COLUMBIA LIBRARIES OFFSITE HEAaH SCIENCES STANDARD ^ Jiip HX64088260 Bwl'' QP905 .M17 Expenmental pharmac M!frli|ii| RECAP '^1 ; iiiiiiiiiiftiii (HaiU^t uf pijgfliriana anb ^trrgpntiB 3Cw JfttttJi Digitized by the Internet Archive in 2010 with funding from Open Knowledge Commons (for the Medical Heritage Library project) http://www.archive.org/details/experimentalpharOOmcgu iTffir'fV EXPERIMENTAL PHAKMACOLOGT BY HUGH McGUIGAN, Ph.D., M.D. PROFESSOR OF PHARMACOLOGY IN THE UNIVERSITY OF ILLINOIS, COLLEGE OF MEDICINE, CHICAGO, ILLINOIS lIllustrateD witb 56 ^Engravings an& 7 ColoreO iplates LEA & FEBIGER IMIILADELPHIA AND NEW YORK 1 M) > iLfoZi Copyright LEA & FEBIGER 1919 PREFACE. Ix the preparation of this manual an attempt has been made to present experimental pharmacology in a brief, concise form, yet to give the student an adequate view of the field. In an elementary course where time is limited, it is neither possible nor necessary that each student or group of ' students should perform each separate experiment. However, every student should endeavor to see the work of all the others and be able to discuss these results, since a knowledge of the action of drugs is more important for the majority than the development of technical skill. On the other hand, it should be emphasized that the performance of as many experiments as possible is the best means of gaining a knowl- edge of drug action. An excellent method of correlating the student's knowledge is to compare the action of one drug with that of another. It is advised, therefore, that the exercises be studied in advance. The efi'ect of each drug studied should be compared in detail with those of the preceding ones; especially should those drugs that are closely related, such as eserin, pilo- carpin, strychnin, caffein, digitalis and epinephrin be studied together. It is only by such comparisons that a knowledge of drug action can be attained. Laboratory work in pharmacology has as its aim three main 1. To give a first-hand knowledge of the action of drugs, and to educate the student in the i)roperties of living, circulating tissues. This knowledge can be obtained in no other way, 2. To illustrate the practice of pharmacologic investigations and the methods of procuring records and tracings. This enables the student better to understand literature and illustrations, 3. To develop the technic and methods^ of research, and the spirit of investigation. This manual attempts to follow and illustrate the most important [jart of the text-book work. Sufficient exi)erimcnts are given U) rlcmonstrate the chief actions of each drug. Some i)oints are rluplicated, but since each student does not perform every iv PREFACE exercise, there may be no actual repetition. Variations may be made as desired and demonstrations added. Those inchided in this outline are the accumulation of several years. No claim to originality is made. In fact an effort has been made to include those exercises which have been standardized by long and general use. In many instances we are not now able to credit the method outlined to its original source. Our chief attention has been devoted to selecting those of instructional value. However, in this connection it affords us pleasure to acknowledge our obliga- tions to such eminent authorities as Cushny, Sollmann, Greene, Stewart, Jackson, Becht, Hatcher, Hirschf elder, Hoskins, Dreyer and others. H. McG. Chicago, 1919. CONTENTS Introduction 17 Defuiitions 17 The Subdivision of Pharmacology 17 Theories and Mode of Pharmacological Action 18 Results of Drug Action 1 g General Protoplasm Actions and Ganeral Poisons 20 Chemical Composition and Pharmacological Action 21 Conditions Modifying the Effects of Drugs 22 The Fate of Drugs in the Body 25 The Object of Pharmacology 25 Methods and Equipment 28 General Technic 28 Care of Tissues and Animals 29 Anesthesia 29 General Principle 30 Morphin Ether 32 Intratracheal Insufflation 32 Insufflation Apparatus 34 Anesthesia by Insufflation 34 Pharj^ngeal Insufflation 34 Artificial Respiration and Resuscitation by the Meltzer Method 35 The Schafer Method of Artificial Respiration and Resuscitation 37 The Marshall Hall Method 39 The Sylvester Method 39 The Third Resuscitation Commission 39 CHAPTER I. Modes of Administering Drugs. Frogs 44 Mammals 44 Operative Technic 47 Exposure of Nerves 47 Stimulation of Nerves 47 Placing a Cannula in the Trachea 47 Injecting into a Vein 49 Inserting a Cannula into the Carotid Artery 49 Opening th(; Thoracic Cavity 50 Rticording lilood-pressure in Mammals 51 (Jleanirig Out the Cannula 52 Ii<;cording R(;.spiration 52 Graphic Records .... 53 vi CONTENTS CHAPTER II. Experimental Pharmacology. Local Action of Drugs 57 Local Anesthesia 57 Demulcents 62 Emollients 63 Dusting Powders 64 Local Irritants 65 Skin Irritants and Rubefacients 68 Steps in the Action of Irritants 68 Caustics or Escharotics 69 Symptoms and Treatment of Caustic Poisoning 70 CHAPTER III. Pharmacology of the Gastro-intestinal Tract. Bitters 71 Simple Bitters 71 Aromatic Bitters 72 Astringent Bitters 72 Compound Bitters 72 Local Action 72 Carminatives 74 Volatile Oils 74 Emetics 77 Purgatives or Cathartics 78 Obstipants or Astringents •. . . ... . . 81 Acids 82 Metallic Salts 82 Calcium Hydroxide 82 Alkaloids 83 Atropin 83 Inert Powders 83 Anthelmintics . . - 84 Secretions — Movements — ^Antisepsis 85 Movements 85 Absorption 85 Excretion of Drugs into the Intestine 86 Intestinal Movements 86 Intestilial Antisepsis 87 CHAPTER IV. Antiseptics and Disinfectants. General Disinfectants and Deodorizers 88 Disinfectants of Surgical SuppUes 88 Genito-urinary Disinfectants 88 CONTENTS Vll Intestinal Antiseptics 89 Antiseptic Dusting Powders 89 Drjing or Absorbent Powders 90 Antiseptic Action of Alcohol 90 CHAPTER V. Drugs Characterized by their Action Chiefly after Absorption. Drugs Acting upon the Cerebrum 91 The Alcohol Group 91 Alcohol as a Food 92 Effect of Drugs on Motor Areas 93 Eflfect of Anesthesia on Motor Areas 94 Effects of Strychnin on Motor Areas 94 CHAPTER VI. Pharmacology of the Cranial Ner\-es. The First Nerve: N. Olfactorius 96 Chemistry and Physics of Odors 97 The Second Nerve: N. Opticus 98 Drugs Acting on the Optic Nerve 98 The Third Nerve : N. Oculomotorius 99 The Fourth Nerve: N. Trochlearis 100 The Fifth Nerve: N. Trigeminus 100 The Sixth Nerve: N. Abducens 100 The Seventh Nerve : N. Facialis 100 The Eighth Nerve: N. Acousticus 101 The Ninth Nerve: N. Glossopharyngeus 101 The Tenth Nerve: N. Vagus 104 The Eleventh Nerve: N. Accessorius 104 The Twelfth Nerve : N. Hypoglossus 104 CHAPTER VII. Pharmacology OF the Heart and Blood-pressure. Blood-pressure Methods of Lowering Blood-pressure Methods of Increasing Blood-pressure Digitaloid Drugs and Digitalis .... Action on the Frog or Turtle Heart . Action on Turtle Heart Strips Effect on I leart Beat Action of Digitalis on the Heart and Resj)iration of a Dog Action of Digitalis on the Heart and Resi)iration Myocardiagram and lilood-pressun; under Digitalis 107 107 108 109 110 110 110 110 112 112 viii . CONTENTS Digitalis as a Diuretic 112 Standardization of Digitalis 112 Hatcher's Cat Method .• 114 Gold Fish Method of Pittinger and Van der Kleed .... 115 Standardization of Suprarenal Gland 115 Aconitin 116 Action of Aconitin on a Frog 117 Action of Aconitin on Blood-pressure . . 117 Effects of Aconitin on a Dog 117 Squibb's Test for Aconitin 118 The Bio-assay of Aconitin 118 The Nitrites 118 Action of Nitrites on the Circulation and Respiration 118 Action of Nitroglycerin 119 Action of Sodium Nitrite Injected Intravenously 119 Influence of Atropin on Nitrite Action . 119 Effect of Amyl Nitrite on Students 119 Action of Nitrites on Frogs 119 Influence of Nitrites on Bloodvessels 119 The Action of the Alcohol Chloral Group on the Pupil, Heart and Reflexes 121 Reflex Time as Changed by Alcohol 121 Crossed Reflex Time • 122 Effect of Alcohol on Reaction Time 123 Ether and Chloroform Anesthesia 124 Action of Alcohol on a Normal Dog 126 Ether Anesthesia 126 Effect of Alcohol on Frogs 127 Effect of Alcohol on Reflex Time 127 Effect of Alcohol on the Heart of a Frog 128 The Effects of General Anesthetics on the Circulation, Respiration and Temperature 129 The Direct and Reflex Effect of Ether and Chloroform on the Heart 130 Effect of Ether and Chloroform on Mammals 130 CHAPTER VIII. The Closed Method of Anesthesia. Nitrous Oxide Anesthesia on the Dog 132 Nitrous Oxide on Frogs 132 The Specific Action of Nitrous Oxide 133 Bromides 133 Cannabis 134 Effect of Cannabis on a Dog 134 Comparison of Action of Morphin Bromides and Cannabis . . . 135 Assay of Cannabis 135 CONTENTS ix CHAPTER IX. Action of Strychnin, Picrotoxin and Curara on the Central Nervous System. Effect of Strychnin on Frogs 237 Seat of Action of Strychnin 2^7 Determination of the Relation of Sensory Stimuli to the Production of Convulsions 100 Claude Bernard's Experiment ^30 Action of Strychnin on Turtle Heart Strips I39 Action of Strychnin on Mammals 23g Action of Strychnin on Heart and Respiration I39 Synergism of Strychnin and Cocain 240 Caffein -..r^ Action of Curara on the Central Nervous System of Mamma's ... 140 Effect of Curara on Muscle Contraction 242 Action of Strychnin on Reaction Time 241 Action of Strychnin on the Ear 241 Action of Strychnin on the Eye 241 CHAPTER X. Paralysis of Motor Nerve Endings. Curara ,.0 Action of Curara on Mammals 243 The Central Action of Curara 243 Determination of Motor Paralysis 244 Action of Curara on Muscle-nerve Preparation I44 Curara on Non-anesthetized Animals 245 Stimulation of Motor Nerve Endings 245 Symptoms Following the Intravenous Injection of Curara ... 146 Respiration as .\ffected by Curara and Physostigmin 146 CHAPTER XI. Pharmacology of Sensory Nerve Ends. Cocain , ,- Local Anesthetic Action of Cocain 247 Cocain Substitute 247 General Action of Cocain on Frog 247 Result of Intravenous Injection of Cocain in Mammal .... 147 Action of Cocain on Heart Musch; 247 l^fTect of Cfjcain on Muscle Tissue; 248 Effect of (Jocain on the Circulation and Respiration of Mammals . 148 Spinal Anesthesia 248 Action of Cocain on Temiierature 248 Local Anesthesia in Man 248 X CONTENTS CHAPTER XII. Autonomic System and Autonomic Drugs. Differences between Sympathetic and Parasympathetic System . . . 149 Autonomic Drugs 152 Atropin and Pilocarpin Group 152 Action of Pilocarpin Nitrate 152 Action of Atropin Sulphate 152 Effect of Atropin on the Eye 153 Action of Atropin on the Frog and Turtle Heart 154 Action of Pilocarpin and Atropin on Turtle Heart Strips . . . . 154 Effect of Atropin and Pilocarpin on the Volume of the Respired Air . 155 Action of Pilocarpin, Physostigmin and Atropin on Uterine Strips . 155 Action of Atropin and Physostigmin on the Intestinal Movement . 155 Action of Atropin and Pilocarpin on a Pithed Dog 155 Antagonism of Atropin to Morphin 157 Nicotin 157 Selective Action of Nicotin on Ganghon Cell 157 Action of Nicotin on Blood-pressure and Heart 158 General Effect of Nicotin on the Frog 158 Nicotin in Tobacco Smoke 159 Toxicity of Nicotin 159 Effect on Respiration when Given Intravenously 159 Effect on Reflexes 159 Influence on Epinephrin Action 159 CHAPTER XIII. Pharmacology of the Eye. Drugs Acting on the Lacrimal Glands ' . 160 Drugs Stimulating the Retinal Cells or Vision 160 Drugs Depressing the Retinal Function 160 The Iris and the CiUary Muscle 161 Drugs Stimulating the Third Nerve (Parasympathetic Endings) . . . 161 Drugs Paralyzing the Third Nerve Endings 161 Drugs Stimulating the Sympathetic Nerves to Radiating Fibers . . . 161 Drugs Paralyzing the Sympathetic Nerve Endings in the Eye . . . 161 Drugs Changing the Size of the Pupil by a Central Action . . . . 161 CHAPTER XIV. Antagonism. Physiological Antagonism 163 Synergism 164 Synergism of Morphin and Scopolamin 165 Synergism of Morphin and Narcotin 165 Synergism of Morphin and Papaverin 165 Synergism of Morphin, Scopolamin and Atropin 165 Action of Scopolamin and Urethane 166 CONTENTS XI Epinephrin 1^6 Action of Epinephrin on Blood-pressure and Respiration .... 166 Action of Epinephrin on Vasodilators 167 Action of Epinephrin on Intestine 168 Jackson's Finger-cot Method 169 Action of Epinephrin on the Uterus 169 Barbour's Method of Studying the Action of Drugs on the Uterus . 170 Action of Epinephrin on the Eye 170 Action of Epinephrin on the Secretions 170 Glycosuria Produced by the Hypodermic Injection of Epinephrin 171 Action of Epinephrin on the Tone of Bronchial Muscle 171 CHAPTER XV. Antipyresis and Antipyretics. AntipjTetics 17^4 Action of AntipjTetics 175 Influence of Peptone on Antipyretics 175 Effect of Chloral Hydrate 175 Hygienic and Drug Treatment of Fever 176 Heat Centers 176 Action of Ergot and Calcium Lactate 176 Effect of Hot Water 176 Destruction of Heat Center 177 CHAPTER XVI. Pharmacology of the Glands. Drugs Affecting the Glands 178 Salivarj' Glands 179 Gastric Secretion 179 Intestinal Secretion 179 Pancreatic Secretion ISO CHAPTER XVII. Pharmacology of the Kidneys. Theories of Diuresis 181 Important Factors Modifying the Secretion of Lhine 181 Diuretics 182 Antidiuretics 182 Elimination of Drugs by the Kidneys 183 Caffein 183 The Diuretic Action of Caffein 183 Action of Caffein on the Heart, Respiration and Kidney .... 184 Action of Caff(!in on the Frog 185 Action of Caffein on the Frog's Heart 186 Action of Caffein on the Turtle Heart 186 .Action of (affein on Turtle Heart Strips 186 Action of Caffein on the Reflex Time of Frogs 186 Action of Caffein on Respiration 187 xii CONTENTS Saline Diuretics 187 Chemicals as Diuretics 188 Diuretic Action of Caffein on Normal Animal 188 Action of Diuretics on Human Being 188 Phenolsulphonephthalein 189 Effect of Chemicals on Excretion of Phenolsulphonephthalein . . 189 Effect of Various Drugs used as Diuretic 189 Test for Phenolsulphonephthalein 189 CHAPTER XVIII. Pharmacology of Sweat Glands. Function 191 Distribution of the Glands 191 Innervation 191 Endocrinal Pharmacology 192 CHAPTER XIX. Pharmacology of the Liver, Mammary Glands, Uterus and Bladder. Pharmacology of the Liver 193 Main Functions of the Liver 193 The Glycogenic Function of the Liver 193 Drugs Influencing the Carbohydrate Metabolism of the Liver . 194 Pharmacology of the Mammary Glands 194 Lactagogues ' 195 Elimination of Drugs in the Milk 195 Pharmacology of the Uterus 195 Epinephrin 195 Atropin 196 Physostigmin and Pilocarpin . 198 Ergot 196 Action of Ergot on the Frog 196 Action of Ergot on the Arterioles 196 Action of Ergot on the Blood-pressure, Respiralion, Pupil and Vagus Tone 196 Action of Ergot on Heart Strips 197 Action of Ergot on the Uterus 197 Standardization of Ergot 198 Pharmacology of the Bladder 200 Antisepsis 200 CHAPTER XX. Pharmacology of the Muscles. Voluntary Muscles 201 Involuntary Muscles 202 Classification of Drugs Acting on Muscles 203 CONTENTS xui Pituitary Extract, Liquor Hypophysis, Pituitrin, Infundiljulin, etc. . 204 Action of Liquor Hypophysis on the Frog 204 Action of Liquor Hypophysis on the Circulation 204 Action of Liquor Hypojjhysis on the Heart 204 Action of Liquor Hypophysis on the Heart, Respiration, Pupils and Kidneys 205 Action of Liquor Hypophysis on the Uterus 206 Standardization of Pituitarj^ Extracts 207 Nitrites 208 Veratrin 208 Quinin 209 Action of Quinin on Yeast Fermentation 210 Action of Quinin on White Corpuscles 210 Action of Quinin on the Frog or Turtle Heart 210 Action of Quinin on the Heart and Respiration of a Mammal . . 210 Quinin Urea Hydrochloride 210 Calcimn, Barium and Magnesium Salts 211 Calcium and Magnesium Antagonism 211 CHAPTER XXI. Pharmacology of the Lymphatics. Effect of Peptone on Rate of Lymph Flow 214 Effect of K. I. sugar, etc., on Rate of Lymph Flow 214 Effect of Pilocarpin and Atropin on Rate of Lymph Flow 214 CHAPTER XXII . General Protoplasm Poisons and Miscellaneous. Hydrocyanic Acid ^ 215 Action of Cyanides on Respiration, Blood-pressure, and Blood and Oxygen Consumption 215 Acids, Alkalies and Corrosives 216 Corrosive Action of Acids and Alkalies 216 Sulphides 217 Action of Sulphides on Yeast Fermentation 217 Oxalates and Fluorides 218 Iodides 218 Excretion of Iodides 218 Heavy Metals 219 UiC'A Action 219 General Action 219 Colloidal Heavy Metals 220 Potassium Salts 220 Al)sori)tion and JOxcretion 220 Action of Pota-:sium Salts on the Heart and Vessels ... 220 Action of Pota.Hsiuni on Reflex Time 220 XIV CONTENTS Ammonium 221 Effect of Intravenous Injection of Ammonium . . . . . . . 221 Inhalation of Ammonia 221 Experimental Glycosuria 222 Bernard's Method of Puncturing the Floor of the Fourth Ventricle . . 222 Ferments, EnzjTnes and Digestants 225 CHAPTER XXIII. Pharmacology of the Blood. Functions of the Blood 227 Volume of the Blood 228 Viscosity 228 Clotting of the Blood 230 Means of Hastening or Retarding Clotting 231 Agents Hastening Clotting 232 The AlkaUnity of the Blood and Acidosis 233 Hydrogen Ion Concentration - . 233 Potential Alkalinity 234 Acidosis .... 235 Specific Gravity of the Blood 235 Laking or Hemolysis 235 Nature, Amount, and Changes in the Hemoglobin 236 Coagulation 237 Effect of Adrenalin and Peptone on Clotting Time 237 Viscosity 237 AlkaUnity and Acidity Changes in the Blood 238 Hemolysis or Laldng 238 Osmotic Resistance of the Corpuscles 238 Fragihty of the Corpuscles 238 Crenation 238- Changes in the Oxygen-carrying Power of the Blood, Toxicology . . . 238 Carbon Monoxide Hemoglobin 238 Methemaglobin .238 Cyanhemoglobin 239 Hematoporphyrin 239 Permeability of the Red Corpuscles 240 The Presence of Drugs in the Blood 240 Carbon Dioxide 242 Lewis-Benedict Methods of Determining Blood-sugar 242 Phloridzin 242 Saponin 243 List of Stock Solutions 244 EXPERIMENTAL PHARMACOLOGY. INTKODUCTION. Definitions. — Pharmacology is the term used to include all knowl- edge pertaining to drugs and their actions. The term drug comes from the Anglo-Saxon word drugan = to dry. It w^as first used because dried plants in early times made up the whole materia medica. The term has grown with the extension of the materials used in medicine, and at present includes everything used as medicine. Experuiiental pharmacology is a biological science, and as such is related to general biology, especially the subjects of: Anatomy. Physiology. Pathology. Chemistry and Biochemistry The relation to biology is evident, since pharmacology is a study of the reactions of living material to changes in environment. These changes in environment are usually produced by drugs. It is related to anatomy, since this science is necessary as a foundation of the study of tissues. If we do not know the anatomy we cannot interpret physiological reactions. Physiology is the study of the functions of tissue and organisms, while pharmacology studies the same functions as modified by drugs. It is related to pathology, since the. introduction of the drugs in itself is a pathological condi- tion and many drugs readily create distinctly pathological states. P'or example, phosphorus may cause fatty degeneration of the liver, uranium salts may cause nephritis, etc. The relation to chemistry and to biochemistry is obvious. Drugs are chemicals, and the reac- tions of drugs with the organism is definitely a branch of organic or biologic chemistry. From this viewpoint pharmacology is a branch of ii])])Vu'(\ organic chemistry. The Subdivisions of Pharmacology are: Materia medica. Pharmacy. 2 18 INTRODUCTION Pharmacognosy. Pharmacodynamics . Therapeutics, including prescription writing and posology or dosage. Toxicology. These subdivisions are not sharply defined, and are for conveni- ence only. Materia Medica. — ^Materia medica treats of the source, consti- tuents, physical and chemical characteristics and doses of drugs. Pharmacy. — A study of the properties, preparation, compounding and dispensing of medicines. Pharmacognosy. — Pharmacognosy, gross and microscopic, may be considered as a part of materia medica, and deals especially with the recognition of drugs and the study of crude materials. In the identification, the origin, the physical properties, chemical reactions, taste, odor, microscopic appearance, etc., may be considered. Pharmacodynamics or Experimental Pharmacology. — ^The study of the action of drugs on the living organism includes clinical observa- tions and experience as well as experimental work. Toxicology may be considered as a branch of pharmacodynamics. In the widest sense, pharmacodynamics is a study of reactions of living matter due to changes in environment. Therapeutics. — The art and practice of treating abnormal states by any means that relieves pain, restores health or prolongs life. Any change in environment of an animal will have this effect, and comes under the term pharmacology in its broadest meaning. Toxicology. — ^Toxicology deals with the symptoms, diagnosis, treatment and detection of poisons. A poison may be defined arbitrarily as any substance which, when taken by mouth in doses of less than 50 gm. will injure health or cause death. The distinction between foods, drugs and poisons is hard to make. A drug is anything that is used as a medicinal agent. Poison has been defined, but we should remember that there is no definition entirely satisfactory or generally accepted. A food is something that supplies energy to the body, does not injure the body when taken by mouth and will build up the tissue and repair waste. Theories and Mode of Pharmacological Action.- — ^The action of drugs may be physical or chemical. Physical Actions. — Physical actions are those in which there is no chemical reaction between the drug and the tissues. The most important physical actions are: INTRODUCTION 19 1. The protective effect of oils, powders, gums, mucilage, collo- dions, and fixed dressings. 2. The osmotic effects (or salt action) of isotonic, hypotonic or h^•pertonic solutions. 3. The adsorptive or absorptive action of carbon, dyes, etc., infusorial earths and colloids generally. Chemical Actions. — Some drugs exert a chemical reaction within the body. The nature of the action may be : 1. Combination. — (a) As the neutralization of an acid with a base, as when the hydrochloric acid of the stomach is neutralized by sodium bicarbonate; and the addition of HCl with NH3. (6) Such unknown reactions as selective affinity are probably chemical. 2. Solution. — The Meyton-Overton theory, which explains anes- thesia as a solution of nervous material by ether, etc., is a chemical reaction. It should be remembered, however, that chemists hold different opinions regarding the nature of even the solution of salt in water, consequently the actual reaction in solutions may mean something different even to experts. Results of Drug Action. — This is only a modification of normal functions or of the fundamental properties of living matter. The fundamental properties of life or living matter are: 1. Metabolism — anabolism and katabolism — which may include all digestive processes. 2. Excitability manifested by contractility, conduction, motility, .secretion, etc. 3. Reproduction. Drugs only modify these properties — they caimot create new functions. Drugs can act then only by stimulation, depression or irritation of the normal processes. This shows clearly the relation of phar- macology to physiology. By stimulation we mean an increase in the function of an organ or tissue. By flepression we mean a decrease in function. In irritation the change is more anatomical than functional, and some of the signs of inflammation are present. These are redness, local increase in temperature, swelling and pain. There may be some changes in function which are of a secondary nature. Drugs may also cause fatigue and paralysis, which are also modifications of function. The causes of fatigue may be due to: 20 INTRODUCTION 1. The exhaustion of energy-yielding material. 2. The accumulation of waste products. Experiments have shown that the order of the occurrence or ease of fatigue in the various tissues are: 1. Nerve center. 2. Nerve endings. 3. Muscle. 4. Nerve fibers. Recovery from fatigue takes place with rest alone {cf. Paralysis) . Paralysis. — This may also be caused by a drug. It is due to a combination of the drug with the cell substance and recovery takes place only when the drug is removed (cf. Fatigue and Curare Action). The curare effect or action is a paralysis. Paralysis may also be caused by anatomical changes or lesions. It is obvious that in some of these recovery cannot be expected. There are also many in which fatigue and paralysis cannot be separated or distinguished, so there are conditions in which there is ground for a legitimate difference of opinion. One must remember that when the problem of life itself is up for explana- tion, dogmatic assertions cannot always be made. Elective Affinity or Selective Action. — ^When a drug is introduced into the body and it acts more on one tissue than another we say its action is selective. It would perhaps be better to say the tissue action is selective, e. g., curare acts on the nerve-endings to striated muscle almost to the exclusion of other actions. Epinephrin acts on the endings of the sjanpathetic nerves. Many other drugs show this tendency to pick out a particular tissue and exert its action on it to the exclusion of others. Such actions are said to be selective. General Protoplasm Actions and General Poisons. — If a drug acts on tissues generally without exhibiting an action on one more than another we say it has a general protoplasmic action, and if toxic it is a general protoplasmic poison. Local, Remote and General Actions. — In many cases whether a drug exerts a local or remote action depends on the concentration and the mode of application. Local Action. — ^Most drugs that are not absorbed have local action only, e. g., demulcents and emollients; Bi and Ag salts; sprays in nose or throat; dusting powders and protectives act only where they are applied and the action is mainly of a physical nature. By remote or indirect action we mean an action elicited in organs away from the site of application. Irritation of the skin, blisters INTRODUCTION 21 or cold applications in any region may influence the rate of the heart indirectly through the nervous system. Cerebral depressants in the same way, by lessening movement, lessen oxidation in the muscles. Atropin injected in the arm has no action locally but causes an increased heart-rate, because when carried in the circula- tion it paralyzes the vagus endings. By general action we mean those actions that cannot be fixed on any one tissue, as the action of tonics, sedatives and the like. Since all drugs may also be poisons, Loew's theory of the action and his classification of poisons may be given. He classifies poisons as: (a) General. — The general poisons are subdivided into: 1. Oxidizing: Ozone. Peroxides. Permanganates. Chromates. Hypochlorites, etc. 2. Catalytic: These do not undergo any apparent change them- selves, but act on protoplasm. The volatile narcotics and enzjmes are examples. 3. Salt-forming: Due to the amphoteric character of the proto- plasm, some drugs, like acids, alkalies, tannins, etc., combine to form salts. 4. Substituting: These include all bodies which react with alde- hydes and amins, forming substitution products. Such drugs are: Hydrazine. Phenol hydrazine. Anilin. Ammonia. Phenol. Hj'drocyanic acid. Hydrogen sulphide and sulphites. (b) Special or Selective Poisons. — These include toxins, anti- toxins and the selective acting drugs, such as: Atropin. Strychnin. Curara. Eserin. Nicotin, etc. Chemical Composition and Pharmacological Action. — All pharma- cological actions are either chemical or i)hysical. Hut all pharma- 22 INTRODUCTION cological action is exerted on and causes changes in the physical and chemical bases of life. The physical bases of life are a viscid medium, a colloidal solution of proteids, salts, and water. The Chemical Essentials of Life Are: 1. An energy-yielding substance. 2. Conditions suitable for their reaction and liberation of energy. 3. Proper temperature. 4. Alkalin reaction. 5. Ferments. 6. The presence of certain apparently essential chemical elements, e. ST., C,K,S, N, CI, Fe, O, P, Mg. With constant conditions we should expect a related action in a homologous chemical series, and in the paraffin series of alcohols, Baer gives the following ratio of toxicity for alcohols: Methyl, 0.8. Ethyl, 1.0. Propyl, 2.0; Butyl, 3.0. Vinyl, 4.0. As a matter of fact, however, such a relation is very rare, and while we might always expect a relation between the action of drugs and their chemical composition, there is more relation between their physical properties and the action. This is largely because we know only the elements of the chemistry of the body. At the same time we must remember that no one can even predict with certainty the action of the pure chemicals whose chemistry is well known. While we would expect the sulphides and the phosphates of the heavy metals to be alike in color and solubilities, there are many exceptions which can be determined by experiment only. With the animal organism the exceptions are more numerous than the conformities. There is no law, therefore, known to exist between the chemistry of a drug and its reaction. Future work, however, will, we believe, ultimately establish such a law. Chemical pharmacology should therefore be studied as much as pharmacodynamics and offers more avenues of advance. Conditions Modifying the Effects of Drugs. — These are : 1. Hahit. — This usually lessens the effect to some extent. 2. Size and Weight. — Smaller persons require less than larger. 3. Age. — ^Young persons or animals require less than old. The rule of dosage is as follows: The adult dose divided by the age plus twelve gives the dose for a child, e. g., the dose for a child of INTRODUCTION 23 foiir years of a drug whose dose is 1 gram for an adult would be |- + 12 = J gram. This is Young's rule. There are other rules, but this one is most used. Opiimi and morphin are exceptions and the dose given should be smaller than the calculated dose. 4. Women, chiefly because oj size, should get only four-fifths of the dose for men (idiosyncrasy is more often found in females) . 5. Temporary conditions, such as meals, irritations and inflamma- tory conditions, neurasthenia, diarrhea and vomiting, pregnancy and lactation (drugs excreted in milk) must be considered in dosage. 6. Time of administration: Stomachics are best given about thirty minutes before meals; cathartics, when convenient for patient and narcotics, at night. 7. Idiosyncrasy: Some persons have a peculiar susceptibility to drugs and react to a small dose in a manner that would indicate that many times the amount had been given. Congenital tolerance may be considered as an idiosyncrasy, but in this case, the organism is exceedingly resistant to the drug. 8. Tolerance differs from immunity in that there are no anti- bodies formed in tolerance. While there are in immunity it has not been shown that any chemical substances except proteins produce antibodies.^ 9. Some drugs exert a cumulative effect due to irregularity of absorption — digitalis(?) — or slower excretion than absorption, which may occur with many drugs when kidney function is depressed. 10. Synergists or Syngerism: Mixtures of purgatives; mixtures of anesthetics; alcohol and acetonitril; narcotin and morphin, etc., act in some cases to accentuate the action of each other, and we get more than the additive action of the two. Such action is called synergistic. Note that it is more than an additive action. 11. Antagonism. — Chemical or Therapeutic Incomyatihility . — Some drugs antagonize the action of others, e. g., strychnin and chloroform, alcohol and caffein, pilocarpin and atropin. Drugs that antagonize each other and should not be administered at the same time. 12. Pathological Conditions. — Modify drug action. Anti])yretics reduce the temi)erature in fever but not in the normal animal. Bromides lessen nervous irritability in epilepsy more than in normal states. Morphin in pain reduces sensitivity, but has less effect in health. ' For a review of the literature ret'ardirifz morpliiti as u prodiifcr of anlilxxlics, see Du Moz, Jour. Am. Med. Amsm., 1919, Ixxii, 1009. 24 INTRODUCTION The Method of Administration Modifies the Action of a Drug.^ — While we cannot in many cases correlate chemical composition and phar- macological action, we know that the concentration or mass action of chemistry holds true in the action of drugs in the body. It is for this reason that drugs react differently, depending on the method of application, 1. Introduction of Drugs hy Mouth. — This is the usual method, and unless there is good reason to the contrary, should be the method used. But absorption is slower by this method than by most others, consequently the drug reaches the tissues slowly and may be oxidized or excreted almost as quickly as absorbed. This explains why drugs act in a relatively mild way when given by mouth. 