vol. LX., p. 957. 1913. ACTION ON THE ALIMENTARY CANAL 245 TABLE I The Mean Toxic Doses of the Various Salicylates (Hanzlik). Drug. Synthetic sodium salicylate Natural sodium salicylate Methyl salicylate (oil of gaultheria). Acetylsalicylic acid (aspirin) Salicylosalicylic acid (diplosal) Mean Toxic Dose (gr.) 180 200 120 minims 165 100 The average dose given in the table is for adult men. For women the toxic quantity is 80 per cent, of the above, i.e., proportional to the difference in weight. 3. On the circulatory system. — The salicylates depress the circu- latory system. This occurs from the fact of toxic depression of the vasomotor center on the one hand, and the direct deleterious influence on the muscles of the blood-vessels and of the heart on the other. Acetyl salicylic acid, for example, produces practically no favorable change in the contractions of the frog heart, but when the drug is sufficiently concentrated (0.001 per cent.) slows the rhythm and ulti- mately to the point of complete suppression. In perfusion experi- ments the cold-blooded heart may be revived, but only after a long latent period, much longer than required for most drugs of this type tested by physiological assay. It is inferred that this toxic action is a factor in the toxic picture in therapeutic practice. 4. On the alimentary canal. — Salicylic acid and the salicylates are readily absorbed from the alimentary tract. They are slightly irritant to the mucous surfaces and interfere to a degree with the normal digestive processes, owing to the fact that they lower the efficiency of the chemical processes in digestion, 1 per cent, solution decidedly diminishing the enzyme action of the digestive ferments. The nausea and vomiting after salicylates are largely of central origin. Waddell 1 says that vomiting is an early symptom in cats, occurring in from 20 to 90 minutes after salicylates by the mouth. He found that " Emesis follows on hypodermic injections of salicylates after a latent period of at least 20 minutes." Salicylates were not found in the vomitus, a fact greatly strengthening the conclusion B8 to central origin of the disturbance. The emetic dose for cats is given as 0.6 grm. per kilo of body weight, the toxic dose, 0.9 to 1.1 grms. per kilo in cats. 1 Waddell, J. A.: Archives of Internal Medicine, December, 1911. 246 THE COAL TAR ANTISEPTICS 5. The antipyretic action. — The simple salicylates are distinctly antipyretic, though not so valuable as the acetanilide series. Their action is multiple. The thermogenic center is markedly depressed, thus lowering the general heat production in the body. At the same time there is a stimulation of the sweat producing glands in the skin associated with cutaneous vascular dilation, thus decidedly increas- ing heat dissipation. 6. Acetyl-salicylic acid.— C 6 H 4 (CH 3 CO).COOH. (aspirin). This compound " acts like salicylic acid, over which it possesses the advantage of producing less of the undesired local and systemic side effects, on account of the slow liberation of the salicylic acid. It is said to pass the stomach unchanged, the decomposition beginning in the intestine. ' ' * Acetyl-salicylic acid has distinct toxic properties indicated by its influence on the nervous system. The therapeutic dose occasionally produces distinct dizziness, weakness, and sometimes fainting. Idiosyncrasy is sometimes present, and clinical cases are reported where a single five-grain dose has led to marked cyanosis and edema. The drug produces a depression of the efficiency of the circulatory system with a great weakening of the activity of the heart. The perfused frog heart retains its usual sensitiveness to vagus regula- tion, even when the cardiac muscle is on the point of yielding its rhythm, which it does to a concentration of 0.001 per , cent, in the usual artificial perfusion solutions. This compound also has the usual amount of antiseptic power and is said to be more readily borne by the body than other forms of the salicylate series. II. Condensed Summary of the Action of the Salicylates. Salicylic acid and the salicylates are less corrosive than phenol and its hydroxy series. Salicylic acid is also readily absorbed into the general circulation, and produces a slight degree of local irrita- tion, but no corrosion of the absorbing surface. The systemic effects are those of a mild stimulation, followed by prolonged depression and mild narcosis. On the central nervous system this leads to a de- crease in the reflex sensibility, particularly of the higher centers of the cortex. There is depression of the thermogenic center as well 1 New and Non-official Remedies, p. 225, 1914. SUMMARY OF ACTION OF SALICYLATES 247 as of the peripheral heat producing mechanisms, hence the salicylates are of importance as antipyretics. The initial therapeutic action on the circulation is to slightly increase blood-pressure. This is partly due to an increase in vasomotor tone through the regulating nerve centers. The later effects are just the opposite because of the narcosis of this nerve center. There is a toxic depression by direct muscular action on the heart. Respiration is at first slightly increased, followed by depression in both the amplitude and rate. These changes are due to a narcosis of the respiratory center. The salicylates are used to produce a degree of germicidal action within the body, and their presence is specifically detrimental to the growth and development of the species that lead to the production of rheumatism, in which disease the salicylates have their greatest thera- peutic application. I. Internal Secretions. CHAPTER XXXI. INTEENAL SECEETIONS OF THE THYEOID AND PAEATHYEOID GLANDS. General Introduction. The internal secretions are denned as those substances which are produced in the body by special glands or gland-like structures and are discharged into the lymphatics or the circulation, ultimately in some way to influence metabolic processes in other tissues of the body. As a matter of fact, all the tissues elaborate materials either pure wastes on the way to elimination or intermediary products, which may be further oxidized, and therefore influence reactions in other parts of the body. Strictly speaking, the waste products are not considered in the class of internal secretions. The term is rather limited to materials which have more specific relations to the func- tions of other parts, relations that are drug-like in character. The manner in which internal secretions act in different organs has been under discussion for many years, and it can scarcely bo claimed that the matter is at present fully determined. The two leading hypotheses are: First, the theory that the secretion removes or renders inert some toxic substance of the body, and second, the theory that the internal secretion contains some specific substance which is necessary to the normal reactions occurring in other parts of the body. The former has been gradually displaced until at the present time it is practically abandoned. Those internal secreting glands and organs which produce substances that have been isolated and chemically identified by their physiological reactions in the body, have been specific enough to bring them within the second class. One need only to mention the active epinephrine from the suprarenal body as an example. An ideal internal secretion therefore would be one to which the tissue of some part of the body has become biologically adapted so that its normal function depends on the presence of the secretion. The general physiological assumption is that such internal secretions 248 HISTORICAL AND CHEMICAL 249 contain a particular and more or less specific substance. To sub- stances of this class Starling 1 has applied the name hormone. Of the glands that are known to produce internal secretions, only a few have had the specific hormone identified. In fact, only two glands, the thyroid (with the parathyroid) and the suprarenal, have had their hormones isolated and identified chemically. However, we may confidently expect as a result of further investigation that addi- tional hormones will ultimately be isolated and their functions more specifically circumscribed. The subject of internal secretions is at present one w T hich concerns the borderland between Physiology and Pharmacology. This is un- doubtedly due to the fact of our incompletely developed knowledge of the actions of the hormones produced by these glands. That the subject will become more and more intensely vital to pharmacology is self-evident, hence its introduction in this discussion at the present time. The organs which produce internal secretions form a rather ex- tensive list, as follows: Thyroid, parathyroid, hypophysis, thymus, suprarenal cortex, suprarenal medulla, chromaffme tissue, pancreas, liver, kidney, duodenal mucosa, also different portions of the repro- ductive organs and reproductive tissues, including the testis, ovary (i.e., the Graafian follicle, and especially the corpus luteum), placenta, and fetus. A. THE THYROID AND THYROIODIN. I. Historical and Chemical. The thyroid glands, apparently including the parathyroid, have been shown to contain the iodine compound, which was isolated in 1895 by Baumann. 9 This substance he purified and analyzed, and found that it contained as much as 9.3 per cent, of iodine (0.01 to 0.9 per cent, of the dry weight of the human thyroid). Baumann's thyroiodin is readily soluble in dilute alkalies, but insoluble in acids. Starling, Erneal EL: Croonian Lectures, 1905. Also Lancet, Pt. 2, p. 579, 1905. 1 Baumann, E.: Boppe-Seyler'a Zeiteohrifi fUr PhysiologUohe Chemie, Vol. XXL, p. 319, 1895-96. 250 INTERNAL SECRETIONS OF THE THYROID It contains from 0.4 to 0.5 per cent, of phosphorus. Thyroiodin has been found in both the thyroid and parathyroid glands, though some question still exists as to the accuracy of the determinations for the parathyroids. II. Outline of Pharmacological Action. 1. The thyroid extracts and thyroiodin produce changes in me- tabolism especially affecting the nervous system and the oxidative processes. 2. The elimination or removal of the secretion deranges normal metabolism, especially of the nervous tissues. III. Details of Pharmacological Action. i. The effects of the removal of the thyroids. — The establish- ment of the function of the internal secreting glands in general has been no easy task. Of the earlier experiments in this field the most satisfactory results have been given by two methods. First, that which depends upon the disturbance of bodily functions after the removal of the gland, and second, the changes in function observed upon administering extracts of the gland. In the case of the thyroid, the later studies have shown that many of the brilliant earlier works were vitiated by a failure to recognize the presence of the parathy- roids. Gley x called attention to the extreme importance of the parathyroids, a point of view that has been fully confirmed since. Vincent and Jolly 2 state that the removal of all four parathyroids, as well as the thyroids, is not necessarily fatal. Although a fatal outcome usually follows, such is not due to surgical injuries to the surrounding structures, hence must be attributed to the loss of the glands. If the thyroid is removed, the parathyroids apparently are capable of replacing to some extent the characteristic thyroid struc- ture, a deduction based on the change in histological appearance, including the development of colloid. The removal of the thyroids is characterized by a marked myxedema, a condition that also char- acterizes certain thyroid diseases. The removal of the parathyroids, on the other hand, generally leads to the early death of the animal, 1 Gley: Comptes Rendus de la Socie'te' de Biologic, p. 843, 1891. 2 Vincent and Jolly: Journal of Physiology, Vol. XXXII., p. 651. ENGRAFTING OF THYROID TISSUE 251 preceded by very characteristic nervous muscular disturbances de- scribed under the name of thyroid " tetany." Edmunds has observed thyroid myxedema in monkeys, though this was not confirmed by Vincent and Jolly. The fact that the two internal parathyroids are deeply imbedded in the lobes of the thyroid and are highly vascular makes it exceedingly difficult to remove the one gland without interference with the other. This statement ap- plies in explanation of certain criticisms which have arisen as re- gards the source of the thyroiodin. 2. The engrafting of the thyroid tissue. — In the operative work for the removal of the glands it has been noticed that if an exceedingly small remnant is left behind, the usual symp- toms do not follow. In other words, a remnant is capable of taking care of the function of the whole gland. This fact has led to at- tempts to engraft thyroid tissue in other parts of the body. These attempts, though at first unsuccessful, have finally succeeded. Mc- Pherson records beneficial results in man from transplantation of thyroid to the extent that symptoms of myxedema disappeared after operation and had not returned within three years. The transplanted thyroid tissues are usually absorbed, but if they " take " and the vascular supply becomes well established, it is assumed that the normal production of the active thyroid hormone occurs. 3. The interrelationship of the thyroids and the parathyroids. — Numerous experiments point to an intricate functional relation be- tween the thyroids and the parathyroids. The most importance rests upon the physiological fact that the removal of the parathyroids is far more fatal than the removal of the thyroids, and that the loss of either of the glands leads to a different type of functional defect from that which characterizes the loss of the other. The embryological and histological observations show that the parathyroids take on the structural characteristics of the thyroids after the removal of the Latter, showing a close relationship between the two. The iodine content varies greatly in the thyroid tissue. There is, according to GUey, many times more iodine in the thyroid tissue than in the parathyroid. However, Mendel ' has confirmed the presence of iodine in the parathyroids. The facts observed have led to the view that the parathyroids prepare the iodine compound, which is later stored in the tissue or colloid of the thyroid. This view of Gley has been strengthened by the observation that there is a disturbance of iodine metabolism when the thyroid is extirpated. 1 Mendel, L. B.: The American Journal of Physiology, Vol. III., p. 203, 1900. 252 INTERNAL SECRETIONS OF THE THYROID 4. Observations from the feeding of the thyroid tissue and of thyroiodin. — Experimental procedure demonstrated the stability of the thyroid hormone, both to digestion and to heat, even before the isolation of thyroiodin. Now both thyroid tissue and the thyro- iodin are given by way of the mouth. Thyroid substance introduced ji.thffr.M— tfiym.m- Fig. 63. — Diagram to show the branchial origin of certain internal secreting glands. I, II, III, IV, the respective branchial arches ; thyr., thyroid ; p. thyr. } parathyroids ; thym., thymus ; pb. &., post-branchial body, which in development becomes imbedded in the thyroid. From Vincent and Jolly. by this channel has the same physiological effects that occur from engrafting the tissues. It would seem that the active hormone is not only not destroyed in digestion, but is absorbed and can reach the circulation and thus influence metabolism in the usual way. Thyro- iodin purified by the method of Baumann is recommended as a substi- tute for the thyroid tissue. While the influence which it has on metabolism seems to be the same, it has not always proved to act with the same vigor and efficiency as the tissue of the gland itself. Certainly iodine, as such, does not take the place of this organic thyroiodin compound, hence it is assumed that the function of the gland is to build up the thyroiodin compound, thus getting the iodin in an available form for the use of other tissues. In confirmation of the point just made, Marine has found that enlarged thyroids with a diminished quantity of thyroiodin present tend to return to the normal upon feeding of iodine. After iodine he found an increased percentage of thyroiodin present in the gland. In other words, as Marine expresses it, " iodine administered to dogs DETAILS OF PHARMACOLOGICAL ACTION 253 with hyperplastic thyroids has a physiological action like the desic- cated thyroid, i.e., it rapidly reduces the body weight, while iodine administered to normal dogs does not." B. PAKATHYKOLDS. We have already stated the fact that the removal of the parathy- roids without interference with the thyroids leads to grave symp- toms and usually the death of the animal, though, as was stated above, Vincent and Jolly showed that death did not always follow. 5. Systemic phenomena following removal of parathyroids. — In a word, the typical symptoms following the removal of the parathy- roid is expressed by the term " tetany." The animals show a pro- gressive development of nerve and muscular incoordination, ending in tetanic spasms and death. There are evidences of central nervous disturbances expressed in the restlessness, anxiety, and mental stress as interpreted from operated dogs. 6. Disturbances of metabolism after parathyroidectomy. — W. F. Koch x has recently examined the effects of parathyroidectomy on dogs from a physiological chemical standpoint. He found the pres- ence of methylguanidine in the urines of six different animals inves- tigated, as well as certain other purine derivatives. After parathy- roidectomy, Koch's dogs died in four or five days, exhibiting the usual muscular and nervous spasms, i.e., " tetany." The chemical showing was supplemented by a study of the histo- logical changes in different tissues. Material from the liver, kidney, and brain showed cellular chromatolysis as a constant characteristic. " The brain sections showed cells in the motor areas with partial loss of Nissl substance and typical tetany nuclei. Various degrees of chromatolysis were also observed in these nuclei." He found degenerating epithelial cells in the intestinal tract, the nuclei of which were converted into solid, deeply staining clumps. The hepatic cells " showed advanced fatty degeneration of the protoplasm. The nuclei of large areas had disappeared entirely in places where the cell form was fairly well preserved." In the liver of certain of his animals there was only a diffuse chromatolysis. In the kidney there was " congestion and hemorrhage in the cortex, some anemic and others congested medulla?. Some glomeruli had lost Bowman's capsule." There was also epithelial degeneration. 1 Koch, \Y. F.: The Journal of Biological Chemistry, Vol XV., p. 43, 1913. 254 INTERNAL SECRETIONS OF THE THYROID Physiologically the dogs were restless and easily excited. The limbs later " showed tremors, especially after slight exertion." Still later the animal exhibited mild convulsions with rigid and extended limbs. In the final stages before death, there were " severe tetany and clonic convulsions," and at times salivation and Cheyne-Stokes breathing. 7. The theoretical significance of Koch's observations. — The discovery of toxic bases, methylguanidine and other guanidine bases, in large quantities in the urines of parathyroidectomized dogs has led Koch to believe that " the parathyroid secretion, therefore, ap- pears to be concerned with anabolic processes closely related with the building of nucleins." Koch comes to this conclusion from the pathological appearance of the tissues, i.e., their chromatolysis, along with the finding in the excretion of the wastes undoubtedly derived from nuclein metabolism. It is generally conceded that the metabol- ism of chromatin is a nuclear function. The failure of different functions in the parathyroidectomized animals drives the tissues to protein starvation and " nuclein atrophy." This is peculiarly sug- gested by the extensive coagulation of the blood in the blood-vessels, and indicates the presence of free nucleic acid in the circulation. In what manner the absence of the parathyroid leads to this marked tissue disruption remains yet to be explained. The work of Koch brings us much nearer the solution of the problem, since it gives for the first time an explanation of the nature of the change in metabolism. It has not yet been shown that the artificial supply of parathyroid substances will alleviate this condition. CHAPTER XXXII. THE PITUITARY GLAND AND THE HYPOPHYSIS. I. Anatomical. The pituitary anatomically consists of three parts: (1) the pars anterior, or pituitary gland proper, (2) the pars intermedia, which is distinctly separated from the anterior and more closely related to (3) the pars posterior or hypophysis proper. The anterior and inter- media portions are derived from the epithelium of the roof of the mouth, while the hypophysis is an evagination of the brain cavity. That these two structures produce internal secretions or hormones can no longer be doubted, though a chemically distinct hormone has been isolated from neither. II. Outline of Pharmacological Action. 1. The evidence indicates that the pituitary increases oxidation and stimulates the growth of the connective and skeletal tissues. 2. The internal secretion of the pituitary has a reciprocal rela- tion to the development of the essential sexual organs. 3. The hypophyseal extracts {posterior lobe) produce an increase in the force of the heartbeat, the contractions of the smooth muscle structures, such as the bladder, uterus, and intestine, increase in car- bohydrate metabolism, and an increase in certain secretions. III. Details of Pharmacological Action. A. Pituitary Gland. i. The changes in metabolism following the removal of the pituitary secretion. — Our knowledge of the pituitary is largely de- rived through observation of changes in function or in growth, which accompany atrophy of the gland or its removal on the one hand, or 255 256 THE PITUITARY GLAND AND THE HYPOPHYSIS the contrary changes that are associated with hypertrophy of tha gland, or with the injection of its extracts. As in the case of the interrelation of the thyroid and parathyroid, so here the mechanical difficulties of separating the pituitary from the hypophysis have contributed largely to the difficulties in deter- mining the function of these two important structures. Recently, through the skill of such investigators as Paulesco, and of Cushing, operations have been performed, removing the anterior or the posterior lobes independently. When the pituitary gland proper is removed, as a rule death soon follows. This can now be recorded as an established fact. The inference offered in explanation is that the disturbing cause is the elimination of the interstitial secretion of the gland. The removal of large portions of the pituitary gland, and in some cases of the entire gland, in early life is survived (three-months-old puppies). However, there is a restriction in the usual growth of the body with certain changes in the general tissues, particularly in the acquirement of fat. The reproductive organs also fail to develop and show atrophic changes. Metabolism experiments on such animals show a diminution of oxidative processes, especially characterized by a lesser amount of carbon dioxide. 2. The administration of pituitary. — Numerous attempts have been made to resupply the pituitary, experimenting along the lines which have long been practiced in the case of the thyroid. Schaefer, and later Cushing, have published numerous observations. Both have fed pituitary and reported that the symptoms which follow the removal of the gland are delayed by this treatment, a fact, however, which has not been always supported. Cushing, in particular, finds that patients suffering from diminished pituitary secretion are bene- fited by the pituitary extracts. Transplantation of anterior lobes was performed by Cushing in an animal from which this lobe had been removed. This delayed for several weeks the fatal results that usually follow the operation. 3. Clinical evidences from atrophy and hypertrophy of the pituitary. — It has been long known that certain individuals have manifested retarded development on the one hand and an extraordi- nary development, acromegaly, on the other. The explanation of these exceptional cases seems now definitely traced to the variation in development of the pituitary gland. A hypertrophied gland so stim : ulates the growth of the bony tissues as to produce an enormous size of the body. On the other hand, atrophy of this organ leads HYPOPHYSIS 257 to the opposite result, namely, infantilism. It is in this latter class that Cushing has attempted to secure benefit by giving the gland in routine medicinal treatment. 4. The interrelation of the pituitary and other organs. — There is a reciprocal relation existing between the pituitary and the thyroid. The operative interference with the thyroid, as by removal, is asso- ciated with a vigorous ' ' taking on " of its function by the pituitary, as manifested by the greater size of the latter. On the other hand, a much more important interrelation exists between the development of the pituitary and the sexual gonads. This has already been men- tioned. In dogs, the development of the ova and spermatogenesis are markedly delayed by removal of the gland, whereas an accelerated sexual development has marked certain cases of giantism. B. Hypophysis. 1. Influence of the hypophysis on the functions of nerve struc- tures. — The hypophysis bears a less crucial relation to the body functions than does the pituitary. The extracts of the gland, however, have been demonstrated to produce definite changes in the physio- logical function of organs of the circulatory system, of the digestive tract, and of the uro-genital system. 2. The heart. — Howell first clearly demonstrated that the pos- terior lobe, which he called the infundibulum, has a marked influence on the circulatory apparatus. The injection of the extracts produces a rise of blood-pressure, with an initial acceleration of the heartbeat. This was followed by some depression of blood-pressure, and there was a marked slowing of the heart rhythm. It has been shown lately that the stimulus to the heart action probably rests on stimulation of peripheral augmentor nerve structures. 3. On smooth muscular structures. — The digestive tract is stim- ulated to increased contraction by the intravenous injection of hypo- physeal extracts. The uterus undergoes excitatory contractions prob- ably through the stimulation of nerve structures of the inferior in. scnteric paths. These paths also supply nerve fibers to the urinary 1)1 a elder, in which increased contraction is also noted. 4. Hypophysin. — The name " hypophysin " has been given to the active principle or extract of the hypophysis or posterior lobe. The true source of this active material is not altogether clear, since the colloidal material found in the pars intermedia and to some extent in the hypophysis may be of extraneous origin so far as the hypo- 258 THE PITUITARY GLAND AND THE HYPOPHYSIS physis is concerned. It is generally conceded- that the secretion of the pituitary is distributed into the spaces of the pars intermedia and the pars intermeninges. It is possible that this secretion may pass into the hypophysis to some extent. By this view one may readily understand the fatal outcome of the removal of the pituitary in that it removes the active tissue forming this internal secretion. The removal of the hypophysis would not interfere with the development, but only with the distribution of the pituitary secretion. J. Irritants and Counter Irritants. CHAPTER XXXIII. THE BACTERIAL TOXINS. General Introduction. There are a great many drugs and materials of general pharmaco- logical interest, the importance of which is chiefly bounded by some local and special action, i.e., a local toxic action to protoplasm, which is associated with more or less profound secondary changes. Some of these lead to a quick dissolution of protoplasm, hence are corrosive in nature. Certain of these drugs are discussed in other connections, i.e., the caustic alkalis and the mineral acids. In this entire group, even with drugs in which the caustic action is very intense, some de- gree of their influence generally calls forth a response in the tissues characterized by the process of inflammation. Such drugs are called Irritants. The number of chemicals and other agents which produce injury, therefore irritative processes, is enormous, hence it will conserve the time of the reader if the principles underlying their action are briefly explained and illustrated by typical members of the series. Irritants may act on any and all tissues of the body or on special structures only. Therefore, the groups of irritants, which we shall emphasize, are of necessity somewhat arbitrarily chosen. They are of four great classes : 1. The Bacterial Toxins, reacting on any and all tissues of the body with which they come in contact, but often quite specific in the case of particular toxins. 2. The Skin Irritants, those drugs generally recognized because they are peculiarly adapted to affect the relatively impermeable ex- ternal skin. 3. The Vegetable Cathartics, that large group of irritant prepara- tions of vegetable origin, which react on the lining of the alimentary canal and which are used in clinical medicine for the production of catharsis. 259 260 THE BACTERIAL TOXINS 4. The Counter Irritants, those drugs primarily of groups 1 or 2, which, in a certain intensity of action, produce marked secondary changes in other parts of the body. Reactions of this class are known in medicine as counter irritations and the causal agencies as counter irritants. I. Historical and Introductory. It is difficult to condense into a few words the essential factors in the discoveries and study of the influences of bacteria and bacterial products on the living organism. This topic is at the foundation of our study of the Germ Theory of Disease, and its fundamental impor- tance permeates a number of essential medical subjects. Bacteria growing in the living body may in themselves through mechanical factors induce stages of inflammation. However, this is quite a sec- ondary influence in contrast with degrees of change induced by what we now know to be chemical substances liberated by such bacteria dur- ing their life cycle. Bacteria induce chemical changes in proteins, setting free toxic disintegrative, i.e., putrefactive substances. These substances are basic in character and have received the class name ptomains. They also produce synthetically and liberate in solution in the circulating fluids a different class of non-basic poisonous substances, which are called toxins. Certain bacteria finally at the time of disintegration after their death liberate yet a third class of toxic materials similar in character to the toxins but less soluble, known as endotoxins. The influence of putrefactive products developed in decaying flesh was first experimentally examined by the physiologist, von Haller, in the eighteenth century. In the middle of the nineteenth century Panum examined these ' substances for their physical and chemical properties, and gave us some notion of their toxicity by experiments on dogs. Breiger in the period from 1882-1886 isolated and determined the chemical context and composition of a number of toxic substances derived from decaying meats. Among others are trimethylamin N(CH 3 ) 8 and mytilotoxin C G H lr ,N0 2 , from the poisonous mussel. The non-basic poisonous substances, which we now call toxins, were in Brieger's scheme of classification named toxalbumins. These toxins have been extensively studied, but not chemically isolated. Toxins. as above defined, do not cover all the toxic substances resulting from THE NATURE OF IRRITANT ACTION 261 bacterial growth. It is found that the dead and disintegrating cell bodies of certain bacteria contain highly toxic but less soluble ma- terials than the toxins. These are the endotoxins. Neither have the endotoxins been chemically isolated. When toxic bacteria are growing in the living body, or in fact, when the toxins derived from their growth are injected into the circu- lation, the body tissues are stimulated to produce chemical substances which are neutralizing to the toxins. These are the antitoxins first described by Behring and Kitasato 1 in 1890. The formation of anti- toxins does not include all the protective processes induced by toxins in the animal body. The studies of Pfeiffer in 1894 on immune cholera serum developed the fact that the serum contained a destructive agent, which we now know under the name bacteriolysin. Without going into detail, attention may be called to the agglutinins and precipitins, which, together with the lysins and antitoxins, contribute to the immunity of an animal against bacterial invasion. II. Details of Pharmacological Action. i. The nature of irritant action. — An irritant, mechanical or chemical, may be defined as an agency which produces a local injury, to which the tissue or tissues react by a reconstructive process, the stages of which constitute acute inflammation. That the drugs of the so-called " Irritant " series possess toxic action for most tissues of the body is a well-known fact and does not need elaborate discus- sion, but the character of the action of the irritant calls for detailed explanation. Chemicals are by no means the only agencies for the production of irritations leading to inflammation. One of the simple causes of the inflammatory process is ordinary mechanical injury, i.e., traumatism. The redness or the blisters from milder burns are responses to heat irritation. Excess! ve nerve reactions may pro- duce similar end results. Bacterial growths, certainly of the infec- tious and often of the saprophytic type, sel up inflammations, due chiefly to chemicals in this case, however. The products of bacterial growth, toxins, are typical irritants, though the discussion of their action because of the great importance in relation to the cause of 1 Behring and Kitasato: "Ueber das Zustandckommen der Diphtherie- Immunjtal und der Tetanus-Immunitat bei Thieren," Deutsche mediciniache Wochenaohrift, p. 1113, 1890. 262 THE BACTERIAL TOXINS disease is now studied in more advanced detail in other medical rela- tions. The response to irritation, i.e., inflammation, may, in fact does, occur in all parts of the body and in all tissues. In the broader sense it is obvious that no logical boundary between susceptible and non-susceptible tissues can be drawn. But in the restricted sense, in which the term is more often used, pharmacological irritants are primarily either skin irritants or irritants of mucous membranes. 2. The inflammatory process a physiological response to irri- tant action. — The basic principle to consider in the study of irritants is the fact that they are injurious to protoplasm of all kinds. Of course different drugs of the various classes injure in different degrees, therefore the degree of the response which is produced will depend on the relative toxicity of the drug as such, or on the rela- tive toxicity as influenced by its time of contact, or by its concentra- tion. The protoplasmic factor is the sensitiveness of the tissue to local injuries. Of all the tissues, the epidermal and the connective tissues are especially responsive to toxic actions of this class. Toxins are only chemicals of a special class. The mild action of practically all irritants can scarcely be dis- tinguished from that of physiological stimulation, which indeed it is. There is no sharp line to be drawn between the physiological meaning of the two terms. If any distinction is to be made, it is the tendency to apply the term ' ' irritant ' ' to causes of reactions which are in the nature of general responses of protoplasm, or perhaps it would it would be better to say responses of general protoplasm. The word " stimulus " in contradistinction to this use is applied to causes of reactions expressed through the more highly differentiated organs and tissues, and by the characteristic power which the special tissue pos- sesses by virtue of its differentiation. To illustrate further, the stimu- lation of a muscle calls for the characteristic contraction. This may be with or without a general change in the protoplasm of the tissue. Irritation applied to a muscle, while it may lead to contraction, has a tendency to produce basic changes in the protoplasm itself, which, if carried far enough, may lead to disintegration with destruction of the tissue. Speaking generally, the incipient irritative process, whether it be produced by drugs or other injurious agencies, is of a stimulative nature. But the reaction tendency in general is that of cell growth, cell proliferation or cell death, rather than that of energy liberation. If the irritation be carried further, then there is injury to the local tissues, which is characterized by definite changes following in a well- described cycle. These are the changes of inflammation that have THE IRKITANT ACTION OF BACTERIA 263 been so admirably presented by Adanii, 1 Councilman, 2 and others. In the section on skin irritants there is presented a detailed de- scription of the process of inflammation as it occurs typically in the skin. This detail should be consulted and is presupposed in connec- tion with the discussion that immediately follows on the irritant action of the bacterial toxins. 3. The irritant action of bacteria and bacterial toxins. — Of all the irritative and toxic agents that affect the human body, those of most practical importance are the bacteria and the toxins, lysins, etc., resulting from their presence, growth, and development. Not all micro-organisms have an irritant action on the human body. Many forms of bacteria inhabit the skin, the mouth, and different divisions of the alimentary tract without producing deteriorating effects on those structures, at any rate not under ordinary conditions. Certain bacteria are in marked contrast, the pathogenic bacteria. These are peculiarly destructive to the tissues of the human body. A great variety of conditions influence and control the rate and character of the invasion of the human body by pathogenic bacteria. Among those that should be mentioned are variation in individual susceptibility, variation in the defensive powers of the individual at different times, the mode of invasion, and the relative virulence of the particular organism concerned. Not all tissues of the body are equally resistant to the invasion of any particular pathogenic bacte- rium. As a rule, the most highly differentiated tissues are the most susceptible, while the tissues of more generalized function, such as the connective tissues, are the least susceptible. "When pathogenic bacteria invade the body they produce, as a result of their growth and development, materials that are highly irritant and peculiarly toxic to the human body. These substances are the toxins. It may happen, however, that the active irritants are not liberated directly by the living bacteria, but are set free upon the destruction of those bacteria that have run their life cycle. These substances have received the name endotoxins. In either case the in- jurious agencies come from the presence of the bacteria, and are strongly disturbing to the normal functional reactions of the proto- plasm of the tissues of the host. The liberation of the toxins resulting from the growth of the colony of invading bacteria of course takes 1 Adami, J. George: Chapter on "Inflammation," Principles of Pathology, 2nd edition, New York, Vol. I., p. 413, 1909. 2 Councilman, Wm. T. : Article, "Inflammation," Buck's Reference Handbook of the Medical Sciences, Vol. V., p. 1, 1902. 264 THE BACTERIAL TOXINS place primarily at the growth center, the focus of invasion. They readily diffuse into the blood stream and the surrounding lymph channels, thus reaching a general systemic distribution. We find, therefore, that the toxic action of the toxins is both local and general in nature: local, because of the more intense concentration of toxin resulting in local inflammation ; general, because, of the ready distri- bution of toxin through the circulation and its contact with all the tissues. Bacterial toxins are, in the last analysis, strongly irritant agencies. They produce the cycle of irritation and inflammation, running a course which is more or less characteristic for the different tissues, and for the different toxins. The interrelations have been strongly put by Adami, 1 when he used the action of toxins to illustrate de- grees of irritation as follows: — ' ' Reverting to the differing degrees of irritation, we may draw up a working scale of, for example, toxins. Certain of these, which we will for the moment designate degree A, are so strong that they kill at once a certain cell with which they come in contact ; others, degree B, are not strong enough to kill instantly, but they so injure the cell that it enters at once into the stages we call cloudy swelling, granular degeneration, or whatever name we employ, and finally dies; this process we call bio-necrosis. Yet others, degree C, injure the cell so that it enters this condition of successive ill-being, but finally re- covers; this is not exactly bio-necrosis, but, if we dare coin a word for present use in this chapter, it might be said that the toxin is bio-necrescent, that is, tending to bio-necrosis. Finally, other toxins, yet weaker, degree D, irritate the cell within the limit of its reactive powers, but without exhausting the same, and its irritation is shown by reproduction, by phagocytosis of chemiotaxis, or any other func- tion we can attribute to the cell that is ' roused.' And this is true, not only in regard to different toxins, but in regard to different de- grees of concentration of the same toxin. We have to recognize, in short, the law that the agent, which in high dilution or small quantity acts as a stimulant to the cell, becomes in greater concentration a poison to the same. 1 ' It will be at once evident that, in the kidney, for example, toxic blood may severely injure a tubule cell (degree B), yet may not be able to do more than rouse the connective tissue to reproduction (degree D). Every cell of the body that comes within the ' sphere of influence ' of a toxin reacts, in some degree thereto, degree A, B, C, 1 Adami, J. Geo.: Keen's Surgery, Vol. I., p. 191, 1906. THE CHARACTERISTICS OF TOXINS 265 or D, and this applies, not only to fixed cells, but to every lymphocyte, leukocyte, or wandering tissue cell whose business calls it into the area of irritation at the time; the result of any inflammation depends, therefore, on the sum total of these million tiny problems, and the total determines whether the balance is in favor of or antagonistic to the body." The broad subject of bacterial toxins and their action has, how- ever, assumed such importance and has become so specialized in rela- tion to disease that the custom has arisen of treating this subject in special texts and monographs, 1 hence the very brief discussion presented in this relation. 