2. Introduction by Rectum. — Drugs are sometimes given by this method to avoid action on the mouth and stomach and reflexes that might be exerted on the heart. They are absorbed more rapidly than when given by mouth, and the dose should be smaller. Usually it is one-half, though some give twice the dose, given by mouth. 3. Hypodermic Injections. — Drugs given in this way are very quickly absorbed. They are absorbed still more rapidly if given by intramuscular injection. 4. Intramuscular Injection. — Deep injection into the skeletal muscles, preferably the gluteus or deltoid. There is less pain and tenderness caused by drugs that are irritating when given deep into the muscles than when the injection is more superficial. Absorption by this method is also quicker than by any other method of adminis- tration except the intravenous method. 5. Intravenous Injection. — ^When drugs are injected into the vein they are applied directly to the point of action as quickly as the circulation can carry them. This was originally a laboratory method, but is much used clinically at present. It is too frequently used in clinical medicine and should not be used except when it is decidedly preferable to other methods. It is surprising how easily and how apparently non-irritating such caustic drugs as sodium carbonate may be injected intravenously, while if injected subcutaneously or intramuscularly they may produce sloughing. Strongly alkalin or acid-reacting solutions should never be given subcutaneously. 6. Transfusion of Blood from the Artery of one person to the vein of another, or from one animal to another, is much used in cases of hemorrhage, anemias, etc., and in investigative work. 7. Inhalation. — Inhalation is the usual method of giving general anesthetics. It depends on the fact that some drugs may be absorbed INTRODUCTION 25 from the lungs. Insufflation or inhalation is also used in nasal douches, etc. The advantages of inhalation is that the amount of the drug is readily controlled and removed. By the other methods if excess has been given it cannot be removed readily. 8. Intraspinal Administration. — By this method drugs are intro- duced into the spinal canal. The needle is introduced between the vertebrae, and the flow of fluid from the needle indicates when the needle is in place. In experimental work the fourth ventricle may also be entered. Care must be used in clinical work to keep the patient in a rigidly fixed position. As the reflex movement that anyone is likely to make when the needle enters the spinal canal may break the needle in the canal and this is a serious accident. It should never be tried on the human being without special instruction. 9. The local application of drugs needs no comment. 10. Sublingual. — Some drugs like nitroglycerin are in some cases best given by holding the tablet under the tongue. It dissolves readily and is absorbed very quickly. 11. Insufflation. — Powders are frequently insufflated or blown on to a surface. Boric acid, e. g., is administered to the ear drum or other relatively inaccessible parts in this way. The Fate of Drugs in the Body. — Drugs in the body may be oxidized and then excreted by any of the excretory organs. Catalytic drugs like ether are excreted unchanged either by the lungs, skin, kidneys or intestinal tract. Most drugs are oxidized to some degree. Others, like the oxalates, are combined with calcium, and still others, like the saline cathartics, may be excreted in great part unchanged. In studying what the action of the drug is on the body, the fate of the drug or what the action of the tissues is on it should also be studied. The Object of Pharmacology. — Pharmacology may be studied as a science without reference to its application. The great interest, however, lies in its relation to the treatment of disease and to the foundations which it may lay for therapeutics. As long as we are ignorant of how a drug acts its use is empirical, unscientific and unsatisfactory. The objects of experimental pharmacology is to make every endeavor to explain the mysteries of therapeutics, and it makes little difference where this is done. In all cases, however the bedside is the court of final ai)peal. But clinical experience must be actual not imaginative. One of the oldest practitioners in America recently said that some physicians make the same mistake one hundred times and call it experience. Experience must be expressed in definite measured physical, chemical, physiological or psychological terms, otherwise experience is of the same value as 26 INTRODUCTION gossip in a court of law. Clinical and laboratory data can be expressed in these terms and are of no value if not so expressed. Mere belief that digitalis raises the blood-pressure or slows the heart is of no value unless it can be proved, and actual measurements are made. All established therapeutic agencies have at one time passed through the experimental stage, some are still in this stage. The following work is framed with the idea that it may aid the methods of recording and the inclination to measure changes in the function of organs produced by drugs. METHODS AND EQUIPMENT. The success of a laboratory course in pharmacology depends to a large degree on the facilities provided. For this reason the apparatus needed should be easily available and in working order. Adequate space should be provided for keeping the apparatus. Some articles needed but rarely may be provided only when required. The greater part, however, should be in the custody of the student All appa- ratus that is returnable in working condition should, as far as pos- sible, be furnished to the student. The lockers for each group of students should contain the following : 2 semicircular stands. 5 clamps. 2 induction coils. 2 electrodes. 1 ether mask. 1 perfusion bottle. 1 Woulff bottle. 2 funnels. 2 flasks— 250 c.c. 2 tumblers. 2 beakers. 2 electric keys. 2 evaporating dishes. 2 frog boards. 1 mesentery board. 1 dissecting needle. 2 25 c.c. graduates. 1 aneurysm needle. 4 Mohr clamps. 1 cork plate with pins. 1 knitting needle. 2 pithing wires. 1 brass T-tube. 1 box with 2 glass Y's, 1 glass T's and 6 vessel cannulse. 2 camel's-hair brushes. 2 tracheal cannulse. 1 screw clamp. 1 large screw clamp. 1 tracheal tube. 2 heart levers. METHODS AND EQUIPMENT 27 4 muscle levers — 2 straight, 2 elbow. 4 watch glasses. 2 bundles of ligatures. 1 suture needle. 2 feathers. 2 10 c.c. pipettes graduated in jVths. 2 10 c.c. pipettes graduated in ^V^hs. 1 clinical thermometer. 1 thermometer, 1° C. to 100° C. 1 blood-pressure pipette. 1 electric signal magnet. 2 glass rods. 1 sjTinge, 10 c.c. graduated jo cc. 1 sjTinge, 1 c.c. graduated juij c.c. 4 needles in a bottle. 1 femur clamp. 2 kj'mographs. 2 extra drums. 1 100 c.c. cylindric graduate. 1 stomach tube and bulb. 2 gags, large and small. 2 G-clamps. 1 mercury manometer. 1 burette, stand, clamp and tube. 10 test-tubes with rack and brush. 1 sauce pan. 1 artificial-respiration bellows. 1 set of ropes. sponge, sandpaper, wax, slides, parchment, towels, electric connection wires. 1 pair of dividers. 1 millimeter rule 10 cm. long. 2 celluloid triangles. In addition to the equipment provided by the laboratory, each student should come provided with the following: For operating: 1 scalpel. 2 scissors. 2 hemostatic forceps. 2 bulldog clamps. 1 operating gown. 2 towels. 2 curved needles, large and small. 2 pairs of thumb forceps — one large and one small curved. For notes: 6 sheets of cross-section paper. 50 sheets of thin note paper. 5 sheets of carbon paper 8] x 12 inches. Laboratory exercises should be assigned in advance. Each student shouUl study them thoroughly before coming to class. He should know what to expect and if the unexpected happens, he should know the reason, because results are always obtained accord- ing to the conditions under which the experiment is ])erf()rmed. Full recfjrds of each exi)eriment should be kept. It is impo.ssible for each man to keep his own record; but those of the group who are busy with the f)perati()n may be provided witli a carl)on copy prepared by the secretary of the group. Before commencing an 28 INTRODUCTION experiment, each student should have a definite part to play and should attend to this alone. Cooperation is essential to good work. GENERAL TECHNIC. Fluids which come in contact with the cells of the body or with living tissues should approximate as closely as possible the fluids which normally bathe these cells or tissues. Lymph and blood are the true physiological solutions. It is obviously impossible to approximate these without great care and time-consuming pro- cedures. Several of the so-called salines are adequate for most operations and can be made with slight effort. They are isotonic, i. e., they have approximately the same osmotic tension as blood. Those most in use are: 1. Physiological Saline. — This is merely a solution of sodium chloride in water. It should be approximately isotonic with the cell protoplasm. For mammals a 0.9 per cent, solution, and for amphibia a 0.65 per cent, solution will be found satisfactory. Although sodium chloride is quantitatively the most important saline constituent of protoplasm, the presence of several other difPusable salts is necessary to normal functioning. When cells are exposed to simple normal saline these substances soon diffuse out. 2. Ringer's Solution. — This more nearly approximates the normal tissue fluid and therefore prevents most of the diffusion. For mammals: NaCl 9.00 gm. KCl 0.42 gm. CaCl2 0.24 gm. NaHCOa 0.30 gm. Water to make lOOO.OOc.c. For amphibia: NaCl 7.00 gm. KCl 0.30 gm. CaCl2 (crystals) 0.26 gm. Water to make lOOO.OOc.c. 3. Locke's Solution. — Same as Ringer's solution for mammals, to which has been added 1.00 gms. of dextrose. 4. Tyrode's Solution.^ — H-ion concentration is 0.2 x 10"^. NaCl 8.00 gm. KCl 0.20 gm. CaCl2 0.20 gm. MgCl2 • . . . . O.lOgm. NaHCOs l.OOgm. NaH2P04 0.05 gm. Water to make lOOO.OOc.c. 1 See Rona and Neukirch, Pfliiger's Arch., 1912, cxlviii, 279. ANESTHESIA 29 CARE OF TISSUES AND ANIMALS. In working with tissues or with animals intelligent care is neces- sary to get results that are dependable. Certain things must be avoided as well as certain conditions fulfilled. In working with tissues or isolated organs, therefore, avoid: Stretching. Overheating. Cooling. H\'per- or hypotonic solutions. Rough manipulation or handling. Exposure to air, or drying. The results of the above are seen especially with uterine, intestinal, or heart strips. Unless the technic and working conditions are adequate, poor and distorted results are obtained. In working with animals avoid: Excitement. Hemorrhage. Shock. Variations in the depth of anesthesia. Reduced temperature. Persistent or abnormal sensory stimulation. Too great voltage to stimulate nerves. Use all caution to preserve the vitality of the animals, as only under such conditions can dependable and uniform results be obtained. It is highly important that the anesthesia be uniform. All drugs and those especially that act on the nervous system are greatly modified by the depth of the anesthesia, e. g., digitalis produces vomiting in the normal dog, but not in the anesthetized; epinephrin will raise the pressure much more in the unanesthetized than in the anesthetized animal. Anesthesia will stop strychnin convulsions. Many other examples might be cited. ANESTHESIA. In most work on mammals an anesthetic is used. The choice depends upon the animal and on the experiments. Ether and chloroform are the most frequently used and unless there is an objection to it, 1 c.c. of morphin 3 per cent. hypodermic3,lly renders the procedure easier and lessens the amount of the anesthetic required. Since anesthesia is the preliminary step to other opera- tions, it will be described first, although a demonstration of anes- 30 INTRODUCTION thesia is vastly superior to any written description. The mammals most used for laboratory experiments are dogs, cats, guinea-pigs and rabbits. Slightly different technic is used in the anesthetization of each. General Principle. — The animal may be held in any convenient position, avoiding pain, excitement, injury or other distracting circumstance. Small animals and e^'en dogs may be enclosed in a box and the anesthetic dropped into the box through a funnel, or a wad of cotton saturated with the anesthetic may be placed in the box (Fig. 1). ^^Tieh the animal is sufficiently anesthetized it may be removed and the anesthetic administered by the drop method. The most Fig. 1. — Method of anesthetizing dog in a box. used and best laboratory anesthetic is ether. Chloroform may also be used and should be studied. A mixture of the two is sometimes used, but it is not advised. The following methods have been found convenient for the usual laboratory animals. Dogs. — ^Hold the animal in the way illustrated (Fig. 2). Use a towel and fold to fit the animal's nose in the form of a cone. Drop the ether or chloroform on at a rate of about 10 drops per second and watch the reflexes. If there is no objection to it the animal may be given a small hypodermic of morphin before the ether. A small dog may be given 1 c.c. of 3 per cent, morphin sulphate and the dose repeated in fifteen minutes if thought advisable. Instead of using a towel a metal cone may be used. This may be prepared from the ordinary ether can by removing the bottom and connecting ANESTHESIA 31 the normal outlet with an ether bottle. The diagrams or photo- graphs will illustrate this. The tests of good anesthesia are: 1. Loss of voluntary movements. 2. No cutaneous reflexes. 3. Slight corneal reflexes or none in deep anesthesia. •4. E^'en and fairly deep respiration. 5. Medium blood-pressure and pulse. Fig. 2. — Drop method of anesthetizing a dog. This sort of anesthesia may be continued by giving chloroform or ether from a dropping bottle at regular intervals of about thirty seconds. The number of drops that each animal requires can be determined by e>rperiment ; 3 to 6 drops every thirty seconds is recommended. It is important to maintain uniform anesthesia. Cats. — Ether or a mixture of chloroform and ether is a good anesthesia for cats. The easiest method to use on cats is as follows: Procure a box of a size to hold the cat conveniently. Be sure that the lid fits tightly. Drop into the box with the cat a small piece of cotton saturated with ether or with a chloroform-ether mixture; 10 CO. in broken doses will anesthetize a cat in ten minutes; glass slides in the box will permit observation. After this, proceed as with the dog. Pure ether very easily kills a cat and chloroform is more dangerous. Rabbits. — Rabbits are best anesthetized with urethane, 2 gm. given by the mouth. Follow this with light and careful use of ether; this is given in the same method as chloroform was given to the cat. Rabbits die very readily under chloroform. Guinea-pigs. — (iuinea-pigs are anesthetized with pure ether or with ether followed by morphin, 0.1 to 0.2 c.c. of 3 per cent. Some of the animals should be anes^etized in the box and com- pared with others anesthetized by the cone method. In this way the effect of the ether on the membranes of the no.se, etc., can be 32 INTRODUCTION seen. The animals in the box show much less excitement than those which are anesthetized by the cone or towel method. Morphin Ether. — Give a dose of 0.01 gm. per kilo (0.3 c.c. per kilo of 3 per cent.) morphin sulphate subcutaneously. After twenty minutes anesthetize the animal sufficiently with ether to permit necessary operations, such as insertion of cannulse and sectioning of nerves. Then allow the animal to recover from the volatile anesthetic for fifteen minutes, watching closely for evidence of pain, and repeating small doses of morphin if necessary. An animal in this condition needs practically no volatile anesthetic after the operation. The objections are: (1) the morphin produces vagus stimulation and an altered heart rate, especially if there is a small amount of any toxic substance administered; (2) resuscitation is more difficult than when a volatile anesthetic is used. Three per cent, morphin is used for ease of calculation in case one wishes to convert the metric into the apothecary system. One c.c. of 3 per cent, is equal to 0.03 gm., which is equal to 0.5 grain. One c.c. of this solution is enough for a small dog. INTRATRACHEAL INSUFFLATION. Meltzer has devised a method of artificial respiration which is specially useful in resuscitation work and in operations where the chest is opened. Anesthesia can also be carried on by the same procedure. The method consists in driving air by means of external pressure through a tube which has been introduced through the mouth and larynx deep into the trachea. In animal work where the trachea is exposed the tube may be placed directly into the trachea. The insufflated air returns through the space between the tube and the wall of the trachea and escapes through the mouth and nose. When the size of the tube and the rate of interruption and the degree of pressure are properly selected this method will main- tain life indefinitely, even in curarized animals with widely open pneumothorax. The Tube and Its Introduction. — The tube should be flexible and elastic. It should be sufficiently large to admit the necessary amount of air and small enough to permit the return of the air between the tube and the wall of the trachea. Introduction. — The mouth of a well-narcotized animal should be kept open by means of a gag, the tongue pulled out, and by means of a curved forceps the frenum of the epiglottis grasped and pulled back. The introduction of the tube into the larynx is then a very simple matter. Meltzer thinks that this method may also be used INTRA TRACHEAL INSUFFLA TION 33 Fig. 3. — Apparatus for anesthesia by intracranial insufflation. By means of a glass blower's foot-bellows (B) air is driven at will through a system of branching tubes into the intratracheal tube (hi.-T.). The first branching of the tubes is introduced for the purpose of regulating the interruption of the air-stream. From the right branch a tube is led off laterally, carrying a stop-cock {St. 3), which is to be used for the interruptions of the air-current. Duri'ng the opening of the stop- cock a part of the air-current continues through the left tube, thus preventing too great a reduction of the pressure, which is undesirable. By means of a screw clamp (S. C.) the amount of air which is to pass through the left tube can be regulated; a narrowing of this tube causes a greater collapse of the lungs during the interruption. The second branching of the tubes is introduced for the purpose of regulating the anesthesia. The ether bottle (E) is interpolated in the left branch; the right branch runs uninterrupted outside of the bottle to unite with the part of the left tube which comes from the ether bottle. When the stop-cock in the right branch {St. 2) is closed, all the air passes through the ether bottle; when, instead, both stop-cocks in the left branch (.S7. / and St. 4) are closed, only pure air reaches the intratracheal tul>c, and when all three stop-cocks are open only one-half of the air is saturated with the anesthetic. By partial closing of the stop-cocks various degrees of anes- thesia can be obtained. The third opening in the ether bottle carries a tube with a funnel {F) through which the bottle is filled with the anesthetic; the tube is otherwise kept tightly closed by means of a screw clamp {S. C). All three rubber stoppers are firmly and permanently wired down to resist various pressures. When the ether bot- tle is to be refilled during insufflation, both stop-cocks on the left side are closed, while the one on the right side is open. The tube which connects the anesthesia circle of tubing with the intratracheal tube {In.-T.) carries two lateral tubes; one is connected with a manometer (M), whi(;h needs no description, and the other leads to a safety- valve (S. V.) of a simple construction. To the ruliber tubing is attached a graduated glass tul>e, the lower end of which is inmiersed under the surface of the mercury in thi.s l>ottle to a fler>th crjrresponding to the pressure which is desired for the intra- tracheal insufflation. For instance, if the pressure should be not more than 20 nini. of mercury, the glass tube is immersed just 20 mm. lielow the surface of the mercury. The glass tube is kept in the desired place by means of a rul)i)er ring resting upon the opening of the mercury bottle. This device gives great safety to the working of the method. No matter how strong and irregular the bellows is worked, the intratracheal iires.sure could never rise above the one arranged for; the surplus of air escapes through the tube from under t ho iriercury. In this arrange- ment a wash bottle can be inserted containing warm Ringer's .solution, wliic^h would sorve as a filter as well as a source for heat and moisture. In our experimental work we never used it and never missed it. 34 INTRODUCTION in human surgery, but it has been found that the vocal cords may be injured and that spasm of the glottis tends to prevent the return of the air. After the tube enters the trachea it should be pushed gently forward until it meets with a resistance; the end of the tube is usually then in a deep place in the right bronchus. The tube should be withdrawn then 5 or 6 cm. (two or three inches). Some arrangement should now be improvised to keep it in place and to protect it from the teeth. Insufflation Apparatus. — The figure (Fig 3) with the attached legend is self-explanatory. This is Meltzer's own description of the apparatus. In working the bellows, interruption in the pressure should be made about eight times per minute. These need not be at abso- lutely regular intervals. The color of the mucous membranes will indicate the degree of oxygenation. The pressure in the manometer should be watched and not raised too high. The tube should always be introduced with care and without force. The diameter should be too small rather than too large. There should be a safety valve to prevent the pressure rising too high. There should be at least six interruptions per minute. There should never be marked collapse of the lungs when the chest is opened, because when they collapse the walls of the vesicles tend to adhere, and it takes a dangerous pressure for distention again. It requires much less pressure to keep the lung distended. Anesthesia by Insufflation. — Fig. 3 and the legend is self-explana- tory. If too much ether has been given the insufflation with pure air is the best cure. PHARYNGEAL INSUFFLATION. The following method also has been developed by Dr. S. J. Meltzer, and is described in detail in the Medical Record, 1917, xcii, 103, and in technical paper 77 (U. S. Department of Interior, Bureau of Mines). The method was developed because of some disadvantages in the method of intratracheal insufflation by the same author. These drawbacks are as follows: (1) The introduction of a tube into the trachea requires some dexterity and practice, and (2) the apparatus available on the market used for keeping up intra- tracheal insufflation is expensive. It is therefore improbable that the apparatus and the experienced operator will be at hand in many cases when needed. The method of intrapharyngeal insufflation is simple and efficient. The apparatus is seen ready for use in Fig. PHARYNGEAL INSUFFLATION 35 4. Instead of the bellows, as seen in the picture, an oxygen tank may be used. Following is the manufacturers' description and explanation of the apparatus, which is not patented and rather inexpensive. Artificial Respiration and Resuscitation ~ Meltzer Method - GEO. TIEMANNl 8r CO NEW YORK Brokea line shows stomach tube, in place.. w/iif/i IS necessary onl/ whert fibdoiTunn/ pressure pod (11 cciri for any reason not hf uied. Fig. 4 Artificial Respiration and Resuscitation by the Meltzer Method. — The Meltzer method of artificial respiration is based upon the prin- ciple of pharyrif/eal iri,Hvj[Jlftti(jn , a process that consists in ex])anding the lungs with air at regular intervals of about twelve to the minute 36 INTRODUCTION and depending on the elasticity of the chest walls to expel a portion of the air during each intervening period. In using the apparatus a board is first strapped tightly over the abdomen, Fig. 4 (//, l),to prevent the stomach instead of the lungs from being expanded with the air. The pharyngeal tube attached to the apparatus is then placed in the mouth and pushed as far back as it will go, Fig. 4 {III), and the tongue is drawn forward and tied to the tube, Fig. 4 (77, 2). The tube pushes the soft palate upward and effectually closes the passageway through the nose. Fig. 4 (777) so that no air can escape through the nostrils, while an opening in the bottom of the tube permits the air to pass freely down the throat. For supplying the air, a foot bellows is used. Fig. 4 (7, 4)- As the air is conducted through the tube it passes a valve (3) which regulates the inspiration and expiration. With watch in hand, or in synchro- nism with his own respiration, the attendant turns the ring that governs this valve alternately to the right and left at regular intervals. When the ring is turned to the right the air is forced into the lungs, and when the ring is turned to the left the air is shut off, at the same time a small vent is opened and the air escapes from the lungs. Just below this valve is another valve for regulating the pressure of the air given the patient, Fig. 4 (7, 77, 5). At the start the pressure used is very low, but is increased by gradual closing of the valve, until the chest shows a regular normal heaving. In case the apparatus is hurriedly called into use during an abdom- inal operation, in which case the abdominal board (1) cannot be strapped on, a stomach tube is passed through the pharyngeal tube, through the esophagus and into the stomach, Fig. 4 (777). An important feature of the apparatus is that it can be operated by one man, who need not be an expert. The bellows is worked by the foot and the respiratory valve is operated by the right hand, leaving the left hand free for making any adjustments that may be necessary. Parts Composing Meltzer's Device for Artificial Respiration by Pharyngeal Insufflation. — 1. Abdominal pressure pad. 2. Pharyngeal tube. 3. Respiratory Valve. 4. Foot bellows. 5. T-tube with a screw clamp, interpolated between the respira- tory valve and the foot bellows. Pharyngeal tube, respiratory PHARYNGEAL INSUFFLATION 37 valve, T-tube and foot bellows should be kept connected by means of good rubber tubing which does not kink. The apparatus will then be in readiness for immediate application. 6. Air bag to give uniform flow of air. 7. Tongue forceps and tape (or gauze bandage) for tying the tongue to the pharyngeal tube. 8. Stomach tube fitting into the opening of the pharyngeal tube to be used for the escape of surplus air from the stomach in cases where no pressure can be exerted upon the abdomen. Order of Procedure. — 1. The pressure pad is applied to the abdo- men. 2. Tongue drawn out. 3. Pharyngeal tube is inserted into the mouth until it reaches the posterior wall of the pharynx and then the drawn out tongue is tied to the pharyngeal tube. This will keep the epiglottis raised and the tube in its proper place. 4. An assistant operates the bellows while he takes the respira- tory valve in his hand and moves the ring from side to side by the thumb, synchronically with his own respirations. 5. The screw clamp on the T-tube is immediately screwed down until the chest shows a proper heaving. The heaving of the chest need not be too strong. A satisfactory number of respirations should be established twelve to fifteen per minute. If the air tends to accumulate in the stomach, or in cases in which the abdomen is open and the board cannot be applied a stomach tube is inserted. The air escapes through and around the tube. Details of the procedure and its application to clinical problems are given clearly in the references. The Schafer Method of Artificial Respiration and Resuscitation. — This method was devised by Dr. E. A. wSchiifer, Professor of Physio- logy in the University of Edinburgh. He recommends that the patient be placed in a prone position with the head slightly lower than the body. The physician or operator is astride or to the side of the patient, and the open hands are placed on the patient's side at the level of the lower ribs, and firm but not too violent pressure is applied. This is done by allowing the weight of the operator to come on the arms. After this pressure has been a])])lie(l for about three seconds (Fig. 5, a) the pressure is relaxed by raising the body (Fig, 5, h). The pressure and relaxation should be made about twelve times a minute; the amount of air entering the hmgs under these conditions is as mu(;h as or more tlian in onhnary resj)irati()n. lie found that in a normal jxTson tlie anionnt of air exchanged 38 INTRODUCTION in a minute is about 585 c.c. when the respirations are thirteen times a minute, or an average of 450 c.c. of tidal air at each breath. With his method of artificial respiration he was able to pump 6760 c.c. through the lungs in a minute; when compared with other methods of respiration he found this method the most efficient. Fig. 5. — Schafer's prone-pressure method of artificial respiration, applied; h, pressure removed. a, pressure being The advantages of the method are: 1. It is fully efiicient. 2. It can be performed without fatigue by a single individual. 3. It is simple and easily learned. 4. It allows the tongue to fall forward and the mucus and water to escape from the mouth, so that the tendency of these to block the passage of air which is inherent to the supine position is alto- gether obviated. Other methods of artificial respiration may be mentioned, but they are of historical interest only : They are : THE THIRD RESUSCITATION COMMISSION 39 The Marshall Hall Method. — The IMarshall Hall method consists of rolling the patient alternately from the prone position to the lateral position and pressing between the shoulder-blades when he is in the prone position. Schafer found that by this method the tidal air volume was 254 c.c. as against 520 c.c. for his own method, or 3300 c.c. per minute as against 6760 c.c. The Sylvester Method. — In this method the patient lies on his back, with the shoulders raised and the head hanging low. The operator takes hold of the patient's arms above the elbow and raises them away from the body until they arrive at about above the patient's head. This raises the ribs and increases the capacity of the chest. The arms are then lowered by his side and the elbows flexed and pressed against the lower part of the chest. This dimin- ishes the air-holding capacity of the chest by driving the air out. The tongue is likely to fall back into the throat and impede respira- tion unless someone grasps it and pulls it forward. The tidal air by this method Schafer found to be only 175 c.c. and the air exchanged a minute only 2280 c.c. as against 520 c.c, and 6760 c.c. respectively for his own method. Other methods were investigated by Schafer and by the recent National Com- mittee, who corroborated Schafer' s findings. The Third Resuscitation Commission. The subject of resuscitation is so important that we cannot do better than include a report of the Third Resuscitation Commission, which explains itself, and which shows the importance of the subject in Medicine. To save space we have eliminated some non-essential matter from the report which is complete in Science, December 6, 1918, p. 563. The commission included leading investigators in physiology, pharmacology, medicine, surgery and engineering, administrative officers of Army, Navy and Public Health Services, and finally representatives from the larger electrical companies where the problems of resuscitation have to be dealt with daily. As originally constituted it consisted of fifteen men. Later four others were added in an advisory capacity.' • There were present at the meeting: Past Assistant Surgeon E. F. Du Bois, U.B.N. R.F., of the Hurcau of Meflicino and Surgery, Navy Department; Dr. D. L. Edsall, Professor of Medicine and Doan of Harvard Medical Sciiool; Mr. W. C. L. Eglin, Chairman of Committee on Safely Rules and Accident Prevention of the National Electric Light Association; Dr. Yandell Henderson, Professor of Physiol- 40 INTRODUCTION The practical difficulties in life-saving problems are these: A mechanical life-saving device is not immediately available, the possession of such an apparatus gives a false sense of security, '^6 that life-guards, policemen, medical students and even hospital physicians are not adequately trained in either handling the appa- ratus or the manual methods. In view of these facts the committee advised that the prone- pressure method of Schafer is preferable to any other manual method. Instruction in this method should be included in the training of all people likely to handle this class of cases. When such an emergency arises the manual method is to be applied at once and continued during the transportation of the individual to hospitals or first-aid stations. Efforts on resuscitation should be continued until spon- taneous breathing is permanently established. This means that patients must be watched for a definite period after respiration is established. In the absence of all signs of life the method is not to be abandoned until after an hour's trial. It is not to be used in cases of coma where normal respiration continues. In cases of gas asphyxia the simultaneous administration of oxygen is advised. During all stages of resuscitation the body heat is to be main- tained. Mechanical devices should be confined to hospitals and institu- tions. They should be investigated further with a view to their perfection. Fourteen members agreed to the above report. Henderson took the stand that really efficient and reliable devices existed already, ogy, Yale University, and Consulting Physiologist of the Bureau of Mines; Dr. William H. Howell, Professor of Physiology and Assistant Director of the School of Hygiene and Public Health, Johns Hopkins University, Member of the National Academy of Sciences; Dr. Reid Hunt, Professor of Pharmacology, Harvard Medical School and Secretary of the Commission; Prof. A. E. Kennelly, Professor of Electri- cal Engineering at Harvard University and the Massachusetts Institute of Tech- nology; Dr. Charles A. Lauffer, Medical Director of the Westinghouse Electric Company, Pittsburgh, Pa.; Dr. S. J. Meltzer, Rockefeller Institute, Chairman of the Commission and Member of the National Academy of Sciences; Dr. Joseph Schereschewsky, Assistant Surgeon-General, U. S. Public Health Service; Dr. G. N. Stewart, Professor of Experimental Medicine, Westei;n Reserve University, Cleveland; Prof. Elihu Thomson, Gt\neral Electric Company, West Lynn, Mass., Member of the National Academy of Sciences; Lieut-Col. Edward B. Vedder, of the Army Medical School; Major Frank G. Young, of the Ordnance DiAasion of the War Department. A telegram was received from Surgeon-General Gorgas that Dr. Charles H. Frazier, Professor of Surgery, University of Pennsylvania, is to represent his office. (In a subsequent communication. Major Frazier accepted his appointment.) Con- ferees: Mr. P. H. Bartlett, Philadelphia Electric Company; Mr. Wills Maclachlan, Electrical Employers' Association, Toronto, Canada; Mr. C. B. Scott, Chairman of the Subcommittee on Accident Prevention National Electric Light Association; Dr. F. E. Schubmehl, General Electric Company, West Lynn, Mass. RESOLUTIONS ADOPTED BY THE COMMISSION 41 but that their results were inferior to manual methods and that they actually contribute to decrease in life saving, because of the false assurance they give. He felt that they should all be abandoned in favor of the manual prone- pressure method. Resolutions Adopted by the Commission. In the discussion following the presentation of methods and evidence to the commission the following important facts were emphasized: 1. That in most accident cases no resuscitation apparatus is at hand for immediate use. 2. That reliance upon the use of special apparatus diminishes greatly the tendency to train persons in the manual methods and discourages the prompt and persevering use of such methods. 3. That police officers or physicians often interfere with the proper execution of manual methods, in that they direct that the patient be removed in an ambulance to some hospital, thus inter- rupting the continuance of artificial respiration. 4. That in many hospitals the members of the staff are not all acquainted with the methods of artificial respiration. 5. That in medical schools instruction is not properly provided for students in the manual methods of artificial respiration. In view of these facts the following resolutions were adopted by the commission: 1. The prone-pressure, or Schafer, method of resuscitation is preferable to any of the other manual methods. 2. Medical schools, hospitals, fire and police departments, the Army and Navy, first-aid associations and industrial establish- ments in general should be urged to give instruction in the use of the prone-pressure method of resuscitation. 3. Individuals who, from accident or any other cause, are in need of artificial respiration should be given manual treatment by the prone-pressure method immediately on the spot where they are found. It is all-important that this aid be rendered at once. The delay incident to removal to a hos])ital or elsewhere may be fatal, and is justifiable only when there is no one at hand competent to give artificial resi)iration. If complications exist or arise, which require hospital treatment, artificial respiration should be main- tained in transit, and after arri\ al at the hospital, until spontaneous respirations begin. 4. Persons receiving artificial rcsjMration should, as much as possible, be kept warm and llic artificial respiration should be 42 INTRODUCTION maintained until spontaneous breathing has been permanently restored, or as long as signs of life are present. Even in cases in which there is no sign of returning animation, artificial respiration should be kept up for an hour or more. 5. A brief return of spontaneous respiration is not a certain indication for terminating the treatment. Not infrequently the patient after a temporary recovery of respiration stops breathing again. The patient must be watched, and if normal breathing stops, the artificial respiration should be resumed at once. 6. Artificial respiration is required only when natural respiration has ceased. In cases of simple unconsciousness from any cause in which natural respiration continues, artificial respiration should not be employed without medical advice. 7. The commission recommends that in cases of gas asphyxia- tion, artificial respiration, whether given by a manual method or by special apparatus, should be combined, when possible, with the inhalation of oxygen from properly constructed apparatus. 8. With regard to the employment of mechanical devices for artificial respiration the commission feels that it ought not at present to take a definite stand either for or against any particular form of apparatus. However, the commission recommends, that the use and installation of apparatus should be confined, for the present, to properly equipped institutions under medical direction. The commission recognizes the great need of simple devices capable of performing artificial respiration reliably and efficiently. It therefore recommends a careful study of the problem, directed toward the development of a reliable method appropriate for general adoption. Such studies can best be carried on in properly equipped hospitals and laboratories which offer opportunities and facilities for critical observation and experimentation. In view of the importance which the knowledge of proper methods of resuscitation possesses for public health and safety, and consider- ing the fact that many practitioners, members of hospital staffs and graduates of medicine are not thoroughly familiar with the methods of resuscitation, especially that of the prone-pressure method, the commission recommends: (a) That medical journals (and other scientific and practical journals which are interested in the problem of resuscitation) be asked to publish the resolutions adopted by the commission. (6) That a copy of these resolutions be sent to the medical col- leges with a request that proper instruction in this subject shall be arranged for in the college schedules. RESOLUTIONS ADOPTED BY THE COMMISSION 43 (c) That these resohitions be sent to as many hospitals as pos- sible, with the recommendation that members of the house staff shall familiarize themselves with the methods of resuscitation. (d) In order that the resolutions of the commission may be brought to the attention of interested circles (fire and police depart- ments, industrial plants, etc.) it was agreed that they be com- municated to the Associated Press (by the National Electric Light Association). CHAPTER I. MODES OF ADMINISTERING DRUGS. Frogs. — Drugs are usually injected into the anterior or posterior lymph sac. Since these beat rhythmically a quick entrance into the circulation is assured. The best method is to introduce a hypodermic needle through the floor of the mouth and down into the anterior lymph sac. Direct injection into the lymph sac may be followed by a leakage through the needle hole, consequently it is a less accurate method. By going through the mouth there is little likeli- hood of this error. Demonstrations of each method should be given. See Fig. 25, p. 112. Mammals. — ^The methods used are: (1) By mouth; (2) subcu- taneously; (3) intramuscularly; (4) intravenously; (5) intraperi- toneally; (6) by rectum; (7) intraspinally or subdurally. 1. By Mouth. — ^When the volume is small the drugs may be given conveniently in a capsule. The animal's mouth is held open, the head back and the capsule thrown back or placed far back on the tongue. Hold the animal's mouth shut, and if he does not swallow it spontaneously slap the throat gently or rub it toward the stomach. There is usually no trouble to get the animal to swallow. Fig. 31, p. 134. The liquids are most conveniently given by stomach tube. Hold the animal firmly; open his mouth and insert an appropriate wooden gag, with a hole in it, behind the molar teeth. Introduce a gum- elastic catheter through the hole of the gag and push it into the stomach. Pour the liquid through the tube by means of a funnel. It is unnecessary to state that the tube may, in some cases, enter the lungs instead of the stomach. This may be ascertained by listening for respiration. If the tube is in the trachea, respiration is heard through it. In such cases, withdraw and reinsert. By pulling the tongue forward one may see the tube in the proper location (Figs. 6 and 7). A demonstration of the serious conse- quences of putting fluid in the lungs is valuable. 2. Hypodermic Injection. — Hold the skin between the fingers and with a quick, firm thrust insert the needle. Since the dog's skin is thick and the animal will move, if not held carefully, care must be taken not to break the needle. MAMMALS 45 Fig. 6. — Method of introducing liquid into the stomach of a rabbit. ViQ. 7. — Method of introducing liquid into the stomacli of a dog. 46 ■ MODES OF ADMINISTERING DRUGS 3. Intramuscular Injections.— This may be made into any large muscle; a quick thrust into the middle of the muscle is best. 4. Intraperitoneal Injection. — This is an excellent method when large volumes are to be injected. Grasp a fold of the skin and muscle of the flank or along the linea alba and inject perpendicularly. 5- Intravenous Injections. — (a) This may be done in unanes- thetized animals by pressing the leg or jugular regions until the veins stand out; then the needle can be readily introduced. (b) When large volumes are to be introduced it may be well to insert a cannula in the vein and attach a burette, with saline solu- tion, by means of a rubber tube. Injections may then be made into the tube and washed in from the burette. Fig. 8. — Method of introducing needle into the fourth ventricle. (c) In case of rabbits the ear vein is used. The injection may be facilitated by shaving the ear and rubbing it with toluol or some irritating drug. A clip attached centrally will make the peripheral bloodvessels stand out so that injection may easily be made. 6. Intraspinally, Suhdurally, or into the Fourth Ventricle. — To inject the fourth ventricle, this at first should be done on an anes- thetized animal. After the technic has been obtained it is easily carried out without an anesthetic, and causes but slight pain. Flex the head of the animal strongly on its chest. Insert a thin needle between the occiput and axis. Point toward the nose of the animal in the flexed position. When the needle has entered the ventricle, a clear fluid escapes freely (Fig. 8). OPERATIVE TECH NIC 47 Injections into the subdural spinal region are made by passing the needle along the side groove of the vertebra, keeping in the straight line as much as possible. Done this way, an entrance between the vertebra can be made. This should first be shown on the skeleton. 7. Rectal Injections.— These are made through a catheter. When the desired amount of fluid is introduced a clamp or forceps may be applied to keep it from being expelled. If the drug is irritating it should be mixed with gum acacia, 6 per cent., or some other col- loidal material. This will lessen the irritation. OPERATIVE TECHNIC. Students in pharmacology have already had a course in physio- logy, so that it is unnecessary to detail operative technic. If this is done it is so voluminous that it detracts from the object of the experiment. If such a course is needed a few minutes of demon- stration is worth hours of reading. For these reasons principles only are given. Exposure of Nerves, — Determine the approximate position of the nerve to be exposed. Make the superficial incision about three times as long as the nerve is below the surface. Work mainly by blunt dissection, but avoid hemorrhage by ligating or clamping bleeding vessels. Do not let the nerve become dry. Keep it moist with a saline or with the body fluids. Keep it covered with the tissues as much as possible. If necessary to pass a ligature to raise it for stimulation, use linen or gauze strips. For very small nerves, silk threads are better. Stimulation of Nerves. — This is done most conveniently in experi- mental work by means of electrodes; salts, etc., may also stimulate. Never stretch or pinch a nerve. Do not let it become dry, but keep it moist with i)hysiological saline. Do not use a current strong enough to burn the nerve. No current should be used on a nerve that is decidedly unpleasant when held to the tongue. Placing a Cannula in the Trachea.— The animal is placed in posi- tion on the operating table and tied securely, with head extended and throat exposed. Make a deep median incision at one cut, through the skin, muscles, etc., down to the trachea with the face of the knife. Do not pick at it, but cut with decided intent. When such a cut is made, place the index fingers in it and pull the fascia apart. In this way the trachea, nerves and vessels may be exposed clearly and without bleeding. In some instances where a goitre 48 MODES OF ADMINISTERING DRUGS lies in the field of operation, special precautions must be taken to stop hemorrhage. The objects of placing a cannula in the trachea are: 1. To render easier the process of anesthesia. 2. To permit artificial respiration. 3. To facilitate resuscitation in cases of accident. Fig. 9. — The most important anatomical structures in the dog's neck. 1, can- nula in the trachea; 2, three-way cannula in the carotid artery; S, trachea; 4> 5, vagosympathetic nerve; 6, thyroid gland; 7, rubber tube from the cannula to the pressure bottle; 8, rubber tube leading to the mercury manometer. A tracheal cannula is never inserted in animals which are to be kept after the operation. To place cannulse in veins, arteries, ducts, etc., little need be said. A knowledge of the anatomy of the region is important and must be gained by dissection and practice, and this is one of the beneficial results of a laboratory course. The object of such cannu- OPERATIVE TECH NIC 49 lation is the obtaining of records of blood flow, salivary secretion and the like. Cannulte are placed in veins for the injection of fluids. This cannot always be easily accomplished by means of hypodermic, because in cases of collapse the veins of small animals are in many cases invisible. When a cannula is inserted, and this may be attached to a burette with a rubber tube, injections can be made into the rubber tube, and the pressure from the burette will carry it into the xe'm exen when the heart is feeble or stopped. Injecting into a Vein. — Fill a burette with salt solution (all solutions injected should be about 40° C.) Attach a rubber tube, with pinch-cock or screw clamp, to the lower end of it, if there is not a glass stop-cock on it. The burette should then be filled with 0.9 per cent. NaCl solution, as also the tube. Make a longitudinal incision about two inches long on the skin over the anterior surfaces of the thigh, near the middle of Poupart's ligament, to expose the femoral vein; the artery can be felt through the intact skin. Blunt dissection with the handle of the knife in Scarpa's triangle will expose the vein; place two ligatures about it as in placing the carotid cannula. Then pick out a cannula of the proper size, allowing for more shrinkage of the vein than of the artery. The distal ligature should then be tied, the vein cut, the cannula introduced and tied in place. Then fill it with 0.9 per cent. NaCl and connect with the rubber tube on the burette. (If any considerable volume is to be injected it should be at body temperature.) Be sure that all air bubbles have been carried out by the liquid. Drugs can be injected by a syringe through the walls of the rubber tube obliquely and the solution carried into the vein by letting in a little salt solution. Inserting a Cannula into the Carotid Artery. — Find the artery in the trough outside and behind the muscles covering the trachea. The vagus nerve, which is in the same sheath, appears white; the internal jugular vein is bluish purple and the artery, light bluish or pink. Separate it entirely from the surrounding structures by blunt dissection for about an inch and a half ; be careful not to injure the vagus nerve. Put two ligatures around the artery, one below and one above where the cannula is to be inserted. The upper one is to be tied tightly. vSelect a cannula whose diameter is almost equal to that of the artery. Put a pair of bulldog forceps on the artery just below the cannula. Make a small incision about half- way through the diameter of the artery into the lumen of the artery. 'J'akc hold of the lower end of the incision with a i)air of fine forceps and iiis(.Tt the cainmla with the projecting end of the beveled tip 4 50 MODES OF ADMINISTERING DRUGS toward the forceps. Put the cannula into place and fasten it with the ligature. Opening the Thoracic Cavity. — The thoracic cavity is opened to study the heart and lungs. To do this the breastplate is removed to such a degree that observations and manipulations may be made. The main points to watch in this operation is not to injure the lungs, and to tie the large vessels either before they are severed or to ligate them quickly if they are bleeding. The whole technic has these objects in mind. Otherwise the method of work has little meaning. Insert a tracheal cannula and see that the ether bottle and accompanying apparatus are all ready for immediate use before work is started. Have a number of hemostats ready. Dissect along the midline of the neck down to the manubrium sterni, using blunt dissection as much as possible. On each side of the midline, make an incision through the skin; also one an inch from the midline for the entire length of the sternum. Use blunt dissection and expose the first rib on each side and begin artificial respiration. In the first right interspace insert an aneurysm needle and turn the handle so that the hook is upward and embraces the first rib. Pull it up. Then cut it through with bone forceps and enlarge the opening. Be sure that the lung is expanding so that the tip is close to, but is not protruding from the opening in the chest wall. Be sure also there is good lung ventilation. Just exposed by the opening, at the margin of the anterior mediastinum, will be found the right internal mam- mary artery; place a clamp about it. Expose and clamp the left internal mammary artery also. With scissors, cut through the muscles covering the right side of the chest and through all the right ribs with bone forceps and scissors, using hemostats on all the bleeding parts. If the index finger is inserted into the thoracic cavity and used as a guide, cutting into the lung may be avoided. The sternum may be cut through with bone forceps. Hemostats will be required to clamp bleeding-points, which are always found at the site of the internal epigastric vessels near the lower end of the sternum. The chest is more easily opened and the contents exposed with less bleeding by a midline incision; but in this case there is little room for work within the chest since it is hard to hold the walls back and give room for such instruments as the my ©cardiograph. Some workers, however, prefer the midline incision, and if the attempt is made to preserve the animal after such an operation, this is the only method applicable. TO RECORD BLOOD-PRESSURE IN MAMMALS 51 RECORDING BLOOD-PRESSURE IN MAMMALS. No one method of recording blood-pressure is satisfactory to all experimenters. The technic varies with the facilities of the laboratory. If the student has become familiar with any of the usual methods he will find it adequate. All methods depend upon the same principle, namely, the insertion of a cannula in an artery and the transmission of the arterial pressure to a recording instru- ment or manometer. Fig. 10. — Apparatus for direct measurement of blood-pressure. -4, 3-way cannula for insertion into artery; B, valves to regulate pressure; C, pre.ssure bottle. To measure the pressure etherize the animal in the usual way and insert a tracheal cannula. The tracheal cannula is convenient though not absolutely necessary. It gives a more perfect control of the animal and artificial ' respiration can be given at any time, should it be needed. Insert the three-way cannula into the central or cardiac end of the carotid artery. The cannula should have a piece of rubber tubing on each of the other ends. After the cannula is tied into the artery connect one end of it by means of a rubber tube with the manometer. See that it is now filled with the anti- coagulant solution, either sodium citrate, 5 to 10 i)er cent.; mag- nesium sulphate, 6 per cent, or other solution as may be provided. 52 MODES OF ADMINISTERING DRUGS See that the system is well filled and contains no air. The other free end of the three-way cannula is connected in the same way with a pressure bottle. The pressure bottle may be used as in the illustration where the pressure is transmitted by a hand pump to the anticoagulant fluid, or if the air system of raising the pressure is not used, the pressure may be raised by a pressure bottle suspended at a height of approxi- mately six to eight feet above the operating table. If the pressure bottle is used it must be made safe as it has been known to fall and injure the operator. This last method is used in many cases where a permanent working place is provided. Either method is satis- factory. Clotting is lessened in the three-way cannula by having a bulbous enlargement and the use of an anticoagulant solution. The enlarge- ment of the three-way cannula permits mixing of the blood with the anticoagulant solution. The pressure in all cases should be raised to nearly that of the blood-pressure of the animal before the clip is released from the artery, because if the blood flows out into the connecting tubes it may clot and thus cause considerable annoyance and inconvenience, and it also takes the blood from the vessels of the animal and lowers the normal blood-pressure to that extent. If it can be made to balance within the three-way cannula this is much more satisfactory from all standpoints. If too great a pressure be placed on the out- side, some of the anticoagulant is forced into the heart with fatal effect in most cases. Cleaning Out the Cannula. — Place a bulldog clamp on the artery again, and place a pinch-cock on the tube connecting with the mano- meter. Slip the tube off of the cannula and swab the cannula with a feather. Fill the cannula system with MgS04 solution (6 per cent.), sodium citrate 5 per cent., or any other anticoagulant solution. The main points to observe in washing out the cannula is that fluid be not injected into the heart, or clots or air washed into the circulation. If the cannula is to be cleaned after it is removed from the body, it may be soaked in 5 per cent. NaOH for some time. This dissolves the blood, fibrin, etc. RECORDING RESPIRATION. Insert a tracheal cannula and connect it with one horizontal limb of a T-tube by means of a short rubber tube. The other hori- zontal limb of the cannula is connected with the ether bottle. The GRAPHIC RECORDS ■ 53 vertical limb of the T-tiibe is connected with a rubber tube long enough to reach a tambour registering on a kymograph drum. (Records of .respiration obtained in this manner are comparable only so long as the openings into and from the ether bottle are kept constant. It is evident that if these are adjusted during the course of the experiment, there is bound to be an inaccuracy in the record. GRAPHIC RECORDS. In making these records, the writing levers, tambour, etc., must be so arranged that all writing points are in the same vertical line. In most cases it is a good idea to have a time record. If the labora- tory has a "time" circuit, this is connected with a signal magnet writing on the drum. If such a circuit is not available, the time magnet is connected in series with a dry cell and key. A student should be prepared, with a watch before him, to make contacts at stated times. Accuracy in this matter is assured by close attention only. The wire connection should be long enough so that the opera- tor will not be in the way of the experimenting. Individual metro- nomes are often used to make and break the time circuit; the time "magnet may be adjusted in blood-pressure experiment's to register the zero pressure. A second signal magnet is arranged to write directly under the first to record the instant and duration of the given procedure. The key controlling this magnet should be on the drum table conveniently near to the operator. When the record is completed, it should be taken from the drum and labeled at once to prevent confusions which might arise. The date and series, if more than one record is made on one day, should be written on the record. It is advisable to put all data possible on the tracing. Each experimental procedure should be legibly speci- fied. The time of each event should be specified on the record in order that calculation may be made later of the duration of the experiment and the intervals between events. A writing board or a large glass plate facilitates the labeling of the records. It should have a base large enough to hold the record and a ledge with a hand rest at each side. After the records are labelled, they should be .shellacked. When a series of records is made and properly labelled, the\' aft'(jrd data on the experiment to be studied at leisure. The important sections may be copied as blue prints and given to rncrribers of the class. Records of blood-pressure may be studied as follows: Careful measurement of the distance of the tracings above tlie base line at 54 MODES OF ADMINISTERING DRUGS various points along the course of the curve should be made. This means, before the drug is injected, after it is injected, and when the action becomes apparent, and at intervals thereafter according to the drug used. When the curve is ordinarily uniform, readings every minute are often enough. The zero line marked on the tracing is always used to determine the blood-pressure. The distance above the base line should be doubled, as there are two arms of mercury in the manometer. The changes in the heart-rate are studied as follows : Two parallel lines are drawn perpendicular to the base line so as to intersect the tracings. The distance of the lines from each other is determined by the rate of the drum as indicated by the time marker. They are usually drawn to include between them a space of ten seconds, in terms of the record. The number of heart beats on the tracing included between the two lines is counted and the rate of the heart per minute is calculated from this; these estimates are made along the curves at the same places where the pressure changes are measured. Mark any other variation in the curve, as irregu- larities of heart action or of respiration. CHAPTER II. EXPERIMENTAL PHARMACOLOGY. Substances Whose Main Action is Local. This will include mainly the pharmacology of: I. The skin. II. The visible mucous membranes of the: Eye. Mouth. Nose. Throat. Rectum. Vagina. Lrethra. III. The aUmentary tract. In presenting pharmacology in the laboratory, the logical sequence that is followed in a lecture course, may be very inconvenient. For this reason sequence is frequently sacrificed to convenience without detracting greatly from the value of the work. I. The Skin. — The functions of the skin are varied and complex. The most important are: 1. It is the protective covering of the body. 2. It is the sensory surface which adjusts the body with the outer world. 3. It regulates the body temperature, or at least is one of the adjusting mechanisms. 4. It is an excretory organ. 5. In some cases it is a secretory organ, (milk for example). Many of these functions will fall better under the heading of Glands, Peripheral Nerves, Intestines, etc. For that reason in the Pharmacology of the Skin we will study (1) those drugs that act locally mainly because of their mechanical effect; (2) those that have an action on the skin due to the excretion of drugs by the skin. Classification in pharmacology is for convenience only and as an aid to the association of drug action. It cannot be anything but arbitrary and overlapping. Drugs used mainly for their action on the skin are: 56 EXPERIMENTAL PHARMACOLOGY 1. Dusting powders. 2. Emollients and demulcents. 3. Collodions. 4. Irritants and counterirritants. Rubefacients. Vesicants. Pustulants. 5. Antiseptics and disinfectants. 6. Corrosives and caustics. 7. Local anesthetics. Drugs that act on the skin either through excretion by the skin or through metabolic changes and includes especially: Iodides. Bromides. Salicylates. Quinin. Arsenic. Chloral. Antypyretics. Sulphonal. Aspirin. 8. Poultices. II. Drugs used for their action on the visible mucous membranes: 1. Demulcents and emollients. 2. Bitters. 3. Astringents. 4. Corrosives and caustics. 5. Antiseptics. 6. Local anesthetics. These may be used in the form of gargles, lozenges, suppositories, nebulae, injections, etc. III. Drugs used mainly for their action on the alimentary tract are: — 1. Demulcents and emollients. 2. Astringents. 3. Antiseptics and disinfectants. 4. Carminatives. 5. Bitters. 6. Digestants. 7. Emetics. 8. Anti-emetics. 9. Acids and antacids. LOCAL ACTIOX OF DRUGS 57 10. Absorbents. 11. Drugs to lessen movement (opiates, etc.) 12. Drugs to increase movements (cathartics.) 13. Anthelmintics. LOCAL ACTION OF DRUGS. Local Anesthesia (an, not; aisthetos, sensible). — Local anesthesia, or terminal anesthesia, may be brought about by suppressing the sensitivity of the nerve ends — terminal anesthesia, or by blocking the nerve impulse in the nerve trunks — nerve blocking. Methods. — Local anesthesia may be brought about by: 1. Compression. 2. Cold applications. 3. Chemical agents. 4. Local anemia. 5. Infiltration with anisotonic solutions — water, salt solutions, etc. — which act purely physically. 6. Cocain and substitutes, which may be considered as a special class of chemical agents. The chief local anesthetics are: Ethyl chloride. Ether spray. Extreme cold. Cocain and substitutes — prococain and tropococain. Chloretone. Antipyrin. Hydrocyanic acid. Creosote, guaiacol. Iodoform. Orthoform. Phenol. Quinin urea hydrochloride. Local Anodynes: Aconite. Veratrin. Belladonna. Menthol. Chloral. Sodium bicarbonate. Zinc oxide. Volatile oils. 58 EXPERIMENTAL PHARMACOLOGY Experiment I. — Cutaneous Sensations. — General Characteristics. — (a) Pundiform Distribution of Cutaneous Senses. — Shave and mark off an area of skin on the back of the hand about one inch square. Blindfold the subject and arrange the hand on a comfortable support. With suitable esthesiometers explore the selected area systematically for warm, cold and pressure spots, marking each variety in a different color, say red, blue and black respectively. It will require close attention to recognize the sensation aroused in a touch spot and to distinguish it from that of a pain spot, the sensa- tion lasting longer in the second case. Observe the arrangement and relative numbers of the several kinds of sensory spots. Note the variation in sensitiveness within each group and select for later experiments a few of the more sensitive cold and warm spots. (b) Sjiecific Nerve Fmergies (Functions) of the Cutaneous Nerves. — Try mechanical or electrical stimulation of a cold spot. Try the paradoxical cold reaction, i. e., stimulation of a cold spot by applica- tion of a warm object with a temperature of 50° to 60° C. (c) Spray the area with ethyl chloride and repeat (a) and (6). (d) Compress the arm to a degree when the circulation is markedly disturbed and repeat (a) and (6). Experiment n.