4. The characteristics of toxins. — The toxins are admittedly chemical substances, although we know very little of their detailed chemical nature. The great mass of our knowledge of the nature of toxins is derived from the influences of these substances on physio- logical processes. One point that has come out in their study is that toxins diffuse through animal membranes with great difficulty. Their action on living protoplasm is more or less specific and in this regard there is some comparison between the toxins and the toxic influence of certain proteins, that is, they are capable of stimulating the tissues to the production of antibodies. The toxins are nearly all destroyed by enzymes, by heat, and, in some cases, by light. Chemical sub- stances of analogous composition are found in both the animal and the plant world. For example, the venom of poisonous snakes and of poisonous insects reacts in a way quite similar to the toxins of bacterial origin. In the plant world the poisonous ricin is possibly also of similar nature. At any rate, it produces similar reactions on protoplasm. Recently some most interesting observations that throw light on the nature of toxins have been made on isolated by-products of bacterial putrefactory changes. Barger and Walpole 2 isolated three pressor principles from putrid meat, namely isoamylamine, de- rived from leucine, phenylethylamine, derived from phenylalanine, and parahydroxyphenylethylamine, derived from tyrosine. These amines have many of the physiological characteristics of the toxins, 1 See Vaughan and Navy: Cellular Toxins. Philadelphia, 1902. Schorer: Vaccine and Serum Therapy. St. Louis, 1909. Oppenheimer: Toxin and Antitoxin. Jena, 1904. Ehrlich: 'csa mm cite Arbeiten zur Immunitdtsf 'orach. Berlin. 1904. Also works on bacteriology, pathology, and on infectious diseases. ■Barger, G., and Walpole, G. S.: Journal of Physiology, Vol. XXXVIII., p. 343, 1909. 266 THE BACTERIAL TOXINS although the isolation of toxins has not been chemically made and we cannot as yet be sure that they are of the same class. At least one may consider these purified amine bodies as showing interesting analogies as between the pharmacological action of the amino-acids and the toxins. This group is of further interest in that it has been lately shown by Barger and Dale that the same active principles are present in the fungus ergot. 5. The type of toxin action. — We get our best conception of the nature of the toxin reaction by comparison of the reactions in the chemical field. Certain complex organic chemicals have a multiplicity of side chains to which other substances may be chemically bonded. This conception has been applied to the toxins of unknown chemical composition by Ehrlich in his Side Chain Theory of the action of toxins and antitoxins. As early as 1885, Ehrlich, in discussing the nature of cell nutrition, expressed the opinion that the great variety of nutrient substances were assimilated by a method of attachment or bonding of these substances to the complex of the "protoplasm. In short, protoplasm by means of its numerous side chains was able to chemically attach to itself the materials entering into its nutrition. This conception applied to the action of toxins resulted in the development of Ehrlich 's Side Chain Theory, a theory that wonder- fully adapts itself to the explanation of the great variety of general biological and chemical processes as well as those physiological processes involved in toxic action. 6. Toxins stimulate the tissues to produce antitoxins. — The presence of toxins in the body affects the protoplasm of the tissues in one highly important way, namely, it stimulates the production of substances which have the general effect of neutralizing or warding off the toxic action of the toxins themselves. The tissues, in other words, produce chemical substances which are antagonistic to the toxins. These are the antibodies and are called antitoxins. Anti- toxins were first described by Behring and Kitasato in 1890. These men produced immunity in animals against tetanus by injecting the serum from certain actively immune animals. The presence of a poisonous amount of toxin which, if it ran its course in the body, would result in the destruction of the life of the organism as a whole is rendered relatively innocuous, provided a sufficient quantity of antitoxin can be developed to take care of the toxin. This is the principal factor in the self-limitation of many of the infectious dis- eases. The development of antitoxins by the body in response to the presence of the toxic bacteria is called active immunization. Medi- SPECIFICITY OF TOXINS 267 cine has now reached a stage of development in which science has been able to produce antitoxins in usable quantity by injecting certain animals that are relatively immune with the pathogenic bacteria for which the antitoxin is specific. Such serum, rich in antitoxin, when introduced into the body of a person also exerts a restraining influ- ence on the growth or invasion of pathogenic bacteria. This method of securing protection is known as passive immunization. 7. Specificity of toxins. — Without discussing the matter in detail, attention may be called to the fact that many of the toxins are notably specific or selective in their reactions among the tissues of the body. As a single example may be mentioned tetanus toxin which attacks nerve tissue. If brain tissue be mixed with a tetanus toxin solution and the brain tissue be separated off, it carries with it the toxin. When the human body has been attacked by certain bacteria, for example tubercle bacilli, the reaction in the tissues leads to a change in the susceptibility of those tissues to the products of the growth of the bacilli. The tuberculin skin test is an example in this case. The epidermis of the tuberculous patient is more susceptible to the irritant action of tuberculin than the skin of a normal person. This increase in susceptibility is great enough to give to the reaction of irritation a specificity which aids in the diagnosis of the disease. There is a close relation between the toxin and the antitoxin developed by the body under the influences of the toxin, a relation that is in this instance entirely specific. Each particular toxin stimulates the tissue to produce an antibody, which reacts with and neutralizes the toxin, thus eliminating, the latter from its poisonous influences on the body tissues themselves. An antitoxin developed in response to one toxin will not combine with a different toxin. In other words, the antitoxins are not interchangeable in antagonizing the toxins. One can find an analogy in the chemical field as between the reaction of chemical substances which have an affinity for each other, but not for chemicals of a different class. The development of antitoxins by the body is, therefore, a protective factor, a response of the tissues to the irritant and toxic action of the toxins. The reaction between the antitoxin and the toxin is, therefore, a reaction of distoxication. In other words, the toxin is rendered chemically inert by the ever present antitoxin. It is the presence of the anti- toxin in the blood and body fluids which seizes upon and fixes any entering toxin irritants and gives to the body the property of im- munity. CHAPTER XXXIV. IREITANTS OF THE EXTERNAL SKIN. I. Historical and Introductory. Numerous chemical groups, with a wide range of representation, induce inflammatory changes in the skin. These chemicals possess two properties, which adapt them to this type of reaction in the body, namely, a high degree of toxic influence on general proto- plasm and general solubility in the skin fats. The conventional members of this series are: — 1. The essential oil group consisting of the volatile oils, often in solution in the tars and resins; 2. The mustard group containing glucosides which, on cleavage, liberate an irritant oil ; 3. The canthari- din group, consisting of soluble and highly irritant neutral bases; and 4. Forms of mechanical energy such as heat, etc. Turpentine serves as a type of the volatile oil series. This is a distillate from certain woods, especially the conifers, and contains a resin dissolved in essential oils. The various volatile oils belong to the benzine group, and contain numerous representatives of the terpenes with the formula C 5 H 8 or some multiple of this grouping. They are easily converted into cymene, which has the structural formula : — CH3/ Nch/ \ / \CI-I S Members of the genus Sinapis, the mustards, contain beside other substances, sinalbin, which is a glucoside, in combination with the oil of mustard. The plant also contains a glycolytic ferment. The pulverized seed of Sinapis alba when mixed with water ferments according to the following formula: — C H NSO 30 42 2 2 15 Sinalbin (non-irritant) H = C H ONCS + CHO+CHNO HSO 2 7 7 ^ 6 12 6 16 24 6 4 Water Oil of mustard Dextrose Sinapin sulphate Oil of mustard (irritant) Cantharidin is a very strong irritant derived from the dried beetle, Cantharis vesicatoria, of southern Europe. This material 268 OUTLINE OF PHARMACOLOGICAL ACTION 269 contains the toxic substance cantharidin, C 10 H 12 O 4 . Cantharidin is slightly soluble in water, in alcohol, etc. There are a number of other materials, notably the toxicodendrol of our common American' poison ivy, which have similar irritant actions. Mechanical agencies such as heat are skin irritants. Heat, for example, may be applied in so many different ways and under such well controlled circumstances that it becomes one of the best of prac- tical agencies for inducing degrees of irritant action for therapeutic purposes. II. Outline of Pharmacological Action. 1. Power to penetrate the corneal layer of the outer skin and produce varying degrees of toxicity to the underlying epidermal tis- sues, nerve endings, etc. Or, in the case of heat, power to produce direct mechanical injury and irritation. 2. Power to produce counter irritant effects on account of the peculiar segmental nervous relations of the shin and the deep-seated organs. III. Details of Pharmacological Action. i. The permeability of the skin to certain irritants. — The gen- eral resistance of the external skin to large classes of injurious sub- stances renders it more or less immune to many agencies which would induce inflammation if brought into contact with unprotected parts of the body. This is primarily due to the relative impermeability of the skin to chemical agents. Members of the volatile oils and others of the chemicals mentioned above more freely penetrate the corneous coat of the skin and reach to the living epidermal cells and the der- mal structures below. In addition there are certain highly volatile chemicals, like chloroform, which are soluble in the skin and which if held in contact with it a sufficient length of time produce irritation. Under ordinary conditions the great volatility prevents the manifesta- tion of their irritant properties. Irritant substances, on account of their ready diffusibility through the corneous layer of the skin, or by virtue of their solubility in some particular constituent of the skin, can readily penetrate this otherwise impervious structure. These materials are injurious to protoplasm and set up changes which are described by the various stages of the process of inflammation. 2. Stages of acute inflammation produced by irritation. — In- flammation of the skin is characterized by the development of redden- 270 IRRITANTS OF THE EXTERNAL SKIN ing, swelling, heat, and pain, i.e., the " rubor, turgor, calor, and dolor ' ' of Celsus. There is naturally a varying degree of disturbance of the function of the part. It is a well established physiological fact that a very mild cutaneous stimulation generally, though not always, leads to a slight vascular constriction, i.e., a heightened vascular tone which in the skin leads to the external manifestation of pallor, etc. If, on the other hand, the stimulation is vigorous, approaching the painful, the response leads always to vascular dilation. Skin irritants produce more than simple stimulation, but we may expect the same physiological reactions from the mild local nerve effects of the irritants. These irritants act through a period of time and with increasing intensity. Hence the reaction on the circulatory system, while it may at the very first show vascular constriction, will later lead to marked dilation of the blood-vessels of the part affected. It is this process that especially characterizes the first stage in inflammation, namely, the reddening of the skin with local increase in temperature. If the irritation is mild, the great increase in the flow of blood through the part, other things being equal, will tend to eliminate the irritating chemical or other agent, thus fulfilling the biological function of the response and stopping the pathological process. Hyperemia favors physiological oxidation and the normal metabo- lism of tissue per unit of time. The increased volume of blood also brings a greater amount of oxygen in contact with the tissue at this stage, a reaction that would favor, not only the washing away of the injurious substances, but in some cases its oxidation and destruction. The physiological correlations induced by anemia and hyperemia are very important in this connection, topics that have been recently clearly and elaborately presented by Guthrie 1 in his book, Blood Vessel Surgery. The second stage of irritation is characterized by swelling, edema, blood stasis, and a great gathering of the migratory and phagocytic cells. This is associated with more or less acute pain and sensitive- ness of the involved local area. Briefly stated, the successive changes are: the gathering of white blood corpuscles along the walls of the dilated blood-vessels, soon followed by ameboid migration of these cells through the vascular endothelium and through the connective tissue and lymph spaces. It is apparent that the resistance of the endothelial tissue is reduced and that the ameboid response of the white blood cells and lymphocytes is increased. This stage is accom- 1 Guthrie, C. C: Blood Vessel Surgery, p. 132. New York, 1912. DETAILS OF PHARMACOLOGICAL ACTION 271 parried by or followed by a corresponding increase in the amount of the exudations so that the plasma passes through the vascular walls, greatly increasing the extra-vascular fluid and producing the swelling or turgor of the part. In many local irritations, this process may be so strongly accentuated as to produce accumulation of fluid under such tension as to lift the corneous layer, forming vesicles or blisters. The fluid of the vesicles may contain the irritant agent Fig. G4. — Gathering of white corpuscles in capillaries of an inflamed area. 1. Ad- hesion to capillary walls. 2. Migration through the wall. From Lavadowsky. in solution. In the later stages of the diffusion there is stasis of the red blood corpuscles with extravasation. The movements of the lymphocytes and of the various white corpuscles is undoubtedly a chemiotactic response. Not only do these cells gather in large num- bers in the inflamed tissues, but they may and often do actively multiply so that their numbers are enormously increased. When the action of the irritant is extraordinarily severe there follows death of the protoplasm of many of the cells and the phe- nomenon of suppuration with disintegration takes place. This latter type of response is characteristic of that called forth by certain infectious organisms. Here there may be an enormous increase in the number of phagocytic cells especially of the polymorphonuclear type. The irritants of the class therapeutically called pustulants pro- duce this type of inflammation. The pus discharged consists of the excessive accumulation of corpuscles together with the disintegrating product of the dying tissue cells. 272 IRRITANTS OF THE EXTERNAL SKIN One can distinguish at least three stages in the process between the incipient irritative action and actual cell death. These stages may be, though they are not always, called forth by the continued action of a strongly toxic irritant. The action may be mild and reach only the first stage, as, for example, simple inflammation. If the action is more vigorous and rapid, then the inflammation is followed by or reaches the stage of vesication. In other words, the edema may reach a point where there is an accumulation of lymph, therefore vesicles. The irritants may finally lead to a fatal termination in the tissue of the local area, for example, in the case of excessive cell disintegration, i.e., pnstulation. In this final or fatal termination, of course the body has failed in the response which would ordinarily meet the injury of the irritant. Where degeneration is only partial and the injurious agent is removed, a definite recuperative process takes place. Or if, as in the case of certain bacterial infections, its further action is prevented or at least diminished by a process in which the agency is walled off by constructive growth changes about the area of the infected focus. These reconstructive changes belong to the provinces of pathology, and the reader is referred to the extensive literature of pathology and bacteriology for its further description. 3. The irritant action of the volatile oils. — The most important of the volatile oils are oil of turpentine, oil of pine, oil of juniper, Canada balsam, and myrrh. Several other substances, the most im- portant of which is chloroform, have similar action and physiologically could be classed in this group, though chemically they are very dif- ferent in character. These oils readily penetrate the skin and are irritants of varying degrees of toxicity to the underlying tissue. They act comparatively slowly and are milder in effect than are some of the other irritants, for example, cantharidin. 4. The toxic gluocosides of the mustard series. — Oil of mustard is a highly irritant material which also readily penetrates the skin. It is derived from different species of Sin apis, the most com- mon being black mustard, or Sinapis nigra, and the white mustard, or Sinapis alba. The irritant oil is present in the seeds of the plant as a chemically inert glucoside. But the seeds contain a ferment which, upon being moistened with water, sets up a fermentive process in the glucoside whereby the actively irritant mustard oil is set free. The reaction proceeds according to the formula given on page 2. This reaction is utilized in the mustard plaster used for medicinal irritation. Ground mustard seed is spread out in a thin layer IRRITANTS OF THE CANTHARIDIN TYPE 273 which, when moistened, slowly undergoes fermentation. When a mustard plaster is applied to the skin it is at first non-irritant, but as the mustard oil is slowly set free, it reacts on the body to produce inflammation. The longer the material is in contact with the skin, the more intense the inflammatory process, largely because of the accumulating quantity of mustard oil. An active clinical mustard plaster will produce redness and mild inflammation in fifteen minutes, and vesication in thirty to forty minutes in a sensitive skin. 5. Irritants of the cantharidin type. — The highly irritant can- tharidin is soluble in oils and alcohol, but is only slightly water soluble though its salts easily pass into solution. It produces the most violent irritative changes in the tissues of any of the irritants thus far considered. It readily penetrates the skin and sets up local inflammation which produces the vesication. As small a quantity as 0.1 milligram is adequate to produce this effect on the human skin. The salts of cantharidin very readily pass into the general cir- culation and lead to vigorous inflammation in other parts of the body, particularly in the kidney, the bladder, and the uro- genital passages. The kidney is especially responsive to cantharidin, and nephritis is a common aftermath of the use of this drug. The glomeruli are the first to respond to its action, though changes take place over the entire nephridium. Cantharidin, taken by the mouth, is quickly absorbed. It has enjoyed a questionable reputation as an aphrodisiac, and too common poisoning occurs from its misuse for this purpose. Its application to the skin as an irritant has to be guarded in practice, lest sufficient of the poison be absorbed to pro- duce acute nephritis and other toxic reactions. The active principle of the American poison oak, or poison ivy, toxicodendrol, is even more highly irritant than cantharidin. In this case as little as 0.0001 of a milligram is sufficient to produce vesication of the skin. This plant is widely distributed and acute intoxication from it is only too common. In more susceptible individuals toxico- dendrol poisoning becomes quite a serious menace to general health. This irritant is soluble in alkalies and in alcohol, but is precipitated by lead acetate. After being exposed to its action, the prophylactic treatment should be to bathe the exposed part in alcohol in order to dissolve the adherent toxicodendrol and follow by an alcoholic solution of lead acetate or other precipitant to remove the poison before its action has proceeded far. CHAPTER XXXV. THE VEGETABLE CATHARTICS. IRRITANTS AFFECTING THE ALIMENTARY CANAL. Introduction. The substances of the vegetable cathartic group, like the skin irritants, are numerous. A large number of these substances are glucosid.es which, when the carbohydrate is split off, leave a highly irritant residue. They are usually divided into three great groups : 1. The resinous glucosides, represented by the jalap group; 2. Vege- table cathartics of the anthracene group ; 3. Neutral oils which, upon digestion, set free an irritant fraction. The important representatives of the jalap group are: Jalap, Colocynthin, Podophyllum, Elaterium. The resin from jalap contains the irritant glucoside, convolvulin. Colocynthin contains in its fruit the glucoside, colocynthin. Podophyllin is a glucoside which has been isolated from the may-apple root. Elaterium is a neutral sub- stance, the most toxic member of the series. It is derived from the fruit of the Ecballium elaterium, or squirting cucumber. Typical members of the anthracene group are, aloes, senna, and rhubarb. These plants yield irritant substances of which the anthra- cene nucleus forms the base. The cathartic oils are two, namely, croton oil, which, upon diges- tion, sets free the highly irritant croton-olic acid, and castor oil, which splits off risinolic acid. These cleavages take place during the digestion of the oil. II. Outline of Pharmacological Action. 1. The acceleration of the peristaltic contractions, both of the small and large intestines. 2. Stimulation of the secretion of fluid by the mucous lining and by the glands of the alimentary tract. 3. The production of local inflammation, which may become drastic when the drugs are used in more concentrated form. 274 THE XATURE OF THE ACTION OF VEGETABLE PURGATIVES 275 III. Details of Pharmacological Action. i. The nature of the reaction by which the vegetable purgatives produce irritation and catharsis in the alimentary canal. — The recognition of the fact of the irritative action of the group called vegetable purgatives gives us a key for the explanation of their purgative action. The different members of this group induce varying degrees of irritation, and in different portions of the mucous mem- brane of the canal. As a result of this irritation there is disturbance, not only in the local area of the mucosa in contact with the drug, but, through the complicated nervous relations, marked changes in the reaction of the nerves controlling alimentary motor behavior and secretory processes. For the explanation, therefore, of the complex of catharsis induced by this series, one must hold in mind the entire physiological mechanism involved. This mechanism is described later in connection with the topic Saline Cathartics. At that point some emphasis is laid on the fact that the physiological movements of the stomach and of the intestinal tract are peristaltic in nature. Also that the large intestine is less vigorously active than the small intestine. Different physiologists, notably Langley, have laid emphasis on the presence and function of the local nervous mechanism, the enteric nervous system. While, the question has not been settled beyond doubt, the present indications are that the muscular walls of the alimentary tract execute their peristaltic actions under the influence and control of the peripheral nervous mechanism. At the same time the connections with the central nervous system supply the tract with general controlling nerve complexes, both motor and sensory. The various diverticula of the mucosa, which have become differ- entiated into the glands of the alimentary canal, are also brought into coordination with the muscular elements of the canal through regulating nervous mechanisms. With these anatomical and physio- logical relations in mind, we may venture to discuss the action of the drugs acting through irritation of the mucosa under the follow- ing points: 2. Irritant action at the point of contact. — There is a great variation in the intensity of the reactions of the alimentary canal to different members of the vegetable cathartic group. This is partly due to the nature and time of contact as between the drug and the mucosa, and in part due to the toxic character of the drug. From 276 THE VEGETABLE CATHARTICS the interaction of these two factors one may explain many of the physiological phenomena produced by members of this series. In making a comparison of the reactions one must constantly keep in mind that he is dealing with a water moist mucosa, a membrane that is very sensitive to contact environment, and a surface in which the time of contact with the cathartic drug is under the influence of the peristaltic contractions. In the very nature of the case only the early stages of the typical inflammatory processes are ordinarily induced. Emphasis has already been given to the fact that the initial irritative process is stimulative to the sensory nerve endings of the mucosa. The reaction to stimulation in the alimentary mucosa is a reflex change in motor activity, typically the induction of a strong increase in peristalsis. Hence, before an extreme inflammation is induced the increased motility will have driven the irritative agent forward, i.e., away from the point of contact before additional ab- sorption and further irritation has time to occur. This is particularly true of the small intestine. The large intestine, which under ordinary circumstances is stimulated to more vigorous persistalsis and final emptying by reflexes occurring at the bend in the rectum, is in many instances caught up in this general local irritative reaction. Not all members of the series produce equally intense reactions at different lengths of the alimentary tract, and the less irritative members, as a rule, react less vigorously on the large intestine. However, accelerated peristalsis will not account for all the phe- nomena observed. Many cathartics produce a great increase in the volume of the intestinal fluids, an effect which has been tested out experimentally on the isolated loops of the intestine. The in- creased fluid, under usual conditions, is not a transudate, since it is not characterized by the presence of albumin. On the other hand, it is held to be a secretion because the fluid contains digestive ferments. The vegetable purgatives, therefore, in the milder reactions pro- duce their local cathartic effect by three processes: (1) Increased secretion at the point of contact due to the mild local inflammation. (2) Stimulation to increased peristalsis, through local reflex mechan- isms, as well as through general nervous reflexes. And (3) reflex stimulation to secretion through the nervous control of the larger glands connected with the alimentary tract. The more irritant purgatives are extremely toxic; for example, elaterium. A very small quantity of this drug induces a violent in- flammation of the intestinal mucosa, which is shown by congestion PURGATIVE ACTION OF THE ANTHRACENE GROUP 277 and destruction of the mucous membrane. Such a process leads to the more violent reflexes through the central nervous system, which at first are characterized by increased secretory and circulatory changes. When the contact is prolonged the systemic reactions may become so profound as to border on collapse. The cholagogue action of many of these drugs is explained by the calling forth of vigorous nerve reflexes, which produce contractions of the gall bladder, rather than by any particular influence they may have on the secretion of bile itself. 3. Irritant action of the vegetable cathartics after absorption. — The majority of the vegetable cathartics are relatively insoluble; in fact, quite insoluble in the acid gastric juice. Their solubility is promoted by the alkaline secretions, which they meet in the duodenum. They are, therefore, absorbed slowly and reach the circulation in highly diluted form. That they are toxic after absorption, however,, is proven by the fact that they tend to induce inflammation in the kidney and in the uro-genital system. Even the mild aloes is some- times followed by renal ulceration. The more vigorous members are- prone to produce inflammation, not only of the kidney, but of other organs of the body not so intimately related to the elimination of the drugs from the system. It is for this reason that the large majority of the vegetable purgatives are contraindicated under certain con- ditions, as in the case of gastric and intestinal inflammation, nephritis, etc. 4. Purgative action of the anthracene group. — The chief and best known members of this group of vegetable purgatives are senna, rhubarb, cascara, frangula, and aloes. Belonging to the same group in general chemical relation is the mild purgative phthaleins, es- pecially in favor since the work of Abel and Rowntree. 1 These authors studied the cathartic action of a number of phthaleins, show- ing that phenolphthalein, and more particularly phenoltetrachlor- phthalein, are mild and relatively non-irritant cathartics after hypo- dermic injection. The materials obtained from the anthracene group of vegetable purgatives have not been purified and isolated. They are used in the form of infusions, extracts, and syrups, made from preparations of the leaves and other parts of the plant. The group owes its purga- 1 Abel, John J., and Rowntree, L. G. : " On the Pharmacological Action of Some Phthaleins and their Derivatives, with Especial Reference to their Be- havior as Purgatives. I.," Journal of Pharmacology and Experimental Thera- peutics, Vol. I., p. 231, 1909. CH CH S\ /\ HC C C i ii ii CH CH 1 II II HC C C \/ \/ CH CH ! CH Yh 278 THE VEGETABLE CATHARTICS tive action to the substances which are apparently derivatives of the irritant anthracene nucleus : CmHk Attempts to isolate pure principles have proven only partially successful. As a group, the preparations are absorbed with difficulty, but when mixed with certain alkalies, for example, bile, they are more efficient. They act, therefore, largely on the intestine, chiefly the large intestine, where they are liable to produce considerable pain and tenesmus. a. Senna. — Preparations of senna are derived from the leaves of different species of cassia. Two cc, a half-gram, of the fluid extract or the equivalent dose of the syrup, the confection, or syrup of sarsaparilla, is usually adequate to produce cathartic action after six or eight hours. b. Rhubarb. — The preparations of rhubarb are derived from the root of Rheum officinale. The usual dose is 1 cc. of the fluid extract or four times as much of the tincture. Preparations of rhubarb were thought to be especially active in promoting the secretion of bile. This, however, is open to question. The facts are that the outpour of bile aids in the solution of rhubarb and facilitates its action by putting it into more intimate contact with the mucqus membrane of the intestinal tract. The presence of a certain amount of tannic acid gives to rhubarb an astringency which is antagonistic to its irri- tant action. c. Cascara is derived from the bark of Rhamnus purshiana. The action of the different preparations of this cathartic are mild and somewhat persistent. Cascara is unusually bitter, a property which is counteracted in practical uses by adding magnesium, licorice or some flavoring substance. d. Frangula is derived from the laxative bark of the alder-buck- thorn, Rhamnus frangula. e. Aloes is a somewhat more vigorous purgative derived from the juices of different species of aloe. It is given in doses of from three to five grains, and is characterized by the rather vigorous griping contractions which it induces in the large intestine and in the rectum. PURGATIVE ACTION OF THE JALAP GROUP 279 It enters into a large number of the compound purgative mixtures of vegetable origin. /. Phenolphtluilein. — In recent years it has been shown that the different phthaleins have a mild laxative action on the alimentary tract. For example. Phenolphthalein, CaH^o'cjIl (OH) produces this effect in doses of .1 to .15 grms. The phthaleins are not very soluble. Abel and Rowntree especially investigated deriva- tives of phthalein, in particular phenoltetrachlorphthalein, which they consider favorable for human use as a hypodermic laxative. The most favorable members of the vegetable laxative series do not lend themselves to hypodermic injection, because of the local irritant action and inflammation which they induce. The phthalein com- pounds are particularly free from this action, inducing their favor- able reaction in the body through a stimulative rather than a strictly irritative process. Phenoltetrachlorphthalein is comparatively in- soluble in water, but is readily soluble in neutral oils. The authorities quoted used olive oil at a temperature of 210° C. in making their solutions. They gave hypodermic doses of .4 of a gram in 20 cc. of the oil. Catharsis did not occur until twenty hours or more, and continued in mild form for five or six days after administration. The phthaleins are soluble in the alkaline bile and are excreted from the liver through the bile. Ina" normal " case this brings the phthaleins into contact with the intestinal mucosa. In the mildly alkaline content of the large intestine some reabsorption takes place and later re-excretion through the liver, which, according to Abel and Rowntree, is a specific excretory organ for these compounds. It is probable that the cycle of excretion and absorption is the reason for the prolonged laxative action of the members of the phthalein group. Excretion takes place with the feces and, therefore, final elimination is assured. 5. Purgative action of the members of the jalap group. — The representative members of this series are jalap, colocynthin. podo- phyllum and elaterium. The activity of this group is primarily due to the presence of irritant resins and glucosides. Here too the active principles have been only partially isolated. In comparison with the anthracene series this group is particularly irritant and toxic. One might raise a question as to the classification of the former group with the irritants, but not so in this group. Of all the members the 280 THE VEGETABLE CATHARTICS most toxic is the squirting cucumber, Ecballium elaterium, which yields the active substance, elaterium. a. Resin of jalap. — .1 to .2 gram of jalap induce defecation in from two to three hours. Larger doses are highly irritant to the stomach and to the intestine. Jalap induces a marked secretion of fluid into the canal, which leads to the production of rice-water stools. The gastric irritation produces nausea and sometimes vomiting. o. Colocynth,. — The extract of colocynth is a purgative in doses of .03 to .05 gram. Its action is accompanied by intense griping, and in larger doses with bloody effusions. Brieger found that a small quantity of colocynth induced hyperemia and increased peristalsis in the isolated intestinal loop. The bloody effusions occasionally noted are due to acute inflammatory processes in the mucosa, which extend to the disintegrative stage and which involve the capillaries. c. Podophyllin. — In doses of from A to .6 gram podophyllin induces purgation in from six to ten hours. In doses of from 1.5 to 2 grams there is nausea with mental depression, pain, and colic. The irritant action is prolonged with this resin, but it is somewhat re- duced or counteracted by hyoscin. d. Elaterium. — This is given in doses of from 1 to 3 milligrams, which induce purgation in two hours. This is the most drastic of all these purgatives. Stronger doses not only produce intense pain, but lead to severe inflammation, mucosal desquamation, and even collapse. 6. The specific action of the neutral oil series. — The purgative oils of this series are castor oil and croton oil. Castor oil is an oil obtained from the seeds of the castor bean, Ricinus communis, by compression. The oil itself is not irritant, but when digested the ricinoleic acid is strongly irritant. Croton oil is obtained from the croton bean, Crotontiglium. Its methyl-crotonolic acid when set free is peculiarly toxic and irritant. The presence of minute traces of methyl-crotonolic acid in the usual commercial grade of this oil ac- counts for its irritant action on the skin and mucous membrane before its digestion takes place. a. Castor oil. — Doses as large as one-half to two ounces of castor oil are used to produce catharsis. This bland oil passes the gastric cavity with little change. It is true, it sometimes induces nausea and vomit- ing, but not from the specific action of the oil other than its disagree- able taste, especially when not perfectly fresh. In the intestines, how- ever, fatty digestion takes place, setting free the irritant ricinoleic acid. This induces a mild inflammation, which, in this particular instance, does not pass much beyond the limit of a general effusion. The ACTION OF CROTON OIL 281 effect is vigorous enough, however, to produce variation of the peri- staltic movements with some reflex stimulation of the secretive mechan- ism, a result comparable to the mild resinous purgatives. Ricinoleic acid is generally regarded as only slightly more irritative and stimu- lative to the alimentary tract than the acids from the ordinary neutral oils ; for example, oleic acid. From this classification it is plain that castor oil has considerable value as a nutritive oil, as has the mild olive oil. In certain parts of the Orient, — for example, China, — castor oil is a general article of food. b. C rot on oil. — Upon intestinal digestion croton oil yields the highly irritant and toxic crotonoleic acid. A dose of croton oil is given by Hatcher and Sollmann as from 0.01 to 0.15 cc. (1-6 to 2 drops). There is usually enough free acid in the preparation to produce local irritation of the external skin ; therefore, to readily produce this change in the mouth and stomach. But when the lipases of the intestinal tract are met, additional neutral oil is dissociated and a more pro- nounced irritant action ensues. It is said that a single drop of the oil is sufficient to produce stools in from one to two hours, and the inflammatory action with its associated reflexes continues until as many as ten or fifteen stools result. In the case of croton oil the primary action is that of irritation and inflammation. A process that is most vigorous in the duodenal and lower intestinal mucosa. It is from such violent irritants as methyl-crotonoleic acid that most ex- tensive lesion of the canal becomes possible. As little as twenty drops is recorded as having produced death. CHAPTER XXXVI. COUNTER IRRITANTS AND THE PHENOMENON OF COUNTER IRRITATION. All agencies that induce local irritations have, beside a specific effect in the local region, reactions, which affect the coordinative mechanisms of the body. Such effects have long been known in practical medicine, and belong to the category of referred pain, counter irritations, etc. i. The theory of counter irritation. — The fundamental effect is that observed clinically when an inflammatory process of a given portion of the body, the skin, for example, induces favorable changes in diseased conditions of other and distant organs, in this illustration deep-seated organs, as the stomach, the lungs, etc. This knowledge has been, and to a considerable extent still is, largely empirical. Brunton x has summarized the facts showing the relation between specific local areas of the skin and particular visceral organs. One of his diagrams we use in Figure 65. The most satisfactory scientific explanation of these remote effects, an explanation that has received quite general acceptance, has been formulated by Head. 2 Head observed that the pain and areas of tenderness in deep-seated organs during visceral disease were associated with areas of tenderness in the local areas of the skin of the patient. In short, the skin tender- ness is an associated condition developed in connection with the diseased condition in the deeper organs. Briefly stated, his view is based on the segmental conception of the structure of the nervous system, viz., that the innervation of the different portions of the body is by nerves derived from segments of the brain and spinal cord. These nerves of each segment are subdivided into somatic and splanchnic branches. The somatic branches are superficial in their distribution, including the skin, muscles, etc., and the splanchnic are deep, including the various visceral organs. Both the sensory and the motor fibers of each typical segment participate in the superficial and deep distribution. 