^ — Temperature Sensations. — (a) Adequate Tempera- ture of a Medium. — This is the temperature of the medium which gives neither warm nor cold sensation. It is not a definite tem- perature, but a temperature range, the extent of which depends on certain physical properties of the medium, such as its specific heat, its conductivity — for heat, the character of its surface, etc. Compare oil and mercury, water and mucilage of acacia, at the same temperature. Practical method of finding the temperature of the skin. (6) Adaptation. — Transfer the finger from a bath of Hg. at the adequate temperature to Hg. a few degrees colder; the initial sensa- tion soon disappears. Repeat this with colloidal solutions at the same temperature. (c) Contrast. — Find the adequate temperature of water for the fingers of both hands (approximately 28° C). Then transfer the right hand finger to water at 15° C, the left hand finger to water at 40° C. After a short interval return both to the water at the adequate temperature — about 28° C. What sensations result? Experiment HI. — Pressure Sensations. — (a) Observe the arrange- ment of the spots in relation to hair follicles and demonstrate the influence of the fine hairs magnifying the effect of weak stimuli. (6) Absolute Threshold — Liminal Stimulus.- — This depends on a number of factors, such as the qualit}^ of the skin, presence or LOCAL ACTION OF DRUGS 59 absence of short hairs, rate of apphcation of pressure, etc. Find its vahie for several regions, inchuhng forehead, terminal phalanx of middle finger (volar surface) and back of hand. (c) Differential ThresJwld.— Determine the differential threshold for some one region, say the skin of the forehead. The method to be followed may be outlined as follows: The weights are applied in succession to the same area. The interval between the two applications should be short (five seconds) and regular. The duration of the stimulus must be constant. There should be no thermal element present and visual and mus- cular sensations must be excluded. Fig. 11. — Method of pithing frog. (d) Discriminative Sensibility of the S/an.— Examine the localiz- ing power of the same regions for which the threshold stimulus has been determined, using the older method of Weber, in which no regard is had for the individual sense spots. Note that the sensi- tiveness of different regions for light touch and for tactile dis- crimination does not vary in the same manner. Observe also the variation in the discriminative sensibility of the skin of the cheek from ear toward the lii)s, and of the arm from shoulder to hand. 60 EXPERIMENTAL PHARMACOLOGY Repeat: (a) After the spots have been anesthetized with ethyl chloride. (b) After the spots have been anesthetized by holding a piece of ice to them. Experiment IV. — Nerve Blocking. — Pith a Frog. — Expose the sciatics; test the response to electric current. Freeze a small section of the nerve with ethyl chloride and stimulate above and below the frozen areas. Apply chloroform and ether in the same way. Results? What can you say of the action of drugs on the nerve trunks? Nerve blocking? Fig. 12.- -Lines showing points to cut to expose or remove, bellum; c, cord with sciatic; d, sciatic. a, cerebrum; b, cere- Experiment V. — Take a piece of filter paper 1 cm. square and soak it in a 1 per cent, cocain solution and apply it to your own tongue. Retain it in position for fifteen seconds, then test the area for sensations of touch, temperature, and taste. Contrast the sensa- tion for quinin, sugar and salt before and after the use of cocain. Cocain in medicine is used chiefly for its local action, and this mainly to abolish pain. Experiment VI. — Dip the foot of a frog into a 1 per cent, cocain solution. In a few minutes compare the excitability of this foot with the other, as regards response to electrical stimulation, mechan- ical stimulation and chemical stimulation — dipping into 1 per cent. LOCAL ACTION OF DRUGS 61 HCl or acetic acid. As soon as the reflex is obtained, wash off the excess of acid with water in another beaker. (Tiirck method of reflex time.) Fig. 1.3. — Tiirck method of taking reflex or reaction time. Experiment VII.— Anesthesia of Cornea. — Touch the cornea of a rabbit with a glass rod or other suitable instrument and note the reaction. Now instil a few drops of cocain 1 per cent, and from time to time determine the change in reflex on stimulation. Compare the reflex of the cocainized eye with that of the normal eye. Note also any change in size of pupil. In a second rabbit test the ane.sthetic effect of quinin urea hydrochloride in the same way. Experiment VIII.— Place one drop of the tincture of aconite on your own lip and note the sensations. A tingling scratching sensa- tion is produced. The drugs of the aconite group are the only drugs whicli act on the sensory receptors when given systemically; i. c, by mouth, intravenously, etc. Squibbs test for aconite is based on this action. It is as follows: Dilute 1 c.c. of the tincture of aconite 62 EXPERIMENTAL PHARMACOLOGY to 70 c.c. with water. Hold 4 c.c. of the diluted solution in the anterior part of the mouth for one minute and expel it. If the original tincture is of standard strength, a tingling sensation will be distinctly apparent in from ten to fifteen minutes. Experiment IX. — Compare Experiment VIII with the result from an equal amount of the tincture of veratrin. These are the only drugs that give this reaction. How would you distinguish between the two? DEMULCENTS. Demulcents are colloidal substances, chiefly gums, dextrins, sugars, starches or other carbohydrate, which are used mainly to protect mucous surfaces, though they may be sometimes used on the skin. Their action is purely mechanical and protective. Bayliss has recently recommended the use by injection, of 6 per cent, gum acacia instead of physiological saline in cases of hemorrhage. The gum solution sustains blood-pressure better, and is, according to Bayliss, without harmful effects. (Note: Give distinctive char- acteristics of each demulcent mentioned above.) Experiment I. — Prepare a 1 per cent, cane-sugar solution in water; also a 1 per cent, cane-sugar in 7 per cent, mucilage of acacia. Com- pare the taste of these. Explain. Experiment II. — Prepare in the same way 0.1 per cent, saccharin (benzosulphonimide) in water and in mucilage of acacia or starch paste; compare taste. Explain. Experiment III. — Reduce a sample of milk and of water to a freez- ing temperature and compare the temperature effect on drinking. Experiment IV. — Prepare 1 per cent, acetic acid in water and 6 per cent, mucilage of acacia. Which tastes the more acid? Experiment V. — Mix 2 drops of the fluidextract of nux vomica with — 1. 10 c.c. of water. 2. 10 c.c. of mucilage of acacia. 3. 10 c.c. fluid extract of glycyrrhizse. Compare the taste of these. Experiment VI. — Add 2 drops of a saturated solution of KI to milk and the same amount to water. Compare the taste of each. KI is best administered in milk. Is there any other advantage besides masking the taste? 1. Explain the above effects. 2. What is the philosophy of giving barley water instead of water in fevers? 3. What are the chief demulcents, their preparations and doses? EMOLLIENTS 63 Experiment VII. — (1) Take blood-pressure of a dog by the usual method. (2) Remove one-fourth of the blood and take record of blood-pressure. (3) Inject the same volume of physiological saline and note effect on blood-pressure. (4) Repeat several times, noting the time which the blood-pressure will hold up after each saline injection. (5) After withdrawal of one-quarter the blood volume, inject an equal volume of 6 per cent, mucilage of acacia. Compare the effect of this with the action of physiological saline. EMOLLIENTS. Oily preparations for application chiefly to the skin. Their actions, like the demulcents, is purely mechanical, and they are used to: Soothe. Protect. Soften. Relax, and as Vehicles for other remedies. They are used especially in : Abrasions. Cuts. Bruises. Chapped hands. Burns. Skin diseases, etc. They are not often given by mouth because of their unpleasant oily taste. They are often used for eye, nose, urethra, vagina, and rectum. The principal emollients are: Adeps. Adeps benzoinatus. Unguentum. Adeps lanae hydrosus. Adeps lanse. Petrolates — Petrolatum liquidum. Petrolatum. Paraffin durum, lilaiid oils — i)[. olivae. 01. gossypii. 64 EXPERIMENTAL PHARMACOLOGY 01. lini. Unguentum aquse rosse. Cera flava. Glycerin. 1. The petrolates are not absorbed and are used to hold medicines to the surface of the skin. 2. Adeps penetrates somewhat but not so much as 3. Adeps lanse, which is given to carry drugs through the skin. It is doubtful if these statements hold in detail. Experiment I. — The class will be divided into groups. Group 1. Take 1 c.c. ol. betulse or oil of wintergreen by mouth. Group 2. Rub 2 c.c. oil of wintergreen or ol. betulse on the arm or other area of the skin. Group 3. Mix 2 c.c. ol. betulse or wintergreen thoroughly with 10 grams of petrolatum and rub on the arm as in 2. Group 4. Mix 2 c.c. of the oil with adeps — 10 grams — and repeat as in 2. Group 5. Mix 2 c.c. with adeps lanse hydrosus and repeat 2. Test the urine every fifteen minutes as follows: Acidify with H2SO4. Add an equal volume of ether. Shake in a separatory funnel; remove the ether; add water to the ether extract, shake and add a few drops of Fe2Cl6. A violet color indicates salicylic acid; explain the reaction. Make a summary of results and compare. DUSTING POWDERS. These are protective and absorbent. They protect from — Air. Clothes. Pressure. Friction, etc. Any inert powder will answer as a dusting powder. The main preparations are: Talcum purificatum — magnesium silicate. Kaolinum — aluminum silicate. Fullers' earth — aluminum silicate. Terra silicea purificata — Si02. Lycopodium. Starch. Zinc oxide. Boric acid. . LOCAL IRRITANTS 65 The essentials of a good dusting powder are: non-irritant, impal- pable, insoluble and light. They may be mixed in any quantities, but heavy powders, like zinc oxide, should not constitute more than 20 per cent, of the weight. Examine all of the above and make a list of the best-known dusting-powder preparations. Dusting powders are an important class of remedies and afford immense relief m cases of irritation from clothing, etc. Their simplicity, extensive use and freedom from the mysterious, to a great extent, prevents the study they deserve. Experiment I. — Study examples of each of the above powders. LOCAL IRRITANTS. (Latin — Irrito — Excite.) These if allowed to act long enough produce the phenomena ot inflammation, i. e., redness, swelling, pain and functional change. What is the difference between irritation and stimulation? Irritants are classified as: 1. Rubefacients. 2. Vesicants. 3. Pustulants. This classification depends on the degree of action, rather than the drug itself. The following are the main representatives: Rubefacients. Vesicants. Mustard. Cantharides. Capsicum. lodin. Camphor. Ammonia. Ammonia. Mustard oil. Arnica. Boiling water. Alcohol. Glacial acetic acid. Ether. Chloroform. Pustulants. lodin. Oil of turpentine. Croton oil. ^'olatile oils. Tartar emetic. Friction. Silver nitrate. Hot water, etc. Experiment I. — Heat. — Touch the end of a hot wire to the skin. Treatment, apply linimentum calcis; explain the action. The sub- ject of burns is pharmac-ological only as the treatment involves pharmacology. Most of the treatment, after the removal of the 5 66 EXPERIMENTAL PHARMACOLOGY caustic agent when this is possible, consists at first in relieving the pain. When this is severe, morphin may be injected. " In many cases the relief from pain is affected by excluding external irritants, such as air, etc. For this purpose carron oil was first used, but has now been supplanted by many modern forms of treatment, which, however, follow out the same principles. Carron oil should be sterile and care should be taken not to infect the burned surface. A coating of paraffin, which melts at a slightly higher temperature than that of the body, forms a "skin," which is said to promote healing and to prevent scar formation. Many other methods of treating burns are advocated. A saturated solution of picric acid applied on strips of sterilized gauze has been strongly recommended (Power). The tincture of iodin (Reclus), thymol iodide, 1 to 8 in vaselin, iodoform, has been recommended in the same way. A solution of sodium bicarbonate or carbonate gives relief in many cases and is said to promote healing. A saturated solution of boric acid has also been advocated. Normal saline applied on cotton has also been recommended. Dusting-powders of different kinds also have been used: acetanilid, ichthyol, resorcinol — anything to pro- tect from the air, and at the same time act as anodynes. Immersion in water, etc. Paraffin, which melts at a temperature slightly higher than the body temperature, has at present a great vogue. It is protective, pliable and easily removable, because the dermis does not grow into it. It is somewhat painful to apply, because of the heat necessary to liquefy it; but this pain is greatly lessened by first applying liquid paraffin. Experiment II. — Apply a drop of sulphuric acid to the skin. When it begins to sting, apply a drop of sodium carbonate or bicarbonate. General Treatment of Burns and Scalds. — 1. Remove the corrosive agent. 2. Neutralize the caustic agent. 3. Linimentum calcis, liquid petrolatum or other emollient, to exclude air or irritants. 4. Special treatment. 5. Symptomatic treatment. Experiment III. — ^Apply 5 per cent, phenol to the skin until it is white. Immediately transfer to alcohol or glycerin. Explain the whitening and the antidotal effect. Phenol is much more soluble in alcohol and glycerin than it is in protoplasm. It is not advisable to dip the finger into phenol. If by any chance the antidote is not effective, the removal of the skin from the entire circumference of the finger or limb, no matter how small, may be a serious affair. LOCAL IRRITANTS 67 Experiment IV. — Anesthetize a dog and introduce 50 c.c. of phenol or HgCl; or other corrosive into the stomach (Fig. 1 and 14). When the animal dies or is killed, make a complete postmortem. How would you treat a case of poisoning by phenol or corrosive sublimate? Any corrosivfe? It may be best to leave this experiment until the end of some experiment in which a dog is used, and as a final experi- ment administer one of these poisons. Fig. 14. — The cone method of anesthetizing a dog. The amount of ether and air may be regulated by the screw clamp and the glass tube in the ether bottle Experiments V. — Irritant Emetics. — With the exception of apo- morphin, all the commonly used emetics act chiefly by peripheral irritation. Give a dog 50 c.c. 1 per cent. CUSO4 by a stomach tube. (See Fig. 7.) ZnS04, ipecac, mustard, etc., act similarly. (See p]metics.) Experiments VI. — Irritants may be compared by placing them on a limited area of the skin and covering them with a capsule, beaker, etc., or with adhesi\'e plaster. Cut several pieces of adhesive plaster about one inch square. Place a drop or its equivalent of the following rubefacients on it and apply to the skin: 1. Croton oil. 2. Ceratum cantharides. 3. Oil of turpentine. 4. Ammonia. 5. Mustard plaster. 6. Oleoresin of capsicum. Kee[) these in place for from thirty minutes to two hours and compare the intensity of the action. Do not let them remain long enough to blister. If this happens, see treatment of burns and sr-alds. Experiments VII. — Remote action of rubefacients. Take the respiration, pulse-rate and blood-pressure of a student while in a 68 EXPERIMENTAL PHARMACOLOGY horizontal position. Remain in the position and apply a turpentine stupe to the abdomen. What is the effect on the heart, respiration, etc.? This may be repeated on different students with chloroform, ammonia, liniment, mustard plaster, etc. Keep a record of the time elapsing between the application and the result. Experiment VIII. — Count the heart-rate and respiration in a rabbit. Let it inhale ammonia, ether, etc., and record the action on the heart and respiration. Explain the nervous pathways involved in the effect. Experiment IX. — Paint some tincture of iodin on the skin and compare the sensation with the effect when it is applied on the mucous membrane inside the lip. Experiment X. — Place a drop or two of chloroform on the back of the hand. On the other place the same amount and cover it with a crucible or small beaker. What is the difference in the sensation? What harmful effects may result from covering an area tightly to which chloroform liniment or ammonia has been applied. Skin Irritants and Rubefacients. — Experiment XL — Mix a table- spoonful of mustard flour and four times its volume of wheat flour with a little water at 40° C. Spread this on a piece of cloth and place a piece of muslin over the mixture on the cloth. Apply to the skin over the stomach and cover with a cloth. Study the sensa- tion until the irritation becomes marked. Take the pulse and respiration-rate before and after the application. This is often used as a domestic remedy in cases of colic, etc. It is valuable as a remedial agent when properly used, but often causes burns which become infected and for this reason must be used with great care. Experiment XII. — ^Apply one drop of chloroform to the arm and cover with a watch-glass or with the mouth of a bottle. Linimentum chloroformi is used as a rubefacient. Experiment XIII. — ^Apply emplastrum cantharidis 2" x 2" to the skin as in Experiment II. Experiment XIV. — Snuff 1 grain of a mixture of saponin, in starch, 1000. Do not take more than 1 grain of the mixture. Experiment XV. — Give a cat 1 c.c. per kilo of saponin, 1 to 1000, by means of a stomach tube. Observe and record the results for an hour. Discuss the results obtained. Steps in the Actions of Irritants. — First: Tissue Injury to Some Degree. — It may be slight or severe. Second: Reaction of the Body to the Injury: 1. Capillaries and small vessels dilate, causing redness. CAUSTICS OR ESCHAROTICS 69 2. The vessels lose their tone and a filtration of serum into the region produces edema and swelHng. 3. The tension of the edema and swelUng, pressing on the nerves, causes pain. The nerves are also sensitized by toxins. 4. Leukocytes in the region may disintegrate, forming pus. 5. Each of the foregoing operates to cause change in function — emesis, lameness, etc., depending on the location of the injury. 6. If the disintegration of tissue is great enough, the products derange the heat regulating centers, and an increased temperature results. 7. If the disintegration of tissue be considerable, scars and cica- trices may result and any complication between restoration and exitus. CAUSTICS OR ESCHAROTICS. These are drugs which destroy the tissues to which they are applied. They are used: 1. To disinfect wounds, bites of animals, etc. — phenol, potassium permanganate, hydrogen peroxide, tincture of iodin, etc. 2. To remove warts, polypi, etc., HNO3, H2SO4, trichloracetic acid, AgNOs chromic acid, etc. 3. To remove hair-depilatories; sometimes used also in tumors, neuralgias, etc. The action is chemical or physicochemical." They precipitate, dissolve, or hydrolyze the proteins of the tissues. Experiment I. — To a solution of the white of an egg in water, add in a series of test-tubes, drop by drop, AgNOs, Fe2Cl6, HgCl2, Pb(C2H302)2,CH3.COOH,HCl,H2S04,NaOH,KOH. Note the con- dition of the precipitate, whether granular, slimy or flocculent. Add an excess of the reagent and note the results. Query: Which of the above, acid, alkali, or salt, would cause the deepest corrosion? Why? What influence would the acid radical have on the action to a corrosive salt? Why has a slight burn with an acid a shrivelled astringent appearance and feeling while that of an alkali has a slimy feeling? Experiment II. — Subject small pieces of muscle, skin, etc., to the action of these corrosives. Note the difference in appearances and feeling. Dip the fingers into 5 per cent, acetic acid, and compare with 5 per cent. NaOH. What is the antidote and treatment for poisoning by each of the above? (jive the symptoms of each and an explanation of the cause of each symptom. Experiment III. — Demondration. Select three dogs and give: 1 . 1 00 milligrams per kilo of mercuric chloride by stomach tube. 70 EXPERIMENTAL PHARMACOLOGY 2. 100 c.c. 10 per cent, nitric acid. 3. 100 c.c. 10 per cent, caustic soda solution. Compare the symptoms carefully and when animals seem in danger, apply the proper treatment. At the end of the period, kill the animals with chloroform and hold postmortem. Compare the gastro-intestinal tracts of the three. For the postmortem appear- ances, other animals may be used which are anesthetized throughout the experiment. Experiments of this kind may be done at the end of other experiments. Symptoms and Treatment of Caustic Poisoning. — Action on the Alimentary Canal. — The introduction of caustics into the mouth is either due to accident or suicidal intent. The symptoms are: Pain, nausea, vomiting, diarrhea, tenesmus, etc., anxiety, vertigo, delirium, convulsions and collapse. The heart and respiration may be stimulated at first, but soon become weakened and fade away. The symptoms are the same for almost all irritants or caustics. Variations are not pathognomonic. General Principles of Treatment. — 1. Neutralize and remove the caustic if possible. 2. Dilute, give water or milk, or other diluent in abundance. This is given for two reasons: {a) to dilute and therefore lessen the corrosive action, since the caustic effect is proportional to the con- centration; (6) dilution favors removal of the poison. 3. Wash out the stomach, using stomach-tube if it is thought the corrosive action has not gone far enough to make perforation of the alimentary tract with the stomach tube a probability. The use of demulcent preparations like diluted starch solutions, milk, etc., are pleasant to the corroded surfaces. 4. Give antidotes: Chemical or physiological as are indicated. 5. Sustain patient by symptomatic treatment — heat if necessary, or cold applications if desirable. Special treatment as indicated. CHAPTER III. PHARMACOLOGY OF THE G ASTRO-INTESTINAL TRACT. The local action of drugs on the intestine: (A) Specific Irritants of the Gastro-intestinnl Tract: These may be classified as: 1. Stomachics, or Bitters. 2. Carminatives. 3. Emetics. 4. Cathartics or Purgatives. (5) Gastro-intestinal Sedatives: Obstipants or Astringents. (C) Drugs Acting on Intestinal Flora and Fauna: 1. Anthelmintics. 2. Intestinal disinfectants. With these general disinfectants may be studied. BITTERS. These have nothing in common, except the bitter taste. As a group, they are characterized by their bitter or aromatic taste. Classification: 1. Simple. 2. Aromatic. 3. Astringent. 4. Compound. 1. Simple Bitters. — A bitter taste is all that characterizes these. They contain practically no tannin nor volatile oil. They can there- fore be used with iron preparations or salt solutions. They are miscible with water. Action of Iron on Tannin? Salts on Oilsf The Chief Simple Bitters are: Calumba. Quassia. Taraxacum. CJcntiana. (Jhirata. Xanthox\lnm. 72 PHARMACOLOGY OF GASTRO-INTESTINAL TRACT Weak preparations of nux vomica, quinin, strychnin, etc., may be used for the same purpose. 2. Aromatic Bitters. — ^These contain aromatic oils and bitter principles but no tannin. They can, therefore, be used with Fe preparations. Their alcoholic preparations cannot be mixed with water. Principal Aromatic Bitters: Calamus-sweet flag. Aurantii amarii cortex. Absinthe. Humulus. 3. Astringent Bitters. — Tannin is the prominent ingredient. Volatile oils may be present in small amounts. The preparations may he mixed with water. They are, however, incompatible with Fe. Principal Astringent Bitters: Cinchona. Serpentaria. Cimicifuga. 4. Compound Bitters. — These are blends of the other preparations. Blending improves them. In most cases, these should be given the preference. Whether or not they may be mixed with water depends on the choice of the mixture. Principal Compound Bitters: 1. Tinctura gentianse composita, U. S. P. This contains no tannin, but the coloring matter darkens with iron. 2. Tinctura cinchonae composita, U. S. P. 3. Elixir gentianse, N. F. Physiological action of the Simple Bitters: These are classified under the locally acting drugs. They are administered by mouth, and their only action is on the alimentary tract. However, some of their action may be psychic. One of the principal reasons for their administration is to increase the appetite and digestion. Digestion, however, has a large psychic element. Local Action. — Mouth. — All sensory nerves connect, directly or indirectly, with all motor nerves. Hence, smell, sight, thought of food, contact with food or drugs, movements of jaw may cause a flow of saliva. Taste reflex may cause a flow via gustatory nerve to the salivary center in the medulla, and via the chorda and sympathetic to the glands. Gastric Secretion. — 1. Bitters cause less immediate secretion on an empty stomach than does an equal volume of water. 2. Thirty minutes later, however, secretion is greatly increased. BITTERS 73 This increase diminishes and ceases after two hours. Hence, the reason for giving bitters half an hour before meals. 3. The peptic glands show histological evidence of activity. (Brekai.) 4. The leukocytes in the blood are increased by bitters in the stomach. Leukocytes very probably aid in absorption. 5. Bitters increase the gastric secretion before a Pavlov meal, and this taste reflex may explain the whole action of bitters. (Cushny.) 6. Gastric secretion is also influenced by events taking place at a distance, and by psychic events. In a boy, whose esophagus was closed by drinking lye, the sight and smell of food caused secretion of gastric juice. Sham feeding, sight, etc., have a great effect. Nerves Involved in the Secretion of Gastric Juice: 1. Cutting the splanchnics has no effect. 2. If the Vagus be cut secretion stops (atropin). 3. After allowing time — three or four days — for the constrictors to degenerate, stimulation of the cut end of the vagus, gives secre- tion — the vagus therefore is the secretory nerve. Hormones or chemical secretogogues also play a part. Therapeutic Uses of the Simple Bitters: 1. To increase the appetite and promote digestion. 2. In Convalescence. 3. In Dyspeptics. 4. In Neurasthenia. 5. Quassia as in infusion is given as an enema in cases of pin worms. Experiment I. — Compare the taste of each of the bitters mentioned above. Experiment II. — Mix tincture of ferric chloride with a member of each class of bitters. Experiment HI. — In a dog with a gastric fistula, take a tracing of the stomach contractions without anesthesia, and while the tracing is being taken place a few drops of a bitter in the animal's mouth. See Fig 15. Experiment IV. — In a dog with a Pavlov fistula, collect the normal .secretion f(;r thirty minutes. Now give 2 c.c. of tincture of gentian by mouth and again collect for thirty minutes. Experiment V. — For three successive days, each student should tak(; c.c. of tinctura gentianae composita, in a glass of water, thirty miimtes before each meal. A record of the general feeling and appetite should be kept. The three following days take 30 c.c. 74 PHARMACOLOGY OF G ASTRO-INTESTINAL TRACT syrupus sarsaparillse compositus in the same way and compare the effect produced by the bitter with that produced by the syrup. If groups of students are Kving together the two series may be run simultaneously. Fig. 15. — Method of recording stomach contractions. A water manometer is used. The float is made of a phenolsulphonephthalein ampoule and the tube to the stomach ends in a soft -rubber thimble of very light rubber. The side tube with screw clamp permits a sUght amount of pressure to be introduced. CARMINATIVES. These are the agents which aid or stimulate the expulsion of gas from the gastro-intestinal tract. They thus prevent flatulency or the distention of the stomach or intestines with gas. The active ingredient is usually a volatile oil or resinous principle. Other carminative bodies are ether, chloroform, ammonia, carbon dioxide, etc. Carminatives have the following properties: 1. Antiseptic and anodyne, e. g., oils of eucalyptus, cloves and cinnamon, are used in tooth cavities in cases of toothache. 2. They are general protoplasmic irritants, so that when rubbed on the skin they are rubefacients. Volatile Oils. — Main actions of volatile oils: 1. Mildly antiseptic — characteristic of benzene derivatives. 2. Irritant and rubifacient. ■3. Carminative and anodvne. CARMINATIVES 75 They are used mainly as : 1. Carminatives. 2. Flavoring agents. 3. Genito-urinary antiseptics. Experiment I. — Examine and taste various specimens. This will best be accomplished by saturating water with the oils and then by tasting the water. Use any volatile oil. Experiment n. — Place a drop of a fixed oil and a drop of a volatile oil on white sized paper, dry at 40° C. and compare. Experiment in. — Heat a drop of a fixed oil in a test-tube with KHSO4 over a free flame. (Compare odor with a volatile oil treated in the same way.) Experiment IV. — Swallow a drop or two of any volatile oil on sugar. What is the feeling? Experiment V. — Volatile oils are excreted in the urine, to which they often impart definite odors. They are also excreted by the lungs. When drugs are taken by the stomach it is difficult to tell whether or not they are excreted by the lungs because the odor may come up by way of the esophagus. To show that they may be excreted by the lungs, anesthetize a dog and take blood-pressure tracings. Insert a cannula into the trachea and inject 1 c.c. of any volatile oil into the femoral vein. (Note the odor of the exhalation in the tracheal cannula.) Connect the tracheal cannula with a bottle of water and see if enough oil is exhaled to impart an odor to the water. Does this eliminate excretion through the esophagus? Experiment VI. — Large doses of any volatile oil may cause con- vulsions. Absinthe acts decidedly on the nervous system after the prolonged use of small doses. Stearoptenes also act as the volatile oils. Administer 10 c.c. per kilo of 20 per cent, camphor in oil, by means of a stomach tube, to a rabbit or inject one-half this amount intraperitoneally. Note the peculiar "bucking" type of the spasm. Experiment VII. — Each student can test at least two of the follow- ing by rubbing some of the drug on the forearm: Oil of turpentine, oil of peppermint, menthol, 2 per cent., dissolved in alcohol, chloro- form, ether, or spiritus ammonise aromaticus. Now, instead of rubbing, j;lace a few drops on the skin and cover tightly with a capsule, crucible or other device to exclude the air. Experiment VIII. — Anesthetize a rabbit, cat or small dog. Take respiration and blood-j^ressure tracings. Inject 20 c.c. i)er kilo of 20 fjer cent, camphor in oil into the peritoneum. Keep the anes- thesia uniform and note the action on the heart and respiration. 76 PHARMACOLOGY OF G ASTRO-INTESTINAL TRACT Experiment IX. — Compare the action of camphor (Experiment VIII) with, the following: Inject hypodermically 1 c.c. per kilo of 0.1 per cent, solution of veratrin. Repeat in twenty minutes if necessary. Experiment X. — Fill six fermentation tubes with 5 per cent, dextrose solution containing yeast. Keep one for a control and to the others add 1, 2, 3, 5 and 10 drops of oil of turpentine. Shake and place in an incubator at 40° C. and note changes every 15 minutes for 3 hours. Experiment XI. — Repeat experiment X, using oil of cloves, 10 per cent, thymol in alcohol, chloroform, oil of peppermint, oil of cinnamon. Experiment XII. — Fill a series of small bottles with urine. Keep one as a control and treat the others with the above volatile oils (1 c.c. volatile oil to 100 c.c. of urine). Set in a warm place and note the odor twenty-four and forty-eight hours later. Experiment XIII. — Separate students may take 1 or 2 drops of one or more of the following drugs on a lump of sugar : Oil of turpentine, oil of peppermint, 2 per cent, menthol dissolved in alcohol; ether, 1 c.c; chloroform, | c.c, spiritus ammonise aromaticus, 2 c.c. in water. Is there any action on heart-rate or respiration? Have they a carminative action? Experiment XIV. — Take 0.3 c.c. eucalyptol, 0.3 gram menthol, 30 c.c. light liquid petrolatum and mix. Use as a spray for the nose. (Results?) Experiment XV. — Test the solubility of volatile oils in alcohol, ether, chloroform and fixed oils. Compare and discuss volatile oils and fixed oils from the point of view of: 1. Their chemistry. 2. Their physical properties. 3. Their economic uses. 4. Their therapeutic uses and 5. Their fate in the body. The following are the main therapeutic uses of volatile oils and other carminatives arranged from Bastedo {Pharmacology and Therapeutics) . 1. As anticolics (in intestinal and uterine cramps): Anise, peppermint, dill water, distilled liquor, essence of ginger, spirit of peppermint, aromatic spirit of ammonia, and Hoffmann's anodyne. 2. As odors and flavors: Anise, bitter almond, caraway, cinnamon coriander, fennel, lavender flowers, lemon, nutmeg, orange peel, peppermint, spearmint, rose and vanilla. EMETICS 77 3. As correctives of irritant cathartics: Oils of anise, caraway, cloves, coriander, fennel and peppermint. 4. For t^inpanites (as in typhoid fever, pneumonia or following operations): By mouth, oil of turpentine or asafetida, in pill or tincture; by rectum, oil of turpentine, tincture of asafetida, added to a soapsuds enema. 5. As anthelmintics: Oil of chenopodium for round- and hook- worms; th\Tnol for hookworms. 6. As stimulants to mucous membranes of nose and throat: Eucal\'ptol, camphor and menthol, about 1 per cent, of each mixed, with light liquid petrolatum, and used as a spray. 7. As antiseptics and anodynes: Oil of cloves or oil of cinnamon, in a decayed tooth, a drop on cotton. 8. As counterirritants : Camphor, capsicum and menthol, and the oils of mustard and turpentine. 9. As stimulants in chronic skin diseases, such as eczema, psoriasis, etc. : The oils of cade and tar in the form of an ointment. 10. As stimulants to the growth of hair: Oil of mace. 11. As antirheumatics: Methyl salicylate in the form of oil of birch or wintergreen. Also used externally as a liniment. 12. As antihysterics : Asafetida, camphor, musk, sumbul and valerian. 13. As anti-asthmatics: Powdered cubebs smoked in cigarette form. 14. As bronchial stimulants: Creosote, oil of turpentine, tere- bene, sjTup of tar. 15. As diuretics: Spirit of juniper; fluidextract of buchu and uva ursi. EMETICS. Experiment I. — Give a dog 1 c.c. per kilo of 0.1 per cent, solution of apomorphin hydrochloride by stomach tube. Repeat every ten minutes until emesis occurs. Record the amount and the time required to produce vomiting. Experiment II. — Give the same amount as in Experiment I sub- cutanecnisly and record as in P^xperiment I. Experiment III. — Inject one-half of the amount into the femoral vein without an anesthetic; compare Experiments I, II and III and also the following. Experiment IV. — Give a dog 50 c.c. 1 per cent. CuvS04 by stomach tulxj. X(jtc that there is little nausea or depression. CJ. Experi- ments I, II and III. 78 PHARMACOLOGY OF GASTRO-INTESTINAL TRACT Experiment V. — Using another dog compare the effect of the same strength and amount of ZnS04, 50 c.c. 1 per cent. Experiment VI. — Tartar emetic; give a dog in the same way 5 c.c. per kilo 0.1 per cent, tartar emetic. Compare nausea and depression with that produced in the preceding experiments. Experiment VIL- — Ipecac; give by stomach tube 0.25 c.c. of the fluidextract per kilo- body weight in 50 c.c. water. Experiment VIII. — Anesthetize a dog with chloroform or ether and give twice the amount of apomorphin as in Experiment I. After fifteen minutes remove the anesthetic. Record results. Experiment IX. — Give a dog a hypodermic of 2 c.c. of 3 per cent, morphin. Repeat dose in fifteen minutes. After thirty minutes repeat Experiment I. Experiment X. — Many other substances cause vomiting when injected intravenously in the unanesthetized dog, while they may be without effect on the anesthetized animal. The following will cause vomiting. (a) 5 c.c. of 5 per cent, peptone solution. (b) 1 mg. per kilo body weight of digitoxin. (c) 100 mg. per kilo of digitalis. According to Hatcher, this acts on the vomiting center because it will cause vomiting in the eviscerated animal. What are the proofs that apomorphin acts direcdy on the vomiting center? (6) Give proofs that CuS04 acts peripherally. PURGATIVES OR CATHARTICS. Purgatives are drugs which cause or hasten evacuation of the contents of the bowel. Classification of Cathartics: 1. Chemical. 2. Therapeutic. Chemical: Inorganic : 1. Salines, sulphates, phosphates, citrates. 2. Sulphur. 3. Mercurials. Organic : 1. Purgative oils, castor and croton. 2. Anthracene derivatives. 3. Resinous anhydride or jalap group. 4. Phenolphthalein. PURGATIVES OR CATHARTICS 79 5. Colloid and emollient laxatives. Agar-agar. Liquid petroleum. Manna. Fruits, etc. Study the mechanism of the action. Is the site of action on the small gut, the large gut or on the entire tract? Therapeutic Classification : 1. Aperients. 2. Laxatives. 3. Eccoproctics. 4. Cathartics. 5. Purgatives. 6. Cholagogues. 7. Hydrogogues. 8. Drastics. Discuss the advantages and limitations of each classification; also discuss the mechanism of the action, the origin of the fluid, the difference between colic and inflammation of the gut, and the uses and abuses of cathartics. Besides the use of drugs, non-phar- macal measures may be used to restore adequate or normal bowel movements. The cathartics should be used only when necessary, since the aim should be to use drugs temporarily. Non-pharmacal Measures: \. Habit formation of the evacuation of the bowel reflexes by a regular time for stool, persistently carried out. 2. An immediate response to the desire to defecate since, if this is not obeyed constipation habits are forced on the gut. 3. Exercise is of the greatest value in developing and sustaining the tone of the muscles and nerves and keeping them in a responsive condition, through better circulation. 4. Massage of the intestines, either normal or with the aid of a ball or roller, working in the direction of the bowel movements. This, however, cannot replace exercise but may act as an adjuvant to exercise. 5. Diet properly selected, to give a large residue, such as vege- tables, whole wheat, oatmeal and other cellulose containing foods. The bowel needs a certain amount of "roughage," since it must have exercise as any other organ. Demonstration of the influence of concentration on the action of a i)urgative. 80 PHARMACOLOGY OF GASTRO-INTESTINAL TRACT Experiment I. — 1. Keep two dogs without food or water for twenty-four hours. 2. Then administer to one 3 c.c. of 35 per cent, sodium sulphate per kilo body weight and place in a cage for observation. 3. To the other give 25 c.c. of water per kilo of body weight. After an hour give 3 c.c. of 35 per cent, sodium sulphate per kilo and in addition 200 c.c. of water. (Compare the cathartic action of the salt in this dilute form with that of Dog 1, in which the concentrated solution was used.) Experiment 11.^ — Action of Cathartics on Man. -Cathartics are perhaps the most important and most used group of drugs. For this reason during the course each student should take one of the following cathartics each week, until all have been taken and keep record of the color, consistence, size and number of stools, griping, etc. Valuable information regarding the action of cathartics can be obtained in this way that can be obtained in no other way. (a) Pilulse aloes, 2 pills. (6) Calomel, 0.06 gram and repeat in two hours. (c) Aromatic fluidextract cascara sagrada, 4 c.c. (d) Epsom salts, 20 gm. in a glass of water followed at once by another glass of water only. (e) Castor oil, 15 to 25 c.c. (/) Petrolatum liquidum, 30 c.c. (g) Phenolphthaleinum, 0.2 gm. (h) Resinapadophyllum, 0.01. (i) Syrupus sennse, 8 c.c. (j) Jalap, 1 gm. For comparison all of these had best be taken in the evening or at bedtime. Experiment in. — Moreau Loop Experiment. — Use physiological salt solution in the middle loop and any of the other cathartic solutions in the other two. Make at least three loops as follows: Anesthetize a dog with ether. Expose the intestines by an incision along the linea alba. Handle with extreme care and keep them warm, so that absorption is as nearly normal as possible. Isolate along loop of the small intestine as near the large intestine as pos- sible. Ligate this at the upper end and carefully squeeze the con- tents toward the large gut. Now divide the emptied small intestine into segments of exactly three or four inches in length. Each segment must be exactly the same length. Place 10 c.c. physio- logical saline in the middle loop. Do this without injuring the gut. Place the same amount of any of the other solutions mentioned below in the loops on each side of the saline loop. PLATE I. CATHARTICS. These diagrams are intended to show the different ways in which cathartics may act. It is not possible to classify strictly, as the action of some is too extensive to be limited to one group or illustrated by a single diagram. The numbers indicate the diagrams that represent what is believed to be the most prominent action in case of each drug, without intending to show the com- plete action in every instance. Group A. LAXATrVT:S. Fruits. (1) Sugar. Sulphur. Purges in small doses. Glycerin (by enema). (2) Group B. PURGES. Anthracenes. (1) Aloe. (1) Mercurials. (4) (5) Oleum Ricini. (.3) (4) Rliamnus Frangula. (1) Cascara Sagrada. (1) Rheum. (1) Magnesia. (3) Senna. (1) Group C. HYDKAGOGUES. Salines. Magnesii Citras. (3) Magnesii Sulphas. (3) Potassii Bitartras. (3) Potassii et Sodii Tarti-as. Sodii Phosphas. (3) Sodii Sulphas. (3) (3) Elaterinmn. (4) Jalapa. (4) Senna. (1) (4) Group D. DKASTICS. Colocynthis. (5) Oleum Tiglii. (5) Elaterinum. (3) (4) (5) Podophyllum. (5) Jalapa. (3) (4) Scammonium. (5) Cambogia. (5) Resins. (5) The red color shows the site of action, and indicates stimulation of motility or secretion. 3. Secretion stimulated. PLATE I. CATHAKTICS. The natural provision for intestinal evanmtion in- cludes three factors: Fineris)altic move- ment of the whole tract (5), causing ])rompt, frequent stools, with severe griping. Tn large dost-s they act as irritant j)oisons, and may cause contractions in the gravid uterus. Clioldi/iifjiies favor the flow of bile into tlie (hiodemnn, probably through the increased peristalsis. The in- fluence of cathartics upon the function of thi' liver seems uncertain and indirect. Tlie rod color shows Iho site of action, ami indicates sliiniilatiou of motility or secretion. OBSTIPANTS OR ASTRINGENTS 81 (a) 20 per cent, magnesium sulphate. (b) 20 per cent, sodium phosphate. (c) 10 c.c. castor oil containing two drops of croton oil, (d) Fluidextract of rhubarb. (e) Fluidextract of senna. (/) 10 per cent, solution of phenolphthalein. (g) Liquid paraffin. At the end of two hours carefully collect the fluid in the loops and measure it. Fig. 16.- -Moreau loop method of studying the absorption of liquids- cathartics— from the intestine. sspecially Compare Results. — If several groups are doing this experiment, water, sugar solutions, serum, etc., may be added to the list and the results of each group tabulated. \Vhile waiting for the two hours to pass, blood-pressure experi- ments, like epinephrin, may be carried out on these animals. Experiment IV. — All cathartic salts precipitate calcium. To a solution of calcium chloride, in a series of test-tubes, add a few drops of: (a) Magnesium sulphate. (6) Sodium phosphate. (c) .Sodium citrate. (d) Sodium and potassium tartrate. Calcium, therefore, has an anticathartic or obstipant action. Attempts have been made to find centrally acting cathartics, but so far no practical, centrally acting cathartic has been found. OBSTIPANTS OR ASTRINGENTS. Obstipants have the opposite action of cathartics and are used when the movements of the bowel are too frequent, or are painful 6 82 PHARMACOLOGY OF GASTRO-INTESTINAL TRACT because of griping. They are in the main locally acting drugs. They are classified as 1. Acids: Tannic acid and tannin, tannalbin, tannigen, etc. 2. Metallic Salts: Bismuth and cerium salts, lead acetate, alum, silver nitrate, ferric chloride, etc. 3. Bases or alkalies: Calcium hydroxide. 4. Alkaloids: Atropin, morphin. 5. Inert Powders: Charcoal, talcum, etc. Acids. — Tannin or tannic acid is the astringent principle of all plants. It acts: 1. By precipitating proteins within the gut and rendering it less irritable. 2. By direct action on the gut, causing a constriction and possible covering of the sensory nerves by a constriction of the surfaces over them. 3. By forming a mechanical coating or precipitate over the sur- face. In all cases they lessen the sensitivity of the gut or nerves, and leave the nerves less exposed to the action of irritating products in the gut. The chief vegetable astringents are: Acidum tannicum: dose, | to 1 gram. Tinctura gambir composita: dose, 2 to 4 c.c. Tinctura kino: dose, 2 to 4 c.c. Extractum krameriee : dose, 2 to 4 c.c. Metallic Salts. — Bismuth subnitrate or subcarbonate are most used. Their action is believed to be chiefly mechanical, acting as a dusting-powder to the intestine and so protecting it from irritation. There may also be some astringent and absorbent effect. These salts were formerly used by roentgenologists for the purpose of photographing the gastro-intestinal tract, but they have largely been supplanted by barium sulphate. Ferrous sulphate, tinctura ferri chloridi, have been used to some extent in diarrhea. Alum has also been used; also silver nitrate. All of these, however, are slightly irritating, and at the present time are used more as local styptics. Calcium Hydroxide. — Chiefly used in the form of liquor calcis, which contains 0.15 per cent. Ca(0H)2. Calcium acts as an obstipant by neutralizing the acid product in the intestine, by lessen- ing the excitability of .the sympathetic system, by a direct depress- ing effect on the muscle and by lessening of the permeability of the capillaries. In case of children, when lime water is mixed with the milk, clotting in the stomach is modified and the clots are smaller, PLATE lie MORPHINE. In form of sulphate, acetate, or HYDROCHLORIDE. Gr. ^-J (Gm. .008-.015). Classified as : Anodrne. Narcotic. Physiologic action ; The action of morphine is essen- tially that of a central nerve depressant, the L^cal action of the drug, wherever applied, being almost 7iil except on the gastro-intestinal tract. Children are very sensitive to this drug, and, if needed, it should be vsed in the weakest preparations, and in less than the proportioruil dose. Ifenmis System. Brain. I)ej)resses cerebrum, especially in its higher intellectual functions. Medulla. Depresses respiratory center. Spinal Cord. Stimulates spinal cord. Vagus Center Vaso Motor Center 'Cervical Sympathetta Nerves. The peripheral nerves are not aSected by ordinary doses. Mimcidar System. Not affected by ordinary doses. Cfirculudon. Not much influenced by ordinary doses. Heart. Opinions diflfer. Any in- fluence of a moderate dose must be slight and probably indirect. I.,arge doses slow the lieart by stimulating inhibition. Capillary area. Not mucli influenced, except that tlie cu- taneous area of the Jiead and neck may show dilatation. Respiration. Depressed to a dcgiee corresj)on
  • ( l'\iy»i CH I ? OCH3 is bitter. Again, the sweetness in an homologous series increases with the increase of hydroxyl groups, e. g., glycocol: CH2OH CH2OH is sweet, but not so sweet as glycerin : CH2OH CHOH CH2OH And glucose: CH3 (CH0H)4 CHO THE OPTIC NERVE 103 is still sweeter. That other factors than the OH groups enter into the production of a sweet taste is shown by the fact that lead acetate is sweet, yet contains no OH groups, and saccharin C6H4< SO2 CO >NH is three hundred times sweeter than sugar and contains no OH groups. It has been suggested that the stimulation of the taste buds is a physical process due to intramolecular vibrations, but we have no way of testing such a suggestion. Again in those aromatic bodies containing an OH group, the position of this in the ring and the relation to other groups is interesting, e. g.: OH /\ / \0H OH OH / \0H OH Pyrocatechol (bitter) NH2 \ . I 1 /COOH Ailthranilic acid (sweet) 'OH Resorcinol (sweet) r' \ ^OK Pyrogallol (bitter) SO: N NH CO^ Saccharin (very sweet) OH\ /OH \/ , Phloroglucinol (sweet) \ SO2 CO-' )NH NH2 (Very sweet) ./\ \ SO2 >NH \/ Br (First sweet, then bitter) \ CO' N02 (Very bitter) This shows that the arrangement of the molecule is of consider- able importance. This is further illustrated by the differences in the taste of optical isomers: dextro-asparagin is sweet while levo- asparagin is not, and dextroglutaminic acid is sweet whereas the levo acid is tasteless. In a recent study of the chemistry of taste, Oertly and Meyers^ ' Jour. Am. Chem. Sdc, 1919, xli, p. 855. 104 PHARMACOLOGY OF THE CRANIAL NERVES have worked out a theory relating to the ahphatic sweet stuffs. They think that taste is dependent on two factors — a glucophoric and an auxoglue. They define a glucophore as a group of atoms which has the power to form sweet compounds by uniting with a number of otherwise tasteless atoms or radicals. An auxoglue is defined as an atom or radical which combined with any of the glucophores yields a sweet compound. The following radicals are found to be glucophores in the sense of their theory: -CO-CHOH-(+H), CHjOH-CHOH-. CO2H.CHNH2-, CH2ONO2- '"Hlx ^Hs -X . y^H2-y — ^Hlx '"Hly Some others may very likely be included later on. The following atoms or radicals seem to act as auxoglucs, yielding with glucophores sweet compounds: (a) H, hydrogen. (6) The radicals CnH2n+l° of saturated hydrocarbons, contain- ing from one to three carbon atoms. Example, CH3CH2. (c) The radicals CnH2n+l° of monohydric alcohols, n being equal to one or two. Example, CH2OH. (d) The radicals CiiH2n— l°n of polyhydric alcohols. Example, CH2OHCHOH. Experiment. — Samples of the various drugs may be tested to determine the accuracy of the above statements. X. The Tenth Nerve: N. Vagus. — The vagus is a mixed nerve, with a wider distribution than any other nerve in the body. It sends sensory nerves to the mucous membranes of the larynx, trachea, lungs, esophagus, stomach, intestines, gall-bladder and ducts. It sends motor fibers to some small intrinsic striated muscles of the larynx and unstriated muscles of the heart, lungs and intestine. From the pharmacological standpoint these last are the most impor- tant, and from this point of view it is mainly an autonomic nerve and the most important of the autonomic nerves. The action of drugs on the vagus endings has been studied under autonomic drugs, atropin and pilocarpin, the glands, the heart and intestines. Nicotin first stimulates and then paralyzes the ganglia on the vagus. The vagus center is stimulated by strychnin, picrotoxin, digitalis, epinephrin, atropin, by asphyxia and high blood-pressure. The THE OPTIC NERVE 105 center is depressed by morphin, the alcohol-chloral groups, bromides, etc. See experiments under Heart, Autonomic Drugs, etc. XI. The Eleventh Nerve : N. Acessorius. — This is a motor nerve supplying the sternomastoid and trapezius muscles. XII. The Twelfth Nerve : N. Hypoglossus. — The twelfth nerve is a motor nerve supplying the muscles of the tongue, the extrinsic muscles of the lar\iix and hyoid bone. The pharmacology of these nerves is unimportant, and if involved could be influenced only in a manner similar to other voluntary nerves. The centers would be stimulated by strychnin, caffein, etc., and depressed by morphin and the alcohol-chloral group. CHAPTER VII. PHARMACOLOGY OF THE HEART AND BLOOD- PRESSURE. Factors concerned in the maintenance of blood-pressure: L The amount and the condition of the fluid in the circulatory system. The amount is about one-thirteenth of the body weight. 2. The viscosity of the blood, or rather its colloidal condition, has an important part to play. It is well known that injected saline will not sustain the pressure as well as 6 per cent, gum acacia or other colloidal solution. Even homogeneous blood beyond a defi- nite volume will not remain in the bloodvessels any length of time. Magnus found that 20 to 50 per cent, of the volume of such injections left the vessels and was expressed into the tissues within three to five minutes after the infusion. 3. The peripheral resistance — due to size of vessels and condi- tion of muscle tone. 4. The condition of the heart itself. A certain blood-pressure seems necessary for the life and func- tioning* of protoplasm. This is vividly manifested in the kidney which stops secreting when the pressure reaches 40 mm. of mercury. In experimental work the condition of the fluid, as to volume amount and to some extent its viscosity, can be varied at will and the effect studied. The peripheral resistance can also be modified mechanically and by the action of drugs. Drugs which increase the tone of the muscles either directly or indirectly will tend to increase blood-pressure. Drugs like nicotin, epinephrin and digitalis that constrict the vessels will raise the pressure, while nitrites, peptones, etc., that dilate the vessels will lower the pressure. The following drugs stimulate the heart either directly or through the nerves, and therefore tend to raise the blood-pressure : Caff e in. Strychnin. A tropin. Cocain. Nicotin. Epinephrin. Pituitrin. Ca, Ba, Pb, and other heavy metals. BLOOD-PRESSURE 107 Heart depressants, which directly or indirectly weaken the heart muscle, reduce the tone of the muscle and lower the blood-pressure: Aconite. The alcohol group. Nitrites. Study the mechanism of the action of these on the heart and vessels under these various drugs. s BLOOD-PRESSURE. The action of drugs on the blood-pressure is so important that the following summary of the main causes affecting the blood-pressure are given. Blood-pressure may be lowered by: I. Slow action of the heart. This may be due to: A. Stimulation of the vagus center, fibers, or endings in the heart. (a) Directly by the action of a drug. (6) Indirectly by increased blood-pressure. (c) Indirectly by increase in the carbon dioxide con- tent of the blood. (fZ) Reflexly by stimulation of any sensory nerve. II. Increased excitability of the vagus endings in the heart. (a) By drugs. (6) By toxins. (c) By changes in the function of ductless glands. (d) Indigestion, products of. III. Paralysis of sympathetic neurons — roots, fibers or endings. IV. Weakness of the heart muscle from any cause. B. Smallness of the amount of blood sent out at each systole; due to (a) Hemorrhage. (6) Shock. (c) Contraction or obstruction of pulmonary vessels. {d) Great dilation of the venous system. (e) Decompensated heart. C. Dilation of the small arteries. This would be difficult to disassociate from dilation of the capillaries. It would occur (a) By paralysis of the vasoconstrictor center. (h) By paralysis of the arterial walls. 108 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE Both of these may be due to the action of drugs or toxins directly, or reflexly through the depressor nerve, division of the cord or section of the splanchnics, ablation of the brain or great depression of the brain by opiates or narcotics. SUBCL. ART. R.VERT SYM. TH.ORAC. Fig. 20. — Diagram of last cervical and first thoracic ganglia in the dog. (After Foster.) Blood-pressure may be increased by: A. By quick action of the heart: (a) By paralysis of any part of the vagus mechanism. (6) Stimulation of the sympathetics. Either of these conditions may be caused directly by drugs. Atropin will paralyze the vagus. Epinephrin will stimulate the sympathetics. Nicotin will first stimulate, later paralyze all ganglion cells. B. (a) By the heart expelling a larger amount of blood at each beat, as after the administration of digitalis. (b) Hypertrophied heart. (c) Increased tone of the heart muscle. C. By contraction of the small arterioles and capillaries: (a) By irritation of the vasoconstrictor center. 1. Directly by drugs or toxins. 2. Indirectly by carbon dioxide accumulation in the blood. DIGITALOID DRUGS AND DIGITALIS 109 3. Reflexly through the cervical sympathetic. 4. Reflexly through other nerves, e. g., the vagus in non-anesthetized animals. 5. Reflexly through any sensory nerves. (6) Direct stimulation of the vascular walls. 1. By drugs. 2. In operations where the peripheral ends of vaso- constrictor nerves are stimulated. D. By conditions which increase the tone of the skeletal muscles. Fig. 21. — Suspension method of recording heart contractions. DIGITALOID DRUGS AND DIGITALIS. The main actions of the digitaloid drugs are: 1. A specific stimulating action on the heart which renders it more irritable, with a tendency to more rapid action. 2. Stimulation of the vagus center which tends to slow the heart. 3. Stimulation of the vasoconstrictor center. 4. Direct stimulation of the musculature of the vessels particu- larly strong in the splanchnic region, with a tendency to lessen the secretion of urine. 5. An irritant action on the stomach or wherever applied; this cau.scs vomiting when taken into the stomach in large quantities and pain when applied to mucous membrane. 110 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE 6. A direct stimulating action on the vomiting center. (Hatcher.) 7. A tonic action on the central nervous system. 8. A tonic action on endothelial and lymphatic tissues. 9. A marked diuretic action in cases of edema through changes in the circulation. Fig. 22. — Suspension method of recording heart tracings. Experiment I. — Action on the Frog or Turtle Heart: Isolate the vagus; take a tracing of the normal heart by the suspension method. Stimulate the vagus. Apply a few drops of an infusion of digitalis to the exposed heart. This may be repeated every five minutes until the heart stops in ventricular systole. Study the action of the vagus every ten minutes and record its effect at the different stages of digitalis action. Experiment II. — Prepare several turtle heart strips and take trac- ings in the usual way. When the strips beating are regularly place: 1. In a bath of 0.002 per cent, digitalis in saline. 2. In a bath of 0.005 per cent, digitalis in saline. 3. In a bath of 0.01 per cent, digitalis in saline. Compare results. Experiment III. — Place a cannula in the vena cava of a frog (Figs. 23 and 24), or turtle and perfuse with 0.001 per cent, digi- talis in Ringer's solution. What is the effect on the heart beat? Take tracing. Experiment IV, — Action of Digitalis on the Heart and Respiration of a Dog. — 1. Weigh animal and record pulse and respiration-rate, general appearance and condition. DIGATALOID DRUGS AND DIGITALIS 111 Cannula connected to aorta Capillar// catheter in median uhdominal vein Fkj. 23. — Frog-perfusion method, to study action of drugs on vessels. (Fuehner.) Fio. 24. — Fuehner apparatus arranged for perfusion. 112 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE 2. Inject slowly into the femoral vein 0.4 c.c. per kilogram of 1 per cent, infusion of digitalis without anesthesia. 3, Record observations as in 1 every five minutes. Experiment V. — Action of Digitalis on the Heart and Respiration. ■ — 1. Record weight, heart-rate and respiration of a dog. 2. Anesthetize in the usual way; isolate one vagus nerve; ligate cut and prepare peripheral and central ends for stimulation. 3. Arrange for blood-pressure and respiration tracings. 4. Take normal tracings and show the influence of vagus stimula- tion, central and peripheral. Also similar stimulation of the sciatic. 5. Slowly inject into the femoral vein 0.2 c.c. of 1 per cent, infusion of digitalis per kilogram. 6. Stimulate vagus and sciatic as in 4. 7. Repeat 5. 8. Stimulate vagus and sciatic as in 4. 9. Repeat 5 if thought advisable. Experiment VI. — Demonstration; Myocardiagram and Blood- pressure under Digitalis. — 1. Anesthetize a dog with ether. Prepare for blood-pressure and myocardiagraph tracings; superimpose the tracings. 2. Inject slowly 0.4 c.c. of 1 per cent, infusion of digitalis per kilogram of body weight into the femoral vein and take continuous tracing. In thirty minutes repeat the dose if necessary. Experiment VII. — Digitalis as a Diuretic— 1. Weigh and anes- thetize a dog. Prepare for blood-pressure tracing. Insert a catheter into the bladder and measure secretion of urine in drops for thirty minutes. 2. Inject 0.5 c.c. of 1 per cent, infusion of digitalis into the femoral vein every five minutes for four or five times or until the animal gets about, 0.4 c.c. per kilo. Note the effect on the urine for thirty minutes. 3. Inject 1 c.c. per kilo of 2 per cent, theobromin sodium salicylate and compare the urine secretion with that of digitalis for thirty minutes. Experiment VIII. — Standardization of Digitalis. Digitalis; Stro- phanthus; Squill. — For the physiological standardization of this series the "one-hour frog" method is recommended. The method consists in ascertaining the dose of the drug or preparation that will bring the heart of a frog weighing 15 to 25 grams to systolic stand- still in one hour. All measurements in the operation should be carried out with the same degree of accuracy used in quantitative chemical estimations. DIGATALOID DRUGS AND DIGITALIS 113 Frog: Use healthy specimens weighing between 15 and 25 grams. Storage: The animals should be kept in a cool room, preferably where the temperature does not rise above 15° C. The bottom of the tanks should be covered with running water, or, if this is not convenient, the water in the tank should be changed four times daily. An hour before the animals are used they should be kept in the laboratory in order to get acclimated to temperature. Weigh within 1 gram. Fig. 25. — Figures showing the lymph sacs of the frog as seen from the ventral surface. Lymph sacs as seen from the side. For pharmacological purposes these sacs need not be named, (.\fter Ecker.) Dosage: Never inject more than 0.015 c.c. for each gram of frog. A larger volume than this is injurious from the volume alone. No attention need be paid to the alcoholic content unless this is over 20 per cent, of the injected material. In such cases evaporate the alcohol on a water-bath and dilute or make up volume with 0.07 per cent, sodium chloride: if there is a cloudiness or a precipi- tate, shake the solution before injecting. Injections should be made through the floor of the mouth into the anterior lymph sac 8 114 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE with a hypodermic. Do not puncture the skin, because there may be a leakage. Since the dose of a standard preparation of digitalis tincture is 0.006 c.c. per gram weight of frog, the first trial should vary from 0.004 c.c. to 0.008 c.c. per gram. At the end of an hour the frogs should be pithed, both brain and cord, and the heart examined. For the correct end-reaction the ventricle is stopped in systole and the auricles dilated. If these are stimulated there may be feeble contraction, but no general contractions is allowed. After this preliminary trial one knows approximately what the standard dose is; for instance, it may be between 0.005 and 0.006 or between 0.006 and 0.007. Another trial, working with dilutions between these figures, will determine the dosage accurately. The U. S. P. adopts the following as standard doses: Gram or milliliter for each gram of body weight of frog. Standard dose of ouabain . 0000005 Digitalis: Leaves (in the form of tincture) 0.0006 Fluidextract 0.0006 Tincture 0.006 Strophanthus : Seed (in the form of tincture) 0.000006 Tincture 0.00006 Squill: Dried squill (in the form of tincture) 0.0006 Fluidextract 0.0006 Tincture 0.006 Experiment IX. — Hatcher's Cat Method of Standardizing Digitalis. — One milligram of crystallin ouabain or 100 mg. of digitalis per kilogram of body weight when introduced slowly intravenously will kill a cat in about an hour. Not less than an hour should elapse in the injection or the method is not advised. Hatcher recommends the following procedure: Anesthetize an animal with ether and place a cannula into the femoral vein for injection from a burette. The preparation to be injected is diluted with normal salt solution to such a strength that roughly 10 c.c. of the dilution per kilogram are required to cause death under the conditions of the experiment (1 c.c. of tincture plus 9 c.c. of normal saline). The injection is made slowly and con- tinuously into the femoral vein of the cat at such a rate that 1 per cent, of the fatal dose is injected in a minute of time until toxic symptoms develop, when the injection is interrupted for ten minutes. If death does not occur the injection is resumed at the same rate as before and continued until the symptoms show the approach of death. If preferred, about half of the fatal dose may be injected within a period of fifteen minutes, after which the injection is inter- rupted for ten minutes and then continued at the rate of about 1 STANDARDIZATION OF SUPRARENAL GLAND 115 per cent, of the estimated fatal dose per minute until the appearance of toxic symptoms, when the injection is interrupted, as already mentioned. Experiment X. — TJie Gold Fish Method of PiUinger and Van der Kleed. — Demonstration: Pittinger and Van der Kleed^ have advo- cated the use of gold fish instead of frogs as a method of standardiza- tion of digitalis. The method has never been completely developed. The advantages claimed were simplicity and cheapness, but the latter does not hold now. The size of the fish is unimportant because the absorbing surface of the gills corresponds in all sizes. The fol- lowing protocol taken at 27.5° C. will illustrate the method. The best temperature to employ still remains to be determined. In the following experiment eight fish were placed in beakers, each contain- ing the same strength of solution in order to determine the individual variation in susceptibility to digitalis. Time required to Dilution of Weight of fish, cause death, fluidextract. grams. Temperature. Minutes 1 to 1000 34.1 27.5° 58 1 to 1000 27.9 27.5° 52 1 to 1000 5.5 27.5° 59 1 to 1000 5.0 27.5° 47 1 to 1000 2.3 27.5° 54 1 to 1000 3.1 27.5° 55 Experiment XL — Students should divide in groups and group: 1. Take 1 c.c. tincture of digitalis every four hours for six times. 