1 Brunton, T. L. : Lectures on the Action of Medicines. New York, 1899. 2 Head, Henry: Brain, Vol. XVI., p. 1, 1893. 282 THE THEORY OF COUNTER IRRITATION 283 From the standpoint of counter irritation, the sensory nerves, the vasomotors, and probably the trophic nerves are of greatest impor- tance. That these groups of nerves are in close physiological, as well as anatomical, relation to each other as regards their centers in the spinal cord, can no longer be doubted, although the explanation of particular cases has not always been perfectly free of question. In Laryngitis tit. Pericar- ditis Gastritis Fig. 65. — Cutaneous areas which are ordinarily used in the application of counter- irritants for the relief of inflammation of the deeper organs in the diseases indicated. From Brunton. Head's words, " Thus to sum up, I think we may conclude that the central connections of the pain fibers from the skin and viscera are closely connected with one another. The central connections of the nerves for heat and cold, and for trophic disturbances in the skin, must also be in somewhat close association, though probably not actually connected." According to the views of Head, and later of McKenzie, it is assumed that the cutaneous sensory nerves from a given segment, for example, from a typical skin area of the trunk region, are in close and intimate relation with the visceral nerves of that particular segment of the spinal cord, or, according to McKenzie, with closely adjacent segments. This relation is so intimate on the 284 COUNTER IRRITANTS sensory side of the nervous complex that a sensory stimulation oc- curring in the viscus may be referred to an origin in the more highly innervated skin, or under certain circumstances vice versa. This is presumably because the collateral connections, either in the basal segment of the cord or at some higher level in the path, permit the nervous overflow of afferent impulse into a common area of perceiving cortex. Ordinary tactile, and for the most part temperature sensa- tions are absent from visceral organs. The visceral sensory or affer- ent impulses are chiefly those of the reflex and automatic type not associated with very definite states of consciousness. Visceral pain and the sensations of " fullness " characteristic of hollow organs (Hertz) are the chief visceral sensations. Perhaps appetite and hunger should be considered of this class. These sensations are not very definitely localized. It is for this reason that the symp- toms noted in connection with excessive visceral stimulation, or sensitiveness from inflammation, are readily interpreted as an ap- parently greater irritability of the corresponding cutaneous sensory areas associated with the same spinal segment. There is in fact an increase in the sensitiveness of the segmental centers, such that the usual cutaneous stimulus produces a greater response. Centrally the effect is the same as if the increase had come either from a stronger peripheral stimulus, or from a more sensitive cutaneous end organ. Cutaneous stimulation that results in vascular reflex dilations in the skin area will at the same time produce a similar degree of vascular change in the deep-seated organ whose coordinating vascular nerves are through the same spinal segment. That is, a light cutaneous stimulus, which is accompanied by a reflexly increased vasomotor tone, i.e., vasoconstriction, will normally produce definite vasoconstric- tions, not only in the skin segment, in which the stimulus arises, but in the corresponding visceral region. In certain particular regions there is a primary antagonistic reaction in these correlated areas. It is observed that a pathological condition, for example an in- flammation, of a deep-seated organ may have its blood-supply pro- foundly influenced by stimulative, i.e., irritative, processes occurring in the corresponding skin segment, and vice versa. Vasodilations favor and constrictions retard the reparative cycle. This is the un- derlying physiological principle justifying the application of skin irritants, such as artificial heat, poultices, mustard plasters, fly blisters, etc., for purposes of counter irritation. By the above hypothesis, the whole explanation of the phenomenon of counter irritation rests upon the anatomical and physiological close association in the cord THE THEORY OF COUNTER IRRITATION 285 and brain-stem of the mechanisms of the automatic and autonomic reflexes coordinating the great nutritive areas of the body. In prac- tical therapeutics the whole process falls back upon the relation of the condition of anemia and hyperemia to metabolism, healing, etc., as suggested above. A question might be raised here in the application of Head's explanation in the consideration of the disease known as Herpes zoster. The cause of herpes, according to Head, has been ascribed to disease of the posterior root ganglia, i.e., inflammation and hypersensitiveness of the sensory paths. There is, therefore, an inter- ference with the reflexes arising from stimuli occurring in the areas to which the sensory fibers are distributed. It is definitely stated by Head 1 : " There is no evidence that deep organs receiving their visceral supply from affected roots become affected during the out. burst of zoster." On the theory of associated innervation it would seem that we have a right to expect an inflammatory process, not only in the skin, which does occur, but also in the corresponding visceral segment, which apparently does not occur in zoster. If the deep visceral reflex were looked for in a region containing antagonistic vascular associations, then the visceral region would display not hyperemia, but anemia, and Head's result would be expected. How- ever, the inflammation of the ganglion interrupts the normal reflexes, therefore the closely coordinating center or centers in the cord will not receive the extensive stimulation which characterizes the usual and uncomplicated process of counter irritation. Irritant drugs or other agents produce the changes associated in counter irritation when acting through some considerable period of time, and with a certain favorable degree of intensity. This is one of the distinguishing factors between a stimulus and a so-called " irritation." If the irritating agent be a drug, for example, a lini- ment, it produces its effect by direct contact with and absorption into the living tissue. Under ordinary conditions this contact is only eliminated by the slower vascular reactions of the body, which remove or isolate the agent, a process illustrated by the reactions to bacteria and to toxins. A large portion of the good influences of a counter irritant un- doubtedly comes from the reflex influences on the circulation. This is shown by the fact that a cutaneous irritant produces a rise of general blood-pressure, a rise that is attributed not to the changes in the blood-vessels of the skin areas alone, but to general vascular con- 1 Head, Henry: Albutt's System of Medicine, Vol. VIII., p. 630. 286 COUNTER IRRITANTS strictions through the splanchnic region. It seems to follow that much of the favorable reaction in the class known as counter irri- tant processes is bound up in the better metabolic conditions induced by the correlations of the vascular mechanism. 2. Conditions which suppress counter irritation. — In the preced- ing paragraphs emphasis has been placed on the segmental relations Fig. 66. — Front view, and Fig. 67. — Back view. — Areas of cutaneous innervation from different segments of the cord. These areas are found to closely correspond to areas of inflammation observed by Head in his study of the disease Herpes zoster. From Head. of the nervous mechanisms as between the skin and the deeper organs, i.e., between the somatic and splanchnic divisions of nervous con- trol. It might be expected from this that any agent which will break the reflex path will tend to prevent the counter irritant changes. This has been found to be the case. A counter irritation, in fact a direct irritation, is relieved from much of its effects if the irritant is applied after an anesthetic for the area. In other words, if analgesia be produced in an area and then an irritant applied, the usual end results are largely prevented. In the same way, if a styptic is applied, so that the reflex blood vascular dilation is pre- vented, the inflammatory process is diminished, at least delayed. COUNTER IRRITANT AGENTS 287 3. Factors in the practical application of counter irritants. — Most text-books on therapeutics give directions for the practical use of counter irritants, and include precautions to be observed in the adaptation to different physiological conditions that may be met where such agencies are called for. A reference to Figures 66 and 67 will at once show the segmental nerve distributions to the skin, which must be kept in mind in the practical use of counter irritants for the relief of congestion in the thoracic or visceral organs. 4. List of counter irritant agents. — From the discussion of the nature of counter irritants it is observed that the number of drugs or other agents which will induce the pharmacological change is large. Some of these agents are mechanical, but most of them are chemical. Of the mechanical agents heat and cold lead the list. Both heat and cold are capable of application in such a way as to cover a wide range of intensity of action, and the facilities by which they may be applied to different parts of the body in these days of special mechan- isms, particularly of the electrical class, make them the most valuable of counter irritants. Cold controlled by the ice bag is valuable in two great ways : first, in controlling the vascular reactions, and second, in depressing metabolism not only of the tissue, which is being acted on by the direct irritant, but, in those cases where there is a bacterial invasion, control of the injurious bacteria themselves. Drugs which produce irritation of any kind may be relied upon in the same moment to produce counter irritation, especially when the primary irritant is applied to the skin. Irritant processes in the visceral mucosa are not to be neglected in this regard, since they may lead to irritant processes in the somatic region. The counter irritant drugs range in intensity of action all the way from the mild processes induced by the saline baths to the violent referred reactions set up by the more vigorous caustics. For the discussion of the action of individual members of this series, the reader is referred to members of the group, Skin Irritants, which are the drugs most in favor for the production of counter irritation. PART II INORGANIC DRUGS. K. Drugs Characterized to Greater or Less Extent by Salt Action. CHAPTER XXXVII. UNDERLYING PRINCIPLES OF SALT ACTION. General Considerations of the Physical and Chemical Character- istics of Salts in Solution. i. Crystalloids and Colloids. — Physiology has, to a great extent, familiarized us with the different behaviors of the great variety of substances which we introduce into the body as foods. We have learned that the different classes of foodstuffs are in reality represent- atives of the great classes of chemicals. The proteins, fats, carbohy- drates, etc., i.e., the organic foodstuffs, undergo elaborate processes of digestion before they can enter the tissues, while the substances of simpler composition, such as the salts of sodium, potassium, calcium, etc., pass from the alimentary canal into the tissues and reach the circulation with little or no change. In a word, the inorganic salts, as soon as they enter the state of solution, can by relatively simple processes pass through the lining tissues of the alimentary tract, as well as through the walls of the blood-vessels, and thus quickly dis- tribute themselves throughout the body. When these great classes of materials are examined more critically the striking characteristic is the fact that the salts pass readily into solution, while the organic substances are dissolved with difficulty or, it may be, not at all. These are differences which rest on a physical basis and are expressed by the terms which designate the classes, namely, crystalloids and colloids, a classification which was made by Graham a half century ago (1861). Graham called the bodies which passed through a membrane crystalloids because they were found to be such substances as the salts of sodium, potassium, lithium, etc.j which exist in the crystalline form. Those substances which do not diffuse through a membrane were designated as colloids. 288 ELECTROLYTES 289 2. Colloids. — This class is characterized by the relatively large size of the molecules, also by the fact that they behave in a charac- teristic way when in solution or suspension. The colloids are of special interest in pharmacology for the reason that they enter so largely into the composition of the tissues. They influence the be- havior of these tissues, not only by virtue of their chemical nature, but also on account of their purely physical characteristics. The presence of the colloid markedly influences the movements and relations of the molecules and ions of the salines, i.e., the crystal- loids. 3. Crystalloids. — Crystalloids are distinguished from the colloids by the fact that they go into solution far more readily. They for the most part pass through animal membranes with comparative ease, and in a general way are far more labile than are the colloids. The size of the molecules in the crystalloids is relatively small, many times smaller on an average than in the colloids. 4. Dissociation. — "When the molecules of a crystalloid pass into solution they undergo dissociation, whereby the atoms or groups of atoms are separated, carrying electric charges. For example, when sodium chloride is dissolved the molecules of the salt break down or dissociate into electrically charged ions. The sodium ion carries a positive charge, and is called the cation. The chlorine ion carries a negative charge, and is called the anion. This process of dissocia- tion, or ionization, occurs in practically all inorganic salts. Dissocia- tion, however, does not necessarily break the molecule into simple atoms electrically charged. Many of the anions and cations consist of groups of atoms as in sodium nitrate, NaN0 3 , which dissociates into positive sodium ions, Na, and negative nitrate ions, N0 3 . Sucli substances as caustic potash, KOH, dissociate into K and OH ions. + the acids as hydrochloric acid, HC1, into H and CI ions. 5. Electrolytes. — Solutions of crystalloids are conductors of elec- trical currents, hence called electrolytes. This is dependent upon the state of ionization; in fact, the conducting power of a given solution is proportional to the content of ions. The cations carry positive electricity, and migrate toward the negative pole when a current is flowing through the solution. The anions migrate in the opposite direction. The conducting power of a solution varies with the dif- ferent chemical substances in solution, depending not only upon the number of ions, but upon other diffusion constants. Certain ions, 290 UNDERLYING PRINCIPLES OF SALT ACTION for example, migrate through a solution with much greater speed than others. 6. Freezing point depression. — The factor of dissociation is shown by the influence which the molecules and ions have on the depression of the freezing point of a solution. In this instance both the molecules and the ions act as individual particles in influencing the freezing point. It is found by experiment that the freezing point depression is directly proportional to the sum of the molecules and ions in solution. "When this factor is measured in terms of known constants it is evident that the freezing point gives a direct measure of the dissociation percentage in any given solution. Sodium chloride, 0.9 per cent., which is isotonic for animal tissue, is found to lower the freezing point by 0.56°C. (Hamburger), i.e., the pressure equiva- lent of 6.5 atmospheres. 7. Osmotic pressure and osmosis. — When chemical substances go into aqueous solution there begins at once the process of distribu- tion of the molecules, also the ions if the chemical be dissociable, throughout the volume of the solvent. The particles of the salt dis- tribute themselves through the solvent according to certain laws. If a certain volume of gas be turned loose at the gas jet in a room, then the laws of gaseous diffusion come into play, and, other things being constant, the molecules of gas will distribute themselves equally throughout the space of the room. Just so is it with a salt dissolving in a beaker of water. The particles of the salt begin to diffuse from their initial location until equilibrium is established. It will then be found that the salt has distributed itself so that each cubic centimeter of the solvent contains the same quantity or number of molecules of the salt. When non-reacting salts are dropped into the solvent at the same time each salt dissolves and diffuses accord- ing to its own volume and properties. Each is independent of the other just as in the case of the diffusion of two or more gases in a mixture. In gases this phenomenon is explained by the fact that each molecule of gas is in free motion with reference to all other molecules in the mixture. Just so is it with the molecules of a salt. Each molecule and ion is in motion and the motion is not hindered by the solvent, hence the ultimate uniform distribution through the solution. 8. Osmosis. — In animals and plants the tissues are separated from each other by surface membranes, though in many animal tissues this surface membrane is not well marked. Such membranes impede the OSMOSIS 291 diffusion of dissolved molecules. Dead membranes prepared for ex- perimentation are found to differ sharply in character. Some will allow the free passage of water, but prevent the passage of dissolved substances. These are called non-permeable membranes. Others will allow the passage of certain molecules of dissolved substance and will hinder the passage of others. These are called semi-permeable mem- branes. If the molecules of the salt as well as the solvent pass freely through the membrane, then it is designated as a permeable mem- brane. Osmotic pressure is shown by instruments which permit the pas- sage of water but prevent the passage of salt molecules. In such an apparatus, where the membrane separates pure water from a solution of a salt in water it can be shown that the water will diffuse into the salt solution as against an ever increasing pressure. When such a diffusion has reached a state of equilibrium the pressure of the salt solution will have increased an amount which is in direct proportion to the increase in number of molecules and ions per unit volume. This passage of water through such a membrane is called osmosis. The pressure which it induces in an osmotic apparatus is called osmotic pressure. If the membrane is semi-permeable, then the relations are some- what different. In this case, if one places on one side of the mem- brane a mixture of salts in solution some of which can penetrate the membrane and some not, and on the opposite side of the mem- brane distilled water, then immediately water begins to pass through the membrane into the salt solution, while the permeable salts will begin to diffuse through the membrane into the distilled water. The non-permeable salts are, of course, retained on the original salt side. In this case the passage of the permeable salts by so much reduces the osmotic pressure of the salt solution. Since the rate of diffusion of the salts will vary in each individual case, the osmotic pressure will be represented by a certain curve, which at first rises, because of the more rapid diffusion of the water through the membrane, then more slowly falls as the diffusible salts pass through and distribute themselves throughout the liquid on the water side of the membrane. When equilibrium is established the osmotic pressure on the saline side of the membrane will be represented by the pressure of the non- diffusible salts only, the diffusible salt being equally distributed on both sides. In permeable membranes a transient osmotic pressure may mani- fest itself on one side of the membrane as compared with the other, 292 UNDERLYING PRINCIPLES OF SALT ACTION because of the different rates of diffusion of the different components of the mixture. The reader will need to consult works on physical chemistry for the mechanism of this process. It is of interest to pharmacologists because osmotic pressures play such an important part in the behavior of living tissues in relation to numerous drugs as well as to salt solutions. The influence in the body of saline solutions exerted by virtue of their osmotic, electrolytic, and other physical factors is designated by the general term salt action. The protoplasm of the tissues in the animal body does not form quite the same type of surface membrane as is found in the dead osmotic membranes. Nor, in fact, do we find such typical membranes as are present often in the botanical tissues. However, osmosis and isotonicity are always operative factors in the animal body. The protoplasm contains colloidal material, and often this material is condensed into a relatively efficient surface membrane over the animal cell, as in the case of the red blood corpuscles. LWhen salt solutions come into contact with the tissues a process of diffusion as between the solution and the tissues immediately takes place. It will continue until a degree of equilibrium has been established./ Unprotected animal tissues will rapidly absorb distilled water by virtue of the osmotic pressure due to the protoplasmic saline content. In like manner they will lose water to solutions of greater concen- tration, as is shown when red blood corpuscles crenate in hypertonic salines. The colloids, as differentiated in the tissues, vary greatly in their permeability to different salines. Certain solutions, as ammonium chloride, penetrate practically all tissues with great facility, acting essentially as so much distilled water. Under its influence the blood corpuscles will swell to the point of bursting, and muscle and other tissues undergo a similar increase in volume. Other salts, as sodium chloride in the case of the red blood corpuscles, or the sulph- ates in the alimentary canal, do not readily pass through the surface of the tissues, and to that extent control the water content of the tissue. A solution of non-permeable salt will lose water to, draw water from, or maintain an equilibrium as regards the water content of a tissue, according as it is hypotonic, hypertonic, or isotonic with the tissue. It is obvious that salt action plays a very important part in maintaining a proper water content of the tissues of the body. GENERAL CONSIDERATIONS 293 In other words, salt action is in a very large degree responsible for maintaining an efficient dilution of the chemical components of living substance, under which the protoplasm carries on with the greatest economy its reactions and its corresponding expenditure of energy. CHAPTER XXXVIII. WATER. The introduction of water into the body or the bringing of water into contact with any portion of the body which it wets leads im- mediately to disturbances of the osmotic balance of the tissues and parts. Of course the skin, which is oily, is relatively impermeable to water, though a certain amount of water is taken up by long contact with the corneous epithelium. The changes induced in the body by the action of water depend chiefly on three factors, namely, the volume of the water, the length of time during which it is kept in contact with a given tissue, and the osmotic permeability of the tissue. i. Action of distilled water on isolated tissues. — When isolated tissue, such as the gastrocnemius muscle or glandular tissue, is immersed in distilled water the cells of the tissue act like osmometers. They imbibe water. The water passes through the surface membrane into the protoplasm as into a colloidal solution. The percentage of water in the tissue, therefore, increases and a condition of hydric edema supervenes. This water-logging of the tissues interferes with the normal physiological reactions, and if carried too far it leads to degeneration, hence the destruction of the tissues. A rhythmically contracting strip of cardiac muscle when im- mersed in distilled water will continue its rhythm for some time, but the relaxation process is interfered with. The rhythm ultimately ceases, therefore, with the muscle in the systolic phase. Skeletal muscle is somewhat similarly influenced. These results are due not only to increase in water content, but to a loss of saline constituents, especially from the interstitial spaces of the muscle. It is not so easy to determine the exact changes in the func- tional activity of glandular tissues, but they too absorb water and swell. Certain living organisms like protozoa, embryos, such as those of the fish, for example, fundulus, and certain special modifications of tissue like the epithelium of the giUs of fishes, withstand the action of distilled water with a remarkable degree of resistance, provided 294 DRINKING WATER 295 the water contains no toxic impurities to vary the normal resistance of these tissues. It is true that organisms often thrive better in waters derived from natural sources, such as springs and the like, but such waters contain one or more saline constituents, which are the favorable ingredients. 2. Drinking water. — An individual takes large quantities of water as a part of his necessary daily food. This water is brought into contact for some time with the lining membrane of the stomach and intestine, through which it is ultimately absorbed. Water taken by the mouth, therefore, ultimately reaches the blood stream and is distributed throughout the body. Experimental physiology teaches us that very little water is absorbed from the stomach, but that ab- sorption from the intestine is free and rapid. Water enters the body so slowly by this channel that it is very gradually distributed, with the result that it never at any time very sharply raises the percentage of water content of the body fluids and tissues. For example, a glass of water, which contains 250 cc, will be absorbed within 20 to 30 minutes. Since the proportion of blood is approximately one-thirteenth the body weight, the glass of water in a man weighing 130 pounds would be distributed in ten pounds of blood, i.e., about 5000 cc. Since this blood comes into contact with the tissues every 30 seconds, the further distribution of the water obviously would take place so rapidly that the water percentage of the tissues would never be increased from the operation more than a fraction of one per cent. Conditions of extreme thirst are usually associated with diminished water in the tissues, i.e., hypertonicity in the system. Under these conditions the absorption of as much as one or two liters of water would only increase the water content of the tissues by one to three per cent., assuming no elimination during the absorption. Whether or not the drinking of large quantities of water with our daily meals is injurious has recently been put to test by Dr. Hawk in the University of Illinois laboratories. It would seem that the taking of large quantities of water with meals, i.e., at the beginning or close of the meal, not with the mastication of the foods, is followed by relatively slight or insignificant influences on either the efficiency of the digestive processes or the utilization of the foods in tissue metabolism when tested against the usual and ordinary methods of taking drinking waters. 3. Mineral waters. — Mineral waters should rather be regarded as solutions of certain salts. Therefore, the reactions of the body to these special waters can best be designated under the headings involv- 296 WATER ing the particular salts contained in the particular waters. The reader is accordingly referred to those sections. 4. The influence of water on metabolism and on the kidney. — There is one phase of the influence of water on metabolism that should not be lost sight of, namely, the fact that a relatively high water content of the tissues is associated with the period of greatest growth and physiological activity during the life cycle. This state- ment is particularly true with regard to the growth processes. The tissues of embryos and of the developing young always contain a relatively high percentage of water as compared with the same tissues of adults. As an example of this fact may be quoted the rate of repair in the epidermis of frogs kept at different isotonic levels as regards the salt content of their tissue fluids. Hypotonic frogs repair their tissues much more rapidly than hypertonic frogs. ■ A hydremic condition is favorable to a greater excretion of water by the kidney. Very excessive ingestion of water, therefore, is rather quickly adjusted by elimination through the excretory organs. In other words, pure water is a sharp and efficient diuretic. The large quantity of urine excreted under this condition eliminates not only water, but the water carries with it both salts and waste organic prod- ucts. These are present, however, in relatively less condensed form. Under extreme toxic conditions where the absorption of water from the alimentary tract is too slow for efficiency sterile distilled water may be injected directly into the veins, of course in moderate and guarded amounts and preferably in the form of isotonic physiological salines. CHAPTER XXXIX. ISOTONIC PHYSIOLOGICAL SOLUTIONS. Artificial physiological solutions have been in general use now since 1869, when Nasse * gave us the basis for our physiological saline. Such solutions primarily attempt to maintain the physical factors of the blood serum and the body fluids. This is accomplished by a mixture of salts in such proportion as to be isotonic with blood serum. Of these solutions the ones in most common use are physiological saline, Ringer's solution, Locke's solution, and other similar solutions with minor variations made to improve the exact physiological balance of the constituents. Artificial physiological solutions are often of extreme practical value in supplying great loss of blood, or in other pathological conditions of one sort or another. They have been of in : estimable value in scientific research on living tissues. Physiology teaches us that many of the protoplasmic differentiations in the ani- mal body continue to live and exhibit normal reactions through re- markably long periods when they are bathed in these solutions. If the saline solutions are kept sterile and adequately aerated they are even quite adequate to the growth needs of isolated tissues for a limited time. i. Physiological saline. — That sodium chloride in 0.6 per cent, solution would maintain the striated muscle of a frog in a living active condition for a long period was first shown by Nasse. Similar experiments were applied to other organs and tissues of the body, the first being the cold-blooded heart. Out of this classical beginning has arisen all the present extensive use of artificial solutions for physiological, pathological, and practical medical purposes. Physiological saline is made up in adaptation to the blood and tissues of each animal according to the isotonicity of its serum. For mammals this isotonicity is represented by a 0.9 per cent, sodium chloride solution. Isolated tissues and organs of the cold-blooded ani- mals, and to an extensive degree of the warm-blooded animals also, remain active and living in physiological saline for several hours. However, physiological saline is not a chemically indifferent solution 1 Nasse, 0.; Arch. f. d. ges. Physiologie, 1869, Vol. 2, p. 118. 297 298 ISOTONIC PHYSIOLOGICAL SOLUTIONS characterized by physical properties alone, as is too often taught. It fails to support continued tissue activity as would the serum of the animal. The solution is not toxic in the usual sense, but merely fails to supply certain needs of the living tissue. Under its influence iso- lated hearts at first contract strongly and with good rhythm, but later rapidly lose their amplitude of contraction, though rhythmicity may be retained for a longer time. Skeletal muscle rapidly diminishes in ir- ritability. Cushing has shown that the power of the nerves to trans- mit a stimulus to the muscle drops out even earlier than the irritability of the muscle to which the nerve may be attached. Such experiments strongly argue against the efficiency of the purely physical factors in all artificial physiological solutions. The matter may be looked at in another light. Isotonicity obtained by a single salt does not and cannot maintain a physical balance against a body fluid in which the osmotic pressure is due to a complex of salts. Living tissues lose to physiological salines certain necessary ions, and this in itself ultimately disturbs the physical balance in such a way as to change the physiological reactive property of the tissue. 2. Perfusions of physiological salines. — Physiological saline is in practice introduced into the body by one of two methods, either by hypodermoclysis or by transfusion directly into a vein. In- the former case the saline enters the body relatively slowly, though large amounts may be introduced by the method. In the second case the saline enters the blood stream directly and is under the control of the manipulator. Sterile physiological saline may be transfused without danger for as much as 20 to 30 per cent, of the total normal blood of an animal, one to two liters in the case of man. It is evident that this gives a valuable agent for quickly returning the necessary volume of blood in cases of excessive loss from traumatism, etc. The amount of blood in a normal average adult is from six to eight liters, i.e., one-thirteenth of the body weight. The introduction of two addi- tional liters, even when one-third the normal blood is lost, will give a blood mixture that contains only approximately 30 per cent, physio- logical saline, and this percentage is very quickly lowered by inter- diffusions between the blood and the tissues of the body. Such a dilution of the blood is far less drastic in its effect on the tissues than is generally supposed, less, in fact, than in experiments on isolated organs immersed in a pure physiological saline. The isotonicity fac- tor throughout is maintained at a constant, the sodium chloride con- tent of the plasma is constant, while the other saline constituents RINGER'S SOLUTION 299 of the plasma and tissues are lowered, yet not so violently disturbed and hence readily regain their balance. There are numerous experiments that indicate that the sodium chloride, as such, is mildly stimulative to protoplasmic activity. Granting this point, it follows that its addition as physiological saline to the extent of as much as 30 per cent, of the volume of the blood will slightly raise the irritability, i.e., the general activity of the tissues. This, of course, is favorable in the case of excessive shock, excessive bleeding, etc., where the clinical use of physiological saline or other normal physiological solution is called for. The introduction of relatively large volumes of physiological saline causes slight rise of blood-pressure purely because of the in- creased volume of blood. This factor is favorable to the eliminative processes, the chief of which is the excretion of fluid through the kidney. Physiological saline is a diuretic, therefore. In driving a large quantity of fluid through the kidney a considerable quantity of the saline constituents of the blood are carried along. The process also favors the elimination of organic waste products, such as urea, etc., and of toxins, drugs, etc., just as happens when there is an increase of the volume of blood by the absorption of drinking water. 3. Ringer's solution and its modifications. — In the early eighties Ringer cleanly showed that physiological saline was inadequate be- cause it lacked certain necessary salts present in the serum, namely, potassium and calcium salts. From his work we have derived the numerous physiological solutions which bear his name. A wide variety of percentages of constituents in Ringer's solution has been used, especially in recent times. This is due to the attempt to maintain the actual saline balance which exists in the blood serum of the animals used in the experimentation, the different species vary- ing widely in this regard. Loeb 1 states : ' ' We have a point of at- tack for the investigation of the role of the salts in the fact that the cells of our body live longest in a liquid which contains the three salts, NaCl, KC1, and CaCl 2 in a definite proportion, namely, 100 molecules NaCl, 2.2 molecules KC1, and 1.5 molecules of CaCL. This proportion is identical with the proportion in which these salts are contained in sea water; but the concentration of the three salts is not the same in both cases. It is about three times as high in the sea water as in our blood serum." In laboratory practice it is found that for cold-blooded vertebrate and for mammalian tissues the percentage of potassium and calcium is a little higher. The physiological bal- 1 Loeb, Jacques: The Mechanistic Conception of Life, p. 169. 300 ISOTONIC PHYSIOLOGICAL SOLUTIONS ance was determined for terrapin ventricular tissue by Greene x and is represented by the following solution: 0.7 per cent, sodium chloride 0.03 " " potassium chloride 0.026" " calcium chloride. Certain laboratories slightly increase the amount of potassium chloride for use with mammalian tissue up to 0.042 per cent., and add a trace of alkaline sodium bicarbonate. The amount of calcium in the above mixture is based on quantitative analytical determinations in sheep serum (Howell) and terrapin serum (Greene). The Kinger's solution not only maintains total isotonicity as such, but it maintains an isotonicity of the three most important salines of the body fluid. In oxygenated Ringer's solution many of the body tissues behave remarkably like normal tissues. The inorganic salts in Ringer's solution are not supposed to furnish potential energy, still these salts are essential to the living activities of the body tissues. Quoting again from Loeb: " If we now raise the question as to why salts are necessary for the preserva- tion of the life of the cell, we can point to a number of cases in which this answer seems clear. Each cell may be considered a chemical factory, in which the work can only go on in the proper way if the diffusion of substances through the cell wall is restricted. This diffusion depends on the nature of the surface layer of the cell. Overton and others assume that this layer consists of a continuous membrane of fat or lipoids. This assumption is not compatible with two facts, namely, that water diffuses very rapidly into the cell, and second, that life depends upon an exchange of water-soluble and not of fat-soluble substances between the cells and the surrounding liquid." A definite nutritive substance was first added to the Ringer's salt solution by Locke. 4. Locke's solution. — Locke added 0.1 per cent, of dextrose to Ringer's solution in the attempt to furnish the tissues with a definite oxidizable energy-giving substance. He found that the addition pro- longed the life of the tissues beyond that of strictly inorganic Ringer 's. The contention of Locke has been confirmed in more recent times, and it is now definitely known that isolated organs when perfused with Locke's solution can utilize the sugar. For example, Lee and Salant 2 1 Greene, Chas. VV. : American Journal of Physiology, Vol. II., p. 125, 1899. 2 Lee, F. S., and Salant, W. : American, Journal of Physiology, Vol. VI., p. 61, 1902. SERA AND LYMPHS AS PHYSIOLOGICAL SOLUTIONS 301 found that if parallel gastrocnemius muscles from the same animal were perfused, one with Kinger 's solution and the other with Locke 's solution, the latter maintained its contractions for a longer time and recovered from fatigue more readily. One of the best demon- strations of this point has recently been given by Knowlton and Starling, 1 who determined the rate of oxidation of sugars by isolated mammalian hearts, showing that oxidation not only occurs, but it occurs in surprisingly constant proportion per gram of tissue. In perfusions with Locke's solution one must not lose sight of the fact that well oxygenated fluid must always be used. Body tissues quickly use up the interstitial oxygen and must receive a supply from the outside. "When mammalian tissues are perfused with inor- ganic solutions, i.e., solutions which do not contain the special oxygen- carrying pigment, hemoglobin, it is customary to insure oxygen satura- tion by bubbling pure oxygen through the artificial solution, or by putting the solution under a positive pressure of pure oxygen. 5. Sera and lymphs as physiological solutions. — In the body the blood plasma or the lymph is the normal fluid for the living tissue. Naturally when artificial solutions are to be used the ideal fluid would be the one in which the tissue has developed. Lymph and serum not only contain the inorganic salts which contribute chiefly to maintain the constant physical factors, but also numerous traces of salts that have been absorbed from the foods or are being excreted after more or less oxidation by the tissues. The organic nutritive substances are also present in the normal body fluids, the proteins and their derivatives, fats, and the various carbohydrates. These are the great classes of organic compounds present. Besides, there are substances always present in the blood and lymph which are developed in response to special conditions which may be impressed upon the organism at some time in its life history. These substances are far from indifferent chemically, if ignorable physically. One has only to refer to the numerous toxins, antitoxins, lysins, etc., which are now of such tremendous bacteriological and hygienic interest. There are also present those materials derived from the reactions of the tissues themselves, i.e., the organ extracts, enzymes, oxidazes, waste products, etc. The serums, therefore, must vary greatly and fundamentally if one takes into consideration their source in different species, and in different individuals even of the same species. Because of this great variation in composition, particularly as regards the subtler 1 Knowlton, F. P., and Starling, E. H.: Jour. Phys., Vol. XLV., p. 146, 1912. 302 ISOTONIC PHYSIOLOGICAL SOLUTIONS chemical constituents, it is found that a serum or a lymph derived from one animal may be not only not normal, but even toxic to another animal. The detail of these factors is discussed in text-books on bacteriology, vaccines, sera, organ therapy, etc. Considered from the present point of view, a physiological solution that maintains through the agency of inorganic constituents normal to sera the physical constants will be safer and more nearly inert in those rela- tions where it is desired to maintain the pharmacological or thera- peutic isotonicity of tissues or organs. 1 6. Summary. — Physiological saline, 0.9 per cent, sodium chloride for mammals, is a valuable agent for increasing the volume of blood. It maintains physiological isotonicity, and has the minimum of react- ive power. It is a diuretic, acting as a , mild stimulus to the renal epithelium and favoring the mechanical separation from the blood of the salines and other wastes. It may be introduced into the circula- tion of a mammal after excessive loss of blood, in man to the amount of one or even two liters. This somewhat lowers the concentration of the other salts of the blood, but not to a level that is injurious under any ordinary condition. Einger's solution is more favorable because it is a more normal solution of the salts in the proportions found in blood. An exactly balanced Ringer's solution represents the best transfusing fluid, and should always be used when available. It maintains isotonicity not only of the sodium chloride, but of other salts of the blood. Under its influence the tissues continue their protoplasmic life for a surpris- ingly long period. Locke's solution has all the advantages of Einger's solution with the added advantage of furnishing an energj^-giving substance which the living tissues, especially the muscular tissues, can immediately use. The heart and the skeletal muscles can oxidize the sugar from a Einger's solution. Lymphs and serum derived from the same species of animal, particularly from the same individual, are more nearly normal to the tissues than the artificial salines. However, species differences in serum, and sometimes individual differences, render the serum toxic. This is particularly true where the individuals have been subjected to disease or experimental treatment, thereby inducing the changes in the serum characteristic of disease. Transfusions of blood, i.e., serum, are much more dangerous on these accounts than are transfusions of balanced saline solutions. L. Detailed Action of Salts Normal to the Body Fluids and of Their Chemical Relatives. Any discussion of the specific reactions of the salts normal to the body fluids leads one at once into that complex of salt action which depends on the ionizing properties of these substances. In other words, the reactions of a salt in the body are at least threefold, i.e., the reactions of the salt molecule as such, the reactions of the positive ion, and finally, the reactions of the negative ion. Take, for example, the most abundant salt in the blood plasma, sodium chloride. This salt dissociates to the extent of some 83 per cent., forming positive + Na ions and negative CI ions. The undissociated molecules and each of the ions can exert an influence on the living protoplasm. This particular salt is considered the most inactive of any present in the body, yet what action it has depends more largely upon the influence of the ions than upon the undissociated molecules. It is similar with other salts, such as potassium chloride, or the calcium and magnesium phosphates, or of any one of the numerous related in- organic salts. In the case of the potassium or calcium salts, for example the chlorides, it is found that the potassium or calcium cation is far more reactive with the body tissues than the chloride anion. According to the most recent views the salts react chemically through the formation of ion proteins. Perhaps to some extent molecular proteins are also formed. Such compounds exert their influence on the protoplasm both chemically and physically. The plasma membrane which covers or bounds the animal cell is a con- trolling agency for the diffusion into or from the cell. Attention has already been called to the influence of the plasma wall on the reactive life of the tissue cell. Variations in the ion protein com- pounds are responsible for the character of this wall. With these general principles in mind we may take up the detailed discussion of the action of the individual salts. 303 CHAPTER XL. THE SODIUM AND POTASSIUM GBOUP, INCLUDING CHLOKIDES, BROMIDES, IODIDES, SULPHATES, NITEATES, ETC. I. The Sodium Salts. The salts of the alkali metals are of special interest because of the action of their bases. Yet these salts have long been considered as the chief agents for maintaining the physical isotonicity of animal tissues. i. Sodium chloride and the sodium salts. — Sodium chloride is normal to the blood plasma and the various lymphs. It is present in larger proportion in these fluids than any other inorganic constituent. It is assumed that sodium chloride is ionized in the plasma fluids just as it is in the simpler solutions. Its action, therefore, can be attributed to the reactions induced by the positive sodium and by the negative chlorine ions. Sodium chloride in pure solutions in- creases the permeability of animal tissues. This point has been established in a peculiarly interesting way by R. Lillie. 1 Lillie found that if the larvae of the sea worm Arenicola are placed in sodium chloride solution isotonic with sea water their muscles strongly contract for some seconds, then slowly relax. The cilia of the surface not only cease contraction but undergo rapid disintegra- tion. Lillie explains this result as due to the increase in permea- bility of the epithelial tissue under the influence of the sodium chlo- ride. In this case the change in permeability is coincident with the stimulative action. In many mammalian tissues, i.e., skeletal muscle, heart, etc., it has been shown that sodium chloride increases the physiological reactions, in other words is stimulative. When this stimulative effect is not prevented by the antagonistic action of other ions it may lead to toxic disintegration. This is the explanation of the so-called toxic influence of pure sodium chloride. It is greater, of course, in the more concentrated solutions. While isotonic sodium chloride solutions are of great benefit in medicine and surgery, the 1 Lillie, R. : "The Physico-chemical Conditions of Anesthetic Action," Science, Vol. XXXVII., p. 959, 1913. 304 THE POTASSIUM SALTS 305 concentrated solutions occasionally used are a positive source of danger. Several accidents are on record of deaths from the erroneous use of concentrated salines as enemas. 2. The bromides. — Of all the sodium salts the chlorides are the most indifferent. The bromides are also relatively indifferent, but exert a greater toxic influence than the chlorides. Certain tissues, like the muscular tissues, can be kept in a living condition and relatively normal in reactions with isotonic sodium bromide solution. This solution reacts in very much the same way as physiological saline solution. The bromides exert a strong depressing action on nerve tissues, reducing the sensitiveness of nerve centers to reflex stimula- tion, therefore acting as sedatives. 3. The iodides. — The sodium iodide is still more toxic than the bromide. The toxicity is due chiefly to the iodide anion which is strongly irritative to mucous surfaces. Sodium iodide is relatively less toxic than some of the other iodides, for example the potassium. This is due primarily to the inactivity of the sodium cation. 4. Sodium nitrate. — Sodium nitrate is still more toxic from the action of the nitrate ion. This salt readily diffuses through the tissues and sodium in this form is rapidly excreted by the urine. The nitrates are, as a matter of fact, stimulative to the renal epithelium and to that extent are diuretic. 5. Sodium sulphate. — Sodium sulphate introduces a new type of anion, since the sulphate ion is relatively non-diffusible. The non- diffusibility of the anion holds back the diffusion of the cation, hence sodium sulphate is not so readily absorbed from the ali- mentary canal. This salt is, therefore, a saline cathartic and will be discussed more fully under that group. Sodium sulphate is strongly stimulative to certain tissues, particularly muscle, both striated and smooth. Loeb long ago showed that striated muscle in sulphate solutions was stimulated to contractions of a rhythmic character. 6. Sodium phosphate. — Sodium phosphate, Na 2 HP0 4 , is a non- diffusible salt, due in this case also to the anion. The salt, as a whole, exerts little influence on the body other than that of its salt action. II. The Potassium Salts. Potassium is the second most important of the alkaline metal bases. Potassium salts, especially the chlorides, bromides, etc., 306 THE SODIUM AND POTASSIUM GROUP readily dissociate in the body fluids. In contrast with sodium salts, potassium salts are very active chemically. The potassium cation may readily form ion protein compounds and these compounds are apparently more fixed than in the case of sodium. Potassium pos- sesses less salt action and more chemical action in the body and is therefore relatively more important. Potassium salts react strongly with muscular tissues, also with nerve, gland, etc. Analyses of muscular tissues and of the fixed elements of the blood show a com- paratively high percentage of potassium. The physiological changes induced by potassium depend upon this chemical affinity. The most important of the potassium re- actions are those on muscle and on nervous tissues. Potassium is of tremendous importance in maintaining a favor- able physiological condition for the heart. Numerous investigations which have been emphasized in the discussions of physiologically balanced solutions go to show that the character of the normal contractions of the heart is absolutely dependent upon the presence of potassium in the blood and lymph. Potassium reacts here with the heart proteins in some sort of opposition to sodium and calcium. When the potassium content of Einger's solution is increased, then the heart beats slower, relaxes more completely, and contracts with less amplitude. If the potassium content is further strengthened the heart will cease to beat. Even with the mammalian heart the addi- tion of potassium chloride to a perfusion of Locke's or Einger's solution is sufficient to bring the contracting heart to a standstill. This standstill is quickly removed by the elimination of the excess of potassium, showing that the condition imposed upon the heart is at least not a strongly fixed chemical combination. This holds true for all forms of vertebrate heart that have been investi- gated. The skeletal muscles contain in their ash a considerable quantity of potassium. If the potassium in the 4 lymph and blood circulating through skeletal muscle is increased, then the contractions of the muscle are weakened and the irritability diminished or lost entirely. This point has also been nicely demonstrated by Lillie on the Are- nicola larvae referred to above. These larvae swim normally by two mechanisms ; first, by the action of trochophoral cilia, which we have already seen are readily poisoned by the sodium chloride solutions, and second, by the contractions of longitudinal muscles in the body wall. Potassium solutions render the muscles inert without inter- fering strongly with the action of the cilia. Larvae poisoned in this AMMONIUM SALTS 307 way remain rigid from inactivity of their longitudinal muscles, but swim about freely by ciliary movement. Undoubtedly potassium is toxic to glandular tissue. This is well shown by the toxicity of potassium solutions on the kidney. On nerve tissue potassium is a marked depressant. This is borne out by the diminished sensitiveness of the peripheral nerves as well as the depression noted in the reactive power of the central nervous system after large doses of potassium salts. This depression is par- ticularly manifest through diminution in the reflexes. In extreme toxicity the condition may amount to central nervous paralysis. The potassium bromides are much more depressant than the chlorides, due to the added action of the potassium ion. In this case, since the bromide acts almost specifically on the nervous tissue, it follows that the potassium bromides will have a much more profound sedative effect on the central nervous tissue. Potassium iodides are still more toxic. The potassium and iodine ions are apparently particularly toxic for the more generalized tis- sues. This salt is used in therapeutics in combating certain in- fections, particularly invasions of spirochsete pallida. Other salts of potassium, namely, the nitrates, sulphates, citrates, and phosphates react in the body in a way comparable to the cor- responding salts of sodium. The principal difference is in the fact that the depressing factor of the potassium cation is added to each salt. Further discussion of this group will be considered under the heading of saline cathartics. III. Ammonium Salts. Because of similarity of chemical reaction, the ammonium salts will be discussed in connection with salts of sodium and potassium. Ammonium chloride is more diffusible than either sodium or potas- sium chloride. In fact, in the body the ready diffusibility of this salt prevents it from exerting an osmotic pressure where salts of sodium or potassium would accomplish this result. Ammonium salts are rapidly absorbed and readily diffuse through the body. i. The secretions. — Ammonium chloride especially acts as a vigorous stimulator of the secretions. This is accomplished through the twofold action on the mechanism, i.e., by reflex stimulation and through direct excitation of the secretory nerve center. Ammo- 308 THE SODIUM AND POTASSIUM GROUP nium chloride is particularly efficient in stimulating the secretions of the respiratory tract and it is on this basis that it has gained its reputation as an expectorant. 2. On the nervous system. — Ammonium salts heighten the irritability of the cord and medulla. This is shown by the increased reflexes and in some cases convulsion-like spasms. The stimulation of the medullary centers shows itself through the various end organs connected therewith. The heart is slowed by vagus inhibition, respiration is accelerated, and the peripheral blood-vessels are con- stricted, though the reaction is mild in all these cases. The salts of ammonia have an irritant effect on mucous mem- branes, leading to excitation of sensory structures found there. These irritations reflexly produce a slowing of the rate of respiration, which is antagonistic to the central effects which come later, a more pronounced cardiac inhibition, and in some cases bronchial contrac- tions. The volatile hydrate of ammonia is particularly irritant to the respiratory tract, a fact which is recognized in the use of am- monias for reviving persons when in a condition of depressed nerve irritability, as for example in fainting, deep anesthesia, etc. 3. Excretion. — Ammonium chloride and the fixed salts of am- monia are eliminated as such through the kidney, but the oxidizable forms of ammonia, for example the acetates, citrates, carbonates, etc., are converted in the body ultimately into urea and eliminated as such. IV. The Lithium, Rubidium, and Cesium Salts. These members of the alkaline metal group are of relative in- significance in pharmacology. These bases are not normally present in the body except perhaps in traces. On the other hand, they have in the past received some medicinal emphasis, especially lithium. Lithium salts do not closely resemble either sodium or potassium in physiological action, but are rather more comparable to calcium. It has long enjoyed a reputation as a saline diuretic. This is due largely to its presence in certain mineral waters of therapeutic value. It was thought, through work in the middle of the last cen- tury, that there was a marked reaction as between lithium and uric acid, whereby the latter was increased in solubility in water. A more careful investigation of this problem was made by Good, 1 who, 1 Good, C. A. : Am. Jour. Medical Sciences, February, 1903. THE LITHIUM, RUBIDIUM. AND CESIUM SALTS 309 as a result of a number of experiments on mammals, came to the conclusion that lithium is excreted in the saliva, in the stomach and intestine, and in the urine, the greater amount being excreted by the latter. It makes its appearance in the secretions within a few minutes after administration, and may still be detected after 23 days. Lithium salts do not possess any diuretic action other than their salt action, and they are not solvents for uric acid or the urates. The lithium salts possess a degree of toxicity to the general system, as shown by the symptoms of nausea, vomiting, and diarrhea, followed by emaciation, weakness, and even death. These symptoms are in part accounted for by marked enteritis indicating an irritative or corrosive action on the mucous membranes, particularly of the stomach. Good's whole investigation would tend to discredit any favorable therapeutic result to be obtained by salts of this metal. CHAPTER XLI. THE SALTS OF THE CALCIUM AND MAGNESIUM GKOUP IN COMBINATION WITH VARIOUS ANIONS. The salts of the alkaline earths play a very important role in the physiological economy of the mammalian body. These salts not only constitute the inorganic constituents of the skeleton and other hard parts of the body, but they, particularly calcium, are vitally important constituents of the tissues and body fluids. Both calcium and magnesium are deposited in the bones of the skeleton as well as in epidermal modifications, i.e., the teeth, etc. The adequate supply of calcium and magnesium available in the food of animals is essen- tially a physiological question. However, attention may be called here to the fact that the amount of these salts called for bears a very close relation to the state of maturity and growth of the animal, as well as the general nutritive factors. Adult animals whose skeletal elements are already fixed require only a very small quantity of calcium and magnesium in comparison with developing young, or with adult females bearing developing young. Deficiency of calcium and magnesium in the food leads to distressing conditions of general metabolism. From a medical point of view these conditions are indicative of malnutrition and are noticed most often in the poorly fed children of the tenement districts of our large cities. Calcium Salts. Calcium salts are present, not only in the bones and hard parts of the body, but in all the body fluids and tissues. The ash of the various tissues contains a small portion of calcium. It is not easy to determine in just what form the calcium is present. Probably in many of the tissues and fluids it exists as a calcium phosphate. In blood plasma, lymph, and in some of the secretions, as for example milk, calcium can be precipitated as a free salt. In the main, how- ever, it is assumed that the calcium forms ion proteins in the tissues. 310 CALCIUM SALTS 311 Calcium enters into the reactions of many forms of tissue metab- olism. Of these may be mentioned blood-clotting, the coagulation of milk, the rhythmic reactions of muscular tissue, etc. Calcium chloride in the percentage 0.026 is a normal constituent of Ringer's and Locke's solutions. It is present in blood plasma in this par- ticular concentration, as already referred to on page 300. Although calcium probably exists in blood as a phosphate, its reactions have, in the main, been demonstrated through the reactions of calcium chloride in which the chloride ion is relatively inactive. i. Calcium in relation to the heart. — Calcium is a salt necessary for the normal contractions of cardiac muscle, a fact that has been Fig. 68. — Calcium on the rhythm and amplitude of the ventricular strip of the terrapin. The strip was contracting rhythmically in 0.7 per cent, physiological saline. At the point marked by the first arrow it was changed to calcium chloride 0.04 per cent. in sodium chloride 0.7 per cent. The rate increased from 12 to 27 per minute. On returning the muscle to 0.7 per cent, sodium chloride, the amplitude remained higher than normal, though diminishing. A bath of potassium chloride 0.06 per cent, in sodium chloride 0.7 per cent, entirely suppresses .the rhythm. However, this quickly returns in normal physiological saline. New tracing by Miss Pile. established through the work of Ringer, Howell, Loeb, and' their numerous students. If the amount of calcium in normal saline solutions be increased and tested on any rhythmic portion of the jheart of the cold-blooded vertebrates, or, in fact, the mammal, it will be found that both the rhythm and the amplitude are favored by quantities slightly above the normal of the blood plasma of the animal. Solutions several times more concentrated than the above are always injurious to the tissues, cardiac tissue tending to develop a strong tonic contraction with marked predisposition to fibrillation, and final loss of fundamental rhythm with inability to relax. The latter is a sort of calcium rigor and is removed with some difficulty. Calcium forms an indispensable antagonist for potassium salts (Howell) and sodium salts (Loeb) of the body fluids. 2. Calcium in the coagulation of blood. — That calcium was a necessary factor in the coagulation of blood was shown by Schmidt, and has been confirmed by numerous later investigators. If the 312 SALTS OF THE CALCIUM AND MAGNESIUM GROUP calcium is eliminated from the blood plasma the clotting cannot occur until free calcium is again introduced. This is shown in the reactions of oxalate plasma. It is obvious that an increase in the amount of calcium above the normal favors the coagulation of blood. This increase must be slight, however, as an excessive quantity of calcium hinders the reaction, hence becomes toxic. 3. Nerve tissue. — Calcium salts favor the normal reactions of nerve tissue. This is demonstrated by the work of Cushing, who showed that the sensitiveness of motor nerve endings that have been depressed by physiological saline is regained by the perfusion of solutions containing calcium in normal amounts. 4. On metabolism. — That calcium is a factor in metabolism is suggested by the behavior of cardiac muscle under its influence. Although the matter is not so clearly worked out, it is generally be- lieved that the pathological condition of osteo-malacea is dependent upon interference with calcium in skeletal metabolism. The matter is not a simple lack of calcium, but rather a failure of some factor entering into the general reaction, whereby normal metabolism is deranged. Calcium is present in blood plasma and takes part in the chemical changes that occur during blood-clotting. It is also a necessary constituent in the formation of casein from caseinogen. Blood-clot- ting can be influenced by varying the amount of calcium present in the plasma. When calcium precipitants, like the citrates or the tartrates, are introduced into the alimentary canal in sufficient quan- tity, or guardedly into the circulation, the elimination of the cal- cium reduces the coagulability of the blood. The raising of the calcium content to increase coagulability, for example to prevent the post-partum hemorrhage, has also been attempted. In the last in- stance the clinical possibilities are complicated by the fact that excess of calcium salts does not aid, but retards the process of coagula- tion, which it is sought to facilitate. 5. Excretion. — Calcium salts are poorly absorbed because of the non-permeability of the mucosa of the digestive tube to the calcium cation. Those salts of calcium, like calcium sulphate, which contain a non-diffusing anion, are, of course, absorbed from the alimentary tract with greater difficulty. It follows, therefore, that calcium salts taken by the mouth are excreted largely with the feces, never having been more than slightly absorbed. But calcium is also excreted in small quantities in the urine, and possibly, to some extent, through the mucous membrane of the lower reaches of the alimentary tract. MAGNESIUM SALTS 313 II. Magnesium Salts. Magnesium salts have not been shown to have the intimate re- lation to normal metabolic processes which characterize the calcium salts. The one exception, of course, is in the large quantity of magnesium present in the bones. It is assumed that the magnesium is deposited there as a result of growth processes taking place in the parenchyma of the skeletal tissue. However, magnesium salts, introduced into the body, do have a marked influence on certain physiological processes. In the chapter on saline cathartics, magnesium action is discussed at length in re- lation to the function of the alimentary canal. More recently, through the work of Meltzer and Auer, 1 it has been pointed out that there is an antagonism between magnesium and calcium salts when these are introduced into the circulation. "When, for example, magnesium chloride is injected into the circulation, animals so tested exhibit a rapid succession of pharmacological phenomena, quickly passing to a narcotic-like condition. Rabbits, for example, at first show accelerated respiration, then lose muscular control, fall over on the floor, and if left alone soon die. If, at the height of the narcotic stage, calcium chloride be injected into the circulation, the unfavor- able condition is quickly removed and the animal will recover, gain its feet, and, in the case of the rabbit, begin eating almost imme- diately. This is an extremely striking phenomenon. The explanation offered by the authors is that magnesium has a narcotic effect, which is anesthetic in character. Guthrie and Ryan 2 advocate a different explanation, namely, that magnesium has a curare-like effect on motor nerve endings. It is this action which destroys the motor control of the animal, and when not antagonized, of respiration itself. The introduction of calcium into the circulation antagonizes the curare-like action and the animal quickly regains control of its skeletal muscles. Magnesium, instead of producing a primary anesthesia, in reality produces a primary stimulation. This is shown by accelerated res- piratory movements and more sensitive reflexes. The stimulating effect passes over into a paralysis with the loss of nerve function. 1 Meltzer, S. J., and Auer, John: American Journal of Physiology, Vol. XIV., p. 366. 2 Guthrie, C. C, and Ryan, A. H.: American Journal of Physiology, Vol. XXVI., p. 329, 1910. 314 SALTS OF THE CALCIUM AND MAGNESIUM GROUP So far as the motor apparatus is concerned this undoubtedly, as Guthrie and Ryan have emphasized, depends upon the action of these salts at the motor nerve endings. They state that: " Results show that magnesium salts in common with numerous other crystal- loids exert a very decided stimulating action when applied directly to the exposed trunk of a sciatic nerve of an otherwise intact frog. In- deed magnesium chloride stimulated more powerfully than certain other of the substances." They are inclined to consider the action of these salts, magnesium included, from the standpoint of interference with the oxidations during nutritional changes, i.e., as asphyxial in character. It is well known that certain toxins, particularly tetanus toxin, produce their poisonous effects by a hyperstimulation of the nervous motor mechanism. Since this is the point which is depressed by the magnesium salts, it is obvious that injections of magnesium chloride solutions, under this special toxic condition, would lead to a reduc- tion in irritability of the motor end apparatus, i.e., would show antagonism against tetanus toxin. This particular fact has been made use of in clinical 1 practice in the saving of life after tetanus had developed. It apparently gives the body a respite in which the tissues may sometimes successfully continue the process of develop- ing antitoxins. III. Barium and Strontium. Barium and strontium salts, which belong to the calcium-mag- nesium group chemically, have proven quite interesting from a phar- macological point of view. Barium, in particular, introduces certain changes, comparable in character to the reactions of digitalis. Ba- rium has already been treated, see page 174. Strontium, however, is of little significance pharmacologically. 1 Kocher. T.: Correspondenz-Blatt fur Aerzte, Basel; Vol. XLIL, p. 969, 1912. Abstract in Journal American Medical Ass'n, Vol. LIX., p. 1490. 1912. CHAPTER XLII. THE SALINE CATHAETICS. Under the heading of alkali metals and the alkaline earths we have discussed the physiological action of a number of salts. Some of these salts are characterized by their ready solubility and the facility with which they are absorbed, while others, sometimes less soluble, are characterized by the difficulty with which they are ab- sorbed from the alimentary tract. Certain of the salts of this latter group produce, by virtue of their physical and chemical characters, special actions on the alimentary canal itself. This group is called the saline cathartics. The saline cathartics hasten evacuation of the bowels. This is accomplished in part by the action of physical characters of the salts, but also in part through their chemical properties. Of the saline cathartics the most important and commonly recog- nized are sodium sulphate, known as Glauber's salt; magnesium sul- plate, known as Epsom salt; and sodium potassium tartrate, known as Rochelle salt. Beside these specific salts any sulphate, citrate, tar- trate, or phosphate of sodium, potassium, megnesium, or lithium will produce saline catharsis, though of course with greatly varying intensities of action. I. Nature of the Action of the Saline Cathartics. An analysis of the nature of saline catharsis must rest upon an understanding of the physiology of the alimentary tract. Foods that are taken into the alimentary canal undergo a process of solu- tion and absorption. The solution is accomplished largely by virtue of the action of enzymes introduced into the canal by the various alimentary secretions, saliva, gastric juice, pancreatic juice, bile, etc. Absorption takes place along the full length of the alimentary tract, occurring more rapidly through the wall of the small intestine and the upper part of the large intestine. Food is moved along the alimentary tract as a result of the 315 316 THE SALINE CATHARTICS muscular contractions of its walls, especially by the contractions which are peristaltic in character. Both secretion and the muscular move- ments of the alimentary tract are under complicated nervous regu- lation, a part of which at least is carried out through local reflex mechanisms. As the algebraic result of the four factors, i.e., quan- tity of food ; rate and quantity of secretion ; rate and time of absorp- tion; and rapidity of the passage of the food along the alimentary tract, there will be a certain quantity of content of a certain con- sistency which will reach the lower portion of the large intestine, the descending colon. Under the control of the reflexes of defecation this residue will pass into the rectum and be evacuated from the canal. Anything either normal or pharmacological, which will vary one or more of the above four factors, will influence either the character or volume, and through these or by other action will stimulate the defecation reflex, hence determine the rate of discharge of the residue of feces. The saline cathartics influence all these factors except the first, namely, the quantity of food. This we will undertake to explain. The typical saline cathartics, the sulphates, citrates, and tartrates, are characterized by non-diffusibility or at least retarded diffusibility. When these salts, therefore, are introduced into the alimentary tract the first and most striking influence noted is that upon the volume of the content of the bowel. Relatively little influence is exerted in this regard in the stomach, but a profound influence in the intestine, especially the small intestine. The presence of non-absorbable ions gives a permanent condition producing osmosis, which in this instance will tend to draw water from the mucosa into the tube of the intestine. Particularly is this true while the concentration of the salts is hyper- tonic to the body fluids and tissues. In fact, the rate of transfer of fluid is in fairly close proportion to the concentration of the non-absorbable ions. The sulphates, for example, are absorbed slowly and with marked, difficulty. They produce, therefore, a withdrawal of water from the blood and tissues. This increases the volume of the alimentary content. If the volume becomes great enough to mechanically distend the intestine that will in itself stimulate the muscular mechanism and therefore cause an increase in the peristalses, thus hastening the driving of the content down the alimentary tube. The net result is that the volume of food, fluid, etc., is passed along the alimentary canal more rapidly than normally and reaches the rectum in a more fluid form. The rate at which the above physical factor acts is largely de- NATURE OF THE ACTION OF THE SALINE CATHARTICS 317 pendent, so far as the particular saline is concerned, upon the amount and concentration of the salt used. There is another factor, however, and that is the condition of the body as regards its normal content of water. Experiment-ally it is shown that if an animal be restricted in its allowance of water and fed a comparatively dry food for say 24 hours or more, its tissues become somewhat hyper- tonic. Under this condition of the body the non- diffusible saline cathartics act more slowly, or fail of purgation. All substances which extract water from the mucous membrane of the alimentary tract have some degree of irritant influence on the mucosa. This irritant influence may vary greatly in intensity, depending not only upon the character of the salt itself, but also upon its concentration, and upon whether or not the stomach and intestine are relatively free of food at the time, i.e., intimacy of contact. A concentrated solution of a cathartic salt, or still better, an undissolved salt, will withdraw water from the mucosa of the stomach, where the salt first comes to rest for a time, so rapidly that the cells become quite hypertonic. This produces local irritation, and in many cases leads to marked reflex stimulation, accompanied by a burning sensation, sometimes nausea and vomiting. But this action of the saline cathartics is not vigorous enough to produce an inflammatory process. The action of this factor of irritation, es- pecially in the duodenum and the upper lengths of the small intes- tine, may lead to quite profound reflex stimulation of the peristaltic mechanism of the canal. This increase in peristalsis may be great enough to lead to evacuation of the bowels within 15 or 20 minutes after the salt is taken, whereas an evacuation from the pure osmotic action would not ordinarily take place under 2 or 3, and usually more hours. Any irritation of the gastric mucosa will inevitably reflexly accelerate the secretions not only of the salivary, but also of the gastric glands. Probably the pancreatic gland, too, is reflexly stimu- lated by irritation of the gastric and of the intestinal mucosa. It follows that there will be a great increase in the total volume of the gland secretions poured into the alimentary tract, and these will add to the quantity of the content. Ordinarily the sum total of the volume of the secretions of the alimentary tract will amount to some 3 or 4 liters per 24 hours, i.e., saliva 800 to 1000 cc, gastric juice 1000 to 2000 cc, bile 500 to 700 cc, pancreatic juice 600 to 800 cc. Under the stimulating effect of a concentrated cathartic these quantities are correspondingly increased. 318 TEE SALINE CATHARTICS We have, therefore, as a result of the general action of the saline cathartics the possibility: 1. of lowering the rate of absorption. 2. of extracting fluid from the mucous membrane. 3. of stimulation of the alimentary glands to increased secretion. 4. of stimulation of the peristaltic movements, thus hastening the content along the tube. 5. of stimulating the reflex mechanisms of defecation. A salt that typically produces the first four of these processes will of course more quickly lead to purgation. i. Sodium sulphate. — Glauber's salt or sodium sulphate disso- ciates into the readily diffusible sodium cation and the almost non- diffusible sulphate anion. If solutions of isotonic concentration are taken by way of the mouth they hinder the normal process of absorp- tion. This factor alone would produce a seemingly more liquid con- tent of the intestine, which is, of course, only a secondary result of the failure of normal absorption. But hypertonic sodium sulphate solutions cause some positive abstraction of fluid from the alimentary mucosa. The result is that there is an addition to the amount of fluid present in the alimentary content instead of a decrease as in normal absorption. The net results of the action of this positive factor is a mild catharsis, even were no other factor involved. However, sodium sulphate stimulates the neuro-muscular mech- anism involved in alimentary peristalsis. This can be shown if one performs the Moreau experiment by introducing sodium sulphate into the primary loop of the intestine. In this instance he will find that vigorous peristaltic contractions are set up almost immediately, in fact making it difficult to fill the loop with the fluid without ex- ternal pressure. This is in contrast to the behavior of other cathartic salts in this regard. It is this vigorous intestinal contraction that produces the griping pain so often noted when Glauber's salts are used therapeutically. The effect is due to the direct stimulation of the mucosa, which leads to a reflex through the local nervous mechanism controlling the contractions of the intestinal wall. Under the above discussion the action of sodium sulphate is ex- plained as due to two processes: osmotic extraction of fluid from the mucosa and increase in physiological activity of the muscular walls. Hertz, however, has revived the theory of stimulation, which was advocated by MacCallum some years ago. Hertz's x studies indicated 1 Hertz, A. F., Cook, F., and Schlesinger, E. G.: Guy's Hospital Reports, Vol. LXIIL, 1901. ACTION OF SODIUM SULPHATE 319 that watery stools from sodium sulphate did not contain an increase in the sulphate ions, in fact showed that the sulphates excreted by the feces were found only several hours after the first watery stool. On the other hand, there was a marked excretion of sulphate by the urine within eight hours after the taking of the salt. These Fig. 60. — The effect of sodium tartrate upon the structures of the kidney. Necrosis involves every convoluted tubule. The glomeruli are normal. From Underhiil, Wells, and Goldschmidt. factors he says indicate that, " The semi-fluid character of the first stool was not a result of water being extracted into the intestine by the salt." He emphasizes the point of view of Aubert, that after absorption the salt acts on the neuro-muscular mechanism of the colon rather than on the small intestine, producing an increase of motor and secretory activity. The sodium sulphate influence on intestinal movements is admitted and strongly emphasized, but that it is an 320 THE SALINE CATHARTICS effect occurring only after absorption is at present a debatable question. 