2. Take 2 c.c. tincture of digitalis every four hours for six times. 3. Take 3 c.c. tiiicture of digitalis every four hours for three times. 4. Take 4 c.c. tincture of digitalis in one dose. Record pulse, respiration and general condition for forty-eight hours. STANDARDIZATION OF SUPRARENAL GLAND. This method depends on the experimental findings that 1 gram of dried suprarenal gland will raise the blood-pressure of a dog to the same degree as 10 mg. of levo-methyl-amino-ethanol-catechol. Standard Solution. — 1. Prepare an aqueous solution of levo- methyl-amino-ethanol-catechol (1 to 1000), using enough dilute hydrochloric acid to get a clear solution. From this solution prepare a solution of 1 to 100,000 by diluting 1 c.c. up to 100 with 0.9 per cent, sodium chloride. 2. Weigh out 1 gram of finely divided j)owder of suprarenal gland. Macerate twenty-four hours in 100 c.c. of distilled water, containing ' Jour. Am. Pharni. A.smii., I!il5, p. 427. 116 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE 10 c.c. dilute hydrochloric acid (10 per cent.), shaking frequently. Filter through a dry filter. Dogs. — Use a medium-size animal. Anesthetize with ether. Insert cannula in carotid for blood-pressure estimation. Insert cannulse in each femoral vein and connect with a burette with a rubber, so that injections may be made. Injections should be made with glass syringes graduated to 0.05 c.c. The animal should be kept deeply anesthetized, and if there is any twitching sufficient curare should be injected to prevent this. Usually this is not needed. Take blood-pressure on a long kymograph. Inject 1 c.c. of the standard solution and wash in with saline. Note the height of the pressure. After five minutes inject 1 c.c. of the gland or solution to be tested. Wait five minutes between each injection and change the dose of one or the other solutions until the blood-pressure rise is the same. In this way the strength of the unknown, in terms of the standard, may be ascertained. ACONITIN. The active principle of aconite is aconitin. Aconitin is an alkaloid, peculiar from the fact that it stimulates sensory nerve-endings — those of common sensation, even when it is given systemically. The only other drug that does this is veratrin. It has a similar action if applied locally. The maiji actions of aconitin are: 1 . A prickling, tingling sensation due to an action on the terminal sensory nerves. Large doses may cause paralysis of these endings. 2. Depression of the heart due to central vagus stimulation — maybe followed by paralysis. 3. Stimulation and paralysis of all medullary centers. 4. A complicated action on the heart. (a) There may be acceleration due to nausea and to gastric irritation. (6) Slowing due to stimulation of the vagus center. (c) Quicker heart from direct action, and fatigue of vagus centers. (d) Irregularities from poisoning of the heart muscle, which may pass into fibrillation. (e) In the frog's heart, aconitin when applied directly may cause (1) slowing, (2) quickening, (3) slowing, (4) quickening. 1. Due to vagus stimulation of vagus-endings. 2. Due to muscular stimulation. 3. Incoordination leading to paralysis. 4. Complete incoordination passing into fibrillation or peristalsis. ACONITIN 117 This peristalsis is characteristic. (/) Aconitin is a general protoplasmic poison, but it will kill from a central action before this is seen. Experiment I. — (a) Inject 0.5 c.c. of 0.1 per cent, aconitin into the lymph sac of a frog (Fig. 25). Compare this with another frog: (b) Into which 0.5 c.c. of 5 per cent, infusion of digitalis is injected in the same way. VOLUNTARY MOVEMENT LOST UNABLE TO RECOVER POSITION WHEN LAID ON ITS BACK SCIATIC NERVE Fig. 26. — To show location of different parts of the brain and effects of their ablation, also the location of the sciatic nerve and the gastrocnemius muscle. (Modi- fied from Dixon.) Experiment H. — Pith a frog and take heart tracings by the sus- pension method. Inject 1 c.c. of 0.1 per cent, aconitin into the anterior lymph sac and take continuous tracings until the heart is paralyzed. Experiment m. — Take a continuous tracing of the blood-pressure and respiration of a dog. Give an intravenous injection of 0.5 c.c. of 0.1 per cent, aconitin every ten minutes until the animal dies. Keep a cfjinj^lete record of the symptoms. Experiment IV. — Count respiration and heart-rate of a dog. Give 1 c.c. of 0.1 i>er cent, aconitin intravenously without anesthesia and record result on heart-rate, resi)iration and general condition. 118 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE Experiment V. — Squibb's Test for Aconitin. — Dilute tincture of aconitin 1 to 70. Hold 4 c.c. of this in the anterior of the mouth for one minute and discharge it. A distinct tingling will be apparent in from ten to fifteen minutes. Note that the aconitin group of drugs is the only one which, when taken systemically, has a selective action on the sensory nerves. Experiment VI. — The Bio-assay of Aconitin. — Method, U. S. P., ix, p. 606. The method of the physiological assay of aconitin con- sists in determining the minimum lethal dose for guinea-pigs. Method. — Select guinea-pigs, 250 to 350 grams weight, in a healthy condition. Drug. — The tincture, extract or fluidextract may be used. Administration. — The drug is administered hypodermically. If the extract is used it must be prepared in a liquid form suitable for injection. After injection the animals are placed in cages and in twelve hours note is taken of those living and dead. Standard. — The standard fatal dose is as follows: Fluidextract 0.00004 c.c. per kilo of body weight. Tincture 0.0004 c.c. " " Extract 0.00001 gm. " " In making the test a series of animals is used, varying the dose on each side of the standard dose until the dose of the preparation to be determined is ascertained. THE NITRITES. The important action of the nitrites is on the circulation. Experiment I. — Action of Nitrites on the Circulation and Respira- tion. — (a) Anesthetize an animal and prepare for blood-pressure and respiratory tracings. Place a cannula in the femoral vein for intravenous injections. Isolate the vagus, stimulate and take tracing. (fe) While taking normal tracings let the animal inhale a little amyl nitrite through the trachea. Allow the pressure to become normal. Stimulate the vagus and let the animal again inhale amyl nitrite, and when pressure is at the lowest point again stimulate the vagus. (c) Inject 1 to 10,000 epinephrin; note the height to which the pressure rises, and when the pressure is high again stimulate the vagus. Study the activity of the vagus at high and low pressures. Continue the administration of amyl nitrite as in (6) and note whether or not it is as effective after several exhibitions. THE NITRITES 119 (d) Take a sample of blood and note the color— methemoglobin. Study with the spectroscope. (e) ^Mien amyl nitrite fails to cause a reduction of pressure, mject 1 c.c. of 1 to 10,000 epinephrin and compare the height to which the pressure rises with that of the injection under (c). Experiment II.— Prepare animal as in 1. In this experiment use nitroglycerin. (a) Take normal tracings. Inject 1 c.c. of 1 to 10,000 epinephrin; when the pressure is normal, inject 1 c.c. of 0.1 per cent, nitroglycerin intravenously. Isolate and stimulate the vagus. (6) Repeat injections of nitroglycerin until the effect is relatively small. It may be advisable to double the dose of the nitrite in the latter injections. (c) Examine the blood with spectroscope (see Figs. 55 and 56.) (d) Stimulate the vagus when pressure is at its lowest and com- pare with the initial effect. (e) \Mien the pressure falls but little on administration of the nitrites give 1 c.c. of 1 to 10,000 epinephrin and compare with the first effect. If epinephrin fails to act or is much weaker in its action, how is it to be explained? Experiment m.— Repeat Experiment II, using 0.1 per cent, sodium nitrite, giving 0.5 to 1 c.c. intravenous doses. Experiment IV.— Anesthetize a dog and prepare for records as in Experiment I. Take normal records. Give the animal 1 c.c. of 0.5 per cent, atropin. Repeat 1. After atropin, compare results with those in which atropin was not used. Experiment V.— Students may experiment on themselves as follows: (a) In sitting position with arm on the table, take the normal pulse record with a standard sphygmograph. (b) Break an amyl nitrite pearl in the handkerchief and inhale the fumes. (c) Take pulse tracings again, immediately, in five minutes and in ten minutes. Study the effects which follow the use of amyl nitrite. Experiment 71.— Action of Nitrites on /Vof/.?. —Inject into the lymph .sac of frog number: 1. 0.5 c.c. of 0.1 per cent, nitroglycerin. 2. 0.5 c.c. of 0.1 per cent, amyl nitrite. 3. 0.5 c.c. of 1.0 per cent, sodium nitrite. Record the eft'ects. Experiment Vn. — Injluence of Nitritefi on the Bloodvessels'. Per- fusif/n Experiments; Lewen-Trendelenhirg Method (Ings. 2.3 and 120 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE 24). Pith a frog or small turtle. Fix to board. Tie a fine cannula in the aorta for perfusion; insert a fine cannula in the large median abdominal vein. Perfuse with Ringer's solution through the aorta and count the drops from the vein. If it is diffi- cult to get a cannula in this vein, so that you fail, cut the vein and elevate the animal and the drops may be counted without the Fig. 27. — Arrangement of apparatus for recording contractions of turtle heart strip. The same arrangement will do for uterine strips if temperature and aeration are controlled. Fig. 28. — Plethysmograph for the study of changes in volume of the arm. cannula. "When the normal is obtained, add to the Ringer solution enough sodium nitrite solution to make 0.01 per cent, sodium nitrite and measure the change in the rate of flow either in drops per minute or in volume. Experiment Vm. — ^Action of sodium nitrite on the contracting ventricular strip may be demonstrated as follows: Set up a strip PLATE IV Danger area 3. Hespiratlon paralyzed 4, Circulation pai'ali/zed Anesthesia area 1. Consciousness abolished 2. Jteflex activity abolished The several sections are numbered iu the order in which they are paralyzed by anes- thetics. The paralysis of 1 and 2 constitutes surgical anesthesia, paralysis of 3 introduces an element of great danger, and that of 4 is usually fatal. [The heart is included iu this diagram of the .several parts of the central nervous sys- tem, for the reason that it contains nerve- ganglia, which, with their highly i.-ritable muscular structure, provides for its auto- matic, rhythmic action. This provision is unite independent of the cerebrospinal sys- tem.] ACTION OF THE ALCOHOL CHLORAL GROUP 121 and take a normal tracing. When the strip beats rhythmically add 0.02 per cent, sodium nitrite (Fig. 27). What is the proof that nitrites act on the vessel wall directly? Compare the action of epinephrin, ergot, nitrites and barium on the bloodvessels. Experiment IX.— Take a normal tracing with the arm in a ple- thysmograph (Fig. 28). After five minutes break and inhale a three- or five-minim ampoule of amyl nitrite and again record for five minutes. THE ACTION OF THE ALCOHOL CHLORAL GROUP ON THE PUPIL, HEART AND REFLEXES. On two series of frogs, perform the following experiments, noting especially the condition of the reflexes, the size of the pupil and the condition of the heart at the end of the experiment. One group of students will work with one series of frogs and the second group with the second series, taking care to select specimens for both groups of about the same size. Injections will be made in the anterior lymph sac. The dose will be varied as follows: Frog No 1 . 2 . .3 . 4 . 5 . 6 . Group I. 1.00 c.c. (25 percent.) 0.10 c.c. 0.50 c.c. 0.25 c.c. 0.50 c.c. (10 per cent.) 0.50 c.c. saturated water solution 1 . 00 c.c. (2 per cent.) 1.00 c.c. (4 per cent.) Control Group II. 2.00 c.c. (25 per cent.) 0.30 c.c. 1.00 c.c. 0.75 c.c. 2.00 c.c. (10 percent.) 2 . 00 c.c. saturated water solution 2.00 c.c. (2 percent.) 2.00 c.c. (4 per cent.) Pith brain and cord. Drug. Alcohol. Chloroform. Ether. Paraldehyde. Ure thane. Chloreton. Chloral. Morphin. At the end of one hour pith all the animals, expose the heart by a small incision and make record tracings of each on the same drum for comparison. State the condition of the heart, pupils and reflexes. Reflex Time as Changed by Alcohol.— 1. What is the function of reflexes? 2. Their importance in every-day life? 3. The modification of reflexes by the alcohol group of drugs? 4. TIow arc reflexes tested? Experiment I.— Turck's method of determining reflex time (see Fig. 13.) Pith a frog waiting twenty minutes for recovery from shock and suspend it })y the head with a clamp. With a small beaker contain- ing 0.5 per cent. IK'l or II2SO4 immerse the toe or foot to a definite point. Note the time of withdrawal by a stop-wat(;h. Wash oft' 122 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE the acid with another beaker containing water. Repeat the process until five concordant results are obtained and take the average. Now take the frog from the position and inject 0.5 c.c. of 25 per cent, alcohol into the anterior lymph sac. In fifteen minutes repeat the determination of reflex time. Repeat the injection of alcohol and the determination of the reflex time until a definite change is obtained. Experiment II. — Crossed Reflex Time (Fig. 29). — In this experi- ment the possibUity of direct stimulation on axon reflexes is ruled out. The movement when obtained is decisively reflex. ^V~ Fig. 29. — Method of taking crossed reflex. Pith a frog as above. Wait fifteen minutes for recovery from shock. Suspend the animal by the head with a muscle clamp. Attach the toe of the foot to a muscle lever to write on a slowly moving drum. Arrange a signal magnet to write below the muscle curve. Insert thin wire electrodes from a secondary induction coil into the skin of the other leg and tie the foot so that this leg cannot move. Adjust the induction coil to produce a stimulus that will give a distinct cross reflex movement. Take the time of the ACTION OF THE ALCOHOL CHLORAL GROUP 123 movement with a stop-watch or from a time mark record on the drum. Get the average of five determinations. Have the time of these determinations sufficiently far apart to eUminate the prob- abihty of fatigue playing a role. When the normal is obtained inject alcohol 0.5 c.c. of 20 per cent, into the dorsal lymph sac and after ten minutes or more repeat the determination. Repeat injections of alcohol every thirty minutes until a definite change in the reflexes is obtained. These experiments may be repeated, using 3 to 5 drops of ether, 3 drops of chloroform, or 1 c.c. of 2 per cent, chloral hydrate. Fig. 30. — Arrangement of apparatus for recording reflex time. (After Jackson.) Experiment HI. — Effect of Alcohol on the Reaction oj the Student. — The following experiment, devised by Jackson, will show the change in the reaction time in human beings: 1. Reaction of sight as affectecf by alcohol. Arrange a signal magnet to write on a swiftly moving drum. Connect this magnet with a cell and in the circuit place two keys or switches. When either key is opened the circuit is broken and the result is indicated on the drum . Two students work this experiment. One, the operator, holds key B, while the other, the subject, whose reaction is to be tested, holds key A. The man at key A keeps his attention centered on the signal magnet, which is writing on the swiftly moving drum. The operator closes key B, which causes the writing-point of the signal magnet on the drum to fall. The subject opens key A as soon as he sees the fall of the writing- point. While the drum keeps running, B is opened by the operator and key A is closed by the subject at once. Key B is again closc.'d and A opened, etc., as rapidly as the sub- 124 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE ject perceives the movement of the needle caused by the opening or closing of B until from twenty to thirty records are made. The average time of the sight reaction is obtained as follows: An electric tuning-fork, vibrating from 50 to 100 times a second, is used to run a time tracing around the drum parallel to the reaction time record. A rule or pair of dividers is used to measure off the time for each reaction and an average for normal sight reaction is then calculated. The next step after determining the time for normal reaction is to determine the time for sight reaction after alcohol has been administered. Five to 10 c.c. of alcohol or whisky or brandy, well diluted in water, and sweetened to render the liquor more pala- table, are taken into the stomach by the subject. After fifteen minutes the same process as that described above is repeated and the results of the two tests compared, to show the effect of alcohol on the time reaction of sight. Ether and Chloroform Anesthesia.^ — The student should be able to explain the effect and the nervous mechanism in each case. The symptoms are conveniently divided into four stages: I. Preliminary or Stage of Disorganized Consciousness and Analgesia. — Struggling due to: 1. Irritant action on mucous membranes, and this causes: 2. Reflex effects : Coughing. Salivation and flow from respiratory mucous mem- brane. Respiratory inhibition and irregularity. Cardiac effects. 3. Disturbances of judgment. 4. Loss of memory and self-control. 5. Emotional tendencies. 6. Disturbances of special senses less acute; hissing and roaring sounds. 7. Analgesia. 8. Vertigo and ataxia. 9. Quickened pulse and rise of blood-pressure, probably asphyxial. 10. Increased respiration. 11. Dilated pupils. ^ As arranged by Dixon : Manual of Pharmacology. ACTION OF THE ALCOHOL CHLORAL GROUP 125 II. Xarcotic Stuge and Uncunsciousness: 1. Coughing, retching, vomiting. 2. Delirium, muttering to shouting. 3. Tonic and clonic muscular spasms. 4. Reflexes diminished but still present. 5. I nconsciousness. (i. Respiration irregular from struggling. 7. Pulse accelerated and pupil dilated, both from excite- ment. III. Surgical Anesthesia: 1. Muscular relaxation. 2. Loss of reflexes. 3. Breathing slower and regular snoring. 4. Decrease in respiratory exchange. 5. Fall of blood-pressure and temperature. Dilatation of skin vessels. Lessened movements. Heat center uncontrolled. 6. Smaller pupil does not react to light. IV. Stage Leading to Bulbar Paralysis — Toxic Stage: 1. Loss of bladder and rectal reflexes. 2. Paralysis of vasomotor center; fall of blood-pressure. 3. Paralysis of respiration center. 4. Pupils dilated. 5. Depression or paralysis of cardiac muscle. The action of alcohol, ether, chloroform and chloral differs mainly in the degree of action. In working with one of these, it is well, to compare the results of all. The chief actions are exerted on or manifested by: 1. The central nervous system. 2. Respiration. 3. Heart. 4. Muscular work. 5. Reflex time. (). Eye. 7, Local action. 8. Cieneral protoplasmic action. The uses of alcohol in medicine aside from solvent and preserva- tive purposes are: 1. Its local and irritant action. 2. Its action on the central nervous system. 3. Its value as a food. 126 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE Ether, chloroform and chloral are not oxidized in the body, hence their use in medicine depends on the jBrst two properties. (Cf. Alcohol.) Study the absorption, local action, fate and excretion of these drugs. In the action of all drugs, part of the action is objective, part subjective. In animal experimentation it is apparent that the objective side of the action is emphasized. The above table, slightly modified from Dixon, gives the symptoms of ether and chloroform anesthesia. Note the symptoms and the stages carefully, and study especially the explanations of these symptoms. Experiment I. — Action of Alcohol on a Normal Dog. — Before administering a drug, always note the weight, sex, appearance, heart-rate, character of pulse, eye, size of pupil and reflexes, condi- tion of muscles, temperature, etc., as outlined on sheet. With a stomach tube introduce 5 c.c. per kilogram of body weight of 50 per cent, alcohol. Make complete observations and records. Repeat observations and records every ten minutes for one hour. At the end of this time anesthetize the animal with ether or chloro- form. Note the symptoms closely and compare the symptoms of anesthesia in an animal drunk with alcohol, with the symptoms produced in the anesthetization of a normal dog. Experiment II. — In a second animal, for comparison with the first, make complete observations and records. Then give the animal 1 c.c. of 50 per cent, alcohol per kilogram of body weight. Note and record symptoms every two to five minutes. Compare with dog 1 and explain difi^erences. Experiment III. — Ether Anesthesia. — 1. Make and record com- plete observations, hold the animal in the usual way or tie him securely on an operating board quietly and gently so that no pain or excitement is caused. 2. Record observations again. 3. Place an etherizing cone in the usual way over the nose of the animal and drop ether on the cone at the rate of about 10 drops per second. Continue this rate until the animal is completely anes- thetized. Make complete observations and records every two minutes. See whether or not you can distinguish the stages of anesthesia as outlined by Dixon. If any of the symptoms cannot be observed, discuss and explain as far as possible. , Compare the action of ether with the action of alcohol. When the surgical anesthesia is complete, remove the ether and allow the animal to come out partially. When he reaches the excite- ACTION OF THE ALCOHOL CHLORAL GROUP 127 ment stage, again administer the ether as before. Continue to administer the anesthetic gradually, increasing the rate if necessary until the animal reaches the fourth stage and respiration is about five per minute. Make complete observations and records at this time. Remove the cone and untie the animal and allow him to recover, making complete records every five minutes during this period. After twenty-four hours make another set of records. Compare the symptoms of ether anesthesia with alcoholic intoxi- cation. Experiment IV. — Repeat Experiment III, using chloroform instead of ether. Experiment V. — Effect of Alcohol on Frogs. — 1. With a hypo- dermic syringe inject into the anterior lymph sac of a frog 2 c.c. of 50 per cent, alcohol. Place the animal under a battery jar or wire basket on a piece of moist cotton and make observations on the reflexes and pupils every five minutes for thirty minutes (Fig. 25.) 2. On a second frog repeat observations using 1 c.c. of alcohol. Place the animal in a cylinder filled with water and inverted in a vessel of water so that the cylinder contains no air. Compare and explain the behavior of this animal with that of a normal frog. 3. On a third animal use 0.5 c.c. alcohol. Note the condition of the reflexes and the size of the pupil. After the observations are complete, place the animals in a tank and observe at the end of twenty-four hours. Experiment VI. — Effect of Alcohol on Reflex Time. — Reaction Time. — Instruments needed; a kymograph, a muscle lever, a signal magnet, probe and scissors. Method: 1 . Pith brain and medulla of frog. Wait fifteen to twenty minutes to allow recovery from shock. 2. Adjust kymograph to run about 2 cm. per second. 3. Attach muscle lever and signal magnet about 3 cm. below it. 4. Insert electrodes from the secondary coil into the skin of the frog; adjust induction coil so as to produce minimal stimulus, given a crossed reflex in about two seconds. 5. Proceed to obtain crossed reflex time, taking average about of five. (a) Normal. (6) 0.5 c.c. of 20 per cent, alcohol into dorsal lymph sac. (c) After five to ten minutes' rest repeat (b) and 4. (d) After thirty minutes' rest repeat (h) " " (e) After sixty minutes' rest repeat (b) " " 128 PHARMACOLOGY OF HEART AND BLOOD-PRESSURE N. B. — Differentiate between direct response to stimulus and crossed reflex when both appear. Take tracings below one another. Between each tracing rest about two minutes, to avoid fatigue. In a second frog prepared in the same way, test the reflex time obtained by dipping the toe into 0.5 per cent. HCl or acetic acid. Dip the toe into the acid, the same amount each time, and note the time taken to withdraw the toe. The time can most conveniently be measured by a stop watch. Conclusion. — ^Record your results in table form. Questions. — 1. On what side of the reflex arc do these drugs act? 2. In what way may drugs effect response? 3. What is the significance of your results as applied to every- day life? 4. Explain the coughing under ether, the vertigo, salivation, dilated pupils, loss of reflexes, etc., throughout the four stages. Experiment VII. — Effect of Alcohol on the Heart of a Frog. — 1. Pith a frog both brain and cord. Expose the heart. Attach a writing lever to the heart by the suspension method. 2. Take a normal heart tracing. (Drum moving 1 cm. in ten seconds.) 3. Drop 5 per cent, alcohol on the heart in a steady stream and continue the tracing. If there is no action use 10 per cent, alcohol. 4. When the action is very pronounced, irrigate the heart with Ringer's solution. 5. On the same animal repeat experiment, using a saturated solution of ether in Ringer's solution. 6. On the same animal repeat experiment, using a saturated solu- tion of chloroform in Ringer's solution. 7. Add a solution of 1 to 1000 adrenalin to the heart when it is almost stopped. 8. Tabulate your results. Normal heart: (a) Rate. (b) Amplitude. Alcoholized heart: (a) Rate. (b) Amplitude. 9. From your experiment, can alcohol be used as a heart stimu- lant? If the results are not definite use weaker or stronger solutions of the alcohol. EFFECT OF GENERAL ANESTHETICS ON CIRCULATION 129 THE EFFECT OF GENERAL ANESTHETICS ON THE CIRCULA- TION, RESPIRATION AND TEMPERATURE. Outline of study of drugs on heart : I. Heart Rate, influence of drugs on, chronotropic influence; irritability of the muscle tissue, bathmotropic influence; conduc- tivity of the tissue, dromotropic; force and energy of contractions; inotropic influence manifested by the blood-pressure and the pulse- pressure. II. Vessels: Constriction; dilations. Record weight, character and rate of respiration and heart beat, rectal temperature, and general appearance of the dog or rabbit. 1. Induce surgical anesthesia with ether. Insert tracheal cannula and the cannula for the blood-pressure. Insert cannula in the femoral vein for injections. Record respiration and blood-pressure on a drum moving about 2 cm. in ten seconds. Get complete records for a period of ten minutes. Push the anesthetic gradually until the animal breathes about ten times per minute. Note carefully blood- pressure and the condition of the heart at this time and compare the influence of other anesthetics on the heart and blood-pressure when the respiration is slowed to the extent that it is in this case. 2. Remove the ether and connect the tracheal cannula with the nitrous oxide apparatus. Adjust this so that the mixture of nitrous oxide and air will produce anesthesia. Take records and continue for ten minutes. Remove the apparatus and take records as the animal is coming out. When this occurs, administer ether again until the blood-pressure and the respiration is constant. .3. Replace the ether by ethyl chloride. This can be done by spraying the ethyl chloride into a bottle connected with the tracheal cannula. Continue the ethyl chloride for ten minutes and take a complete set of tracings. Allow the animal to come out; take tracings during the recovery. Compare the time of recovery from ethyl chloride and nitrous oxide. 4. Administer ether again and push it gradually until the animal breathes about ten times per minute. Take tracings and records at this time. Allow the animal to come out; take records as before. Again administer ether until the respiration and blood- pressure are constant. F). Give chloroform by the drop method (see Fig. 2), increasing gradually until the animal breathes about ten times per mimite. Allow the animal to recover, ancripli('rul j^aralysis. If, however, curara is injected into the fourth ventricle of a dog, spasms resembling strychnin soon develop. 144 PARALYSIS OF MOTOR NERVE ENDINGS Demonstration. — Inject 1 c.c. of 1 per cent, curara into the fourth ventricle and note the effect on the animal for an hour or longer. When satisfied as to the central action, inject the same amount intravenously and watch the effect. Repeat the intravenous injec- tion if necessary. Experiment III. — ^To determine whether a motor" paralysis is central or peripheral, the sciatic nerve in a frog is exposed and stimulated electrically. If there is no response the paralysis is peripheral. If the muscle contracts the central seat of the paralysis is located by successive stimulation of the cord and medulla and cerebrum, or by ablation in the reverse direction, cerebrum, medulla and cord. A peripheral paralysis may be in the nerve trunk, the endings or the muscle fibers. No drug is known which has a selective action on the motor nerve trunk when applied systemically. The pos- sibility of this action may be excluded by the curara experiments described below. If the motor endings are paralyzed the muscle will contract if the electrodes are laid directly upon it. Claude Bernard'' s Experiment. — 1. Observe frog and note whether or not the reflexes are normal. 2. Pith the brain and prevent as little loss of blood as possible. The better the circulation the quicker the absorption. Expose the sciatic on one side in the thigh for half an inch. Pass a strong thread under the nerve and tie tightly around the limb, excluding the nerve. This should stop the circulation in the limb. Inject into one of the lymph sacs 0.5 c.c. of 1 per cent, curara in 0.75 per cent, salt solution. When the paralysis is complete, isolate both sciatics up to the vertebral column. Stimulate the anterior part of the animal with the electrodes and note results. Now lay both sciatics on the electrodes; stimulate. The muscles of the ligatured limb will contract. This proves that the nerve trunks are not paralyzed. Now stimulate the muscles of the poisoned leg directly. This proves whether the muscles are paralyzed or not. Where, then, must the action of curara be located? If the action were on the central nervous system what would be the results of the above stimulation ? Experiment IV. — Action of Curara on Muscle-nerve Preparation. — Lay a slide across a small evaporating dish containing the drug dis- solved in normal saline; the solution should not reach the slide. Make two muscle-nerve preparations; preserve the entire length of the sciatic nerve in a fresh frog. Lay the muscle of one prepara- tion on the slide, letting the nerve dip in the solution. Lay the nerve of the other preparation on the slide, letting the muscle lie CURARA 145 in the solution. Stimulation of the immersed nerve gives a con- traction in (Xo. 2) as does stimulation of the muscle directly. This proves the nerve fiber is not affected. Stimulation of the muscle in two gives contraction, therefore the muscle is not poisoned. Stimula- tion of the nerve of two gives no contraction, therefore the muscle is not affected nor is the nerve ; the toxic effect of the curara must be between the two or on the nerve endings. Compare this action with fatigue. The order of fatigue is nerve-cell, nerve-ending, muscle. Demonstration. — Drugs acting similarly to curara when injected into the lymph sac of frogs. 1. All quaternary ammonium bases. 2. Camphor, 0.1 gram in oil or saline. 3. Lobelin, 0.210 gram. 4. Coniin, 0.010 gram. 5. Magnesium sulphate, 1.5 c.c. of 50 per cent, solution. 