2. Sodium potassium tartrate. — The double salt of sodium and potassium tartrate owes its cathartic action to the low diffusibility of the tartrate anion. The cathartic action of this salt is milder than that of sodium sulphate. It does not produce such vigorous intestinal muscular contractions, hence is relatively bland in its effects. The anion in this case is slowly absorbed, but unlike most organic acid radicles, is not readily oxidized in the body. It is slowly excreted by the kidney unchanged. But while the tartrate is unchanged, one cannot say as much for the kidney after the tartrate has passed. Underbill, "Wells, and Goldschmidt 1 have quite recently shown that tartaric acid is vigorously toxic for the renal tubules, pro- ducing marked nephritis with extensive necrosis. Curiously enough the glomerular capsules escape the injury, apparently due to the fact that they are not the main excretory organ for this injurious organic acid. The authors have given both morphological and physio- logical evidence for the contention offered. More recently Pearce and Ringer 2 have re-investigated the action of the tartrates in the production of experimental nephritis. Their conclusions from ex- periments on dogs are expressed in the following quotation : — " The administration to the dog of tartrates, by mouth, intra- peritoneally or subcutaneously, causes a severe renal disturbance, characterized by albumin and casts in the urine and diminished flow of urine or complete anuria. The urine passed before complete sup- pression is water clear of low specific gravity, and the solid con- stituents are greatly decreased. The most striking histological change in the kidney is necrosis of the convoluted tubules, with fatty changes in the loops of Henle and sometimes also in the collecting tubules. Exudative glomerular lesions occur in about half the animals with tubular lesions. " The mode of administration does not influence the character of the renal lesion, except in as much as diarrhea, following administra- tion by mouth, may cause rapid removal of the salt from the in- testine, and thus by reducing the amount of absorption prevent the severer types of lesion." It has not yet been determined how toxic the tartrates are for 1 Underhill, Wells, and Goldschmidt: Journal of Exper. Medicine. Vol. XVIII., p. 317, 1913. 2 Pearce, R. M., and Ringer, A. I.: Journ. Medical Research, Vol. XXIX., p. 57, 1913. ACTION OF MAGNESIUM SULPHATE 321 the alimentary mucosa. The current view that they are mild and non-toxic should now be questioned on account of the action demon- strated on the renal parenchyma. It is probable that the mucosa does not escape an influence comparable to that observed in the kidney. If so its cathartic action of sodium and potassium tartrate more nearly approaches the character of that of the vegetable purgatives than other members of this group. 3. Magnesium sulphate. — Magnesium sulphate owes its saline purgative action to the slow diffusibility of both the positive mag- nesium and the negative sulphate ions. Magnesium is absorbed from the alimentary canal with difficulty, and we have already seen that the sulphate ion is greatly retarded in its passage through the in- testinal wall. Therefore the presence of this salt produces a very effective condition of interference with the ordinary absorptive process. The content of the alimentary tube is kept relatively con- stant in fluid during its passage toward the colon. If the magnesium sulphate is comparatively concenerated, then the hypertonic solution will draw fluids from the intestinal mucosa, as has already been described. The salt is not strongly irritant to this membrane and we may assume here a more vigorous physical action than with other members of the salts. The intestinal content reaches the colon in a more fluid form and in greater bulk and this leads to the cathartic action. The comparatively non-irritant qualities of magnesium sul- phate make this salt a sufficient one for mild catharsis. If highly concentrated solutions in too great amount be used, then there is greater absorption of the salt itself, a process that may be sufficient to carry enough into the circulation to produce its specific depressant action. The systemic action has already been described, page 313. "When such increased absorption occurs there is a tendency to suppression of intes- tinal peristalsis and to the appearance of a degree of the toxic action of the magnesium ion, as manifested on the respiratory mechanism and the skeletal muscular complex. In the case of magnesium sulphate a process of precipitation and elimination of the magnesium cation goes on in two ways; first, through the formation of carbonates from the carbon dioxide con- tent of the blood, and second, by the formation of magnesium soaps from the fatty acid liberated during fat digestion. Each of these compounds reduces the magnesium to a molecular basis. The sul- phate ion, under these conditions, is slowly absorbed and combines with hydrogen ions derived from the blood and tissues to form acids, or with the alkaline bases to form soluble sulphates, which are ex- 322 THE SALINE CATHARTICS creted through the kidney. Either process tends to work against the alkalinity of the blood and toward relative acidosis. MacCallum * has studied the cathartic action of the magnesium salts by the method of hypodermic injections. He came to the con- clusion that the magnesium sulphate produced its cathartic effects through the direct stimulation of the secretory nerve mechanism, controlling the flow of fluids into the colon and the mechanism of defecation. He describes the appearance of catharsis as occurring after a constant and rather short time interval, thus throwing doubt on the osmotic properties and relations described above. Hertz has to some degree supported this view of saline catharsis in general as previously mentioned. However, this work of MacCallum 's has been questioned more recently, and it has been suggested that his position is erroneous, largely through the unfortunate choice of rabbits as investigation animals. Babbits are ill adapted to this type of experiment. One may, in the circumstances, take a conservative position. The introduction of magnesium sulphate by way of the mouth is said to be favorable in certain types of edema. In fact, magnesium sulphate may, through its vigorous extraction of fluid from the mucosa, quite strongly reduce the water content of the tissues. Even the normal tissues may be rendered hypertonic. If the tissues are already hypotonic from edematous processes, then saline catharsis favors the elimination from the body of such injurious materials as toxins, poisons, etc. The carrying out of the body of a large amount of fluid by either the alimentary canal or the kidney will of neces- sity wash out large quantities of such special materials. If the toxins are derived from the putrefying masses in the alimentary canal, then, of course, the beneficial influence consists largely in removing the source of the injurious agency. It is this latter factor which is utilized by the clinician in the course of many infectious conditions of the alimentary tract. It would seem, at first sight, that if the tract were already inflamed and in the over-active condition ex- pressed by diarrhea, the giving of a purgative of any kind would be contraindicated. But the mild saline purgatives do not add much to the pathological inflammatory process and they have the further advantage that their action begins at the upper or duodenal lengths of the alimentary tract, hence they tend to dislodge and remove the putre- fying or infecting agency wherever it may be located. The specific poi- sonous action of the magnesium ion of magnesium sulphate and the tar- trate ion from the tartrates justified the caution against the use of these 1 MacCallum: American Jour. Physiol., Vol. X., 1903. THE SALINE CATHARTICS AS ENEMAS 323 drugs in conditions of marked inflammation or possible necrosis of the alimentary canal. Where the protective mucous membrane of any sur- face has for any reason been injured there is always the danger of the absorption of such toxic ions, an absorption that may produce very unfavorable, even dangerous, results. 4. The saline cathartics as enemas. — The discussion of the action of the saline cathartics presented above is based on the changes which follow their introduction into the alimentary tract by way of the mouth. Clinically speaking, there are many conditions in which evacuation of the bowel is desired, yet in which this route is un- favorable or prohibited. Rectal injections or enemas are utilized under these conditions. Pure cold water is one of the most active agencies for this purpose. It stimulates mildly and therefore sets up rectal peristalsis, thus producing evacuation. On the other hand, if the content of the rectum is relatively dry and firm, a slow absorp- tion of water by the fecal matter may be desired in order to soften and facilitate the evacuation. In this case enemas of any of the above saline cathartics, or, in fact, of the more mildly acting saline soaps, may be used. Sodium sulphate favors the development of peristalsis, which may in some cases amount to rather violent tenes- mus. Magnesium sulphate facilitates a relatively slow secretion of considerable fluid into the bowel, the consequent softening of the content, and the development of mild defecatory impulses. The use of salines as enemas rests chiefly on the factor number five, previously mentioned, i.e., the stimulation of some portion of the reflex mechan- ism controlling the act of defecation. For agencies which act particularly on the large intestine, the reader is referred to the discussion of the vegetable purgatives. CHAPTER XLIII. ALKALIS AND ACIDS. The displacement of the usual salt anions, i.e., chloride, bromide, sulphate, etc., by hydroxyl, OH, and the substitution of the usual salt cations, i.e., sodium, potassium, magnesium, etc., with hydrogen, H, gives to these substances properties whereby they are peculiarly toxic. The alkalis, especially in the stronger solutions, are particu- larly caustic. The acids, on the other hand, are many of them pre- cipitants to proteins, and in more concentrated solutions also caustic, therefore toxic. Alkalis. The alkalis of most general interest are the hydrates of sodium, potassium, ammonium, calcium, etc. The carbonates of these bases are alkaline in reaction, but this is due to the fact that the dissociated carbonate anion tends to combine with one hydrogen of water, set- ting free hydroxyl ions. Hence in both cases the alkalinity and, therefore, the caustic action is due to the hydroxyl ion. The action of the cation of the alkalis is the same as in the corresponding salts which have already been discussed. A mild degree of alkalinity is normal to living protoplasm. The physiological fluids are slightly alkaline in reaction and blood plasma from the presence of sodium carbonate and disodium phosphate nor- mally has the percentage of alkalinity 182 to 218 mgr. NaOH per 100 cc. of blood, Simon. The blood plasma holds tenaciously to the alkaline reaction. The chemical reactions of protoplasm take place best under this condition of mild alkalinity. If the alkalinity is overcome and the reaction reduced to acid, then the physiological processes of protoplasm are hindered or cease altogether. A slight increase in alkalinity above the normal limit hastens physiological activity. Hydroxyl ions promote hydration processes in the tissues, hence the favorable action just mentioned is in all probability due to a cor- responding increase in the fluidity and permeability of the tissues. The favorable limits or range of increase in alkalinity are re- 824 ALKALIS 325 stricted. The higher concentrations tend to produce injurious hydrolysis of the tissues. The alkalis are therefore peculiarly caustic. i. The cauterizing action of the alkalis. — Sodium hydrate in 5 per cent, solution applied to the skin quickly leads to hydrolysis of the corneous layers. The solution readily penetrates to the deeper layers of the corium, producing dissolution and corrosion. The concen- trated solutions of the hydroxides kill, but do not dissolve the tissues until the alkali is diluted, at which time solution quickly takes place. Many violent accidents constantly occur from this action of the alkalis. If the corrosive agent is not removed or neutralized, then it continues to penetrate deeply into the tissues and may lead to the death and dissolution of extensive areas. 2. The physiological action of the alkalis. — Alkaline salts of the hydrates produce changes in physiological responses of the body in two ways. One is through the mild stimulation of reflex nervous mechanisms, especially in the mouth and gastric region. The second is through the change in the degree of alkalinity of the body proto- plasm. When alkalis, carbonates or hydrates, are taken by way of the mouth, the first effect is a neutralization of the acid gastric juice, accompanied by a mild reflex stimulation of the gastric mucosa. When these solutions pass into the intestine they favor the normal alkalinity that already exists in this region. Alkalis are readily absorbed. When they pass into the blood stream and are distributed throughout the body they favor protoplasmic processes chiefly through their favorable influence on oxidations. Muscles contract more vigor- ously, glands secrete more efficiently, as for example the increased quantity of the bile. However, once in the circulation, the added alkalinity is quickly adjusted by virtue of the ability of the tissues to neutralize any marked variation from the normal per cent, of alkali or acid. As an example, one needs only to note the excess of carbon dioxide con- stantly being formed, which can take up and balance any increase in the alkalis. The alkalis arc readily excreted through the kidney, and it is said that uric acid excretion is increased by the alkalis. The body can handle considerable amounts of alkali, enough to reduce the normal acidity of the urine or even produce a slight alkalinity. Clinicians utilize this factor in combating those condi- tions of hyperacidity present in certain types of acidosis. 326 ALKALIS AND ACIDS II. Acids. The mineral and the organic acids may be considered together, though they vary strikingly in certain properties. On the whole, the acids are generally toxic to protoplasm. The mineral acids are peculiarly so. Although hydrochloric acid is a normal constituent of at least one body fluid, i.e., gastric juice, yet it is one of the most toxic of the group. However, in the percentage represented in the gastric juice the hydrochloric acid is mildly antiseptic. In fact, this antiseptic action is normally great enough to destroy large numbers of bacteria, which would otherwise enter the lower part of the alimentary tract, and become positive sources of disease in the body. Nitric acid is strongly oxidative and precipitative, as is also sulphuric. Both are corrosive in concentrated form. If the stronger mineral acids are applied to the skin they produce at once precipitation of the protein constituent and death of the epidermis. The precipitation of the tissues tends to hinder the further diffusion of the acid, yet when not neutralized there is slow diffusion and destruction of the deeper tissues. The process is violently irri- tant, hence there is great pain from the continued hyperstimulation, often leading to nervous shock and collapse. The mineral acids exert the same type of cauterizing action on the mucous membranes as on the skin, that is, there is a tendency to precipitate proteins, resulting in the forming of layers or coats, which delay the diffusion of the acid into the deeper parts. The reflex effects of this type of corro- sion on the mouth and alimentary tract are tremendous. There occurs an over-stimulation of the great medullary centers leading ultimately to vascular dilation, cardiac irregularity, and in some cases collapse with the accompanying shock. The organic acids are also strongly irritative, but not so corrosive. In the body they more quickly become diluted and certain of the acids are oxidized; for example, acetic, citric, etc. Among this group tartaric acid is not readily oxidized, therefore its irritative properties continue up until the time of complete elimination. i. The action of dilute acids. — The normal 0.2 per cent, hydro- chloric acid present in the gastric juice performs several interesting functions. These have been described by Cannon in his discussion and demonstration of the acid closure of the pylorus and of the cardia. The presence of 50 cc. or so of 0.2 per cent, hydrochloric THE ACTION OF DILUTE ACIDS 327 acid suddenly introduced in the upper end of the duodenum leads to local reflex contraction of the pyloric sphincter, and, therefore, closure of the pylorus. The cardiac sphincter reacts in much the same way. Both instances are examples of reflex stimulation of sensory structures in the mucosa by the dilute acid. Dilute acids act in like manner in other parts of the alimentary tract, as for example the stimulating effect of acetic or citric acid in the mouth. A taste of lemon juice is sufficient to set up a quite vigorous secre- tion of saliva. The same reflex mechanism can be set into action by dilute inorganic acids, hydrochloric acid, sulphuric, etc. The fruit acids play an important physiological and pharmacological role in the body by virtue of this property. Dilute acids, both organic and inorganic, are readily absorbed, possibly in part by virtue of the formation of acid proteins. When introduced into the circulation the acids meet the alkalis resulting from tissue metabolism and are either oxidized or neutralized. For- tunately the body possesses a complex and adequate mechanism for doing this very thing. A quantitative excess of acid becomes in- jurious since it leads to the precipitation and destruction of proteins and a corresponding freeing of basic nitrogen for the elimination of the acid. However, before this takes place a considerable excess of acids may be taken care of by the body by virtue of the conversion of neutral salts into acid salts, such as the conversion of sodium carbonate into bicarbonate, monohydrogen phosphate into dihydrogen phosphate, etc. Any free ammonia in the body fluids or tissues fixes acid ions, forming the corresponding salts. Ammonia nitrogen is always an available base for neutralizing excess of acid ions. Acids, therefore, tend to increase the ammonia output in the urine, and in direct ratio to reduce the urea output by the equivalent interference with the usual formation of urea of ammonia wastes. The kidney excretes acids largely as acid salts. If the quantitj 7 is great enough to lead to an excess of acid there will be a positive irritation and necrosis of the renal epithelium, which, of course, is unfavorable. The organic acids, like acetic, citric, etc., are oxidized by the body. Under normal conditions, therefore, these acids are eliminated with- out injury to the organism. Tartaric acid is an exception in the group. If for any reason the oxidative power of the body is reduced, then a portion of the organic acids may pass through the body in- sufficiently oxidized and prove injurious. The therapeutic condi- 328 ALKALIS AND ACIDS tion of acidosis is a condition in which, for reasons of incomplete oxidations an excess of acids occurs. These acids may be derived from the incomplete oxidation of fats on the one hand, or of carbon- hydrates on the other, as well as from acids taken into the body from without. CHAPTER XLIV. OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC. Oxygen. That oxygen is necessary to the life of animal tissues was long ago established. The part played by oxygen in respiration in general was made known by the ancient experiments of Lavoisier and of Priestly. In the mammalian body the amount of oxygen is kept relatively near the saturation point in the animal fluids. That is, considering the partial pressure of oxygen in the air it is found that the amount of oxygen in the blood plasma and in the body lymphs is high and comparatively constant. It is assumed in physiol- ogy that the interstitial oxygen is held in some form of fixed compound with the living protoplasm. Such a favorable condition is made possible only by the development of respiratory pigments, in the case of man and mammals the hemoglobin. Experiments on isolated tissues readily demonstrate the necessity for oxygen. Loeb has given special emphasis to this point, calling attention to the fact that if free oxygen is removed from about developing eggs of marine invertebrates the developmental process slows or ceases. It is immaterial whether the oxygen is removed directly or its utilization prevented by the presence of some salt, as for example sodium or potassium cyanide. The various methods for studying the isolated organs, such as portions of the intestine, uterus, etc., all provide for an adequate supply of free oxygen in contact with the tissue. When this free oxygen is withheld, then the normal physiological processes are reduced or tend to disappear. Under ordinary physiological conditions an oxygen environment, rep- resented by the atmospheric pressure at ordinary levels, is sufficient. "When this percentage is reduced by extreme heights, as in aerial navigation, it may happen that the percentage of free oxygen is below the necessities of the body and unconsciousness and death may result. A diminished percentage of oxygen acts as a stimulus to the nervous tissue, particularly the respiratory center, though one must remember that the condition is usually associated with an increase of 330 OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC. carbon dioxide, which stimulates the respiratory center even more strongly. This particular center is, in a way, a special case. The accelerating influence of oxygen-lack occurs only within restricted limits. If the deficiency of oxygen is too great, then even the res- piratory center loses its irritability and becomes paralyzed. The recent work of the Pike's Peak Expedition 1 served to show that there is a certain amount of adaptation which the body can make to rarefied atmospheres. If, under such an environment, physical exertion is reduced to a minimum life is maintained with a much lower percentage of oxygen in the air than would otherwise be required. i. Effects of increase of oxygen. — The respiration of pure oxygen does not increase the amount of available oxygen in the body to the extent that one would suppose. Normal respiration of ordi- nary air is adequate to saturate about 0.9 the hemoglobin, hence we have only the remaining 0.1 as a variant for increasing the amount of oxygen carried into the tissues. Of course in certain diseases or in certain environmental conditions of a physiological nature there is great reduction in the total amount of oxygen secured by absorp- tion. Under these circumstances the substitution of oxygen for ordi- nary air will prove favorable. The higher percentage of oxygen respired will facilitate the amount absorbed by increasing the differ- ence in the absorption level. Thus, in cases where the active portion of the lung is reduced to a fraction of its normal, there might possibly be enough oxygen absorbed from the pure gas to supply the physiological needs of the body, where such would fail if ordinary air were breathed. In the mammalian body the percentage of oxygen in the blood plasma and in the lymph of the capillary bed is below the saturation point. In the tissue itself it is generally assumed that the free oxygen is fixed as soon as it enters the protoplasm. It has been stated above that the cutting off of the supply of free oxygen quickly stops protoplasmic activity. Its readmission leads to a re- establishment of metabolism, a point proven in the development of fertilized egg cells, and more fully elucidated by Loeb. If pure oxygen is made to saturate the lymph bathing a tissue, that will facilitate or stimulate the intensity of physiological processes. Though the excess of oxygen in contact with protoplasm increases oxidative 1 C. G. Douglas, J. S. Haldane, Y. Henderson, and E. C. Schneider: Philo- sophical Transactions of the Royal Society, Series B, Vol. CCIIL, pp. 185-318, 1912. THE PEROXIDES 331 processes it must not be forgotten that excess of oxygen in the respira- tory gases does not necessarily provide this excess around the tissue itself. It seems that this point may be over-emphasized because of the general assumption of the contrary proposition. II. The Peroxides. Of all the oxidizing agencies the peroxides are probably the simplest and most active. Hydrogen peroxide, H 2 2 , serves as an ideal representative of the class. The oxidizing power of hydrogen peroxide on living tissues is recognized in the therapeutic use of the chemical for sterilizing and disinfecting purposes. A solution of 1 to 10,000 in water is sufficient to kill ciliate infusoria in from 15 to 30 minutes (Paul Bert). Hydrogen peroxide in the stronger solutions- prevents development and leads to the destruction of many forms of bacteria, in particular the anaerobes. Hydrogen peroxide brings about oxidation in certain types of chemical reaction where the presence of ordinary atmospheric oxygen fails of reaction. In the human body there are reductions which occur in the presence of normal protoplasm in particular groups of chemicals the oxidations of which cannot be produced outside of the body except in the presence of hydrogen peroxide. This has led physiological chemists to certain theories of auto-oxidation. These views, together with an illustration, are presented distinctly in the following quotation from Dakin x : "It is generally believed that living cells contain labile sub- stances capable of taking up molecular oxygen from the oxyhemo- globin of the blood with the formation of unstable peroxides possess- ing marked oxidizing properties. Schonbein, and later Bach, have shown that a large number of substances of the most diverse kinds when undergoing slow oxidation yield substances giving the reactions of hydrogen peroxide. " In addition, Baeyer and others have actually isolated a number of superoxides and substituted hydrogen peroxides derived from many different types of aldehydes and ketones. It certainly appears likely that substances of this type are concerned with the oxidations of substances in living tissues, and indeed such knowledge as has been 1 Dakin, H. D. : Oxidations and Reductions in the Animal Body. New York, p. 7, 1912. 332 OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC. derived from a study of the various oxidations effected by enzymes found in the living cells strongly supports such a supposition. The occurrence of certain metallic salts, especially those of iron and manganese, in conjunction with certain vegetable oxidases, and the extraordinary influence they have upon the ferment activity, is paral- leled by the catalytic action of these same salts in accelerating oxi- dations in vitro by means of hydrogen peroxide. " "Within the last few years other evidence has been secured in favor of the belief of the formation of unstable superoxides as the active oxidizing reagents of the body. If the hypothesis of super- oxide formation is correct, one would expect a certain similarity between the oxidations effected in the body and those brought about by the simplest superoxide, namely hydrogen peroxide. As a matter of fact, an extraordinarily close similarity as regards the types of reaction exists between the two sets of phenomena. Thus the normal saturated fatty acids in the body undergo oxidation in the /^-position, butyric acid yielding acetoacetic acid — a truly remarkable change. " Hydrogen peroxide alone of all the various chemical oxidizing agents brings about precisely the same reaction : — CH .CH .CH .GOOH — * CH .CO.CH .COOH" 3 2 2 3 2 Butyric acid Acetoacetic acid A number of vigorously acting chemical oxidizing agents are very toxic to living protoplasm. Of these may be mentioned chromic acid, permanganic acid, chlorine, bromine, arsenic acid, phosphorus, all of which owe their extreme toxicity to the formation of fast oxygen compounds. These are outside the field of oxidizing agents in the physiological sense, and are discussed under the head of Toxic Action in the appropriate place. M. The Salts of the Heavy Metals. CHAPTER XLV. THE GENERAL EEACTIONS OF SALTS OF THE HEAVY METALS. Salts of metals, roughly classified pharmacologically as the heavy metals, have certain general reactions which influence the functions of the mammalian body. There is no strict line to be drawn from the pharmacological point of view as regards the salts included in this group. But the more important metals included in the discussion are: Copper, lead, zinc, sulphur, phosphorus, iron, mercury, silver, and bismuth. Beside these, a number of other members of the chemical group are pharmacologically active but in no way peculiarly distinct from the action of the members of the group chosen, and of no special practical significance. Chiefly for these reasons they are not in- cluded in this discussion. i. The formation of metal albuminates. — "What changes the dif- ferent salts of a given metal will induce and the comparisons of the reactions of salts of the different metals depend upon several chemical and pharmacological factors which will be briefly discussed. The most typical reaction of the salts of this group consists in the formation of albumin compounds. Most of the heavy metals react with different proteins and protein-like substances to form the cor- responding albuminates. In this regard the organic substances act like acids, displacing the acid in combination with the metal. For ex- ample, lead acetate in contact with protoplasm forms a soluble lead albuminate of the protein moiety of the protoplasm, at the same time setting free acetate with the coincident formation of acetic acid. The same may be illustrated by silver nitrate, mercuric chloride, etc The intensity and rapidity of this reaction depend upon the solubility and the ionizing properties of the particular salt. If the salt is very soluble and ionizes freely, it will produce a more vigorous and rapid precipitation of protein and a corresponding greater pharmacological reaction if that protein is a constituent part of living protoplasm. Organic compounds of the metals are for this 333 334 REACTIONS OF SALTS OF THE HEAVY METALS very reason less intense in their actions than inorganic compounds. In general the reactions of the salts of the heavy metals are astringent, stimulative, irritant, or corrosive. The action is not en- tirely due to the metal factor, but in some forms it is partly due to the action of the acid ion liberated. The metal albuminate is in many instances soluble in excess of the albumin. Some organic compounds, as metal vitellinate, are gen- erally soluble. Most metal albuminates when in small quantity are soluble in excess of the albumin. The different metals vary greatly in this regard. Albuminates of mercury are rather more readily soluble in excess of the albumin than are, for example, silver albumi- nates. Another factor in the human body that greatly influences the solubility of the metal albuminates is the presence of the salts of the alkaline earths. An insoluble excess of albuminate of mercury in neutral watery solution is readily soluble in a physiological saline solution. In the body this factor undoubtedly increases the solubility of not only albuminate of mercury, but of other organic compounds of the heavy metals. Sodium chloride is a constituent of every normal body fluid. "When a metal salt is brought into contact with an animal membrane, as an example the mucous membrane, the characteristic reaction with the formation of albuminate occurs. The reaction is more intensive at the surface of contact, and a layer of albuminate over the mucous membrane is the result. If this albuminate is not very soluble it forms a protective coating to the deeper structures. The film of albuminate forms a resisting membrane to the further penetration and absorption of substances in solution in contact with it. By far the most important constituent of this solution is the hydrogen salt of the acid ion set free when the albuminate formation occurs. If this acid be in itself a toxic and corrosive one, as in the case of mercuric chloride, then it will have its usual effect on the protoplasm. The film of protecting albuminate delays the diffusion of the hydro- chloric acid, hence modifies its corrosive action. If the acid ion of the metal salt be comparatively non-irritant or oxidizable, as in the case of lead acetate, then the influence of the salt as a whole will be astringent. In salts of this nature the concentration and solubility factors are of very great importance in the modification of the form of reac- tion of the tissues. Take, for example, mercuric chloride ; if the solu- tion is present in concentrated form, then the albuminate formed will be deeper, but the more concentrated acid ions liberated will penetrate FORMATION OF METAL ALBUMINATES 335 deeper and quickly, notwithstanding the presence of the albuminate. Inflammation will, of course, be induced. The more dilute solutions, for example the 1 to 1000, do not ordinarily induce inflammation unless held in contact with the tissue for a long time, notwithstand- ing the formation of a surface layer of albuminate. It is obvious that the difference between a stimulative irritant and a corrosive action with such a salt as this is bounded almost wholly by the con- centration factor. The purgative salt, calomel or mercurous chloride, is a splendid example in this connection. Mercurous chloride is so slightly soluble in the alimentary canal that there are never at any one time sufficient ions present to produce more than a mild stimula- tive effect on the mucous membrane. Lead acetate is somewhat illus- trative of this variation in the action of metal salts, since the acetate is comparatively less irritant than the chloride of the mercuric salts. Although lead acetate is readily soluble, the acetic acid formed during its dissociation and reaction in the tissue is not so strong in its toxic effects on the protoplasm. Hence the albuminate coat modifies the action of the acetate down to the point where the total effect is only that of a pure astringent. But in this case a larger quantity of highly concentrated solution of lead acetate may become irritant or even corrosive in its action. Instances of acute gastritis are on record, illustrating this point. The salts of the organic compounds of the heavy metals, such as metal caseinate or soluble albuminate, are comparatively non-toxic. Although these salts are soluble, they ionize very slowly, if at all, and are, therefore, non-irritant. It is for this reason that the newer organic compounds of the heavy metals have been strongly recom- mended in order to displace the irritant and acute toxic action of the inorganic compounds. Speaking generally, the pure metals, as such, are inert. This, however, is only a comparative truth. One may take a piece of iron, a copper coin, or a drop of mercury into the mouth, or it may be swallowed and pass through the alimentary canal with comparatively no injury. However, the alimentary tissues and fluids do dissolve traces of metal, apparently with the direct formation of albuminates. This is held to be the case with metal mercury. If the mercury be in fine division, as, for example, in blue mass, enough of the metal may be taken up to produce a typical mercurial reaction. The presence of hydrochloric acid in the gastric juices may, and probably does, induce this reaction with certain metals. A state of fine divi- sion of the metal would favor this solution in hydrochloric acid. 336 REACTIONS OF SALTS OF THE HEAVY METALS However, this point is based more on theoretical grounds than on the results of wide investigations. In recent years the metals have been recommended and used in practical therapeutics, as in the colloidal solutions. Colloidal metals are in a state of fine division, and in this form become available for the formation of albuminates and may, in fact in some instances do, enter the body quite rapidly, and produce the usual and typical reactions. 2. The absorption of salts of the heavy metals. — Under the general heading of this division we may introduce the general under- lying principles which, with minor variations only, hold for practically all of the heavy metals. The basis for these observations has already been laid in the discussion of the general action of the heavy metals. Salts of the heavy metals are absorbed by the human body only through mucous membranes or from abraded surfaces, as, for ex- ample, wounds, ulcers, sores, etc. Absorption in any case is slow and occurs with difficulty. The very process of the formation of metal albuminates, as discussed above, for the time being delays or even stops the passage of those metals through any layer of living cells. In comparing different metals one can see at once that the rapidity of absorption in each instance will certainly depend upon the relative solubility of the albuminate formed. Since the albuminates are soluble in excess of protein, and that solubility is increased by the presence of salines, it is obvious that in the human body there are factors acting which are quite adequate to ultimately carry the metal into the circulation and thus distribute it throughout the body. The slowness of absorption is adequate to account for the fact that the heavy metals rarely produce acute general toxic symptoms. Not enough of the metal enters the system at one time to lead to the general reaction. Where apparent acute general toxicity occurs it is very apt to be complicated by the local reaction from the acute cor- rosion of a particular area, as, for example, in acute gastritis from the action of silver nitrate. Absorption takes place with fair rapidity from extensive abrasions or ulcers. The slow and long continued absorption will ultimately introduce enough metal of most heavy metals to lead to chronic toxic action. Perhaps the most typical example of this kind of metal poisoning is that of chronic lead poisoning. 3. The distribution and excretion of the heavy metals in the body. — Under the action of the principles outlined in the preceding paragraphs, the salts of the heavy metals are introduced with more or DISTRIBUTION AXD EXCRETION OF THE HEAVY METALS 337 less delay into the general circulation. In the majority of cases this absorption is extremely slow, and scarcely detectable traces are thrown in the circulation in any short period of time. Once in the blood, the metals are distributed throughout the body. They do not remain long in the blood; in fact, they are rapidly removed. Apparently they are taken up by the epithelial tissue of the vascular bed and passed over to the adjacent parenchyma of whatever organ they come in contact with. The liver is no doubt an important de- pository for heavy metals. Higher percentages of the metals are extracted from the liver than from any other organ of the body, but the metals are deposited in practically all organs, especially glandular organs and organs rich in connective tissue. The excretion of the metals takes place through all glandular structures. This includes not only the kidney, but the glands of the alimentary canal, and especially the alimentary mucosa. The mucosa of the large intestine has been proven to be a channel for the ex- cretion of a number of heavy metals, possibly because the important metal precipitant, hydrogen sulphide, is present in this tissue in greater quantity than in other portions of the digestive tract. The slow ex- cretion of the metals into the upper reaches of the alimentary tract brings about a condition favorable to their reabsorption. In fact, re- absorption occurs in greater or less degree with most all of the heavy metals. The net result is a cycle of reabsorption and reexcretion, oft repeated through a vicious circle which prolongs the general toxic action on the body tissues. It is this factor which so strikingly delays the final excretion of metals after their introduction into the body, a delay that is known to extend over several months. In the case of silver, the deposits in certain tissues, especially the subdermal con- nective tissues, become permanent, i.e., never dissolve. 1 With these general factors in mind, we may take up the more im- portant individual metals of this series. The elements, iron, sulphur, and phosphorus, differ from the other heavy metals owing to the fact that these metals are present in normal protoplasm. They are, there- fore, singled out and treated first in the series. 1 Dr. Crispin has just reported an interesting case of argyria from the use of collargol, Jour. Am. Med. Ass'n. Vol. LXIL, p. 1394, 1914. A laparotomy on this case revealed the interesting fact that the " tissues, muscles, and in- testines had a bluish tinge." It is of further interest that the treatment of the case for another affection by 10-grain doses of hexamethylamine led to a clearing of the skin and to partial disappearance of the argyria. CHAPTER XLVL IRON. The numerous iron salts known to chemists are not of pharmaco- logical interest as such. They for the most part ionize, in which process iron is set free as active cations. The physiological action of iron may be illustrated by consideration of ferric chloride. i. The normal relations of iron in the body. — The most typical iron-containing substance in the mammalian body is hemoglobin, present primarily in the red blood corpuscles, but also in smaller quantity in the muscles, certain glands, etc. Hemoglobin has the distinction also of being the most complex organic molecule of the mammalian body. It has the enormous atomic weight of 16,660. Iron is also yielded, though only in smaller quantities, by the muscles, liver, skeleton, in fact by most of the tissues of the body. It is present only in traces and possibly some portion of the iron attributed to certain tissues may have been derived from corpuscles of the blood still in the vessels of the organ, especially the iron of analytical chemical determination. The iron of skeletal muscle is attributed to a definite pigment muscle hemoglobin. "Whether this will hold for the iron of the liver is not so clear. Many conditions arise in the body in which there is great de- struction of the red blood cells with a corresponding loss of hemo- globin. This loss must be compensated for. In human diet the compensation is generally adequate through the iron content of the various materials of the food. In disease, for example in malaria, the iron may be so completely removed as to greatly weaken the indi- vidual concerned. In malaria the destruction of red blood corpuscles and the accompanying loss of hemoglobin may be so great as to lower the oxygen absorbing capacity of the blood for 50 to 70 per cent. Iron seems to be intimately bound up with general metabolism. If iron chloride is administered in small doses, a total of 10 to 30 minims of the tincture of iron per day, it accelerates metabolism, acting very much as a mild tonic. However, the inorganic ferric chloride is metabolized with difficulty. In fact, it has been ques- tioned as to whether or not this compound can be utilized by the 338 IROX-PROTEIN COMPOUNDS 339 body. It is certain, however, that the administration of the inor- ganic iron is favorable and one is compelled to assume that it is either directly utilized or that it acts as an iron sparer. By this latter view the ferric chloride would serve the purposes of iron excretion, thus conserving to the tissues for further metabolism such iron as would otherwise be excreted. 2. Evidence of the absorption of iron. — A number of valuable experiments have been performed on mammals with the attempt to demonstrate the absorption of inorganic iron. If an animal be fed with an iron salt and after a sufficient time for absorption be killed and the alimentary canal be opened for its full length, and the mucous mem- brane painted with ammonium sulphide, it is found that two areas of the mucosa are blackened. The first one is in the upper portion of the small intestine, the duodenum; the second is in the lower portion of the colon and rectum. The experiments of Hall and others have given indication of the direct absorption of iron by the duodenum. It is not so clear whether the rectal iron is that being absorbed or iron on the way to excretion. Fistulas of the intestine have been established, and then iron fed on the assumption that any unabsorbed iron passing through the small intestine would be re- moved through the fistula without reaching the colon. Under these conditions iron is found in the content of the rectum, and it is as- sumed it reaches this point by excretion through the rectal mucosa. 3. Iron-protein compounds. — Iron, especially in the form of chloride, acts as a precipitant of proteins. In the normal relations in the body the iron is present undoubtedly as an iron-protein, of which hemoglobin is the typical example. This has raised the ques- tion as to the form in which the iron is absorbed. It seems probable that it enters into a protein compound with substances of the food or of the mucosa and is absorbed into the body as such. Hall, by micro-chemical methods, has been able to demonstrate the presence of iron as such in the epithelium of the intestinal villi which he considers to be iron in process of absorption. Basing the procedure on the tendency of iron to form organic compounds, numerous organic iron compounds have been introduced into therapeutics in the hope that in this form the chemical will be more available to the body. Some of these preparations are less objectionable to the taste and less astringent in their influence on the mucous membrane, but on the whole they do not seem to favor- ably improve the protoplasmic reactions of the body more than do the inorganic compounds. 340 IRON 4. Astringent action. — Iron chlorides have for a long time been known to be markedly astringent to the mucous membranes of the body. "When taken by the mouth they have an acrid, " astringent " taste, and when swallowed in too large quantity lead to some reflex nausea and possibly vomiting. Owing to this local action there is a tendency to gastric inflammation. The local astringent action of iron has given the perchloride a reputation as a styptic in cases of local bleeding. The iron in this case has its usual chemical action of precipitating proteins, and thereby tends to hasten blood-clotting and the formation of a mechanical coat that obstructs the bleeding. It is effective in this regard both for external wounds and in bleeding from the nasal or buccal cavities, or in some deeper portion of the alimentary tract. However, the practical use of iron as a styptic is now more or less superseded by other agencies, for example preparations of epinephrine. CHAPTER XLVII. SULPHUR AND THE SULPHUR COMPOUNDS. In physiological chemistry we have already learned to know the importance of sulphur in the composition of protoplasm. All pro- tein bodies contain sulphur, along with nitrogen, oxygen, hydrogen, and carbon. Sulphur is present in various proteins in from 0.3 to 2.2 per cent. Sulphur, therefore, is of an importance comparable to nitrogen in the reactions of protoplasm. The primary interest in the sulphur compounds is, therefore, physiological chemical. Among the questions of importance are the sources of sulphur and the forms in which it leaves the body through the excretions. The determination of the excretion of sulphur has come to be almost as important as the determination of nitrogen, in the light which it throws upon metabolic processes. The consideration of the detailed reactions of a normal nature will have to be left for discussion in connection with physiological chemical questions. We give here only a brief discussion of the be- havior of sulphur and sulphur compounds as such. i. Sulphur. — Sulphur in its pure form is a very inactive drug. If applied to the skin or when taken into the alimentary tract by way of the mouth it undergoes comparatively little change, and is thrown out of the body as sulphur in the stools. A certain amount is trans- formed into hydrogen sulphide in the intestinal tract. As sulphides this sulphur is absorbed and makes its appearance in the circulation to be excreted as sulphates in the urine, or to some extent as sulphides through respiration, where it gives a characteristic disagreeable odor to the breath. It is still an open question whether the display of neutral sulphur exerts any favorable action upon metabolism as such. Its presence in the alimentary tract acts as a mild cathartic, possibly contributing to the normal reactions of the bowel when this organ is relatively sluggish. 2. Sulphides. — The sulphides are Bomewhat irritant and toxic. If introduced into the circulation they lead to depression of function of both the nerves and the muscular tissue; from the latter action 341 342 SULPHUR AND THE SULPHUR COMPOUNDS they weaken the circulation, and from the former produce some slight degree of narcosis. Harnack x has described a type of convul- sion in the frog following a toxic injection of hydrogen sulphide. It is probable that the small proportion of sulphides formed from neutral sulphur in the alimentary tract tends to produce this charac- teristic change in the important nervous and muscular mechanisms of the body. Traces of sulphide formed during intestinal digestion would be toxic to the extent of their concentration. 3. Sulphates. — The oxidation of sulphur and sulphur compounds in the body is largely to the form of acid sulphur, the sulphates ; and to neutral sulphur, the various organic compounds. The sulphates are eliminated from the kidney as such. Their excretion is in acid form, hence any great increase in the quantity of sulphur excreted in this form tends to produce a degree of mild irritation of the renal tissue. This condition has been mentioned under the chapter on Saline Cathartics. 4. The organic sulphur compounds. — A number of organic sulphurs are of some pharmacological interest. Of these may be mentioned sulphonal, which is mildly antiseptic, and ichthyol, which is a compound containing as much as 10 per cent, of sulphur, and has enjoyed some reputation as a mild antiseptic lotion. 1 Harnack, Erich: Schmiedeberg's Arch., Vol. XXXIV., p. 156, 1894. CHAPTER XLVIII. PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS. I. Historical. Phosphorus was first discovered by Brandt, in 1669, in the residue from the evaporation of urine. Tunnicliffe x states that it was a century later before phosphorus was shown to be present in the bones. Phosphorus plays a most important physiological role in the mam- malian body. It is a constituent of the most vitally necessary sub- stance of the nucleus, nucleo-protein, also of the phosphatids which serve so important a function in the process of nutrition of the young oviparous and ovoviviparous animals. Milk for the nourish- ment of the mammalian young also contains phosphorus in abun- dant quantities in the casein, and as salts of phosphorus. Here, as in the case of iron and sulphur, we find that the problem of the metabolism of phosphorus is of importance primarily to physio- logical chemistry. Still the influence of the substance on the body has both a toxicological and a pharmacological interest. Phosphorus is not tolerated by the body, except in combined form, i.e., as organic or as inorganic phosphates. If therapeutic quantities of free phosphorus be taken by way of the mouth, the substance is absorbed and slowly oxidized to the acid. The acid then forms salts with calcium, magnesium, or potassium. But very minute quantities are toxic. On the other hand, both inorganic and organic phosphates are constituents of every normal mixed food. The inorganic phosphates are constantly being excreted, chiefly through the urine. Phosphates are found to be necessary constituents of the food of both plants and animals. Plants are able to take up and utilize inorganic phosphates, deriving them from the soils and the soil waters. It is not so clear to what extent animals may utilize inorganic phosphates. That they do utilize organic phosphates has been clearly demonstrated, a point that will be discussed a little later. 1 Tunnicliffe, F. W. : Archives internationales de Pharmacodynamic et de TMrapie, Vol. XVI., p. 207, 1906. 343 344 PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS II. Outline of Pharmacological Action. 1. Phosphorus is a general protoplasmic poison. 2. It is characterized by excessive nitrogen elimination and by fatty degeneration. 3. It interferes with specific functions, largely through derange- ment of general metabolism. 4. Inorganic salts of phosphorus are non-toxic, but are available for the production of bone and stimulate bone growth. 5. Organic phosphorus compounds are stimulative to general metabolic processes; they favor the utilization of nitrogen and the growth of muscular, glandular, and nervous tissues. III. Details of Pharmacological Action. i. Phosphorus as a general protoplasmic poison. — The element phosphorus is intensely toxic to animal tissues. This substance has been of interest for the last half century owing to the fact that it is a constituent of the preparation used in the manufacture of matches. Ordinary match heads contain from one to three milligrams of phos- phorus. Workers exposed to the phosphorus fumes and dust are subject to definite types of phosphorus poisoning. These present pictures of marked change in the calcareous structure of the bones, as well as of the teeth, produced by the absorbed phosphorus. They also are subjected to a condition of respiratory irritation affecting the mucous membrane down relatively deep into the lungs. Phos- phorus in this form is a vigorous irritant. If it be taken into the stomach the irritative change leads to an inflammatory condition of the mucosa, with accompanying griping pains, and generally with vomiting. All three of these lines of toxic influence show that uncombined phosphorus is poisonous to protoplasm. If the reaction throughout the body is followed, it is found that practically all tissues yield to its influence. The changes in the tissues are essentially of a patho- logical nature, beginning with absorption of water, cloudy swelling, disintegration, and ultimately fatty degeneration. According to Lusk, 1 the reaction is characterized by an increase in total metabo- 1 Lusk, Graham: American Journal of Physiology, Vol. XIX., p. 461. PHOSPHORUS POISONING 345 lism, as indicated by an increase in total nitrogen eliminated. There is also an excretion of lactic acid, which indicates interference with carbohydrate combustion. 2. Fatty degeneration after phosphorus poisoning. — The ad- ministration of pure phosphorus has long been used to demonstrate the phenomenon of fatty degeneration. In the beginning the assump- tion was that phosphorus poisoning led to a breaking down of the protoplasm and to the formation, from its residue or during the process of its disintegration, of fat. In more recent years important and crucial tests have been made casting doubt upon the truth of this assumption. The question hinges on whether or not the observed disintegration of the proteins, which process is associated with an in- crease of nitrogenous wastes, leads to the formation of fats from the fatty or from the carbonaceous residues, thus accounting for the accumulation of visible fats in certain organs; or whether the fatty accumulations in phosphorus degeneration, so-called, are only trans- ferences of fat from other depots. Two methods have more recently proven fruitful in attacking the problem. Taylor 1 found that frogs, in which he produced fatty degeneration, contained less total fat than the normal controls. By the current theories, there should have been a gain rather than a loss of fat. Rosenfeld 2 attacked the problem from two angles. He demonstrated first that the increase of fat in the liver is associated with a decrease in the amount of fat in other fat depots of the body. His second point of attack hinges on the fact that the type of fat of each animal is characteristic. By feeding tallow, which is easily identified in comparison with dog fat, and at the same time producing phosphorus poisoning, Rosenfeld found that so-called fatty degenerated liver fat was composed of a high percentage of the foreign fat. Rosenfeld came to the conclu- sion that the fatty degenerations of this type are in reality fat trans- portations and do not arise in a breaking up or disintegration of the tissues. As a result of the tissue disintegration by phosphorus poisoning, there is a temporary increase in the formation of tissue enzymes, of which it is safe to assume lipase is one. An increase of the lipase sets up a series of interdependent physiological conditions, which quite adequately explain many of the cases of fatty accumulation in pathological degenerations, of which phosphorus poisoning is one. Taylor, A. E.: Journal of Eaperimental Medicine, Vol. IV., p. 300, 1800. 2 Rosenfeld: Verhandlungen der deutschen pathologischen Gesellscliaft, Vol. VI., p. 71, 1904. 346 PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS As Lusk has stated the case, " the sugar-hungry cells attract fat in greater quantity than they can burn," a statement that calls for a mechanism of lipase for the manipulation of the fats. 3. The action on the skeletal structures. — The toxic action on the bony tissues was already mentioned. If phosphorus is given in A. Fig. 70. — Comparison of the humerus of a calf to show the influence of phosphorus feeding. A, section of the normal bone. B, after eight weeks of phosphorus feeding. There is little difference in the thickness of the shaft, hut a marked increase of the ossifications around the ends of the epiphyses. The spongy bone is greatly Increased and extends further into the shaft. From Wegner. sufficiently small doses through a considerable interval of time it produces a profound effect on the structural characteristics of bone. Phosphorus at first stimulates to bone formation. Evidently the activity of the osteoblasts is increased so that the laying down of bone, especially in young animals, takes place more rapidly than usual. In the long bones the denser portion of the shaft becomes relatively thicker, 1 and the cancelous tissue extends further down 1 Wegner, Geo.: Virchow's Archiv fur Anatomie, Vol. LV., p. 11. THE RELATIONS OF THE INORGANIC PHOSPHATES 347 the shaft, and the lamellae are thicker. The bone formation stimu- lated by phosphorus does not lead to a greater bone length. In the late and toxic stages of the administration there is a tendency to resorption of the bone salts, which finally weakens the bones and makes them more fragile. There are many points at present not fully explained as regards the toxic action of phosphorus, but ap- parently we are to look for the source in the interference with the metabolism of the bone-forming cells. 4. The relations of the inorganic phosphates. — Aside from the toxic actions of pure phosphorus, the chief interest relates to the role and fate of its compounds in the body. Forbes x has recently reviewed this problem. He indicates that the organic compounds only are available for most of the tissues, but that the inorganic compounds can be utilized by such tissues as are particularly rich in this group of phosphates. The bones serve as the most typical example. Milk also contains a high percentage of inorganic phosphates. The usual salts are calcium, magnesium, iron, sodium, and potassium phosphates. The mineral bases form strong compounds, and are not readily displaced by the organic bases. On the other hand, organic phosphorus compounds contain a ready phosphorus supply, though an expensive one, for the inorganic uses of the body, especially where an adequate supply of mineral base is present (Forbes). With these principles in mind, it is evident that one of the most important influences of inorganic phosphates is that on bone metabo- lism. In the growth of bone the chief mineral constituent is calcium phosphate. If calcium and phosphate salts are not both present, then they must be supplied from their organic compounds or else mal- nutrition of bone results, i.e., osteomalacia, rickets, etc. Table showing the percentage of the constituents of the ash of the femur (Carnot). Man. Calcium phosphate. . . 87.45 Magnesium phosphate 1.57 Calcium fluoride .35 Calcium chloride. . Calcium carhonate. Iron oxide .23 10.15 .10 Ox. 85.72 1.53 .45 .30 11.96 1.13 Inorganic phosphates serve two purposes, therefore they form a direct supply of mineral nutrients for inorganic phosphate purposes; 1 Forbes, E. B. : Bulletin of the Ohio Agricultural Experiment Station, No. 201, p. 121, 1909. 348 PHOSPHORUS AND THE PHOSPHORUS COMPOUNDS and they, as with inorganic iron, are phosphorus sparers. They conserve to the organism for the more complex reactions the higher compounds of the lecithins, nucleo-protein, etc. Forbes, feeding pigs with different phosphorus compounds in the supplement ration, found that raw bone meal and bone flour ' ' increased the density, the volume, and the ash per cubic centimeter of volume, of the bones." There was no obvious advantage in muscular development. In the Rocky Mountain and western region of the United States, where alfalfa forms the winter ration for the great sheep flocks, it has been noted that the young lambs in utero grow such large skele- tons that many are killed at birth. 1 Alfalfa has the largest mineral content of the vegetable feeds. It is particularly rich in calcium, potassium, and phosphorus, as well as in protein. The phosphorus stimulates to greater bone growth, especially in the presence of an abundance of mineral bases, of which calcium is of the chief impor- tance in this instance. A favorable combination in the feeds of protein with the saline substances produces in addition to the skeletal growth an unusual mass development of the soft tissues. 5. Organic phosphorus compounds. — It is well established that organic phosphorus compounds are necessary for the growth and activities of all the tissues of the animal body. Deficiency in this element in organic form leads quickly to malnutrition, and in ex- treme cases malformation. The most abundant organic phosphates in the foods are: (1) phosphatids, the lecithins; (2) phospho-proteins, of which the casein of milk is an example; and (3), the nucleo-pro- teins, always present in the cell nuclei as compounds of nucleinic acid. Eepresentatives of these classes of organic phosphates are all available, both for the organic and the inorganic phosphorus supply. The brain is especially rich in phosphorus, 3.7 to 4 per cent, and more, chiefly present in the glycero-phosphoric acid of the brain leci- thins. It is to be expected that interference with brain metabolism will occur if there is a dearth of organic phosphorus in the food supply. Under these circumstances one cannot escape the inference that phosphorus compounds are very vital to the reactions of the brain, including those processes in which conscious thought have their physiological foundations. Organic phosphorus stimulates growth. Tuniii cliff e found that the addition of the phosphorus of a casein and a sodium glycerophosphate preparation to the diet of two children was followed by an increase 1 Unpublished results used by permission of President H. J. Waters of the Kansas State Agricultural College. ORGANIC PHOSPHORUS COMPOUNDS 349 in the amount of phosphorus assimilated and retained in the body. There was also an increase in the amount of the food nitrogen, assimilated, a fact that had been previously demonstrated. It is this favorable stimulation of metabolism that has given lecithins and the caseins such a strong position among the food drugs. The nucleo-proteins are also stimulative, but not to a favorable increase in constructive metabolism. The nucleins lead to a leucocy- tosis, or increase in the number of white blood cells. This is fol- lowed by a rise of the amount of phosphorus excreted greater than can be accounted for by the nuclein phosphorus given. CHAPTER XLIX. ARSENIC AND ANTIMONY. A. ARSENIC. I. Introductory and Historical. The pharmacological importance of arsenic received a new im- petus when Ehrlich introduced synthetic compounds of arsenic as specific poisons for certain infectious organisms. The element arsenic is non-toxic as such. The metal is non-soluble in water, therefore cannot be absorbed from the alimentary canal. Arsenic compounds, especially the trioxide, the arsenites, and the sulphites, are peculiarly toxic to all forms of living matter. This toxicity has been known for many centuries. At the present time arsenic is used extensively in the arts. This gives opportunity for accidental poisoning. For example, Paris green, which is an arsenite of copper, and arsenate of lead are the chief insecticides used in vegetable and fruit garden- ing. Where such vegetables or fruits are carelessly prepared for food opportunity is given for arsenic poisoning. Arsenic is also present as an impurity in certain of the chemicals used commer- cially, for example sulphuric acid, a fact which gives secondary opportunity for arsenic poisoning. The compounds of special interest are arsenious acid and its oxida- tion product, arsenic acid. Of the numerous synthetic arsenic com- pounds which have been introduced into medicine the more impor- tant are atoxyl, or sodium arsanilate, C 6 H 4 (NH 2 ).(AsO.OH.ONa) + 3H 2 0; cacodylic acid, (CH 3 ) 2 AsO.OH, and salvarsan, or arseno- benzol, HCLNH 2 .OH.C 6 H 3 As :As.C 6 H 3 .OH.NH 2 .HCl+2H 2 0. CH 3 / AS \OH /OH O = As— OH \OH Arsenic acid Dicacodylic acid As /\ HC1.NH 3 I | NH 2 .H» OH OH Arseno-benzol 350 OUTLINE OF PHARMACOLOGICAL ACTION 351 II. Outline of Pharmacological Action. Arsenic compounds interfere with metabolism, hence 1. Arsenic is a general protoplasmic poisoning. 2. The systemic effects are largely secondary to toxic derange- ment. 3. In minute quantities arsenic is stimulative to growth. III. Details of Pharmacological Action. i. General toxicity of arsenic compounds. — Arsenic acid is one of the most toxic of the forms in which arsenic is administered to the body, and it will serve as a type for the discussion of further details. Arsenic poisoning leads to a chain of obscure symptoms which have their expression through the perverted functions inci- dent to general toxic action on the tissue protoplasm. For example, arsenic acid, which is dissolved with difficulty and ionizes slowly, leads to a slow poisoning of the cellular protoplasm. The toxic symptoms come on so slowly and are so obscure that diagnosis is difficult. Even in the acute cases this statement holds. The effects last for long periods, and chronic arsenic poisoning persists for weeks after the cessation of the drug. Where arsenic is used as a cosmetic and the administration oft repeated, pronounced chronic effects may arise and be far advanced before they are identified. The phenomenon of arsenic poisoning may be divided into stages, of which the first consists only of general weakness associated with derangement of nutrition. The person does not desire food and the food that is taken is imperfectly digested, and there may be a marked disturbance of the alimentary canal accompanied by diarrhea. A little later, when the arsenic has acted more generally through- out the body, there is swelling of the mucous surfaces, including the membranes of the respiratory tract, of the alimentary tract, and the uro-genital system. The epidermis is also markedly affected. Sometimes actual disin- tegration takes place. Uusually there is an increase in pigmentation, and the skin becomes noticeably darker. In this stage arsenic is to be found in the skin and skin appendages, and it can be easily identi- fied chemically from the hair. In the later final stages of chronic poisoning there is paralysis 352 ARSENIC AND ANTIMONY of the neuromuscular mechanisms. There is also a disturbance of the sensory side of the nervous system. Inflammation occurs, whereby the ordinary normal physiological sensory responses are greatly ex- aggerated. There is a tingling and stinging sensation in the skin, especially in the extremities. Localized areas often give rise to acute pains. The muscular disturbances are associated with paralysis of the motor nerves, in which case the muscles themselves tend to degenerate. General in- coordination of locomotor activity is, therefore, characteristic of the late chronic stage. 2. Action of arsenic on the circulatory system. — While arsenic must be classed as a general poison, its influence on the circulatory system creates a pronounced secondary effect on other portions of the. body. In the early chronic stage of arsenic poisoning there is a certain degree of edema. This can best be explained on the assump- tion that the endothelial linings are directly affected by arsenic to such an extent as to interfere with their normal resistance. While the extremely minute dose may stimulate endothelial activity, the toxic reactions lead to degeneration. There is, therefore, a loss of tone in the smaller blood-vessels, especially of the capillaries, with a corresponding dilation. Arsenic acid is toxic to the heart. If isolated hearts, either of the lower vertebrates or of mammals, be perfused with a solution containing this drug, both the rate of contractions and the amplitudes are diminished. Only a very small margin of drug concentration exists between that strength which will reduce the rate of the heart and that which will completely eliminate its rhythm. The heart will recover readily from a short period of action, but prolonged contact with the arsenic is severely toxic. The action is primarily on the cardiac muscle. 3. The action of arsenic on the alimentary tract. — The acute toxic action of arsenic on the alimentary tract produces a vigorous en- teritis. The symptoms appear early. The mucous membrane of the stomach shows the usual inflammatory condition with redness and con- gestion. The process is slower than with the ordinary corrosives, yet there is undoubted degeneration of the lining epithelium, accom- panied by the usual change in resistance. The inflammation may take the form of a violent enough gastritis. The reflexes then produce vomiting, marked increase in the secretions, and often an increase in the intestinal peristalsis. Where the action is intense there is also a fall of blood-pressure with symptoms of shock. ARSENIC ON METABOLISM 353 On the intestine arsenic leads to a paralysis of the capillaries with corresponding congestion. A reduction of epithelial resistance occurs, thereby increasing the loss of fluids from the epithelium into the cavity of the canal. If the corrosion is intense and prolonged, then there may be shedding of the epithelium. This adds to the exudates, and in association with the increase in peristalsis contributes to the so-called " rice water " stools, which are characteristic of this form of poisoning. The local action along the alimentary canal is so acute that the whole process often becomes decidedly violent. If so, the final death may come on rapidly because of extreme exhaustion. In the milder arsenic toxication the action on the alimentary mucous membrane is less intense. There often is a slow chronic degeneration of these cells associated with similar degenerative stages in other parts of the body. The condition comes on so gradually that the acute phenomena just described are passed over and the opposite state of a sluggish and inert canal, i.e., a condition of gen- eral constipation, may be the prominent picture. 4. Arsenic on metabolism. — "With arsenic compounds, as with the phosphorus compounds, minute doses are at first beneficial in their influence on protoplasm. For example, there is an increase in the growth of the epidermal structures, a laying down of fat in the subdermal adipose tissues, and apparently a favorable reaction on the neuro-muscular tissues. This influence, as also in the case of phosphorus, quickly passes into the toxic injurious stage. In the toxic stage practically all the tissues undergo degeneration in some degree. The typical pathological picture induced is one of an initial cloudy swelling, followed either by inflammation or by rapid disintegration. In the nervous tissues these stages first produce a hypersensitiveness, then later paralysis. In the glandular tissues there is an increase of secretion followed by degeneration and loss of secretory power. In the alimentary canal the phenomena have already been given above. In the liver, however, there is at first an increase in the formation of bile, but later a marked degeneration of the parenchyma. In the skin the increased growth is followed by pigmentation and then by degeneration, and in the kidney a mild nephritis, followed by degeneration with suppression of the urine. 5. The excretion of arsenic. — Arsenic is excreted in practically all of the secretions of the body, particularly in the secretions of the skin, namely, the sweat and milk, and of the kidney. Some arsenic is lost by way of the alimentary canal, but most of it is thrown off through the urine. Arsenic is only slowly excreted. Following a 354 ARSENIC AND ANTIMONY single dose the process of excretion may last through ten or twelve days. In fact, it has been observed in the urine as high as 160 days after the last administration. Evidently the drug, is stored in the different organs of the body in a form from which it is only slowly liberated and finally thrown off. IV. Organic and Synthetic Arsenic Compounds. Eeference was made in the introduction to the work of Bhrlich in deriving the synthetic arsenic compound salvarsan. The general toxicity of arsenic led Ehrlich to the special attempt to build up arsenic compounds of reduced toxicity to .the tissues of the host while retaining the usual toxic action for invading organisms. Ehr- lich 's ambition was to secure a selective antisepsis by this means. The organic arsenic compounds, namely, cacodylic acid and arsanilic acid, have long been known to possess a high degree of toxicity for certain pathogenic germs. Ehrlich developed a series of instructive and valuable synthetic products by the attachment of arsenic to vari- ous derivatives of the benzine ring compounds. 6. The arsanilates. — Arsanilic acid is a compound produced from arsenic acid, in which anilin takes the place of one hydroxyl. Various metallic salts are derived from arsanilic acid, producing arsanilates that have been introduced into New and Non-official Remedies under special names, usually proprietary. Sodium arsanilate (atoxyl), C 6 H 4 (NH 2 ).(AsO.OH.ONa)+3H 2 0, is described by the 1914 edition of New and Non-official Remedies in the following terms: " The arsenic of the arsanilic acid is liberated very slowly in the system, thus producing the ordinary therapeutic effects of arsenic, with a more continuous and less toxic action and less irritation. Toxic effects from excessive doses have been frequently noted, although the toxicity of sodium arsanilate is stated to be about 1-40 of that of arsenic trioxide. The poisonous effects appear to be due largely to the arsenic component, the aniline taking no part in them. It is claimed that the use of sodium arsanilate is not followed by irritation, abscess forma- tion, etc., which sometimes follow the use of other preparations of arsenic. The use of sodium arsanilate in large doses has occasionally been followed by degeneration of the optic nerve, leading to blindness. " Sodium arsanilate has been recommended for the conditions which are favorably influenced by arsenic, such as anemia, nervous con- ditions, and diseases of the skin. It is said to have been very success- ORGANIC AND SYNTHETIC ARSENIC COMPOUNDS 355 ful as a remedy for trypano-somiasis, both of animals and of man, and is also said to be useful in other protozoal diseases, such as syphilis, malaria, and kala-azar. " The importance of this anilin arsenic compound is in association with its toxicity for the infectious organisms, such as in syphilis, malaria, etc. In the body the compounds break up, liberating arsenic in such form as to be specifically toxic for the invading organism, It was at first thought that this compound was not toxic for the body tissues, but numerous cases have arisen leading to disintegration and loss of function of special structures, the most distressing of which is that of blindness from degeneration of the optic nerve. 7. Salvarsan. — At this point may be discussed the synthetic work of Ehrlich in the building up of compounds with a maximum of toxicity to invading organisms, associated with a minimum of toxicity for the tissues of the host. Ehrlich has exhaustively considered this question on theoretical grounds. His views led him to construct numer- ous synthetic compounds, some of which he has shown to be practically selective in their toxicity for invading organisms. In 1910 the medical world was electrified by the announcement of a compound, number 606 of his series, which was specifically toxic for the spirillum of syphilis. This compound is arseno-benzol, or salvarsan. It presum- ably owes its action to the special form in which the arsenic is car- ried. The serum studies which have led to the development of special means of detecting invading organisms have given practical diagnos- tic signs for many of our most dreaded diseases, the Wiedal reaction for typhoid, the tuberculin reaction for tuberculosis, and the "Wasser- mann reaction for syphilis. By the application of the specific syphi- litic test it is now possible to determine positively whether or not the body of a given individual has been invaded by this dreaded organ- ism. The arsenic treatment, through the specific salvarsan, is borne especially well by the body in which the spirillum is present. Some condition developed by the spirillum seems to make the body toler- ant of the arsenic compounds in this form. This tolerance is greater than that possessed by the normal body, hence in practical treatment the safe method is first to determine the presence of the organism by the Wassermann reaction and then give the specific salvarsan in the belief that the tissues will resist the toxic substance and the in- vading organism will succumb without danger to the host. Ehrlich has announced the almost unbelievable result that after single injections of salvarsan the invading organisms completely dis- 356 ARSENIC AND ANTIMONY appear. Numerous clinical treatments in Europe and in America have abundantly established the specific value of this agency along clinical lines. B. ANTIMONY. Antimony, which is the chemical relative of arsenic, has also been used in medicine for many years. Like arsenic, antimony is gen- erally toxic and more or less irritant to the tissue cells. The form used in medicine is tartrate of antimony or tartar emetic. i. The irritant action of antimony. — Antimony is far more di- rectly irritant than arsenic, and therefore can be used externally as a skin irritant and internally as a strong gastric irritant. It is this last factor which has given to the compound the name of tartar emetic. The application of antimony to the skin leads to local in- flammation. Around the mouths of the sweat glands and the sebaceous glands, where the drug is absorbed more deeply, it tends to produce pustules. This reaction produces stimulations of the nerve endings, reflexes which are discussed more fully under the head of Counter Irritants. Antimony given internally in relatively small doses, 30 mgr., produces at once an acute irritation of the lining of the stomach. This irritation also leads to vigorous nerve reflexes. The result is an increase of the secretions, both salivary and gastric, in the milder stages of its actions, and nausea and vomiting in the more intense stages. This function of inducing vomiting is the one that has been most used in therapeutics. Antimony is not so readily absorbed as some drugs, unless by mischance there be gastric ulcer or other form of abraded surface. The systemic effects of antimony are toxic, somewhat comparable to arsenic in this regard. There is, therefore, danger of nervous, of vascular, and other disturbance of vital functions, such as occasionally lead to severe and dangerous collapse. Antimony is primarily excreted with the feces, but it is present in traces in the secretions. The antidote is tannic acid, which forms an insoluble precipitate, in which form it can be removed from the stomach by the usual methods of lavage. CHAPTER L. LEAD SALTS. I. Historical and Chemical. Lead is a toxic metal, the salts of which vary in virulence very largely in proportion to their solubility in water and in the body fluids. The salts of especial interest are the insoluble salts, such as litharge, or lead monoxide, PbO, sulphate PbS0 4 carbonate, or white lead, PbC0 3 , and the iodide, Pbl 2 . The important soluble salts of lead are the nitrate, Pb(N0 3 ) 2 , and the acetate, Pb(C 2 H 3 2 ) 2 , or sugar of lead, is the most soluble of all, and is the salt most used in prac- tical therapeutics. Lead salts are of chief pharmacological interest because of the great intensity of their toxic action, rather than be- cause of their value in therapeutic practice. II. Outline of Pharmacological Action. The reactions of lead in the body may be summarized as follows : 1. General toxicity to protoplasm because of the formation of lead protein compounds after absorption. 2. A cluir act eristic astringent action of the dilute salts. 3. Concentrated lead salts are irritative, and hence produce local inflammation. 