6. Strychnin — paralytic doses. This does not kill frogs as rapidly as mammals. 7. Methyl strychnin. 8. Amyl quinin. 9. Phosphorus arsenic compounds corresponding to the quater- nary ammonium bases. Fio. 33.- -Method of injection into the femoral vein. The same method can be used to withdraw blood from the vein. Experiment V. — Curara on Non-anesthetized Animals. — Inject 1 c.c. of 1 per cent, curara into the femoral vein of a dog (Fig. 33.) Observe closely the progress of paralysis. If this dose is not suffi- cient inject more. When paralysis of the leg muscles is complete give artificial resi)iration if necessary. The animal may be saved in this way. Physostigmin, 4 to 5 mg. per kilo, has an antidotal effect. Stimulation of Motor Nerve Endings. — Choi in, guanadin and pliy.iostigrrnii stimulate motor-iuTvc endings and so facilitate the passage of impulses to the muscles. 10 146 PARALYSIS OF MOTOR NERVE ENDINGS Experiment VI. — Inject a dog hypodermically, or very slowly intra- venously, with 1 c.c. of 1 per cent, solution of curara and observe the animal for ten minutes. Repeat the injection until complete motor paralysis is apparent. If too much has not been given the animal will recover. Study the symptoms during recovery. In another animal treated in the same way, study the effect of the intravenous injection of 1 per cent, physostigmin in 0.5 c.c. doses. Experiment VII. — Anesthetize a dog. Introduce a tracheal cannula and take respiratory tracing. Take- the blood-pressure at the same time. Arrange for artificial respiration when needed. Inject into the femoral vein 0.5 c.c. per cent, curara solution. Repeat this occa- sionally until the respiratory muscles are paralyzed. When this happens use artificial respiration intratracheally. Now inject intra- venously a 1 per cent, solution of physostigmin 0.5 c.c. at a time. This will stimulate the nerve-endings. The animal soon regains the power of automatic respiration. If too much curara has been given the animal will not recover its power of respiration. Study the influence of the drug on the heart-rate, blood-pressure and respiration. Observe especially the time of cessation of heart and respiration. What are the factors involved in sustaining blood-pressure, and how are these modified by the use of curara? Note. — ^Nearly any drug in sufficient concentration will effect nerve fibers if applied directly to them. There is no drug known that shows a selective action for nerve fibers, and when drugs are administered systemically they will cause the death of an animal from an action on some other part before any significant action can be observed on the nerve fiber. Curara in larger doses may influence ganglion cells or other parts of the nervous system, but its main action is on the motor endings to striated muscle. Since the experiments above definitely locate the action of curara on the nerve-endings, and since physostigmin counteracts the action of the curara, its action is on the same point. (For the probable mechanism of this action, see Meyer and Gottlieb, Dixon, Cushny and Sollmann.) PLATE V. Vagus Center Vaso Motor Center Cervical Sympathetic COCAINE. The poisonous effects of Coca, or the secondary effects of a large dose, aie depressant, following quite definitely the lines of pre- vious stimulation. Nervous System. Brain. Cerebral functions are first stimulated, then de- pressed, frequently with pro- duction of narcosis or con- vulsions. Medulla. Depi-esses respira- tory center and probably vaso-motor center. Spinal cord. Depresses re- flex centers. Circulation. Arterial pressure is lessened. Heart. Depressed by direct action of the drug. Capillary area. Arterioles relaxed, probably through paralysis of vasomotor cen- ter. Eye is dilated. Acts as a nerve block. Respiration. Depresses the respi- ratory functions by lessening the irritability of the center in the nieduila. In genei'al, the depressant ac- tion is that of a general proto- plasmic poison, the commonest evidence of which is its paral- yzant influence upon nerve tissue when locally applied. The sen- sory nerves are more susceptil>le. For local analgesic purposes the alkaloid Cocaine is employed in from \ to 4 per cent, solutions. It acts ])y blocking the sensory The bliK^ color indicates the depressant eCTccts of a toxic impulses so that they never reach dose of (-'ocainc. the brain or pain area- CHAPTER XI. PHARMACOLOGY OF SENSORY NERVE ENDS. COCAIN. Only the aconitin group of drugs has an action on afferent nerve-ends (receptive surfaces) when given by mouth or intra- venously. The local anesthetic action of cocain is obtained only by the direct application of the drug. It is used in medicine princi- pally for its local action. If sufficient is given systemically the animal dies from a central action before the receptive surfaces are influenced. Experiment I.^ — Cut a piece of filter paper about 2 cm. square; dip it in 1 per cent, cocain solution and apply to the side of the tongue. In a few minutes compare the sensitivity of this point with that of the other side. Experiment II. — (a) Place 2 to 3 drops of 1 per cent, cocain hydro- chloride in the eye of a rabbit; in a few minutes test the corneal reflex and sensitivity of the eye and compare it with the normal. (6) After injection of cocain, note the size of the pupil and con- dition of the eyeball. Explain. Experiment HI. — Inject hypodermically into the leg of a dog 0.1 per cent, solution of cocain hydrochloride according to Shleich's method and determine whether you can operate in this part without causing pain. Experiment IV. — Repeat III, using prococain or other cocahi substitute. Experiment V. — Inject cocain, 0.5 c.c. of 0.5 per cent, cocain hydrochloride into the lymph sac of a frog and note results. ^ Experiment VI. — Count respiration and heart-rate in a dog. Note condition of the pupil; inject 5 c.c. of 0.5 per cent, cocain intravenously and in five minutes again take records. Experiment VII. — ^Take records of the frogs and turtle heart by the suspension method. Irrigate with O.OI per cent, cocain hydro- chlorifle in normal saline and note results in the tracing. Experiment VIII. — Prepare turtle heart strips and take tracings of the coiitnictiojis in 0.8 per cent. NaCl. Rej)]ace with saline con- taining 0.01 per cent, cocain solution. What is the result? 148 PHARMACOLOGY OF SENSORY NERVE ENDS Experiment K. — Ligate one leg of a frog as high up as possible. Inject 0.5 c.c. of 0.5 per cent, cocain into the dorsal lymph sac. In thirty minutes prepare the muscles of both legs for superimposed tracings, weighting both muscles to the same extent, about 50 grams, and stimulate the nerves by the same electrode. Take tracings on a slowly moving drum and note which muscle fatigues first (see Fig. 25.) Experiment X. — 1 . Effect of cocain on the circulation and respira- tion of a mammal; anesthetize a mammal with ether; insert tracheal cannula and prepare for respiratory and blood-pressure tracings. Inject 1 c.c. of 1 to 10,000 epinephrin. Repeat after five minutes. 2. Inject 5 c.c. of 0.5 per cent, cocain intravenously; note effect on the heart, respiration and eye. 3. In three minutes repeat the injection of epinephrin. Is there any difference in the height or character of the epinephrin curve? Experiment XI. — Spinal Anesthesia. — Without the use of an anesthetic inject 0.1 per cent, cocain or 1 per cent, prococain or any other cocain substitute into the membranes of the cord in the lumbar region of a dog. Use a thin needle. In five minutes test the sensitivity in the hind legs. What are the dangers of spinal anes- thesia? Can an animal walk if the feet are anesthetized ? Explain. Experiment Xn. — Action of Cocain on the Temperature. — ^Take the rectal temperature of a dog or rabbit. Inject 1 c.c. per kilo of 5 per cent, cocain intravenously in the dog or 2 c.c. hypodermically in the rabbit. Take temperature every ten minutes for four times. If the animal is not in convulsions, repeat the injection until definite symptoms occur. Make a notation of the variation from the normal. Treatment of cocain poisoning. This is purely symptomatic. Local Anesthesia in Man. — Sterilize a small hypodermic syringe and needle by boiling. In the same way boil about 10 c.c. of 2 per cent, cocain hydrochloride for two minutes. Boil needles for testing sensation in the same way. Wash the skin of the arm with soap and water, alcohol, ether and finally paint with tincture of iodin. Inject about 0.2 to 3 c.c. of the cocain solution, under the painted area, with aseptic precaution. In a minute test the sensation to the prick of the needle. CHAPTER XII. AUTONOMIC SYSTEM AND AUTONOMIC DRUGS. Those drugs which act especially on the autonomic sympa- thetic or the sympathetic-parasympathetic systems are known as autonomic drugs. The used nomenclature of this system is not definitely established. At present it is current only among physiol- ogists and pharmacologists. Anatomists are not yet agreed on it, and it is still in a state of change. The classification is based mainly on the reaction of parts of the nervous system to the action of drugs, and these reactions are so striking and constant that they must indicate fundamental anatomical differences. The unstable condi- tion of the nomenclature is due to the newness of this field and the minor changes which detailed investigation always brings. Langley has done most work on this system and the nomenclature is due for the most part to him. He divides the involuntary nervous system, or the vegetative nervous system, into — 1. Autonomic or parasympathetic. 2. Sympathetic. 3. Enteric system. The great difference between this system and the mhintary system is that in the voluntary system the motor fibers go direct from the anterior horn cells to the end-organ or the effector organ. In the involuntary nervous system the nerve fibers, after leaving the central nervous system, first pass to a ganglion before going to the end-organ. Just why we have control over the organs that receive their nerve supply direct from the central system and have no control over those innervated by the sympathetic is not known. So far as we know there is no reason for the difference. Differences between the Sympathetic and Parasympathetic System. —The sympathetic system leaves the cord from the first thoracic to the fourth or fifth lumbar. They include vasomotor, sweat, pilo- motor and secretory fibers. The system differs anatomically, embryologically, physiologically and pharmacologically from the parasympathetic system. The Parasympathetic System.— The parasympathetic system is also called the craniosacral autonomic system or the craniobulbar 150 AUTONOMIC SYSTEM AND AUTONOMIC DRUGS and sacral sympathetic systems. The fibers forming this system arise from the brain, medulla and midbrain and are carried especially in the third, seventh, ninth, tenth and eleventh cranial nerves. The sacral part of this system leaves the central system mainly in the GUoiVessAs ojthc •ftear'C B.o«ki bUlnRcW Lwet P.. IviKcv Pfox Colon CoVoftRp.cliitt Fig. 34. — Distribution of the various divisions of the vegetative system. Sym- pathetic fibers are indicated by dotted Unes; parasympathetic (autonomic) by unbroken lines. (Kraus, modified from Meyer and Gottlieb.) AUTOXOMIC SYSTEM AXD AUTONOMIC DRUGS 151 "o c _c a 1 i s CD £ o s o "S 1— ( s 1 o 6i C _o '-3 "C 2 3 O Dilatation N. pelvic. Inhil)ition N. X. Stimulation N. X. Stimulation N. X. Increases N. X. Increases N. X. Increases N. X. Stimulation N. X. Stimulation N. pelvicus Spasm N. pelvicus. Contraction N. X. Stimulation N. X. Stimulation N. X. 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" -s to ."i z Z Z -^ ^ ^- -rs -3 -75 « > "3 > 'S .t: rt rt rt .- P •" •:: 'r: « •- rt •- -3 0/ a> 0/ -3 Oola. a;c:CL,QpHQJ«««« U >; 1 3 X "3 > 1— 1 • • . c|3 3 g c ■^3 3 3 'x; 2. 3 3 a rt fl ctj K 152 AUTONOMIC SYSTEM AND AUTONOMIC DRUGS first sacral nerve, and the N. pelvicus supplies the descending colon, rectum, anus, bladder and genital organs. The Enteric System. — The enteric system, which controls the autonomic movements of the hollow viscera, receives fibers from both the sympathetic and the parasympathetic systems, but is not yet sufficiently marked to consider it as an independent system. AUTONOMIC DRUGS. I. The drugs which act especially on the autonomic system are the atropin group, the pilocarpin, eserin groups and choline. These drugs act especially on the yarasympathetic system. II. The epinephrin group of drugs, which act on the sympathetic. III. The nicotin group, which acts especially on the ganglion cells and acts on all ganglion cells of both systems. IV. Morphin acts on the enteric system. The action is peripheral on Auerbach's plexus. This is the only undoubted peripheral action of morphin. The chief actions of atropin are: Paralysis of the parasympa- thetic nerve-endings, with consequent — Dilation of the pupil. Eapid heart. Xerostomia due to suppression of the saliva. Anhydrotic action. Suppression of the mucous secretion. Diminution of the gastric and the intestinal secretions. Suppression of excessive peristalsis. Antagonistic action to eserin, pilocarpin, etc. ATROPIN AND PILOCARPIN GROUP. Experiment I. — Take a normal dog, count the pulse and respiration -and note the size of the pupil and the flow of the saliva. Give him a hypodermic injection of 0.5 c.c. of 1 per cent, pilocarpin nitrate. Note the effect on respiration, heart-rate, pupils and salivary flow. When a marked flow of saliva has been obtained, inject 1 c.c. of 0.1 per cent, atropin sulphate and make observations again. Experiment II. — ^This experiment may be done only when it is desirable to study the mechanism of atropin action. Anesthetize a dog, cat or rabbit and prepare for blood-pressure and respiratory tracing and for vagus stimulation. Insert a cannula in Wharton's duct and isolate the chorda tympani and prepare for stimulating it. PLATE VI BELLADONNA. Leaves and root of Atropa B. The alkaloid Atropine represents tlie drug fully. Classified as : Cerebral stimulant. Deliriaiit narcotic. Mydriatic. Cardiac stimulant. Anodyne. Antihidrotic. Physiologic action : In general, '" atropine acts as a stimulant to the central nervous system and paralyzes the terminations of a number of the nerves, more especially of those that supply invol- untary muscle, secretory glands and the heart." [Cushny.] It paralyzes peripheral inhibition. It decreases the secretions generally, except the urine, and increases the body temperature, producing a condition simulating fever. Nervous System. Brain. Stimulates the cerebrum, especially in its motor areas. Medulla. Stimulates respiratory and vasomotor centers. Spinal cord. Depresses inhibitory centei's. Nerves.' Sensory. Depresses sensory nerve endings. Motor. Depresses motor nerves. Secretory. Paralyzes the endings of many of the secretory nerves, causing a diminu- tion or arrest of the secretion ; hence there result dryness of the mouth, lessened secretion of gastric and pancreatic j uices and of milk. The sweat glands are rendered less active. Vagus. Paralyzes the inhibitory terminations of the vagus within the heart, and the secretory terminations within the digestive system. Muscular System. Depresses unstriped muscle, but has no influence upon voluntary muscle. Lessens the movements of stomach, intestines, bladder, uterus, and in gen- eral the organs containing unstriped muscle, except the arterial walls. [Cushny.] Eye. Pupils are dilated by paralysis of terminals of the motor oculi nerve in the iris, with possible stimulation of the sympathetic terminals. It paralyzes accommodation. Most authorities state that it increases inti-aocular pressure. Circulation. Arterial pressure is increased, chiefly by centi-al vasomotor stimulation. Heart. Increases pulse rate by paralyzing inhibition (peripheral ends of vagus). The heart muscle or its accelerator nerves may feebly be stimulated. Capillary area. Arterioles are contracted. Respiration. Stimulated by action upon respiratory center. Excretion. Perspiration is lessened. The drug is excreted rapidly by the kidneys, but its influence upon their activity is uncertain. PLATE VI Arterioles contracted Sweat glands less active- Motor nerves and sensory nerve endings depressed. Varjus Center Vaso Motor Center Cervical SympathetiG, Solar Plexus Pelvic Plexus Tlic rcil color iiii?iciitcs stiiniiliitioM, iiiid the, liliic color (lci)rcssion ATROPIX AXD PILOCARPIN GROUP 153 1. Take normal tracings. 2. Stimulate the chorda tympani; stimulate the vagus. 3. Stimulate both simultaneously. 4. Inject 0.5 c.c. pilocarpin nitrate intravenously. Note results in the eye, saliva, heart, respiration and blood-pressure. Stimulate the chorda and vagus separately. Inject 0.5 c.c. of 1 per cent, atropin sulphate and repeat stimulations. Wharton)s duct Parihohn's duct Lingual nerves /^ylo-hyoid muscle Chorda tympani^^ Xtylo-hyoid wax. -, ^g^ t Ay P:v J Hypoglossal nerve Fig. 35. — Dissection to show region of Wharton's duct. The lingual and chorda tj-mpani nerves are sometimes called the chorda linguae in descriptions. 5. When .stimulation of the chorda gives no saliva, place the electrfxles in the hilus of the gland and stimulate. Stimulation of the s\-mpathetics, either with the electrodes or with adrenalin, still causes a flow of saliva, hence the gland cells are not paralyzed. The action, therefore, is not on the gland cells. Either isolate and stimulate the cervical sympathetic, peripheral to the superior cer- vical ganglion or give the animal 1 c.c. of 1 to 10,000 epinephrin and note the results on the saliva. Experiment Til.— Effect of Atropin on the Eye.— Take a number of animals— dog, cat, rabbit, guinea-pig, chicken or pigeon— and drop 1 per cent, atropin sulphate in one eye and 1 per cent, eserin in the 154 AUTONOMIC SYSTEM AND AUTONOMIC DRUGS other. Record the action. Take a frog, pith and remove the eyes. Place one in a solution of 1 per cent, atropin and the other in a solu- tion of 1 per cent, pilocarpin or eserin; set in a dark place. Why in a dark place? Compare and record the results on all animals. Experiment IV. — Action of Atroinn on the Frog and Turtle Heart. — 1. Take a frog and turtle and isolate the heart and vagus. Take a tracing by the suspension method. Stimulate the vagus. Now apply 1 per cent. pilocarpin"and again stimulate the vagus. Repeat this several times. 2. Apply 1 per cent, atropin and again stimulate the vagus. When the vagus stimulation is ineffective, again apply pilocarpin. What is the result? Discuss the antagonism of atropin and pilo- carpin. VAGUS NERVE R.AURICLE SINUS VENOSUS PERIOR VENA CAVA Fig. 36. — Relation of the vagus nerve in the frog as modified from Schafer. Experiment V. — Action of Pilocarjnn and Atropin on Turtle Heart Strips. — Set up heart strips in saline in the usual way. When the contractions are regular add a 1 per cent, solution of pilocarpin nitrate in saline until the bath around the strip is 0.1 per cent, of pilocarpin. After thirty minutes, or when good records are obtained, replace the bath with normal saline. When contractions are again regular, add 1 per cent, atropin in successive amounts until the bath contains 0.001, 0.01 and 0.1 per cent, atropin sulphate. Experiment VI. — ^Repeat Experiment V, using the atropin before the pilocarpin. ATROPIN AND PILOCARPIN GROUP 155 Experiment Vn. — Use physostigmin salicylate instead of pilo- carpin nitrate (a) before atropin and (6) following atropin. Experiment Vin.^ — Effect of Atropin and Pilocarpi7i on the Volume of the Respired Air. — 1. This experiment may be carried out in connection with some of the previous experiments; anesthetize the animal and arrange for blood-pressure and respiration tracings. Take the respiration tracing from a band around the chest or abdo- men. Insert a tracheal cannula for connection with a spirometer. Take normal tracing and measure the volume of expired air per minute and the rate of respiration. 2. Inject slowly 1 c.c. of 0.5 per cent, pilocarpin nitrate intra- venously and note change in blood-pressure, heart-rate, respiration- rate and volume. Repeat injection if necessary. After fifteen minutes, measure the respiratory volume and inject slowly 0.1 per cent, physostigmin until the first effect of the blood-pressure is noticed. IMeasure the respiratory volume again. 3. Now inject 1 c.c. of 0.5 per cent, atropin sulphate and record the influence on the heart and respiration. Repeat if necessary. Experiment IX. — Action of Pilocarpin, Physostigmin and Atropin on Uterine Strips. — Remove the uterus from a guinea-pig, cat or rabbit and place it in warm saline and keep a current of air or oxygen running«through the saline. Movmt a small piece of it in warm saline and take a record of the contractions. When contrac- tions are regular add pilocarpin until the solution contains 0.01 per cent, then 0.1 per cent. What is the result? Now change the saline and when contractions are regular add 0.001 per cent, atropin sulphate, 0.01 and 0.1 per cent, and note results. Experiment X. — Repeat Experiment IX, using atropin first. Experiment XI. — Repeat Experiment IX, using physostigmin 0.01 and 0.1 per cent, instead of pilocarpin. Experiment XII. — Action of Atropin and Physostigmin on the Intestinal Movement. — From the animal used in the previous experiments, carefully remove rings of the small intestine and take tracings as with uterine strips. To obtain the best contractions an adequate weight must be applied. The best condition can only be obtained by experimenting. Use the same drugs as in the uterine strips. Experiment Xni. — Use a dog that has been one day without food. Insert a tracheal cannula and attach to an ether bottle. 1. Pith the dorsal spinal cord in the following manner: Cut down to the lainijiji' of the first and second lumbar vertebra', detaching the muscles from the spinous processes. With bone forceps remove 156 AUTONOMIC SYSTEM AND AUTONOMIC DRUGS these processes and the laminse (controlling hemorrhages with pledgets of cotton saturated with ferric sulphate solution, 5 per cent.), exposing the spinal cord. With rotary motion insert ante- riorly a soft wire with the end recurved to form an open hook about 4 or 5 mm. across. Eemove the wire. Insert a cotton pledget and close the incision (see Fig. 17). 2, Prepare the gut for tracings as described under epinephrin. Experiment IV (2) (page 167). Fig. 37. — ^Apparatus for recording contractions of uterine or intestinal strips. The air is supplied through a hypodermic needle. Instead of the siphon a vessel may be prepared, where the outlets can be made directly through the vessel wall. 3. Arrange for injections into the femoral vein with a burette. Take preliminary control tracings, one complete revolution, showing at the beginning the effect of (1) lifting gut; (2) inserting a needle into the gut; (3) replacing the gut and at another place the intro- duction of Ringer's solution into the abdominal cavity at body temperature. Note the effects of respiration on the curve. Then note the effects of the following procedures : 1. Injection of 20 c.c. of 5 per cent. NaCl solution into the lumen of the gut (one revolution). 2. Intravenous injection of pilocarpin solution, 1 c.c. of 1 to 1000. 3. Intravenous injection of 5 c.c. of 0.5 per cent, atropin sulphate. N I COT IN 157 Experiment Xr7. — Antagonism of Atropin to Morphin. — 1. Take the normal respiration and heart-rate of a dog. Note the condition of the pupil. Give him a hypodermic of 1 c.c. of 3 per cent, morphin sulphate. After thirty minutes repeat the records. 2. Give an intravenous injection or a hypodermic of atropin sulphate, 1 c.c. of 0.5 per cent., and again make records. If the animal is much depressed from the morphin give the atropin intravenously. Experiment XV. — Students will divide into groups. Count the heart and the respiratory rate. Note the size of the pupil, condition of skin, reflexes, etc. Group I. Each pupil take | grain (0.01 gram of pilocarpin.) II. I grain, 0.02 gram. Ill, 5 grain, 0.03 gram. Observe as above until sweating commences. If sweating is excessive take j^-^ grain of atropin every fifteen minutes until sweating is arrested. Do not take more than two doses of the atropin unless sweating is excessive. Groups IV, V and VI. Take t¥o" grain of atropin first, then after fifteen minutes take the amount of pilocarpin used by Groups I, II and III. NICOTIN. Nicotin, like curara, is an important drug in research work and in illustrating selective action. Because of the widespread use of tobacco the action of nicotin is important from an economic point of view. It is also a violent poison. Its first action is on the ganglion cells. All ganglion cells, sympathetic and parasympathetic, are acted upon. Experiment I. — To show the selective action of nicotin on the ganglion cells: Anesthetize a rabbit, cat or dog and dissect the cervical sympathetic and lay bare the superior cervical ganglion. Stimulate the nerve below, on, and peripheral to the ganglion. Note the dilation of the pupil and the constriction of the ear vessels. Paint the nerve below the ganglion with 1 per cent, nicotin. Stimu- lation over this painted area or below it shows no block of the impulse. Now paint the ganglion. In a few minutes stimulation below or on the ganglion shows that the impulses are blocked while stimulation peripheral to the ganglion still gives dilation of the pupil and dilation of the ear vessels. If the animal is in condition, prepare for blood-pressure and respiration as in Experiment II. 158 AUTONOMIC SYSTEM AND AUTONOMIC DRUGS Experiment II. — Prepare a dog or rabbit for blood-pressure and respiration tracings and for stimulation of the vagus. 1. Inject intravenously 1 c.c. of 1 to 10,000 epineplirin. Note results on heart-rate j blood-pressure and respiration. 2. Stimulate the vagus again, 3. Inject 5 c.c. of 0.1 per cent, nicotin solution and note the effect on the heart-rate, blood-pressure and respiration. Carotid arter2J_ Trachea- Subc^civianA Cervical sj/mpaiheticN. Vagrus nerve J)epressor nerve Inf. cervical otrnalia .VeriehralA ;^^^. ... SviclavianA . Thvracicffanylia Tfioracic sym Rec Ictrn/zqeal ntrve Va(^us nerve Fig. 38. — Diagram of inferior cervical and thoracic ganglia in the rabbit. (After Foster.) 4. Stimulate the vagus again. If it is still active repeat the injection of nicotin. 5. Inject 1 c.c. of 1 per cent, pilocarpin nitrate and note effect as before. 6. Stimulate the vagus again. 7. Inject 5 c.c. of 0.1 per cent, nicotin solution again in five minutes. 8. Inject 1 c.c. of 1 per cent, atropin sulphate and note the influ- ence on the heart-rate, blood-pressure and respiration. 9. Stimulate the vagus again. 10. Inject 5 c.c. of 0.1 per cent, nicotin solution and compare the effect with previous injections. 11. Inject 1 c.c. of 1 to 10,000 epinephrin. Discuss results. Experiment III. — Inject 1 c.c. of 0.1 per cent, nicotin into the lymph sac of a frog. Note and make diagrams of the position of the animal from time to time. Note the twitchings of the muscles. What is NICOTIN ]59 the infiiience of cutting the sciatic on the twitchings? Stimulate the peripheral end of the sciatic. 2. Compare this action on the muscles with that of another frog in which one injects 1 c.c. of 1 per cent, physostigmin. Twitchhigs of the muscles should develop in this animal, too, but they do not stop when the nerve is cut. Curara causes the physostigmin twitchings to stop. Strong ■MgS04 also causes them to stop. Experiment IV .—Demonstration; Nicotin in Tobacco Smoke.— The main active ingredient of tobacco smoke is nicotin. To show the nicotin-like action of tobacco smoke, place a couple of frogs in a large bottle or under a bell- jar and insert a two-holed stopper in the vessel used. In one hole place a pipe or thistle tube containing tobacco. In the other place a glass tube reaching to the bottom of the vessel. Attach a rubber tube to the glass tube and light the tobacco. Aspirate the smoke into the bottle and notice the influence on the frogs. Compare these animalg with those that got pure nicotin. Experiment V. — Place one drop of nicotin on the tongue of a mouse, guinea-pig or other small animal and notice effect. Experiment VI.— Count the respiration and heart-beat and note the size of the pupil and the salivary . flow in a dog. Give intra- venously, without an anesthetic, 5 c.c. of 0.01 per cent, nicotin and note the changes. Repeat injection of nicotin if necessary. Experiment VII. — Anesthetize a dog and inject 0.5 c.c. of 0.1 per cent, nicotin into the lumbar cord. Note the result on the reflexes. Experiment Vin. — The influence of nicotin in modifying the tracing of epinephrin. Take the blood-pressure in a dog hi the usual way. Inject 0.5 c.c. of 1 to 10,000 epinephrin into the femoral vein. When the pressure returns to normal give 0.025 c.c. of 1 per cent nicotin solution and record the effect on the blood-pressure. Alternate the epinephrin and nicotin injections until definite results are obtained. After a time nicotin gives no rise of blood-pressure, but epinephrin is still effective. How do you explain these actions? Note.— See Epinephrin, page IGG, which should be included in autonomic drugs. CHAPTER XIII. PHARMACOLOGY OF THE EYE. Function. — Vision. Essential Organ. — The retina and optic nerve. Accessory Organs. — ^The internal and external muscles, lacrimal glands, lens, etc. The retinal ganglionic layer may be considered similar to the spinal sensory ganglion cells. The peripheral parts being receptive endings and the optic nerve the continuation centralward of the afferent nerve. These facts explain why methyl alcohol, quinin, santonin, tobacco, male fern, alcohol, pelletierin, carbon bisulphide, napthols, etc., which injure the retinal ganglion cells may also injure the optic nerve. Drug's Acting on the Lacrimal Glands. — ^The atropin group causes a lessened secretion of tears. The pilocarpin group stimulates. In eye work when these drugs are used the drying effect of atropin is not a serious drawback in the use of the drug. After large doses of pilocarpin the tears are markedly stimulated. However, moisten- ing of the eyeball is not due entirely to the lacrimal glands because after their removal or disintegration the eye does not become dry. The secretion of the conjunctiva itself and its mucous glands aid in the moistening of the eye. The nerves to the lacrimal glands are the lacrimal, a branch of the ophthalmic nerve, which in turn is one of the three primary divisions of the fifth nerve, a parasympathetic nerve. Drugs Stimulating the Retinal Cells or Vision. — Strychnin increases the acuteness and also enlarges the field of vision. '^ The caffein group of drugs have a similar action. Drugs Depressing the Retinal Function. — Drugs are not known that definitely reduce the retinal hyperesthesia with severe pain. Pain arising from the conjunctiva may be reduced by the local application of cocain and by the central action of the alcoholic group or morphin. 1 Filenhe: Pfliiger's Archives, 1901, vol. iii. PHARMACOLOGY OF THE EYE 161 The Iris and the Ciliary Muscle. — The function of these is to con- strict and enlarge the pupil, hence to regulate the amount of light that reaches the retina (see Fig. 19, page 99). The iris consists of two sets of muscle fibers: (1) circular and (2) radiating. Stimulation of the constrictor fibers narrows the pupil. The third nerve governs the action of the circular muscle fibers while the sympathetic system governs the radiating. Any of the drugs acting on smooth muscle would act on the muscles of the eye if applied directly; practically, however, direct muscular action is unimportant. The important action is due to an action on the nerves. Drugs Stimulating the Third Nerve (Parasympathetic Endings). — (1) Eserin and (2) pilocarpin. Drugs Paralyzing the Third Nerve Endings. — (1) Atropin and (2) substitutes. Drugs Stimulating the Sympathetic Nerves to Radiating Fibers. — (1) Epinephrin and (2) cocain. Drugs Paralyzing the Sympathetic Nerve Endings in the Eye. — (1) Cocain in large amounts paralyzes all nerve endings. Ergo- toxin will paralyze the constrictors. However these actions are not especially prominent in the eye and are psrhaps little in operation here. Drugs Changing the Size of the Pupil by a Central Action. — 1. Morphin, pin-point pupil. 2. Chloral, pin-point pupil. 3. Asphyxia, first constricts then dilates. 4. Drugs causing dilation due to paralysis of the central end of the third nerve — certain ptomains, for example, fish, muscles, cheese, sausage, etc. Proof that Atropin Dilates the Pupil by Paralysis of the Third Nerve Endings. — 1. The action is peripheral because when applied to the eye locally and the drug is kept from being absorbed it dilates the pupil. 2. It will dilate the pupil after degeneration of the sympathetic nerve. 