4. There is a strong tendency to chronic irritation after prolonged absorption of minute quantities. III. Details of Pharmacological Action. i. The general toxic action of lead salts. — Lead salts owe their toxicity primarily to the fact that they precipitate proteins. The formation of lead protein compounds in the protoplasm of the cells destroys the normal power of physiological reaction of the tissues 357 358 LEAD SALTS concerned. This statement holds whether the action be on free mucous surfaces or on abrasions, as in the use of lead salts as astrin- gents. The reactions are the same when the salts have entered the circulation and reached the tissues by the paths of general distribu- tion. The toxic picture, as expressed through changes in the coordi- nations throughout the body, varies, therefore, according to the degree of poisoning on one or the other tissue, as the case may be. The insoluble salts are not absorbed unless they be converted while in contact with the moist tissues into soluble forms, as happens typically with the lead carbonates. Most soluble lead salts, like salts of mercury, penetrate the tissues comparatively rapidly. When a solution of a salt of lead is taken into the stomach, it begins at once to diffuse through the mucous membrane.- However, it quickly forms a superficial layer of insoluble lead protein; in other words, produces a tanning effect on the surface layers of the mucosa. In consequence of this initial action the further absorption of lead is delayed, though not prevented. The intensity of the local action of lead depends largely on the concentration of the solution. If the dilu- tion is great, then there will be only a local astringent action. If the concentration is medium, the astringent action will pass over into a definite irritation that will involve the sensory nerve endings, which will in turn lead to reflex changes in secretion, peristalsis, etc. The solutions of greater concentration lead to an immediate irrita- tive process and acute toxic action, which produces nausea and vomiting, and ends in acute inflammation. "When the lead salts reach the intestines the cycle of changes which have been described for the stomach are repeated. The more rapid absorption from the intestinal region induces a greater intensity of local action. This local action affects the vascular channels, pro- ducing a stricture of the blood-vessels, which takes the character of a vascular spasm, therefore producing an asphyxial condition of the tissues of the regions supplied. The direct lead action on the smooth muscle of the intestinal walls produces prolonged contractions, with the griping pains which characterize the so-called lead colic. In acute lead poisoning, this cycle of symptoms may occur within a very short period, i.e., within a few hours. Systemic effects not mentioned but associated with acute lead poisoning are great thirst, nervous distress, and prostration, sluggish circulation, with cold ex- tremities. In the later periods of the cycle a suppression of the urine sometimes occurs, and there are general muscular cramps, which may end fatally in convulsions or in paralysis. As a rule, however, this CHRONIC LEAD POISONING 359 extreme acute toxicity does not occur, and the victim may slowly recover even after large doses of sugar of lead, the most soluble of the lead salts. The obvious antidote for acute lead poisoning is administra- tion of an indifferent sulphate or carbonate, such as sodium sulphate or carbonate, with the hope that the soluble lead may be converted into an insoluble salt, and in that inert form be eliminated from the body. 2. Chronic lead poisoning. — Acute lead poisoning, as described above, is rare as compared with the number of cases of chronic lead poisoning. Lead in one form or another is used very extensively in the arts, and, as may be expected, chronic lead poisoning, there- fore, is commonly found among painters, lead workers, plumbers, glass workers, and pottery glaziers. Lead may enter the body by inhalation from the dust, may be absorbed through skin abrasions, but it is more commonly taken up by slow and continual absorption from the alimentary canal after entrance by way of the mouth. Drinking water may contain lead from lead pipes, foods also preserved in lead sealed containers may be the source of lead intoxication, but uncleanliness in handling lead-containing substances is the usual source of intoxication. The slow and continual absorption of lead gradually introduced into the general circulation and distributed throughout the body is the most common history of lead poisoning. The reaction with protein renders it difficult of excretion, therefore there is a gradual and accumulative action. The acute or local symptoms may be entirely absent, but in due time general toxic symptoms make their appearance. The more common introductory symptom is acute in- testinal cramps, i.e., " lead colic." This is followed, after a few days or weeks, often without other premonitory warning, with muscular paralysis. It is an interesting observation that the paralysis most always affects the nerves of the upper extremities, beginning at the points of distribution of the nerves to the muscles of the fingers, hand, and arm. Muscular control is lost in a definite order. The first affected are the extensors of the middle fingers, then of the thumb and little finger, and then gradually of the wrist, leading to the characteristic " wrist drop." The attack is usually, but not al- ways, bilateral, and gradually extends to other muscles. The fuller details of this condition may be had from more extensive works on toxicology. Other nerve symptoms are due to the loss of sensory functions. 360 LEAD SALTS The organs of excretion, especially the kidney, and to less extent the salivary and other glands of the alimentary tract, are strongly affected in chronic lead poisoning. Early nephritis occurs, followed by marked degeneration and necrosis of the nephridial tubules. 3. The action of lead on the digestive tract. — Under the head- ing of the toxic action of lead we have already discussed some of the changes produced on the alimentary tract. However, further em- phasis should be given to the fact that the gastric and intestinal symptoms represent a complex, not only due to local action, but to special action after absorption. For example, the intravenous injection of lead salts produces diarrhea, and the characteristic lead colic. Diarrhea from this method of treatment is accompanied by violent intestinal muscular spasms. The muscular walls do not completely relax, but persist in clonic contraction. In fact, in the chronic stage the intestinal spasm loses more and more its peristaltic character, and hence constipation becomes a constant and persistent symptom from the peculiar type of interference with the normal movements of the intestinal tube. It is not fully clear whether the intestinal spasms are due to the direct stimulation of the smooth muscle, as such, or to primary action of the lead on the local nervous mechanism. If one may draw conclu- sions from evidences of the toxic nature of the lead reactions in other parts of the body, he would infer that the nerve explanation was the more probable. During the muscular spasm of the intestine there is also a marked spasm of the blood-vessels, which produces a local asphyxiation contributory to the general toxicity. 4. Excretion of lead by the salivary and intestinal glands. — Lead is excreted to a slight extent by the salivary glands. It is present in the saliva and the mouth in quantity sufficient to produce the characteristic blue line along the teeth near the margin of the gums. The insoluble lead sulphide is formed and deposited at this region, especially if any uncleanliness of the teeth exists. The glands of the stomach and of the intestines also excrete lead salts. In fact, the mucosa itself possesses this function, accounting, in part, for the final loss of lead through this channel. But in this instance, as in the case of morohine, there is a considerable reabsorp- tion of the lead, which establishes a vicious circle. This fact con- tributes to the difficulties with which lead is finally and entirely ex- creted from the body. 5. Excretion of lead by the kidney. — The major portion of the lead is slowly excreted by the kidney. It is the excretion by this organ THE REACTIOX OF LEAD OX THE NERVOUS SYSTEM 361 that brings the toxic metal in intimate contact with the nephridial epithelium, hence the result is more or less disastrous. The situa- tion is very similar to that of the excretion of the salts of mercury. There is a tendency toward protoplasmic precipitation, which leads to acute inflammation or nephritis, and this is followed by parenchymatous necrosis. Profound functional disturbance is in- evitable. A voluminous urine of low specific gravity characterizes the early stages of the disease, uremia and dropsy the later chronic stages. 6. The reaction of lead on the circulatory system. — After the absorption of lead into the blood stream it tends to react both with the constituents of the blood and with the lining epithelium of the blood-vessels. As a result of the former reaction there is some change in the character of the blood plasma. It is true that this leads to only secondary stages in lead poisoning. The chief damage to the blood falls upon the white corpuscles and the erythrocytes. The white corpuscles lose their ameboid character, become sluggish, and tend to disintegrate, hence their activities are reduced below the normal. Disintegration of the red corpuscles, with a tendency toward the formation of methemoglobin, has been described. This process leads to a reduction of the percentage amount of respiratory pigment, and there follows the chain of symptoms expressed by anemia and malnutrition. The reaction of lead salts on the epithelium of the blood-vessels produces a toxic condition which, when prolonged, leads to two unfavorable symptoms. The first of these, which arises early, is characterized by a tendency to contraction or spasms of the arterioles and capillaries. The second and later symptom is charac- terized by developing arterio-sclerosis, with the secondary accompany- ing symptoms, which that term implies. Various interferences with the normal rhythm and force of the heart's contraction have been ascribed to the effect of lead salts. How- ever, lead only slowly combines with striated muscle substance, of which cardiac muscle is a type. After prolonged action there is a tendency to muscular weakness and cardiac paralysis, quite com- parable to the chronic changes in skeletal muscle. 7. The reaction of lead on the nervous system. — Harnack * also made a study of the influence of lead on the nervous system of frogs and mammals. It is to his classical work that we owe our experi- mental conception of this field. He found that lead salts after ab- 1 Harnack, E.: Archiv fiir experiment elle Pathologie und Pharmakologie, Vol. IV., p. 152, 1878. 362 LEAD SALTS sorption produced strong initial stimulating effects on certain cen- ters of the nervous system. These facts were demonstrated through the muscular responses given by dogs. In determining the action on the blood vascular system it was found that lead salts injected into the circulation after section of the cervical sympathetic nerve on one side produced general blood vascular spasms. The contrac- tions were stronger on the unoperated side, showing that lead stimu- lated the vasomotor center as well as the smooth muscles of the ves- sels. In the later or chronic action of lead, this nervous reaction becomes toxic, producing paralysis of certain nerve centers. The paralysis is not specific and varies much in different individuals. It is this toxic effect on the cortical areas which constitutes the en- cephalopathia saturnalis. As a result of the cortical disturbance there is a marked interference with the psychic factors as expressed by restlessness, occasional delirium, usually followed in the end by marked depression and central paralysis. In closing the discussion, one may emphasize the fact that sec- ondary physiological effects of lead poisoning produce variations in the primary symptoms. The uremic convulsions, which follow the destruction of the renal function, will suffice as a single example of such secondary results. The peripheral nerves are poisoned in the later stages of lead action. In fact, the most typical phenomenon of lead poisoning, namely wrist-drop, is due to paralysis of the motor nerves rather than of the muscles concerned. The action is not directly upon the motor nerve ending, but upon the axis cylinders along the course of the nerves. 8. Muscular effect of lead poisoning. — Harnack's classical pic- ture of the effects of lead on striated and other muscles shows a marked interference with the typical muscular contraction and the expenditure of muscular energy. His diagrams indicate a very char- acteristic onset of fatigue with a minimum of recuperative power, also a typical arrest of the relaxation phase at the last third. This change in a way resembles that which characterizes veratrine, but it does not come so early in the relaxation. This phenomenon was observed in the muscles of frogs and rab- bits, and it involved the striated skeletal and cardiac muscles. As the lead action proceeded the muscle substance lost its irritability and finally became paralyzed, or at least unresponsive. Strange to say, the muscles of the dog were, in Harnack's hands, quite immune from these typical changes. MUSCULAR EFFECT OF LEAD POISONING 363 That there are additional factors involved has been shown by Cash. 1 Cash studied lead muscular poisoning under the influence of variations in temperature. At temperatures of from 15.5° to 17° C. the muscles did not give the characteristic lead contractions. At temperatures of 30° C. and more the lead poisoned muscles did give this result. Cash came to the conclusion that for some unknown reason the combination of lead with the muscular substance is pre- vented by certain unfavorable temperatures and favored by others. Cardiac muscle seems to fall into the same class as skeletal muscle, so far as lead action is concerned. We find the heart, there- fore, contracting more feebly and at a slower rate, and with a ten- dency to prolonged diastole. However, the heart responds to its nerves so long as its muscle remains sensitive to direct stimulation. Smooth muscle also is changed by the formation of lead proteins in its protoplasm. This is indicated by Harnack's experiment quoted above on the circulation in the ear of the rabbit after the section of the vasomotor nerves. The contraction of the blood-vessels on the isolated side can only be explained as a direct muscular effect. This view is strengthened by the actions on the alimentary canal, which have been discussed above. 1 Cash, Th.: "Archiv fur Experimentelle Pathologie und Pharmakologie," Supplementband, Schmiedeberg's Festschrift, p. 93, 1908. CHAPTER LI. ZINC SALTS. I. Details of Pharmacological Action. The zinc salts, that are of interest in a pharmacological way, are the oxide ZnO, the sulphate ZnS0 4 and the chloride ZnCl 2 . The oxide is insoluble, while the sulphate and chloride are very soluble, therefore the more readily absorbed by the mucous membrane of the alimentary canal. i. General toxic and disinfectant action of zinc salts. — The salts of zinc precipitate proteins as in the case of the lead salts. The formation of insoluble albuminates on protoplasmic surfaces gives to the zinc salts their characteristic astringent property. Zinc albuminates are even less soluble than lead albuminates. When the action is more intense, as in the more concentrated solutions of zinc, the effect on protoplasm is merely irritant. Zinc chloride being more soluble, therefore penetrates more readily into the tissues, hence it is the more irritant of the zinc series. The chemical action of zinc on protoplasm gives to its salts their antiseptic property. Zinc chloride enters into the composition of special disinfectant solutions such as in Pott's solution. 2. The local action of zinc salts. — In the human body the local application of zinc salts produces its effects according to the surface involved. The skin is non-absorbent, therefore zinc salts have little or no influence. The more soluble and stronger salts, as for instance zinc chloride, will produce local inflammation, but this comes on slowly and is insignificant unless prolonged. On the other hand, the comparatively insoluble zinc oxide is only a mildly antiseptic and stimulative medium, since just sufficient of the salt is dissolved to produce this general effect. It therefore finds a use in clinical medi- cine as a healing salve to cover exposed and ulcerating surfaces. 3. The systemic action of zinc after absorption. — The more soluble zinc salts are slowly absorbed from abraded surfaces, and par- ticularly by the alimentary mucosa. Yet it is claimed that direct cases of chronic zinc poisoning are rare, if not entirely absent. 364 ACTION OF ZINC AFTER ABSORPTION 365 However, if a solution of a zinc salt is introduced into the circula- tion, a procedure that can be accomplished by using some one of the double salts of zinc which does not so readily precipitate protein, a cycle of symptoms follows directly due to the toxic action of the metal. It has long been known that zinc sulphate is an emetic. In the earlier history of medicine a solution of this salt was a favorite medium for the production of vomiting. In this instance the ex- planation is that the zinc, after absorption, directly stimulates the nerve centers concerned in vomiting. With excessive and toxic doses death follows, primarily through the paralysis of the nervous system and of the cardiac muscle. Take it all in all, the zinc salts are considerably less toxic than the salts of lead. For therapeutic purposes they are relatively un- important. CHAPTER LII. THE SALTS OF COPPEE. I. Details of Pharmacological Action. The salts of copper, like those of lead and zinc, enter into com- bination with protein. This reaction is the foundation of such toxic effects as they produce on animal and plant' tissues. The copper salts are relatively soluble. The ones most commonly met with in pharmacological experiments are copper sulphate, copper acetate, and the double salts of copper and arsenic, as the copper arsenite. i. General toxic and disinfectant action of copper salts. — Living tissues respond with great variation to contact with solutions of copper salts. This may be explained in part by the fact that copper is normally present in a number of plants and in certain animal tissues. As an example, it is a well-known fact that copper takes the place of iron in the respiratory pigments of some lower forms of animals. The blood of certain species of crustaceans, of which the common edible crab is an example, and of certain molluscs, contains the respiratory pigment hemocyanin, which differs chemically from hemoglobin in that copper displaces the iron of the pigment molecule. Fredricq x has shown that hemocyanin chemically unites with oxygen in a very unstable combination, comparable with that of oxygen and hemoglobin. The oxyhemocyanin, however, is of a pale blue color instead of the usual scarlet red, which characterizes oxyhemoglobin. It has been shown also that certain plants contain traces of copper. However, numerous observations also show that many of the lower plant forms are very susceptible to the toxic action of copper. This? fact is taken advantage of in the practical purification of water supplies, especially in the ridding of reservoirs of the infesting fresh water algas. Minute traces of copper, such as are given to the water by dragging a sack of copper sulphate through a reservoir, are suffi- cient to kill the spirogyra and other species of pond algas. Locke has shown that copper salts are toxic to lower forms of 1 Fredricq, L. : Archives de Zoolbgie Escperimentale, 1878. 366 THE ELIMINATION OF COPPER SALTS 367 animal life. As dilute a solution as one in two hundred thousand is sufficient to kill ciliated infusoria and isolated ciliated epithelial cells. On the other hand, the tissues of man and mammals are relatively resistant to the toxic action of copper sulphate. Certain tissues with- stand, for a short time, as high a concentration as one per cent., though this concentration finally becomes toxic. Some molds are said to be resistant to copper, while certain yeasts are very susceptible to its action, though copper sulphate is the principal ingredient of the well-known Bordeaux mixture which is used as a spray to rid plants of fungus diseases. 2. Systemic symptoms of the action of copper. — Copper salts owe their toxicity to the formation of protein compounds, just as in the cases of lead and zinc. This property gives them the usual astringent action, and with sufficient concentration an irritant and corrosive toxic end result. Copper is an old-time emetic, depending upon its irritation of the mucous lining of the stomach. It produces nausea with pain from local irritation. After absorption the salts react chiefly on the nerves and muscles to produce an increase in the respiratory rate and a slow weak pulse accompanied by dizziness and ending in paralysis or sometimes convulsions. Copper salts are not so toxic as lead salts, in fact chronic action does not often, if ever, occur. That the continued use of applications is detrimental cannot be questioned. Its irritant action on the ali- mentary tract when often repeated, as in the use of foods preserved with copper cooked in copper vessels, have a tendency to produce a gastric and intestinal catarrh and a chain of secondary symptoms depending thereon. 3. The elimination of copper salts. — Copper salts are compara- tively easily absorbed from the alimentary tract. They are distributed by the blood throughout the body. The liver has been found to con- tain a higher percentage of copper, though traces have been observed in most every tissue. The metal is slowly eliminated through the excretory glands, especially the kidney. However, traces of copper have been found in the excretions of the skin and in the hair. It is re-excreted into the alimentary canal to a certain extent, chiefly by the salivary and digestive glands. A portion of the copper is dis- charged from the body in the feces. CHAPTER LIII. THE MERCURY SALTS. I. Introductory. Mercury is one of the most active of the heavy metals. It is toxic in the body, not only from the action of the ions derived from the salts, but following the absorption of the metal itself. The most common salts of mercury used for pharmacological and medicinal purposes are: Mercuric chloride, HgCl 2 , mercurous chloride, Hg 2 Cl 2 , mercuric iodide, Hgl 2 , and the metal itself. II. Outline of Pharmacological Action. The most important changes in the behavior of living protoplasm introduced by mercury are: 1. Mercury has a cathartic action on the alimentary canal. 2. Salts of mercury are highly toxic for micro-organisms. 3. In very dilute solutions, as one in three hundred thousand or less, salts of mercury are stimulative to protoplasm, producing an increase in the red blood cells, diuresis, etc. 4. Salts of mercury, in the more concentrated solutions, are very toxic for animal and vegetable protoplasm. III. Details of Pharmacological Action. i. The absorption of salts of mercury. — The extraordinary toxicity of mercury depends primarily upon two factors : (1) The rela- tive solubility of its salts as compared with other heavy metals ; (2) the solubility of its protein compounds in animal fluids. Of the different mercury salts calomel or mercurous chloride is com- paratively insoluble. When it is introduced into the alimentary canal it only slowly dissolves, and is correspondingly slowly absorbed. 368 ACTION OF MERCURIAL SALTS OX BACTERIA 369 This accounts for the fact that relatively large quantities of this salt may be swallowed with impunity, since they pass through the canal without being absorbed. Mercuric chloride, on the other hand, is highly soluble and correspondingly toxic. Whenever mercury is brought into contact with either the fluids of the body or the tissues, it enters into chemical combination with the protein constituents forming protein compounds. Proteins are in this way precipitated, but the precipitate, when in small amount, is readily soluble in excess of fluid largely on account of the sodium chloride content of the body fluids. Mercury, therefore, present in the mammalian body takes the form of albuminates. These, in solu- tion, pass readily to all parts of the body and lead to the characteristic mercurial action. This action is merely stimulative when the sub- stance is present in extremely diluted solution, i.e., traces, but strongly corrosive when the concentration reaches the toxic level. The action of the metal mercury follows when the substance enters the body either by absorption of its vapor through the pul- monary tracts or by absorption from the skin when the metal is applied in the form of a fine emulsion, as in inunction of mercurial ointment. 2. The action of mercurial salts on bacteria and other lower forms of life. — Mercury has come to be recognized as one of the most valuable of the antiseptic substances. Its soluble mercuric chloride is the form used for the purpose of antisepsis and disin- fection. It has a powerful and toxic action on the lower forms of living matter. For purposes of disinfection, the bichloride in solu- tions of one part in one thousand is the strength generally used. For the disinfection of excreta and other highly infectious sub- stances, other chemicals are probably more available, but a solution of bichloride of mercury one part in one thousand will kill all active forms of bacteria if allowed to stand in contact a sufficient length of time. For many bacteria, one part in a million will inhibit growth. Other forms of bacteria, of which the tubercle bacillus is an example, are more resistant to the action of mercuric chloride. Even one in one thousand must stand in contact with tubercle bacilli for several hours to insure their death. Resting spores are naturally more resistant and require a more vigorous treatment for steriliza- tion, if it be produced by solutions of mercury. In surgical procedure, the antiseptic action of mercuric salts is relied upon at the present day, where asepsis is not practical. The solutions, from the standpoint of the human patient, are bland and 370 THE MERCURY SALTS not acutely irritant, hence not painful. However, in surgical dress- ing it must be remembered that the tissues of the body are also sus- ceptible to local mercurial poisoning. A prolonged contact with stronger antiseptic solutions may lead to superficial irritation and possibly necrosis and death of the cells of the area. Soluble mercuric salts are also toxic to generalized protoplasm, such as infusoria, white blood corpuscles and the like. A solution of one in ten thousand is sufficient to inhibit the movement of white blood corpuscles. This fact can be demonstrated in the incipient stage of inflammation produced by mercuric chloride. An inflam- matory process in the frog's web, started by mercuric chloride solu- tion, will exhibit the fact that the white corpuscles have lost their migratory powers. 3. The action of mercury on differentiated animal protoplasm. — From what has been said above, it is evident that mercuric chloride solutions have a varied action on the individual tissues of the animal body. In concentrated solutions this action is a toxic one, while in the very diluted solutions just the opposite, i.e., a temporary beneficial and stimulative effect, may be seen. The concentrated solutions convert enough of the protein of the tissues into the albuminate to destroy the characteristic cell life. On the other hand, the extremely diluted solutions do not bring to the tissues enough of the mercurial salts to immediately produce destruction of the tissues. In the latter case a very slight formation of albuminate in the protoplasm has the rather unexpected effect of increasing the activity of the tissues concerned. It is obvious that the increase of functional activity in certain tissues will have secondary effects that are more or less favorable to the organism as a whole. If the intensity of action is toxic and tissue-necrosis occurs at any point, then the elimination of function of that tissue will lead to secondary actions that are, in the nature of the case, injurious to the life of the organism as a whole. One need only to refer to the fatal necrosis of the kidney in chronic and fatal mercurial poisoning as an example. The favorable action of minute quantities of mercury has been taken advantage of by clini- cians in certain pathological conditions, for example in anemia follow- ing infectious disease. Fortunately the margin of safety between the concentration of salts of mercury which is toxic for the body tissues and that which is toxic for the invading bacteria attacking those tissues is great enough to allow of the use of the drug as an antiseptic. This factor ACTION ON THE CENTRAL NERVOUS SYSTEM 371 is particularly applicable for cutaneous surfaces because of the re- sistance which the iskin offers to absorption. If an abrasion exists* as in the case of an ulcer, or following a surgical operation, or if mucous surfaces of the body are to be disinfected with mercurial salts, as in the case of the mouth cavity, the rectum, or the vagina, then care must be taken lest excessive absorption occur and the body receive a toxic quantity of the drug. Keeping in mind these general factors, we may examine next the action on particular organs in the body. 4. The action of salts of mercury on the alimentary tract. — Salts of mercury have long enjoyed a favorable reputation because of their cathartic action. Calomel, or mercurous chloride, because of its relative insolubility and correspondingly slow absorption rate, serves as a splendid cathartic. Mercuric chloride is violently irritant to the alimentary tract, but is available as a purge where it is desirable to use only an intense acting drug. The cathartic action of calomel depends upon the fact that it is slowly dissolved. Its concentration is ordinarily never great enough to produce more than a mild irri- tation before it is absorbed from the alimentary tract, hence pro- duces a relatively mild cathartic action. The local inflammation which it induces in the mucous lining produces only a slight amount of exudation, which is favorable from the standpoint of a cathartic. The cathartic action of calomel often fails of the final defecation reflex, hence leads to an accumulation of refuse in the large intestine. Mercuric chloride is violently irritant. It leads not only to local inflammation, but induces vigorous reflexes, beginning with those from the gastric cavity. As a result the salivary and gastric secre- tions are increased and there is a tendency to nausea and vomiting. If the action is strong enough, there is an interference with the circulation and respiration, and if extremely severe collapse may supervene. This last extreme is usually not reached. With toxic quantities of mercuric chloride, as in the case of accidental poisoning from corrosive tablets, there is rapid absorp- tion and enough mercury enters the system to produce acute poisoning. In such cases, the poisonous action is prolonged and death follows from the continued contact with mercury at the points of excretion, particularly in the colon and in the kidney. 5. Action on the central nervous system. — Salts of mercury are relatively inactive so far as the function of the central nervous system is concerned. Even in toxic quantities, when the poisonous effects proceed to the climax in death, consciousness continues until 372 THE MERCURY SALTS the last. Certain nervous derangements do occur after prolonged mercurial poisoning. There is an increased irritability to sensory stimulation, a degree of loss of muscular control shown by the feel- ing of muscular fatigue and by mercurial palsy. As in lead poison- ing the muscular disturbances usually appear first in the upper ex- tremities and extend thence over the body. Other local nervous symptoms have been described in chronic mercurial poisoning, but they are not of sufficient constancy to be enumerated in this con- nection. 6. The action of mercurial salts on the circulatory and respira- tory systems. — Of all the parts of the body, the least to be affected are the organs of the circulation. The nerve control of the heart and blood-vessels remains intact to the last.- The same is true for respiration. Such derangements as occur are primarily due to mus- cular disturbance in the later toxic action. Experiments indicate that the heart, at least of the frog, responds with a more favorable rhythm and force in the presence of very dilute solutions of mercuric chloride. Strips of cardiac muscle, ventricle of the terrapin, con- tracting in physiological solutions, withstand the action of one in one thousand solutions of mercuric chloride many minutes, main- taining a very uniform rhythm and only slowly decreasing the ampli- tude as the muscle protoplasm is slowly coagulated by the mercuric salt. 7. Action of mercury on the kidney. — The kidney, of all the organs of the body, is one of the most susceptible to mercurial salts. This is no doubt due to the condensation of mercury in the nephridia during the process of excretion. Both the glomerulus and the secret- ing tubules are sharply affected. The toxic action takes the form of irritation, followed by inflammation. There is an early suppression of the excretion of urine, accompanied by the presence of blood products in the urine, i.e., red corpuscles, albumin, and in many cases sugar. As the inflammatory process continues, the renal parenchyma undergoes necrosis, and a deposit of calcium salts may take place both in the cells and in the cavity of the tubules. Such a pathological condition is accompanied by complete anuria leading to uremia. Very minute quantities of mercury are stimulative to urinary secretion. This has been shown by Cohnstein 1 on rabbits. He found that an intravenous injection of calomel leads to an increased secre- 1 Cohnstein, W. : Archiv fur Pathologie und Pharmakologie, Vol. XXX., p. 132, 1892. THE EXCRETION OF MERCURY 373 tion of urine; a fact that has been often observed clinically after the administration of the salt. The effect of intravenous injection of mercurous chloride on the secretion of urine in the rabbit (Cohnstein). Period op Secretion. Amount of urine per ten minutes. Rabbit No. 16. Rabbit No. 17. 1. Normal .15 cc. .13 cc. .16cc. .01 cc. 9.21 cc. 4.47 cc. 2.75 cc. 1.01 CC. 2. " 0.87 cc. 3. " Dose Hg 2 Cl 2 in jugular 0.87 cc. .004 cc. 4. Mercury 3 09 cc. 5. " 5.95 cc. 6. " 5 96 cc. These experiments indicate an increase in the secretion of urine of from one to six and more, per unit of time. This effect on the kidney is probably due to direct stimulative action of small quantities of mercury on the renal epithelium, an action which can and does readily pass over to one of toxic injury as expressed in inflammation and necrosis. A different explanation has been offered, namely, that the great fluidity of the intestinal con- tent in the region of the large intestine leads to a hydremia, and that this condition indirectly stimulates the kidneys to a greater secretion. 8. The excretion of mercury. — The formation of albuminates of mercury tends to the storage of this metal in the body tissues. The complete secretion of mercury, therefore, takes place only after a long interval. Indeed, mercury may be found in the excretions of the body for months after its last administration. However, the elimination of mercury begins within a few minutes after its absorp- tion and its slow excretion continues until its ultimate removal. The channels by which the mercury leaves the body are the alimentary canal on the one hand, and the kidney and skin on the other. All intestinal and cutaneous glands excrete mercury. It is thought that the greater portion leaves the body by way of the kidney, except in cases of extreme cathartic action. This state- ment applies, of course, only to mercury after absorption. The large amount lost by way of the alimentary canal after absorp- tion is that thrown off in the secretion of the salivary, gastric, and pancreatic glands, and by the intestinal mucosa itself. It is gen- erally claimed that the mucosa excretes a large percentage of the 374 THE MERCURY SALTS salts of mercury. Mercury, as was found to be the case also with lead, detected in the epithelial cells of the colon and rectum is con- sidered to be excretion mercury, not mercury in the process of ab- sorption. A number of the local effects of mercury, especially observed in chronic mercurial poisoning, are due to its condensation at the point of excretion. Salivation is an example, as is also mercurial nephritis, and the ulceration that occurs in the lower bowel and at points on the skin. 9. Acute toxic action of mercury. — Cases of mercurial poisoning are more or less common, and generally arise from the actions of the soluble mercuric chloride or corrosive sublimate. The solubility of this salt and the rapidity with which it is absorbed accounts for the chain of symptoms which characterize the condition. The primary effects are due to the local irritation of the alimentary tract. There is acute gastritis accompanied by nausea, usually vomit- ing and diarrhea with intense griping pains. If the inflammation has progressed far enough the vomit will contain flecks of blood, and sometimes disintegrated epithelium from the corrosion of the mucous membrane. The stools are usually voluminous and watery, and may also contain, besides the usual fecal matter, dis- integrated epithelial tissue. These symptoms occur almost immedi- ately, certainly within a few hours. If the corrosion is unusually severe there is a degree of collapse from the extensive visceral reflexes. The acute symptoms occurring from action of mercury after absorption are those which might be expected from the coagulation of the protoplasm of the tissues in various portions of the body. The most important of all is acute nephritis with suppression of the urine. A weak and irregular heartbeat also follows, with low blood-pressure, and an increase in the secretion of saliva and of perspiration. "While there may be muscular weakness, the general muscular and nervous reactions are little if at all interfered with. 10. Chronic mercurial poisoning. — Chronic mercurial poison- ing, called mercurialism, occurs after prolonged absorption of the salts of mercury. This class of toxic action is rendered more common because of the widespread use of mercury in the treatment of syphilis and other venereal infections. The early symptoms are found in inflammation of the mouth, including the gums, and an increase in the secretion of saliva or insalivation. The inflammatory process about the gums may progress to an actual necrosis, beginning CHRONIC MERCURIAL POISONING 375 in the bone around the bases of the teeth and involving more or less of the jawbones. The alimentary canal shows the effect of the poison especially along the lengths of the intestine, particularly the large intestine. This usually takes the form of chronic diarrhea. The concentration of the action at this point is presumably associated with its excre- tion here.* Other regions through which mercury is excreted begin to show the effect of its toxic action. For example the irritant effect on the skin leads to local foci of an erythematous type of inflammation, usually in association with the sweat glands. This is to be attributed to the direct action of the mercury as a result of the cutaneous excretion. The chronic effects of mercury on the kidney have already been indicated. Following the acute suppression of function arid the beginning of renal inflammation, there is a progressive degeneration especially of the secreting cells of the convoluted tubules. The glomeruli are also involved in this necrosis. When the lesion is extensive enough, it leads to a failure to excrete the waste products of the body, and therefore to general toxic uremia and death. It is evi- dent that a poison so toxic in its action will produce an inevitable depression of metabolism. This is shown in the general weakness and in the final anemic condition of the victim. CHAPTER LIV. SALTS OF SILVER. I. Details of Pharmacological Action. Silver nitrate has long been extensively used for medicinal pur- poses, but in recent years has been more or less displaced by a num- ber of organic silver compounds. Of the organic compounds, the silver vitellate and silver caseinate are soluble in water and not pre- cipitated by the albumin or the chlorides of the blood. i. The local and antiseptic action of silver salts. — For many years the fused silver nitrate crystals have been used locally as a caustic for mucous surfaces and especially for local infections. When a cauterizing stick is applied to a mucous surface, the nitrate crystals begin to dissolve and to form a surface film of albuminate. The action is strongly antiseptic, destroying the infectious bacteria as well as the surface albumin. The irritant action of silver nitrate depends upon the formation of this local eschar. Silver, like lead, prevents its own rapid and extensive absorption by the process of precipitation of albumin. But silver is more irritant than lead, though less astringent. Solutions of silver nitrate are disinfectants for mucous mem- branes. They have been used especially to combat local infection of the mouth and throat, for the disinfection of the eyes and rather ex- tensively for the disinfection of the uro-genital apparatus. The soluble organic preparations of silver are not precipitated by albumins and are non-irritant. Therefore, a higher percentage of silver may be brought in contact with surfaces in this form. 2. The toxic action of silver salts. — Silver poisoning by the accidental swallowing of lunar caustic or from the accidental injec- tion of silver nitrate has occurred. Crystallized nitrate in the stomach dissolves rapidly and forms extensive local lesions. These are accompanied by a precipitation of albumin over the surface of the mucosa. This is followed by inflammation with intense burning pain, and still later by extensive corrosion, which may terminate 376 SYSTEMIC EFFECTS 377 fatally. A fatal case from 30 grains taken by an adult has been re- ported, while half that quantity swallowed as lunar caustic proved fatal in a child of fifteen months. The accidental subcutaneous injection of a four per cent, solu- tion of silver nitrate is reported to have been accompanied by intense burning pain, followed in a couple of hours by more general deep- seated pains associated with the bones of the neighboring parts. In twenty-four hours the injected tissues appeared pale and began to slough. Extensive inflammation occurred in the neighboring tis- sues and extended for some distance along the lymphatic channels. Healing in such cases is extremely slow, apparently from inter- ference with a sufficient vascular supply. 3. Systemic effects. — The general systemic effects of silver are not extensive. This is due to the formation of soluble silver com- pounds and the elimination of this salt from toxic activity. If given by way of the mouth, silver solutions are in part transformed into insoluble lead sulphides and are lost with the feces. Absorption albuminates are formed, converting the silver to a less active form. Certain toxic nerve effects have been described. The spinal cord and the medulla are slightly stimulated at first, then general paralysis is produced. The various automatic centers in the medulla are involved in this process, especially the vasomotor, cardio-inhibi- tory, and the respiratory centers. Cohnstein describes a striking increase in renal secretion in the rabbit after ten milligram doses of silver chloride in solution in sodium hyposulphite given subcuta- neously. In one experiment the urine per hour was increased from 1.64 to 11.60 grams; in another experiment from 1.50 to 6.39 grams. He records only a trace of albumin in the urine in a single experi- ment. However, silver salts have not been described as excreted by the urine. Silver that has been absorbed becomes fixed in various organs, particularly in the connective tissues and muscles, where it is pre- cipitated in insoluble form. In the continued clinical use of silver salts it lias been known for many years that precipitation of the silver in the connective tissues leads to a permanent pigmentation. Ex- tensive deposits of silver lake place in the subdernial connective tissue. giving to the unfortunate a peculiar bluish color known as argyria. This pigmentation is permanent, at least we have found no means for its removal up to the present time, unless the solvent action of hexa- methylamine, described by Dr. Crispin, proves the efficient agenl (see note, page 337 ) . CHAPTER LV. SALTS OF BISMUTH. Details of Pharmacological Action. Bismuth is still another heavy metal that possesses therapeutic interest of high degree. The soluble salts of -bismuth are readily absorbed and toxic. These are the bismuth salts of certain inorganic acids, especially bismuth ammonium citrate. The insoluble salts bismuth subnitrate, subcarbonate, also bismuth subcitrate as well as certain other bismuth organic compounds that are not soluble in water, are only slightly soluble in the body fluids. These salts are non-toxic. i. The action of soluble bismuth compounds. — Soluble bismuth compounds are toxic after introduction into the system, and poison- ous effects are similar to that of certain other heavy metals, perhaps to mercury more than to any other. In the nervous system the toxic action falls heavily on the spinal cord and medulla. The symptoms are those of strong stimulation accompanied by rapid respiration, by muscular cramps, and generally by vomiting, later by motor paralysis and consequent suppression of respiration. The action on the cir- culatory system affects primarily the cardiac muscle, leading to weak circulation. In the symptoms of salivation and stomatitis, comparable to that of mercurialism which has been described, there is a tendency to diarrhea with ulceration and often necrosis of the large intestine, and to nephritis. The toxic action of bismuth sometimes appears from the exten- sive application of insoluble salts to ulcerating surfaces. This un- doubtedly depends upon some unknown condition favoring solution and absorption of the basic compounds. 2. The action of insoluble bismuth salts. — The insoluble bismuth salts have, in recent years, widely extended use, especially in con- nection with the study of the alimentary tract by the Kontgen-ray method. Bismuth subnitrate, which is the usual salt used for this purpose, is very opaque to the rays, hence gives a sharp picture of 378 DETAILS OF PHARMACOLOGICAL ACTION 379 the boundaries of the alimentary cavities. Difficult physiological problems as regards the alimentary movements have been explained by this method. Notable among these are the studies of Cannon ' on the movements of the stomach and of the intestines. Preparations of the bismuth subnitrate are also used for certain Rontgen-ray pic- tures of the uro-genital apparatus, particularly of the ureters and of the pelvis of the kidney. No untoward results come from this treatment, either in man or mammals. The subnitrate of bismuth is absorbent. When brought in contact with the living tissues, as in the case of the surface of an ulcer or the mucosa of the alimentary canal, it acts as an absorbent and a mild antiseptic. The antiseptic properties are due to the solution of traces of the bismuth. This is explained by the solvent action of the tissue fluids. In the case of the stomach, if there is an ex- cessive secretion of hydrochloric acid in the gastric juices, a portion of the subnitrate will be reduced, giving rise to a small amount of bismuth chloride. The subnitrate remaining insoluble is carried for- ward along the canal by the peristalses. The traces of soluble salts are absorbed and enter the circulation and are excreted by the kidney. When bismuth subnitrate passes the cecum it meets and reacts with the sulphides, which are present in greater or less quantities in the large intestine, thus forming bismuth sulphide. The sulphide has a toxic influence, not only on the mucosa, but on the capillaries and smaller blood-vessels of the intestinal wall. Whether the bismuth sulphide acts to obstruct the circulation by small thrombi, as has been claimed, or by other toxic influences, it results in a tendency to ulceration with necrosis in local areas. In general, bismuth has a slight sedative influence on the movements of the alimentary canal, probably due largely to the reduction of the subnitrate by such salts as sodium sulphate, thus eliminating the stimulative effects of the sulphate ion. Bacteria, which produce fermentation in the large intestine of the animal body, have a tendency to liberate nitrites from the bismuth subnitrate, a process that has been de- scribed by B6hme. a He found in tests on the rabbit that after the introduction of subnitrate of bismuth into the loop of the large in- testine the urine of the animal reacted strongly to tests for nitrites 1 Cannon, W. B. : The American Journal of Physiology, Vol. L, p. 359, 1898; Vol. VI., p. 251, 1902. 2 Bohme, A.: " Uber Nitritvergiftung nach interner Darreichung von Bis muthum subnitricum," Archiv fur experimentalle Pathologie und Pharmakologie, Vol. LVIL, p. 441, 1907. 380 SALTS OF BISMUTH within a few hours. He also showed that nitrites could be detected in the blood of the animal. The toxic influence of nitrites from this source are sufficient to produce death of an animal (see nitrites, page 178). DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IN USE. The following Dose Table contains the average individual doses and the maximum doses. The average dosage is taken from Useful Remedies, compiled by the Council on Pharmacy and Chemistry of the American Medical Association, and published by the American Medical Association Press. The maximum dosage is taken from William Wood and Company's Physician's Diary for 1914. APPENDIX. Adult Doses (by the mouth) Drug. Acetanilide Acet-phenetidin .... Acid, aceticum dil. . Acid, benzoicum . . . Acid, boricum Acid, carbolicum . . Acid, citricum .... Acid. hydrochlori- cum dil Acid, hvdrocyanicum dil. * Acid, salicylicum . . Acid, tannicum Aconiti tinctura . . Aconitina Adrenaline, 1/1000. (See epinephrine) ^Ether JEtheris nitrosi spir- itus yEtheris spiritus . . . ^Etheris spiritus compositus Aloe Aloes extr Aloes tinct Aloin Ammoniacum Ammoniac spiritus.. Amnionii chloriduni Ammonii phosphas. Amyl nitris Average Dose. 0.25 gm. 0.5 gm. 0.5 gm. 0.5 gm. 0.5 gm. 1.00 cc. 0.1 0.5 0.5 0.6 cc. gm. gm. cc. 0.5 cc. 1.00 cc. 2.00 cc. 4.00 cc. 4.00 cc. 0.250 gm. 0.125 gm. 0.065. gm. 0.5 gm. 0.2 cc. 4 gr. 7.5 gr. 7.5 gr. 7.5 gr. 7.5 gr. 15 min. 1.5 min. 7.5 gr. 7.5 gr. 10 min. 7.5 min. 15 min. 30 1 1 4 o nun. fl. dr il. dr gr. gr. 1 gr- 7.5 gr. 3 min. 381 Maximum Dose. 0.50 gm. 1.00 gm. 4.00 cc. 2.00 gm. 1.00 gm. 0.13 gm. 2.00 gm. 2.00 cc. 0.20 cc. 1.30 gm. 0.65 gm. 0.30 cc. 0.00026 gm. 1.00 4.00 s.oo 6.00 6.00 0.65 0.65 8.00 0.20 2.00 4.00 0.65 1.30 0.30 cc. cc. cc. cc. cc. gm gm cc. gm gm cc. gm gm cc. 8 16 1 30 15 2 30 30 3 20 10 5 gr. gr. dr. (Troy) gr- gr- gr- gr- min. min. gr. gr- min. 1/250 gr. 15 min. 1 fl. dr. 2 dr. (Troy) 1.5 dr. (Troy) 1.5 dr. (Troy) 10 gr. dr.(Ti gr. gr. dr. (Troy) gr. gr. min. 382 DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IN USE Adult Doses (by the mouth). — Continued. Drug. Antimonii et potas- sii tartras (emet- ic) Antipyrin Apocynum Apomorphinse hydro- chloras (emetic) . Argenti lactas Argenti nitras Arsenii iodidum . . . Aspirin Atophan Atropine sulphas . . . Average Dose. Barii chloridum . . . Belladonnas foliorum tinct Belladonnas radix . . . Benzoini tinct Bismuthi citras . . . Bismuthi subnitras. 0.03 0.25 gin. gm. mg. 0.01 gm. 0.5 gm. 0.4 mg. 0.5 cc. Caffeina Caffeina citrata . Caffeinae sulphas . Calcii chloridum . Calcii hypophosphis Calomel Camphorse spiritus Cantharis Cantharidis tinct. . Cascara sagrada ext. Chloral Chloretone Chloroformum . . . Chichonse tinct. . . . Coca Cocainse hydrochlo- ras Codeina Conine Copaiba Creosotum Cupri arsenitis Cupri sulphas (emetic) ' Curare 0.5 gm. 0.065 gm. 0.125 gm. 0.5 gm. 0.5 gm. 0.065 gm. 1.00 cc. 0.5 gr. 4 gr. 0.1 gr. 6.5 gr. 7.5 gr. 1/160 gr. 7.5 gr. gr. gr. gm. Digitaline (cryst. Nativelle ) .... Digitalis extr. fl.. Digitalis tinct. . . Elaterium 0.15 cc. 4.00 cc. 0.03 gm. 0.03 gm. 1.00 cc. 0.2 cc. 0.25 gm. 7.5 7.5 1 15 gr. gr. min. 15 gr. mm. fl. dr. 0.5 gr. 0.5 gr. 15 3 min. min. gr. 1.00 cc. 0.005 gm. 15 min. 0.1 gr. Maximum Dose. 0.06 gm. 1.00 gm. 1.30 gm. 0.006 gm. 0.32 gm. 0.06 0.01 2.00 1.00 gm. gm. gm. gm. 0.00065 gm. 0.065 gm. 1.00 cc. 0.06 gm. 2.00 cc. 0.30 gm. 2.00 gm. 0.20 0.32 0.30 1.30 1.00 1.30 2.00 0.03 0.65 0.50 2.00 0.65 0.65 8.00 8.00 gm. gm. gm. gm. gm. gm. cc. gm. cc. gm. gm. gm. cc. cc. cc. 0.13 gm. 0.65 gm. 0.006 gm. 2.00 cc. 0.30 cc. 0.0006 gm. 0.32 gm. 0.006 gm. 0.002 gm. 0.12 cc. 1.30 cc. 0.004 gm. gr- gr- gr. 0.1 gr. 5 gr. 1 gr- 1/6 gr. 30 gr. 15 gr. 0.01 gr. 1 gr. mm. gr- min. gr- gr. gr. gr. gr- gr- gr- gr- min. 0.5 gr. 10 min. gr. gr- gr- min. fl. dr. gr- 2 dr. (Troy) 1 gr. 0.1 gr. 30 min. 4 min. 0.01 gr. 5 gr. 0.1 gr. 1/30 gr. 2 min. 20 min. 1/16 gr. DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IN USE 383 Adult Doses (by the mouth). — Continued. Drug. Average Dose. Emetina (alkaloid) . Epinephrine, 1/1000 Ergota fl. ext. Eserina Eserinae salicylas . . Eucainae hydrochlo- ras /3 0.5 cc. 2.00 cc. 0.001 gr. Ferri arsenas Ferri chloridum . . . Ferri chloridi tinct. Ferri et quininee ci- tras Ferri et strychnine citras Frangulae extr. fl. . . Gaultheriae oleum . . Gelsemina ( alka- loid) Gelsemii extr. fl.. . . Gentianae extr Glonoin Heroin Homatropinae hydro- bromas Hydrargyri chlori- dum corros Hydrargyri massa . . Hydrastinae hydro- chloras Hydrastis tinct. . . . Hyoscinae hydrobro- mas Hyoscyaminae hydro- bromas Iodi tinct. Iodothvrin Jalapae resina Litliii citras . Magnesia Magnesii citras granulatus .... Magnesii sulphas Manna Menthae piperita aqua 0.5 0.25 gm. 0.003 gm. 0.0005 gm. 0.003 gm. 0.250 gm. 7.5 min. 30 min. 0.065 gr. gr. 0.05 gr. 1/128 gr. 1/20 gr. 4 gr. 2.00 gm. 16 gm. 30 gr. 240 gr. Maximum Dose. ( 0.002 gm. ] to ( 0.02 gm. 1 cc. 4.00 cc. 0.0013 gm. 0.003 gm. 2.00 cc. 0.006 gm. 0.25 gm. 2.00 cc. 0.65 gm. 0.12 gm. 2.00 cc. 1.00 cc. 0.003 gm. 0.65 cc. 0.65 gm. 0.001 gm. 0.01 gm. 0.003 gm. 0.006 gm. 0.40 gm. 0.65 gm. 4.00 cc. 0.001 gm. 0.001 gm. 0.32 cc. 1.30 gm. 0.40 gm. 1.80 gm. 4.00 gm. , 30.00 gm. 30.oo gm. i 30.00 gm. 16.00 cc. 1/30 gr. to 1/3 gr. 15 min. 1 dr. 1/50 gr. 1/20 gr. 30 min. 6^ c sol. 0.1 gr. min. 10 gr. gr ; min. 1/29 gr. 10 min. 10 gr. 1/60 gr. 1/6 gr. 0.05 gr. 0.1 gr. 6 gr. 1 gr. 1 dr. (Troy) 1/60 gr. 1/60 gr. 5 min. 20 err. gr. gr- dr. (Troy) oz.n < OZ.I I OZ. ('I I dr. (Troy) 384 DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IN USE Adult Doses (by the mouth). — Continued. Drug. piperita? Menthae spiritus Menthol Methylis salicylas . Monobrom - acetani - lide Morphina Morphinae hydro- chloras Morphinse sulphas . . Morrhuae oleum . . . Muscarine nitras . . Myrrhae tinct Naphthol p.. Nicotinum Nitroglycerinum . . . Nucis vomicae extr. . Nucis vomicae tinct Opium Ouabain Ovariin Pancrea tin Papain Para-acet-phenetidin Pepsinum Phenacetine Phenol ( absolute ) . . Phenolphthalein . . . Phosphorus Physostigmatis extr. Physostigminae sul- phas Pilocarpina Pilocarpinae hydro- chloras Plumbi acetas Podophyllum Podophylli extr. . . . Podophyllin Potassii acetas .... Potassii bromidum . Potassii citras Potassi cyanidum . . Potassii et sodii tar- tras Potassii iodidum... Potassi sulphas . . . Quillaiae tinct. (1 to 10) Quininae hydrobro- mas Average Dose. 2 cc. 0.065 gm. 1 cc. 0.01 gm. 0.015 gm. 0.015 gm. 16 cc. 0.015 gm. 0.6 cc. 0.5 0.25 gm. 0.065 gm. 0.1 gm. 0.5 mg. mg. 0.01 gm. 0.065 gm. 0.015 gm. 2 gm. 1 gm. 1 gm. 8 gm. 0.5 gm. 30 1 15 mm. gr. 0.20 gr. 0.25 gr. 0.25 gr. 4 fl. dr. 15 0.25 gr. 10 min. 7.5 gr. gr. 1 gr. 1.5 gr. 1/125 gr. 1/62 gr. 0.20 gr. 1 gr. 0.25 gr. 30 15 15 gr. gr. 120 gr. 7.5 gr. Maximum Dose. 1.00 cc. 0.065 gm. 2.00 cc. 1.00 0.03 gm. gm. 0.03 gm. 0.03 gm. 16.00 cc. 0.06 gm. 1.00 cc. 0.30 gm. 0.001 gm. 0.001 gm. 0.03 gm. 1.30 cc. 0.12 gm. 0.00026 gm. 0.36 gm. 2.00 0.50 1.00 1.30 1.00 0.20 2.00 gm. gm. gm. gm. gm. cc. gm. 0.0013 gm. 0.006 gm. 0.0006 gm. 0.05 gm. 0.05 0.20 1.30 0.32 0.03 2.00 2.65 4.00 gm. gm. gm. gm. gm. gm. gm. gm. 0.0065 gm. 1.30 16.00 gm. gm. 4.00 cc. 1.30 gm. 15 min. 1 gr. 30 min. 15 gr. 0.5 gr. 0.5 gr. 0.5 gr. 4 dr. (Troy) 1 gr. 15 min. 5 gr. 1/60 gr. 1/60 gr. 0.5 gr. 20 min. 2 gr. 1/250 gr. 6 gr. g r - gr. gr. gr- gr- gr- gr- 1/50 gr. 0.1 gr. 0.01 gr. 0.75 gr. 0.75 gr. 3 20 5 0.5 30 40 1 0.1 1 20 4 gr- gr- gr- gr- gr. gr- dr. (Troy) gr- oz. gr- dr. (Troy) 1 dr. (Troy) 20 gr. DOSE TABLE FOR THE MORE IMPORTANT DRUGS NOW IX USE Adult Doses (by the mouth).— Continued. Drug. Average Dose. Maximum Doee. Quininae hydrochlo- ras Quininae sulphas . . . Rhamni purshianae extr. fl Rhei extr. fl Rosein (Fuchsin) . . 0.25 0.25 1.00 gm. gm. cc. 4 4 15 gr. gr- min. 1.00 gm. 1.00 gm. 16.00 cc. 2. no cc. 0.25 gm. 2.00 gm. 4.00 0.20 gin. 0.20 cc. 4.00 cc. 0.001 gm. 15 gr. 15 gr. 4 dr. (Troy) 30 min. 4 gr. 30 g 1 dr. (Troy) 3 Salol Sarsaparillae ext. fl. Scilla 0.125 gm. 2 gr- Scillae extr. fl. Scillae syr Scopolamine hydro- bromate Senna 2 0.5 4 2 4 cc. mg. gm. cc. cc. 30 l/12c 60 30 1 min. Igr. gr. min. fl. dr. 1 dr.iT: 1/64 gr. Sennae extr. fl Sennae svr 16.00 cc. 4 dr. (Troy) Serpentaria 2.00 gm. 0.008 gm. 4.00 gm. 4.00 gm. 4.00 gm. 4.00 gm. 2.00 gm. 30.00 gm. 0.005 gm. 0.006 gm 0.005 gm. 0.30 gm. 4.00 gm. 1.30 gm. 0.30 gm. 0.12 gm. 0.50 gm. 0.40 cc. 4.00 gm. 4.00 0.003 gm. 0.20 oc. 0.12 gm 2.oo gm. 30 gr. 1/8 gr. 1 dr. (Troy) 1 dr.(Ti 1 dr.(Ti Sodii arsenas Sodii bicarbonas . . . Sodii bromidum . . . Sodii citras 5 1 1 mg. gm. gm. 0.1 15 15 g r - gr- gr- Sodii phosphas .... Sodii sulphas Strophantin(g) . . . Strvehninae nitras.. 2 16 0.3 gm. gm. gm. mg. 30 gr. 15 gr. 240 gr. 1/200 gr. 1 d] 30 | 1 oz.(Ti 1/12 gr. 0.1 gr. Strvehninae sulphas. Suprarenal gland . . 1 mg. 1/64 gr. 1/12 gr. 5 gr. Taraxaci extr. fl. . . 1 fir. (T: Terpin hydras Theobromine Thvmol 0.125 gm. 0.3 gm. 0.125 gm. 2 5 2 gr. gr. gr. 20 gr. 5 gr. 2 gr. 8 gr. Thvroid extract . . . Trimethvlamina . . . min. Urethane 1 dr.i'l: Valerianae extr. fl. . . Veratrina 2.00 cc. 30 min. 1 dr.(Ti 0.05 gr. Veratri viridis extr. fl. 3 min. Zinci acetas Zinci sulphas (emet- ic) 0.125 gm. 1 gm. 2 15 gr. gr. 2 Jr. INDEX Acetanilide, 232, 23G; and see Antipy- retics, coal tar Acetic acid, 326, 327 Acetphenetidine, 232, 236; and see An- tipyretics, coal tar Acetyl-salicylic acid, 246 Acid, acetic, 326, 327 acetyl-salicylic, 246 arsenic, 350 cacodylic, 350 carbolic, see Phenol citric, 326, 327 crotonoleic, 281 dicacodylic, 350 ergotinic, 165 hydrochloric, 326 hydrocyanic, 197 nitric, 326 phenol-sulphuric, 239 prussic, see Hydrocyanic acid salicylic, 238, 244 sulphuric, 326 tartaric, 326, 327 tropic, 112 uric, 90 Acids, 326 dilute, action of, 326 mineral, 326 organic, 326, 327 Aconine, 201 Aconite, 201 action of. 201, 202 antipyrei ic, 20 I on blood-vessels, 204 on central nervous system, 202 on circulatory system, 203 on glands, 204 Bummary of, 205 mic, 202 and Vera! rine group, 201 chemical, 201 historical 201 Aconitine, 201 Aconil inn napellus, 201 Adrenaline, 152; and see Epinephrine Age, dosage proportioned to, 7 influence of. 7 Agroste a githago, 105 Albumin compounds of metal, Albuminates, metal, formation ol Alcohol, 10 as B local irritant. 20 chemical relationships <»f, in Alcohol, effects of, local, 20, 37 summary of, 37 systemic, 22 elimination of, 36 group of drugs, 19 habit, and disease, 37 local action of, 20 effects of, on mouth, 21 on skin, 20 , on stomach, 21 percentage of, in liquors. 20 systemic effects of, 22, 37 on blood, 32 on cardiac centers in medulla, 30 on circulatory system, 27, 31 on digestive tract, 33 on fertility, 36 on germ-plasm, 36 on heart, 27, 28, 30 on liver, 34 on metabolism, .'!.") on muscular tissue, 26 on nervous system, 22, 23, 24, 25, 30 on peripheral blood-vessels, 31 on respiratory system, 33 tolerance of, 36 toxicity of various forms of. 20 Alcoholization, 22 Alkalis. 324 cauterizing action of, 325 physiological action (^'. 325 Aloes, 278; and see Vegetable cathartics Alpha-eucaine, 219 Amanita muscarius, 128 Ammonium carbonate, 32 i chloride, ::«'7 hydrate, 324 307 ;ict ion of. on secrel iona on nervous bj stem, 308 excretion of. Amygdalin, L97 Amy] nitrite. I7s ; and n < Nitrites Anesthesia, stages of. ij. 10, Ancstli.'t i, Ani- Anthi iup "i' eathari ics, pi f ive ad ion of Vntiaris, 181 Ant imony Antipyren 8; and tet Antipy- ret Ecs. coal 'i i 388 INDEX Antipyretics, coal tar, 321 action of, 233 general antipyretic, 233 narcotic, 234, 235 on blood, 235 on blood-vessels, 235 on central nervous system, 234 on circulation, 234 chemical, 231 comparison of, 236 historical, 231 susceptibility to, 235 Antiseptics, coal tar, 237 action of, 239, 243 corrosive, 241 on central nervous system, 240 on circulatory system, 241 on protoplasm, 239 summary of, 243 toxic, 239 chemical, 237 excretion of, 241 historical, 237 toxicology of, 241 Antitoxins, 261, 266 Apocodeine, 84 action of, 84 on alimentary canal, 87 on nervous structures, 87 on urinary motor system, 87 and pharmacological investigation, 88 Apocynum, 181 Apomorphine, 84 action of, 84 on central nervous system, 85 on muscular tissue, 86 Argyria, 337, 377 Arrow poison, 107; and see Curare Arsanilates, 354 Arsenic, 350 action of, 351 on alimentary tract, 352 on circulatory system, 352 on metabolism, 353 compounds of, 350 excretion of, 353 historical, 350 organic compounds of, 354 synthetic compounds of, 350, 354 toxicity of compounds of, 351 Arsenic acid, 350; and see Arsenic Arseno-benzol, 350, 355; and see Ar- senic Aspirin, 232, 246 ; and see Antipyretics, coal tar Atoxyl, 350, 354; and see Arsenic Atropa belladonna, 112 Atropine, 112 action of, 112, 113. 120 general symptoms of, 113 Atropine, action of, on alimentary canal, 118 on bladder, 119 on central nervous system, 113 on circulatory system, 116 on eye, 114 on glands, 115 on heart, 117 on intestine, 118 on stomach, 118 on uro-genital apparatus, 119 summary of, 120 chemical relations of, 112 compared with other members of the group, 135 excretion of, 120 group, 112 Auto-oxidation, 331 Bacteria, irritant action of, 263 Bacterial toxins, 260 action of, 261 irritant, 263 production of antitoxins, 266 type of, 266 characteristics of, 265 historical, 260 specificity of, 267 Bacteriolysin, 261 Barium chloride, action of, 174 local, 176 on alimentary canal, 176 on central nervous system, 176 on circulatory system, 174 on heart, 174 on peripheral arterioles, 175 on skeletal muscle, 176 on uro-genital muscle, 176 salts, 314 therapeutic indications for, 177 Belladonna, 112; and see Atropine Benzaconine, 201 Benzene, 237 Beta-eucaine, 219 Bismuth, ammonium citrate, 378 and its salts, 378 action of, 378 subcarbonate, 378 subcitrate, 378 subnitrate, 378 Bone, action of phosphorus on, 346 composition of, 347 Broom plant, 151 Brucine, 96, 105 Bufonine, 194 Bufotaline, 194 Cacodylic acid, 350 Caffeine, 89 absorption of, 94 action of, 90, 95 I^DEX 389 Caffeine, action of, diuretic, 94 • on cardiac mechanism, 93 on central nervous system, 90 on circulation, 92 on medulla, 91 on metabolism, 94 on respiratory mechanism, 94 on skeletal muscle, 91 on spinal cord.. 91 on vasomotor apparatus, 93 summary of, 95 chemical relationships of, 89 excretion of, 94 group, 89 Calabar bean, 130 Calcium carbonate, 324 hydrate, 324 salts, 310 action of. in coagulation of blood, 311 on heart. 311 on metabolism, 312 on nerve tissue, 312 excretion of, 312 Calomel. 371; and see Mercury, salts of Cantharidin, 269 ; and see Irritants irritant action of, 273 type, irritants of, 273 Cantliari- ve-icatoria, 269 Carbolic acid, see Phenol ira, 278; and see Vegetable cathar- tics Cassia, 278 i oil, 280; and see Vegetable ca- thartics Catharsis, 275 Cathartics, see Purgatives table, 274; and see Vegetable cathartics Cations, Cephselis Ipecacuanha, 212 Mill -IlltS. Chemical changes, 6 Chloral hydrai action of. 63. 8 l on nervo '■ 64 chemica I -;ii symptoms produced by, 64 histories ' Chloroform, 50 absorption of. action <>f. 50, ..n alimentary canal, - r >"» r,n blood-pressure, 52 on blood-vessels, 5 t on central nervous system, - r 'l on circulatory system, nn heart, on voluntary muscles, 55 summary of. 57 excretion of, 58 Chloroform, stages of anesthesia, 50 Choline, 129 Cinchona, 222 succirubra, 222 Cinchonidine. 222; and see Quinine Cinchonine, 222; and see Quinine Citric acid, 326, 327 Claviceps purpurea, 165 Coal tar antipyretics, 231; and see An- tipyretics, coal tar antiseptics, 237 ; and sec Antisep- tic-, coal tar series, 231 Cocaine. 213 action of, 214, 220 anesthetic, 217 local, 217 on central nervous system, 214 on circulatory system, 215 on eye, 217 on heart, 216 on peripheral blood-vessels, 215 on skeletal muscle. 216 summary of, 220 anesthetic action of, 217 chemical. 213 elimination of. 217 habit, 218 historical. 213 spinal analgesia by, 218 substances which produce anes- thesia similar to, 219 Codeine, action of. 79 chemistry of, 06, 67 retion of, 81 Colchicein, 210 Colchicine, 210 action of, 210 on white blood corpuscles, 210 niic. 210 toxic. 210 chemical, 210 historical, 210 Colehicum autumnale, 210 Cold, a- counter irritant. 281 Colloids. 288, ( olocynth, 280; and see Vegetable ca- thari ics Conhydrine, l 17 Coniine, 136, 147; and see Nicotine action «>f. on autonomic oervous •.•in. 1 18 on central nervous system, l » s on circulatory apparatus, l 19 on heart, 149 on motor nerve endin on respiratory movements, 1 19 and sparteine group, l 17 action of, l 17, l I s chemical, 147 retion of, 150 390 INDEX Coniine, historical, 147 methyl, 147 Conium maculatum, 136, 147 Convallaria, 181 Copper acetate, 366 and its salts, 366 action of, 366 disinfectant, 366 systemic, 367 toxic, 366 elimination of, 366 arsenite, 366 sulphate, 366 Corncockle, 195 Cornutine, 165 Counter irritants, 259, 282; and see Counter irritation application of, 283, 287 list of, 287 Counter irritation, 282 agents used for, 287 conditions which suppress, 286 sites for application of, 283 theory of, 282 Croton oil, 281; and see Vegetable ca- thartics tiglium, 280 Crotonoleic acid, 281 Crystalloids, 288, 289 Cumulative effect of drugs, 16 Curare, 107 absorption of, from stomach, 109 action of, 107, 108 on motor nerve endings, 108 on peripheral ganglia, 109 comparison of, with related drugs, 110 group, 107 Curine, 107 Cyanides, 197; and see Hydrocyanic acid Cyan-methemoglobin, 199 Cyanogen, 197 Cytisus scoparius, 151 Delphinine, 201 Dicacodylic acid, 350 Digitalein, 181; and see Digitalis Digitaline, 181; and see Digitalis Digitalis, 181 action of, 182. 183, 193 cumulative, 192 diuretic, 191 irritant, 192 local, 192 on blood-pressure, 188 on central nervous axis, 190 on circulatory svstem, 183 on heart. 183, 184, 185 on peripheral arterioles, 187 on respiration, 188 Digitalis, action of, summary of, 193 chemical, 181 glucosides of, 181 group, 181 historical, 181 Digitophylline, 181; and see Digitalis Digitoxin, 181; and see Digitalis Dissociation, 289 Dosage, age as a factor in determin- ing, 7 Fried's rule for, 9 tables of, 380 Young's rule for, 8 Dose table, 380 Drugs, action of, general, 4 indirect, 5 local, 4 nature of, 3 relation of, to chemical compo- sition, 6 specific, 4 changes induced by in body, 11 cumulative effect of, 16 denned, 2, 3 excretion of, 18 fate of, in body, 18 methods of administering, 13 by hypodermic injection, 14 by inhalation, 15 by insufflation, 15 by intramuscular injection. 14 by intravenous injection, 14 by local application, 15 by mouth, 13 by rectum, 13 by transfusion, 15 pharmacologic versus therapeutic action of, 17 specific, 4 summation of, 16 tolerance of, 17 Duboisia Hopwoodii, 136 myoporoides, 112 Duboisine, 112; and see Atropine Ecgonine, 213 Elaterium, 276. 280; and see Vegetable cathartics Electrolytes. 289 Emetics, irritant, action of, 88 peripheral acting, 88 Emetine. 212 action of. 212 chemical. 212 historical. 212 Empirical treatment, 3 • Enoephalopathia satnrnalis. 362 Endotoxins. 260. 263 Enemas, saline cathartics as, 323 Epinephrine, 152 INDEX 391 Epinephrine, action of, 152, 153, 163 general discussion of, 161 on blood-pressure, 153 on eye, 159 on gastric movements, 158 on glands, 158 on heart, 157 on intestinal movements, 158 on mammalian body, 159 on nervous system, 153 on salivary glands, 158 on uro-genital apparatus, 158 summary of, 163 chemical, 152 glycosuria caused by, 161 historical, 152 vasoconstriction caused by, 153 Epsom salt, see Magnesium sulphate Ergot, 165 action of, 166 chemically pure principles, 166 extracts of ergot, 169 on alimentary canal, 173 on circulatory system, 171 on eye, 173 on heart, 172 on nerve centers, 173 on secreting glands, 173 on urinary bladder, 173 on uterus, 170 chemical, 165 effect of, in connection with epi- nephrine, 159 gangrene following use of, 171 historical, 165 series, 165 Ergotinic acid. 165 Ergotoxine, 165; and see Ergot action of, 167 Erythrophloeum, 181 Erythroxylon coca, 213 Eserine, 130; and see Physostigmine Ether, 39 absorption of, 47 action of, 42, 48 on alimentary canal, 47 on blood-pressure, 44 on blood-vessels, 45 on central nervous system, 42 on circulatory system, 44 on heart, 44 on respiratory center, 44 on voluntary muscle, 47 summary of, 48 and chloroform, relative safety of 40 distribution of, 17 exsrel ion of, 47, 48 general acl ton of, in stages of anesthesia, 40, 42 Ether and chloroform group, 89 Ethyl alcohol, 19; and see Alcohol Eucaine, 219 Excretion of drugs, 18 Frangula, 278; and see Vegetable ca- thartics Freezing point, depression of, 290 Fried's rule for dosage, 9 Gelsemium sempervirens, 150 Gelsemine, 150 Gelseminine, 150 Glauber's salt, see Sodium sulphate Headache remedies, 235 Heat as counter irritant, 287 loss of, 225 production of, 224, 227 regulation of, 224, 226 Hellebore, 206 Helleborine, 206 action of, on skeletal muscle, 207 Helleborus, 181 Hemoglobin, 338 Henbane, 112 Heroin, action of, 80 chemistry of, 67 Holocaine, 219 Hydrochloric acid, 326 Hydrocyanic acid, 197 action of, 197 on central nervous system, 197 on circulatory system, 199 on heart, 199 on metabolism, 199 on respiration, 198 chemical, 197 Hydrogen peroxide, 331 Hyoscine, 112, 121; and see Atropine Hyoseyamine, 112; and see Atropine - Hyoscyamus niger, 112 Hypodermic injection of drugs, 14 Hypophysis, 257 influence of, on heart, 257 on nerve functions, 257 on smooth muscle, 257 infundibulum of, 257 Hypophysin, 257 Ichthyol, 342 [gnatia, 98 [nflammation, 262 due to irritation, 270 [nfundibulnm of hypophysis, 267 [nhalation of drugs. 15 [nsufflation of drugi [nternal secretions, 248 organs producing, 2 in [ntestines, normal movement of. 73 [ntramuscular Injection of drugs, U 392 INDEX Intravenous injection of drugs, 14 Ions, 289 Ipecacuanha, 212 Iron, 338 astringent action of, 340 chloride, 340 evidence of absorption of, 339 normal relations of, in body, 338 -protein compounds, 339 Irritant action, nature of, 261, 262 of cantharidin type, 273 of mustard series, 272 of volatile oils, 272 Irritants, 259 of alimentary canal, 274 of skin, 268 action of, 269 by permeability of skin, 269 inflammatory, 270 historical, 268 Irritation, degrees of, 264 Isoamylamine, 165, 166; and see Ergot action of, 167 Iso-pilocarpine, 122 Isotonic physiological solutions, 297; and see Solution Jalap, 280; and see Vegetable cathar- tics group, purgative action of, 279 Laughing gas, see Nitrous oxide Lead, 357 acetate, 357 action of, 357 on circulatory system, 361 on digestive tract, 360 on muscles, 362 on nervous system, 361 toxic, 357, 362 antidote for, 359 carbonate, 357 chemical, 357 chronic poisoning by, 359 colic, 359 excretion of, 360 historical, 357 iodide, 357 monoxide, 357 nitrate, 357 salts of, 357 sugar of, 357 sulphate, 357 toxic action of salts of, 357, 359, 362 white, 357 Lecithins, 348 Liquors, percentage of alcohol in, 20 Lithium salts, 308 Liver, in relation to alcohol oxidations, 34 Lobelia inflata, 136, 150 Lobeline, 136, 150; and see Nicotine Local application of drugs, 15 Locke's solution, 300, 302 Lymph, as physiological solution, 301, 302 Magnesium salts, action of, 313 sulphate, 321 Malaria, action of quinine in, 223 Mandragora autumnalis, 112 Mandragorine, 112; and see Atropine Mandrake, 112 Materia medica, defined, 2 Mercuric chloride, 368; and see Mer- cury iodide, 368; and see Mercury Mercurous chloride, 368; and see Mer- cury Mercury, absorption of, 368 albuminate of, 334 and its salts, 368 action of, 368 antiseptic, 369 on alimentary tract, 371 on animal protoplasm, 370 on bacteria, 369 on circulatory system, 372 on kidney, 372 on respiratory system, 372 toxic, 368, 374 excretion of, 373 poisoning by, 374 toxicity of, 368, 374 Metal albuminates, formation of, 333 Methyl coniine, 147 Monkshood, 201 Morphine, and see Opium action of, 68, 82 on alimentary tract, 75 on central nervous system, 68 on circulatory system, 70 on eye, 78 on frog, 78 on heart, 70 on intestines, 75 on metabolism, 79 on stomach, 75 summary of, S2 and opium series, 66 chemistry of, 66, 67 effect of, on electrocardiogram, 73 excretion of, 80 Mouth, administration of drugs by, 13 Muscarine, 128 action of, 129 on alimentary tract, 130 on blood-pressure, 130 on circulatory system, 129 on eye, 130 on glands, 130 IXDEX 393 Muscarine, action of, on heart, 129 on skeletal muscle, 207 compared with other members of the group, 135 group, 122 Mustard, 268; and see Irritants series, toxic glucosides of, 272 Myxedema, 250 Xarcotine, action of, 80 chemistry of, 66 Xicotiana tabacum, 136 Nicotine, 136 action of, 137 compared with curare. 110 on alimentary canal. 142 on cardiac muscle, 140 on central nervous system, 137 on cerebral cortex, 137 on circulatory system, 139, 140 on eye, 142 on glandular apparatus, 142 on medulla, 137 on nervous apparatus of heart, 140 on peripheral ganglia, 138 on spinal cord, 138 on vasomotor system. 142 excretion of, 143 general svmptoms of, 137 habit, 143 series, 136 tolerance of. 145 Xitric acid, 326 Xitrites and nitroglycerine*. 178 action of, 178, ISO on circulatory system. 178 on heart, 179 on respiratory apparatus, 180 summary of, 180 as methemoglobin formers. 180 Nitro-glycerine, 178; and see Xitrites Nitroglycerines, 178 Nitrons oxide art inn of. 58 adminisi ration of, anesthetic eff< -. 62 Novocaine, 220 Xucleo-proteins, 348 Xux vomit ■ tychnine Oil of mustard, 272 of wintergreen, 232. 238; and see Antipyretics, coal tar Opium. (;•;•. and n ■<■ Morphine abuse of, s ! alkaloids chemistry of, 67 Osmosis, 290, 291 Osmotic pressure, 200. 291 Ox'dizing agents, 329 Oxygen, 329 effect of increase of, 330 Papaverine, action of, 80 chemistry of, 66 Parahydroxyphenylethylamine, 16 5, 166; and see Ergot action of, 168 Parathyroidectomy, results of, 250, 253 Parathyroids, 249, 253; and see Thy- roid effect of removal of. 250, 253 Koch's observations on, 253. 254 relation of, to thyroids, 251 tetany, 253 Peroxides^ 329 Pharmacist, defined. 2 Pharmacognosy, defined, 2 Pharmacologic versus therapeutic ac- tion of drugs, 17 Pharmacological action, relation of, to chemical composition, 6 agencies, 2 factors, 1 Pharmacology, defined, 1 Pharmacy, defined. 2 Phenol. 232. 237. 238. 239 action of, 239, 243 corrosive, 241 on central nervous system, 240 on circulatory system, 241 on protoplasm. 239 summary of, 243 toxic. 239 chemical, 237 excretion of, 241 historical, 237 toxicology of, 241 Phenol sulphuric acid. 239 Phenolphthalein. 27!>: and see \ table cathartic- Phenols, 239 Phosphates, in body. 3 1:; action of. 347 relation of inorganic, 3 17 iphatids, 34S PhoBpho-proteins, 3 Phosphorus, 343 ad ion of, 3 1 1 on Bkeletal structure, 346 poisonous, 3 1 1 as a protoplasmic poison, 3 l 1 compounds of. 343 fatty degeneral i«>n due to. 3 1:> historical, 343 organic compounds of, 3 I s poisoning, 344 Phthaleins, 279 Physical-chemical changt Physiological factors modifying phar- macological responses, 7 394 INDEX Physiological solutions, 297; and see Solution Pliysostigma venenosum, 135 Physostigniine, 130 action of, 131, 134 on central nervous system, 133 on circulatory apparatus, 132 on eye, 131 on muscles of stomach and in- testines, 133 on striped muscle, 133 summary of, 134 compared with other members of the group, 135 group, 122 Pilocarpidine, 122 Pilocarpine, 122 action of, 122, 123, 128 on alimentary tract, 126 on blood-vessels, 126 on central nervous system, 126 on circulatory apparatus, 125 on eye. 127 on glands, 123 on heart, 125 on respiratory tract, 126 summary of, 128 compared with other members of the group, 135 group, 122 . comparison of members of, 135 Pilocarpus jaborandi, 122 Piperidine, 147, 150 Pituitary gland, 255 action of, 255 administration of, 256 anatomical, 255 atrophy of, 256 hypertrophy of, 256 relation of, to other organs, 257 result of removal of secretion of. 255 Piturine, 136; and see Nicotine Podophyllin. 280 ; and see Vegetable ca- thartics Poison, defined, 2 Poison ivy, 269 irritant action of, 273 Potassium, carbonate, 324 cyanide, see Hydrocyanic acid hydrate, 324 salts. 305; and sec Sodium salts Protocurarine, 107 Protocuridine. 107 Protocurine, 107 Provera trine, 206 Prussic acid. 197; and see Hydrocyanic acid Pseudoaconitine, 201 Ptomains, 260 Purine, 89; and see Caffeine Purine, bodies, chemical relationships of, 89 Pustulation, 272 Pyridine, 147, 150 Pyrogallol, 238, 243; and see Antisep- tics, coal tar Quillaja saponaria, 195 Quinidine, 222; and see Quinine Quinine, 222 action of, 222, 230 antipyretic, 224, 228 on body temperature, 224 on central nervous system, 229 on digestion, 228 on digestive tract, 228 on liver, 229 on malaria, 223 on muscle, 228 on undifferentiated protoplasm, 223 summary of, 230 systemic, 222 chemical, 222 elimination of, 229 historical, 222 Quinoline, 222; and see Quinine Race and species, susceptibility due to, 9 Rational treatment, 3 Rectum, administration of drugs by, 13 Resorcin, 238, 243 ; and see Antiseptics, coal tar Rhamnus frangula, 278 purshiana, 278 Rheum officinale, 278 Rhubarb, 278; and see Vegetable ca- thartics Ricinus communis, 280 Ringer's solution, 299, 302 Rochelle salt, see Sodium potassium tartrate Rubidium salts, 308 Salicylates, 244 action of, 244, 246 antipyretic, 246 on alimentary canal, 245 on central nervous system, 244 on circulatory system, 254 on protoplasm, 244 summary of. 246 toxicity of. 244 Salicylic acid. 238. 244; and see Salicy- lates Saline cathartics. 315 as enemas. 323 nature of action of, 315, 318 Salol, 238. 243; and see Antiseptics, coal tar INDEX 395 Salt action, 292 principles underlying, 288 Salts, and see Saline action of, 303; and see Sodium, Potassium, etc. in solution, physical and chemical characteristics of. 288 of heavy metals, absorption of, 336 distribution of, in body, 336 excretion of, 336 general reaction of, 333 Salvarsan, 350, 354, 355; and see Ar- senic Saponaria officinalis. 195 Saponin, action of, 195, 196 and sapotoxin group, 195 chemical, 195 historical, 195 Sapotoxin, 195; and see Saponin Sarsaparilla, 195 Scilla. 181; and see Digitalis Scopolamine, 121 Senna, 278; and see Vegetable cathar- tics Sera, as physiological solutions, 301, 302" Sex, susceptibility due to, 10 Silver and its salts, 376 action of. 37G antiseptic, 376 local toxic, 376 nitrate of. temic effects of, 377 Sinalbin, 26S Sinapis, 208. 272; and see Irritants Smilax, 195 Soapbark, 195 Soapwort. 195 Sodium and potassium group, 304 arsanilate, 350. 354 bromide. carbonate] chloride. 304 action of. 303 cyanide, see llydrooyanic acid hydrate. 324 iodide. 305 iiitrnto. 305 nitrite. 17$: and see Xitri phosphate . potassium tartrate, action of. 320 salts. 304 sulphate. 305 aetion of 318 Solanin. 105. 100 Solanum. 105 Solutions, i^otonie physiological, 207 Loeke's. 300, 302' lymph, as physiological, 301. 302 Solutions, physiological saline, 297, 302 perfusion of, 298 summary of, 302 Pdnger's, 299, 302 sera, as physiological, 301, 302' Sparteine, 151 Sphacelinic acid, 1G5 Stomach, normal movements of, 73 Stovaine, 219 Strontium salts, 314 Strophanthine, 181; and see Digitalis Strophantus, 181; and see Digitalis Strychnine, 96 * action of, 96, 97, 106 on alimentary canal, 104 on brain-stem, 97 on cardiac muscles, 101 on circulation, 100 on medulla, 99 on metabolism, 104 on respiration, 100 on skeletal muscle, 103 on special sense organs, 104 on spinal cord. 97 summary of. 106 alkaloids of, 96 excretion of, 105 group, 96 poisoning by, 105 Strychnos nux vomica, 96, 107 slmea, 107 ignatia, 96 toxifera, 107 Sugar of lead. 357 Sulphates, 342 Sulphides, 341 Sulphonal. 342 Sulphur. 341 compounds of, 341 organic compounds of. 342 Sulphuric acid. 326 Summation. 10 Superoxides, 331 Suprarenal gland, srr Kpinephrine Suprarenin, 15:!: and see Epinephrine iptibility, individual. due i<> race and speci due to sox. 10 due to weight. 1 1 Tartaric acid, 320. 327 Tetany, thyroid, 251 parathyroid, Thebaine, loo aetion of, SO ehemistry of, 00. r,7 Theobromine, oo : and srr Caffeine Theophyline, 89; and see Caffeine Therapeutics, defined, 2 Thorn apple, 112 Thyroid gland, 249 396 INDEX Thyroid gland, action- of, 250 chemical, 249 effect of removal of, 250 engrafting of, 251 historical, 249 myxedema, 250 relation of, to parathyroids, 251 to pituitary gland, 257 result of feeding, 252 tetany, 251 Thyroiodin, 249; and see Thyroid Tobacco, 136; and see Nicotine Tolerance of drugs, 17 Toxicodendrol, 269, 273 Toxicology, defined, 2 Toxins, 263 bacterial, 260; and see Bacterial toxins Transfusions, 15 Tropacocaine, 214, 219 Tropic acid, 112 Tropine, 112, 213 Tubocurarine, 107 Turpentine, 268; and see Irritants Tyramine, 166; and see Ergot Uric acid, 90; and see Caffeine Vegetable cathartics, 274 action of, 274, 275 cathartic, 275, 276 irritant, 275, 277 anthracene group of, 277 groups of, 274 jalap group of, 279 neutral oil series of, 280 Veratrine, 201, 206 Veratrine, action of, 206 on lieart muscle, 208 on nervous mechanism, 206 on sensory mechanism, 206 on skeletal muscle, 207 on smooth muscle, 209 chemical, 206 historical, 206 Veratrum sabadilla, 206 viride, 206 Vesication, 272 Volatile oils, 268; and see Irritants irritant action of, 272 Water, 294 distilled, action of, on tissues, 294 drinking, 295 influence of, on kidney, 296 on metabolism, 296 mineral, 295 Weight, susceptibility due to, 11 White lead, 357 Xanthine, 89; and see Caffeine Yohimbine, 220 Young's rule for dosage, 8 Zinc, 364 action of, 364 disinfectant, 364 local, 364 systemic, 364 toxic, 364 chloride, 364 oxide, 364 salts of, 364 sulphate, 364