3. The action is peripheral, since it acts on the enucleated eye. 4. Stimulation of the third nerve peripheral to the ganglion is not effective after atropin, though active before. Direct stimula- tion of the muscle in such cases is eftective. 5. Atropin antagonizes the action of eserin and pilocarpin. (). Atropin has no action on the sympathetic nerves to the eye. 7. It is not known to have any action on the muscles of the eye. 11 162 PHARMACOLOGY OF THE EYE Proof that Eserin and Pilocarpin Stimulate the Third Nerve Endings. — 1. They act on the enucleated eye, therefore the action is per- ipheral. 2. Stimulation of the sympathetic peripheral to the superior cervical ganglion is still effective after these drugs, therefore the action is not due to a paralysis of the sympathetic. 3. The action does not occur after degeneration of the nerves, therefore it is not on the muscle. 4. Direct stimulation of the muscle still produces contraction. 5. The opinion that the action is on the nerve-endings of the third nerve is corroborated by the action on other locations innervated by the parasympathetics. Some Differences in the Action of Eserin and Pilocarpin. — ^The chief differences in the action of eserin and pilocarpin are : 1. Pilocarpin actually stimulates the nerve-endings while eserin merely sensitizes the endings and renders them very responsive to stimuli, reaching them from the nerve. The basis for this belief is: If the chorda tympani nerve be cut, eserin often fails to cause secre- tion while pilocarpin causes secretion. 2. Eserin injected into Wharton's duct to reach the endings directly will cause no secretion if impulses from the center are blocked while pilocarpin causes secretion. 3. Eserin likewise fails to contract the pupil after degeneration of the postciliary branches, while pilocarpin is still effective. CHAPTER XIV. ^ ANTAGONISM. By antagonism we mean counteraction of the effects of one drug by another: It may be one of two kinds: I. Chemical. II. Physiological. Chemical antagonism is easily understood in most cases. When gastric hj^Deracidity is neutralized by sodium bicarbonate or when the action due to the intravenous injection of an acid is neutralized by a similar injection of sodium bicarbonate the explanation is apparent. Some writers call this chemical antagonism, distoxica- tion or neutralization, and reserve the term antagonism to physio- logical actions, PHYSIOLOGICAL ANTAGONISM. The classic example of antagonism is atropin and pilocarpin. So far as we know these drugs have no chemical affinity for each other; both are alkaloids, yet they produce exactly opposite effects on the eye, salivary glands, heart, intestine, etc. The antagonism in this case, as in most cases, is not mutual, i. e., the action of one drug is not equal and opposite to the action of the other. Small doses of atropin will counteract the effects of large doses of pilocarpin, but pilocarpin is not antagonistic to large doses of atropin. In this as in m.ost cases the paralyzing drug is much stronger than the stimulating drug. The antagonism may be explained in this case by assuming that these drugs act on the same place: the myoneural junctions, one stimulating, the other depressing. When the ending is paralyzed by atropin, of course, no further acticm can be expected, since paralysis requires a i)eriod of recuperation before the ending is again rcsjxmsive to any stimulus. On striix'd muscle, curara i)aralyzes the nerve-endings; eserin here is antagonistic, but the degree of the antagonism is again limited. The effect of curara soon wears off, but eserin facilitates the r(!Cuperation and actually stimulates the endings. 164 ANTAGONISM In the case of veratrin, which acts directly on muscle and stimu- lates it, potassium chloride and fatigue products are antagonistic, and again the paralyzing drugs are stronger than the stimulating. Barium and the nitrites are antagonistic on muscle, but we do not know whether they act on the same substance in the muscle. Barium, veratrin and digitalis increase the force of contraction of the heart while chloroform, chloral and potassium salts diminish it. In this and in many other cases of antagonism it is difficult to analyze the mechanism because there are so many possible factors. It is not at all necessary that antagonistic drugs act on the same point, since the reciprocal nerves in many organs are antagonistic in their physiological effect, as has already been pointed out. HCN, CH3, CN, and other nitrils, in the presence of active sulphur compounds, are converted into less toxic sulphocyanides. They also retard or modify the power of the body to break down substances which in themselves are not toxic, yet their decom- position products are toxic. Hunt's acetonitril test illustrates this type of antagonism. Hunt found that the administration of thyroid gland extract to white mice for a few days markedly increases their resistance to an acetonitril. He found that after thyroid feeding, acetonitril, which is toxic, by being broken into HCN is less toxic after feeding thyroid. Certain foods, not well understood, may have a similar influence, since dextrose, oatmeal, liver and kidney also increase this antagonism. Little is known regarding this type of antagonism or the antago- nism resulting from internal secretions or hormones. Epinephrin sensitizes sympathetic nerve-endings. Cholin is thought to sensitize autonomic ganglia. The chemical functions of the liver are modified by the amount of epinephrin in the blood and also by the condition of the thyroid. Modifications of these and other fmictions undoubtedly synergize or antagonize drug action, but too little is known about such action to give an explanation. Disease, climate, food and perhaps other conditions may antago- nize morphin. In cold climates purgatives are less effective than in warm. Many other unknown conditions may modify the action of drugs. Synergism. — Synergism is the opposite of antagonism. The term is confused with additive action. In true synergism the sum of the influence of two drugs is more than the addition reaction of the two. There is a sensitizing action by one of them, so that the other pro- duces more than its normal action. For example: PHYSIOLOGICAL ANTAGONISM 165 1. A mLxture of purgatives increases the activity of both. 2. ]Morphin and chloral and 3. Morphin and scopolamin as h^-pnotics. 4. ^Mercury and arsenic in syphiUs. No explanation of synergism is at present available. Scopolamin, Morphin, Synergism} — In the following experi- ments record respiration and heart-rate, corneal reflex and general appearance and condition of animals before and during the experi- ment. Experiment I. — Give a rabbit 0.03 gram of morphin per kilo subcutaneously and observe and record the effect for one hour. Experiment H. — Give a rabbit 0.02 gram per kilo (1 c.c. of 2 per cent.) scopolamin subcutaneously and observe and record the effect for one hour. Experiment m, — Give a rabbit 0.04 gram of morphin per kilo (1 c.c, 4 per cent.) subcutaneously and observe and record the effect for one hour. Experiment IV. — Give a rabbit 0.03 gram of morphin per kilo (1 c.c, 3 per cent.) and 0.01 gram per kilo (1 c.c, 1 per cent.) sco- polamin and observe and record the effect for one hour. Compare the results of these four experiments. Experiment V. — Give a rabbit 0.01 gram of morphin and 0.01 gram of scopolamin (1 c.c, 1 per cent.) per kilo and observe for one hour. Experiment VI. — Select two cats the same size, (a) Give one as a control 0.05 gram of morphin (1 c.c, 5 per cent, or equivalent) and notice the effect after thirty minutes. (6) Give the second animal 0.1 00 gram of narcotin subcutaneously. Note the influence of this for one hour. Then give the same amount of morphin (0.05 gram) as the control and observe for one hour. ic) Take A and after one and a half hours give the same dose of narcotin as B (0.100 gram) and compare the two animals.^ Experiment Vn. — Synergism oj Morphin and Paparerin. — Repeat Experiment VI, using papaverin instead of narcotin. Experiment Vm. — Synergism of Morphin, Scopolamin and Atropin. — Take five cats. Inject three cats each with 25 mg. per kilo of morphin subcutaneously. 1. Use as a control. 2. Give the second animal 1 c.c. of 0.1 per cent. scoi)()lamin hypfnlermically. • Madclung: Arch, of Exp. Path. u. Pharm., 1910, Ixii, 422. « Straub: Hiochomischc ZtHf:hr., 1912, xli, 4.'/J. 166 ANTAGONISM 3. Give this animal 1 c.c. of 0.01 per cent, atropin. 4. Give 1 c.c. of 0.1 per cent, scopolamin as control. 5. Give 1 c.c. of 0.1 per cent, atropin as control. Compare and record results. Scopolamin and urethane are also synergistic/ also morphin and urethane. The narcotic dose of urethane for a rabbit is 1.5 gram per kilo by mouth or 1 gram per kilo subcutaneously. Experiment IX. — Give two rabbits each 0.1 gram per kilo of scopolamin subcutaneously. Save one for control. Give the other 0.2 gram per kilo urethane subcutaneously. To a third give 1 gram per kilo urethane by stomach tube. Experiment X. — Give two rabbits 0.2 gram per kilo of urethane subcutaneously. Save one for control. Give the other 0.1 gram per kilo of scopolamin. Compare the results of this in both experi- ments. In the same way Burgi has found that the antipyretics have some anesthetic action and increase the action of morphin and urethane. EXAMINE AND STUDY THE VARIOUS PREPARATIONS IN WHICH EPINEPHRIN IS FOUND IN THE MARKET. Experiment I. — 1. Prepare a dog or cat for blood-pressure and respiration tracings. Note the condition of the pupil before and after each injection. Insert a cannula into the femoral vein for intravenous injections from a burette. Make an incision along the linea alba, about four inches long, and observe the condition of the intestine during each injection. Keep the part warm and closed when not under observation. Take three samples of the blood and determine clotting time. 2. Take normal tracings, then tracings of the action of 1 c.c. of 1 to 10,000 epinephrin subcutaneously. 3. After five minutes inject 1 to 50,000 epinephrin intravenously; when pressure is high stimulate the vagus, compare with stimula- tion when the pressure is normal. 4. Isolate and cut one vagus and again inject 1 to 10,000 epi- nephrin. 5. Isolate and cut the other vagus and inject 1 to 10,000 epi- nephrin. Is there any change in the height or character of the curve after cutting the vagi? Is there a secondary rise in the pressure following a primary fall? If so how do you explain it? 1 Burgi: Deut. Med. Wchschr., 1910, pp. 20 and 62, PREPARATIONS IN WHICH EPINEPHRIN IS FOUND 167 6. When the pressure is again normal, stimulate the peripheral vagus. 7. Take the clotting time of the blood and compare with the normal. 8. Inject intravenously 2 c.c. of pituitrin (liquor hypophysis), 1 to 5 in water. Compare this action with the action of epinephrin. 9. When the pressure is again normal inject double the amount of pituitrin (liquor hypophysis) subcutaneously. Note effects for thirty minutes. 10. At this stage inject 1 c.c. of 1 per cent, atropin sulphate solution. What is the effect on the heart, respiration and eye? Study the changes in the tracings under the various drugs. Experiment 11. — Prepare for tracings as in Experiment I. Watch the effects on the pupils, heart, respiration, intestine and salivary flow. Determine the clotting time of the blood. 1. Inject 2 c.c. of 1 to 5 solution of pituitrin (liquor hypophysis) intravenously. Wait until the pressure has returned to normal. Determine clotting time. Then — 2. Inject 1 c.c. of 1 to 10,000 epinephrin. When pressure is again normal — 3. Inject 1 c.c. of 1 per cent, atropin sulphate, in five minutes — 4. Inject 1 c.c. of 1 to 10,000 epinephrin and compare the result with 2 to 5, Experiment I. Determine clotting time again. 0. Expose the intestines to produce a condition of shock and when the blood-pressure has been much reduced, again inject 1 c.c. of 1 to 10,000 epinephrin. Experiment HI. — Action of Epinephrin on Vasodilators. — Prepare for tracings as in Experiment I and 11. 1. Take normal tracing. 2. Inject intravenously \ c.c. per kilo of 1 to 100,000 epinephrin solution. Repeat this and vary the dose and see if you can get a dose that will give a fall only. Note that a slight rise may be fol- lowed by a fall and again by a secondary rise. How do you account for this? 3. Inject slowly j\ c.c. per kilo of the fluidextract of ergot. 4. Refxjat (2). 5. Repeat (3). 0. Repeat (2). Instead of ergot, ergotoxin may be used if it is available. Pre- pare a solution of ergotoxin as follows: Weigh out 0.1 gram and place in a beaker. Moisten with 10 per cent. XaOII. Add water slowly, and about 1 c.c. at a time, until the powder is dissolved. Make 168 ANTAGONISM to 20 c.c. This is 0.5 per cent., and 1 c.c. equals 0.005 gram. Ergotoxin paralyzes the vasoconstrictors before the dilators. Experiment IV. — The Action of Epinephrin on the Intestine. — Anesthetize the animal and prepare for recording the intestinal movements by the Trendelenburg method or by Jackson's finger- cot method. Fig. 39. — Jackson's finger-cot method of recording intestinal contraction. 1. Trendelenburg's method as described by Dr. R. G. Hoskins: Use a dog that has been one day without food. Insert a tracheal cannula and attach to an ether bottle (see Fig. 17, page 86.) Pith the Dorsal Spinal Cord in the Following Manner: Cut down to the laminse of the first and second lumbar vertebrae, detaching the muscles from the spinous processes. With bone forceps remove these processes and laminse (controlling hemorrhages with pledgets of cotton saturated with ferric sulphate solution, 5 per cent.), exposing the spinal cord. With rotary motion insert anteriorly a soft wire, with the end recurved, to form an open hook about 4 or 5 mm. across. Remove the wire. Insert a cotton pledget and close the incision. 2. Prepare gut for tracing as follows: Make an opening in the abdominal wall along the linea alba and sew in an iron ring PREPARATIONS IN WHICH EPINEPHRIN IS FOUND 169 about 14 cm. in diameter. Fasten the ring to a stand and fill the abdominal cavity with Ringer's solution at body temperature. Avoid all rough handling. Pass a guide ligature around the gut (to be used for drawing the gut up when injections are to be made into it); and 25 to 30 cm. below it, by means of a small surgical needle pass a silk thread, fifteen inches long, in a transverse direction through the superficial layer of the gut, and after tying pass the end through the glass cylinder (finger plethysmograph) . One-half inch above this thread sew a single superficial stitch. Sew the opposite end of the cylinder to the gut a half-inch below in the same way. Fix the cylinder perpendicularly in a burette clamp and attach the long thread to a heart lever arranged to magnify seven times and to write on a kymograph drum. (The cylinder decreases the displacement of the gut respiratory movements.) 3. Arrange for injections into the femoral vein from a burette. It usually requires thirty to sixty minutes for good contractions to commence. Experiment V. — Jackson's Finger-cot Method. — Arrange a burette, catheter and finger-cot or rubber glove finger as shown (Fig. 39), and make a small longitudinal incision in a loop of the small intestine. Slip the end of the catheter over which the finger cot is attached about four or five inches down the lumen of the intestine from the incision. (The tip of the catheter reaches entirely to the end of the finger cot and thus forces the cot along.) Fill the burette half-full of water and move the catheter in and out a little to be sure that the finger cot is filled with water and the air is expelled. Stitch together the incision in the intestine around the catheter and close the abdomen with hemostats. The intestinal tambour should write just above the blood-pressure, respiration and base line. Experiment VI. — Action of Epinephrin on the Uterus. — (a) Remove the uterus of a guinea-pig, rabbit or cat. Place in a warm saline solution. Take a piece of one horn, about one-half inch long, and set up as for muscle contractions in a warm saline bath (Fig. 37). Keep oxygen or air bubbling through the immersing fluid. When contractions are regular add a drop or two of 1 to 1000 epinephrin solution . (6) Remove and add saline again. When contractions are again regular adrj 1 c.c, of 1 to 10 pituitrin. (c) Iicmove the pituitrin fluid and i)hysiological saline. When contractions are regular add (d) 1 c.c. of 1 to 10 fluidextract of ergot. Other drugs may be tried as desired. 170 ANTAGONISM Experiment VII. — Barbour's Method of Studying the Action of Drugs on the Uterus.^ — Get this journal and read the article. Barbour's method of recording uterine contractions is much like the Trendelen- burg method for intestinal movements. An opening is made in the linea alba and the horns of the uterus loosened and brought forward together and a thread tied around the ends of both. Now place a glass tube, like a finger plethysmograph, perpendicular in the abdomen, so that it contains the uterus and protects it from the other abdominal organs. Bring the thread that is around the uterine horns through the tube and attach to a light writing lever. . Fill the abdomen with liquid paraffin for protection and sew the skin of the abdomen around the tube. Inject the drugs to be studied into the femoral veia. This method should give a more accurate indica- tion of drugs on the uterus than a method that applies the drugs directly to the uterus, a form in which they never reach it when given therapeutically. Cats are the best animals for this work. Experiment VIII. — The Action on the Eye. — (a) The eye should have been observed in all the foregoing experiments. (b) Take the eyes of a frog and place them, one in saline, 0.8 per cent., the other in saline containing 1 to 10,000 epinephrin. Place in a dark place and observe every fifteen minutes. What is the result? Why does this occur in the dark more easily than in daylight? Experiment IX. — The Action of Epinephrin on the Secretions. — (a) Anesthetize a dog and place a cannula in Wharton's duct and prepare for blood-pressure tracings, stimulation of the chorda tympanum and cervical sympathetics. Take normal tracing and record of blood-pressure and salivary flow. Stimulate the chorda and sym- pathetic separately. Note the results. If the sympathetic cannot be conveniently isolated proceed without it. (6) Inject 1 c.c. of 1 to 10,000 epinephrin and note the effect on the salivary flow. Repeat. (c) Inject epinephrin. When satisfied with the action of epi- nephrin on the secretion again stimulate the chorda. (d) Inject intravenously 1 c.c. of 1 per cent, atropin sulphate and in five minutes repeat stimulation of the chorda. (e) When the stimulation of the chorda is ineffective repeat injec- tions of epinephrin 1 to 10,000 and note results. If the sympathetics have been isolated stimulate directly. 1 Journal of Pharm. and Exp. Ther., 1915, vii, 547. PREPARATIONS IN WHICH EPINEPHRIN IS FOUND 171 Experiment X. — Glycosuria Produced by the Hypodermic Injection of Epinephrin. — Catheterize a rabbit and test the urine for sugar. If there is sugar, inject 1 c.c. per kilo of 1 to 10,000 epinephrin subcutaneously. In two to three hours catheterize and again test the urine for sugar. The test rarely fails. Experiment XI. — The Action of Epinephrin on theTone of Bronchial Muscle. — The bronchial muscles are acted on by drugs that act on non-striated muscle. They are relaxed by atropin and constricted by drugs of the pilocarpin-eserin group, etc. Elimination of the indirect action of the drug on respiration and vasomotor apparatus makes the measurement of the bronchial tone rather difficult. Care must be taken to avoid an action on the respiratory center being in- terpreted as an action on the bronchial muscles. For this reason the animal is pithed and artificial respiration is carried out. Changes in the blood flow through the lungs must also be accounted and not confused with bronchial changes. Methods have been developed by Dixon and Brodie/ Golla and Symes,^ and D. E. Jackson.^ The method is essentially as follows: Anesthetize a dog and insert a three-way tracheal cannula for artificial respiration. Isolate the carotid arteries and ligate one. With a large needle pass ligatures through all the muscles of the neck close to the vertebra so that the entire return circulation from the head can be shut off. When ready to do this inject 2 c.c. of chloroform into the central end of the carotid. This will kill the brain and has the effect of pithing. Commence artificial respiration at once. This method will kill the animal if enough chloroform reaches the heart. It is important, therefore, that as soon as injec- tions of chloroform are made ligation of the return vessels be made at once. A safer method of pithing is to open the skull with a trephin and pith with an iron rod. Pack tightly with cotton to avoid hemor- rhage. Pithing should be sufficiently low to destroy the respiratory center. The simplest method of pithing is to inject 1 c.c. of CHCI3 into the fourth ventricle. This will also destroy the respii*atory centre, so that artificial respiration should be established as soon as the injection is made.'' Insert a cannula into the jugular or femoral vein for injection. Shave the chest on one side near the diaphragm and insert a flanged ' Jour. Physi'ol., 190.3 xxix, 97. 2 .Jcur. Pharmacol., 1914, v, 92. ' Ibid., iv and v; also Expcr. Pharrn. Text horjk, 1017. * .lour, f'f Lab. and Chcm. Med., 1919, iv, 491. 172 ANTAGONISM cannula into the pleura. The opening or incision around the cannula must be air-tight. A little collodion around the incision will help. Connect with a tambour or water manometer and make a tracing of the pulmonary excursions. Keep the respiration regular. If the blood volume in the lungs remains constant and the artificial respiration is regular an increase or decrease in the excursions of the tambour is assumed to be due to changes in the bronchial muscles. Criticize this assumption. 1. Study the effect of the intravenous injection of 1 c.c. of 1 to 10,000 epinephrin. 2. 1 c.c. of 0.1 per cent, pilocarpin. 3. 1 to 10,000 epinephrin. 4. 1 c.c. of pilocarpin, 1 per cent. . 5. 1 c.c. of 0.5 per cent, atropin sulphate. 6. Repeat 1. 7. 1 c.c. of 1 to 5 pituitrin. 8. Before killing the animal inject 1 c.c. of 1 per cent, barium chloride. Note to student: Criticize the technic and conclusions of this experiment. Wherein may the results not indicate an action on the bronchioles? CHAPTER XV. ANTIPYRESIS AND ANTIPYRETICS. In the normal animal heat production and heat loss are main- tained at a constant level — the normal body temperature. The normal temperature of different animals is as follows:^ Birc Is. ^ [ammals. Goose . . . 41.70° C. Tiger . . . . 37.20° C. / 39.08° C. / 36.80° C ■ • ■ \ 37.50° C Sparrow • ■\42.10°C. H orse . Pigeon . / 41.80° C. Rat . . . . . 38.50° C. • •\42.50°C. Hare . . 37.80° C Turkey . . . . 42.70° C. Cat . . . / 38.30° C • • \ 38.90° C Guinea fowl . . 43.90° C. Duck . . . / 43.90° C. • ■ \ 42.50° C. Guinea-pig . . 38.80° C. f 37.40° C Crow . . 41.17°C. Dog . . . . 39.00° C Swallow . . 44.03° C. [ 39.60° C Gull . . . . . 37.80° C. Panther . . 38.90° C Mouse . . . 41.10° C Sheep . / 37.30° C ■ ■ \ 40.50° C Ape . . 35.50° C Guinea-pig / 35.76° C • • • 1 38.00° C Rabbit . . / 37.50° C \ 38.00° C Ox . . . . . 37.50° C Ass . . . 36.95° C Anything that increases heat loss or lessens heat production will lower the temperature. This is regulated by the central nervous system. Heat output is lessened reflexly by constriction of the cutaneous vessels and heat loss increased in the same way by vasodilationa nd by sweating. The heat-regulating center is "set" so that shivering (to increase heat production) or sweating (to increase heat loss) occurs with a slight change in the temperature. A normal dog, with a temperature of 38.6° C, will shiver when the temperature is lowered 0.7° C, and perspire, i. e., show the signs of perspiration, when the temperature is raised 0.5° C, Our knowledge of the location and mechanism of the heat-regulating > Landois and Stirling, 1891, p. 406. 174 ANTIPYRESIS AND ANTIPYRETICS center or centers is still very incomplete. However, toxins, cocain and other pyrogenous poisons will derange the regulating center, and, depending on the infection or drug, the regulating mechanism instead of being set at 38.6° C. may be set at 40° C. or higher. The sensitivity of the center to heat and cold at this higher tem- perature is the same as at the lower. The reaction to cold probably means an augmented state of excitability or stimulation of the heat-regulating centers, while increase in temperature depresses them. Overheating of the carotid blood is known to depress the medullary centers, while at the same time the cooperative or reciprocal centers, sweat-glands and the respiration center (heat dyspnea) may be stimulated. Fever is thought to be due to a stimulation of the heat-regulating centers by toxins and pyrogenous poisons. Heat puncture also stimulates these centers in the same way. The mechanism of anti- pyresis is not well understood, but the coal-tar antipyretics reduce the temperature in hyperpyrexia by a sedation or depressing action on the heat-regulating mechanism by "setting" the temperature mechanism at a lower state as one sets a thermostat in the laboratory. In fever the nitrogen eliminated as urea and oxygen consumed is lessened by antipyretics, but this is a result rather than the cause of the fall of temperature, because: 1. No such result occurs in the normal individual. 2. The excessive excretion of urea does not run parallel with the increase of temperature but is generally most marked after the crisis. 3. In fever produced by the injection of bacterial toxins, increase in oxygen consumption and urea excretion occurs even when the rise of temperature is prevented. ANTIPYRETICS. The immediate active agent in the coal-tar antipyretics is para- amidophenol, and if this formed too rapidly, collapse may follow. Hence only those that yield para-amidophenol slowly can be used. These coal-tar antipyretics act on the heat-regulating center to depress it, but the actual reduction of temperature is due to heat loss from the surface of the body. If the fevered animal be wrapped in a cotton blanket or placed in an incubator, so that no loss from the surface can take place, antipyrin has little effect. Antipyrin differs from a cold bath in lowering the temperature by the fact that it has a central action and tends to permanently lower the temperature. That it acts on the heat centers in the brain ANTIPYRETICS 175 is sho^^^l by the fact that high section of the cord prevents its action and it has no local or general action as has quinin, while after a cold bath the tendency is for the temperature again to rise, due to increased heat formation. A cold bath does not at least immediately "set" the regulating mechanism. Alcohol and the nitrites dilate the superficial vessels, but do not set the center. Quinin lessens temperature by decreasing oxidation in the muscles and gland cells. The temperature fall is secondary to diminished metabolism. Quinin inhibits oxidation by oxidases in vitro, and it reduces the temperature of the normal animal. The action is not on the brain, since it reduces the temperature of an animal whose cord is cut. The coaltar antipyretics will not act if the cord is cut. Experiment I. — ia) Take the rectal temperature of eight rabbits. (6) Give each a hypodermic injection of 2 c.c. of 5 per cent, cocain per kilo. (c) Record the temperature each fifteen minutes until a maximum is obtained ; then give — 1. Two c.c. of 2 per cent, solution of a quinin salt; repeat every fifteen minutes until the temperature falls. 2. Wrap in cotton and treat the same as in 1. 3. Give an injection of 5 c.c. per kilo of 2 per cent, acetanilid in alcohol. 4. Treat the same as in 3. First wrap in cotton; repeat every fifteen minutes until the temperature falls. .5. Immerse in a water-bath at 25° C, 6. Immerse in a water-bath at 40° C. 7. Give by mouth 10 c.c. per kilo of 2 per cent, acetanilid solution in alcohol. 8. Give 10 c.c. per kilo of 2 per cent, antipyrin by mouth. Make complete records and discuss the mode of action of each of these drugs. As a control, if sufficient animals' are available, treat eight other rabbits in the same way without giving the cocain. Experiment II. — Take the temperature of eight rabbits and inject hypodermically with 1 c.c. per kilo of })ody weight of 20 per cent, peptone in water twelve hours before class work. Then treat as in Experiment I. Experiment HI. Take the normal tem])erature and note the chaiig<-s produced in the following experiments: Ilydruted Chloral. — Administer ().)) gram of iiN'dratcd ciiloral to a cat (0.0 gram to a rabbit; by the rcctiini. Note the degree of anesthesia induced. 176 ANTIPYRESIS AND ANTIPYRETICS Morphin. — Administer 100 mg. of morphin sulphate (3 c.c. of 3 per cent, solution) per kilo to a rabbit subcutaneously (half of the relative amount to a dog) ; compare the anesthetic action with that of hydra ted chloral. The temperature of a dog may or may not fall; that of a rabbit falls. Antipyrin in Health. — Administer 100 mg. of antipyrin to a normal rabbit through a stomach-tube; little change in temperature. Note that the temperature of rabbits undergoes marked changes, with changes in external temperature, with careless handling, fright or excitement; hence the success of these experiments demands careful work. Experiment IV. — ^Each student should record his own temperature and take 0.5 gram of antipyrin or other antipyretic. Record the temperature every hour for four hours. Experiment V. — Record the temperature and respiration of four rabbits. Place in an adequately ventilated box and raise the tem- perature in the box to 43° C. by means of an electric light within the box. In two hours record the temperature again. Give two 10 c.c. per kilo of 2 per ceat. antipyrin by mouth and replace in the heated box ; allow the otheT two to remain at the room temperature without antipyrin. At the end of an hour again record the tempera- ture and respiration. Discuss the hygienic and drug treatment of fever. Experiment VI. — Heat Centers. — Demonstration.- — Puncture of the median part of the corpus striatum and other parts of the nervous system often causes a rise in temperature. The centers are not definitely localized. It has been suggested that the rise in tem- perature in fevers is due to bacterial toxins acting on these centers and that antipyretics restore these centers to their normal state either by preventing the formation of these toxins, neutralizing them or causing their more rapid elimination. Study the mechanism of each antipyretic in the text. Experiment VII. — 1. Record rectal temperature of two rabbits: Into one inject intravenously 1 to 1.5 c.c. per kilo fluidextract of ergot and record the temperature every thirty minutes. 2. Into two, inject in same way 5 to 8 c.c. of 1 to 20 solution of calcium lactate and record temperature in the same way.^ Experiment VIII. — ^Record the blood-pressure and respiration of a dog. Lay bare the carotid and place it on a copper jacket so con- structed that a stream of hot water may be circulated around the 1 See Hill: Jour, of Pharm. and Exp. Therap. ANTIPYRETICS 177 carotid artery as it passes to the brain. What is the effect on the heart and respiration? Experiment IX.— Anesthetize a cat or rabbit with ether. Prepare for aseptic operation. ISIake central incision in the skin of head along the sagittal suture. Peel back the skin and make a trephine hole 5 mm. lateral to the sagittal suture and the same distance anterior to the coronal suture. When the bone is removed, pmicture with a hat- pm or small probe, directed downward until it touches the base of the skull, and is twisted around in this location. Watch the con- dition of the ear vessels. Close the operative wound aseptically, remove the ether and record the rectal temperature every fifteen minutes for three hours or more.^ I See Prince and Hahn: Am. Jour. Physiol., 1918, xlvi, 412. This gives refer- ences to other literature, aho Gottlieb, Arch. Expt. Path. u. Pharm 1890 xxvi 419. . • , 12 CHAPTER XVI. PHARMACOLOGY OF THE GLANDS. The word glands comes from the Latin glans — acorn, referring to the shape of glands in general, (see Fig. 19, page 99.) The function of glands is secretion. This may be external or internal. The chief glands of external secretion are: 1. The Lacrimal. 2. Salivary. 3. Gastro-intestinal. 4. Pancreatic. 5. Liver, bile. 6. Kidneys. 7. Mammary. 8. Sweat and sebaceous. Glands of internal secretion (endocrinal) : L Thyroid. 2. Thymus. 3. Adrenals. 4. Liver. 5. Spleen. 6. Testes and ovaries. 7. Perhaps all glands and tissues to some extent. Lacrimal Glands. — ^Function to moisten the eye. The nerves of the lacrimal glands are: Sympathetic from the superior cervical ganglion. Parasympathetic from the fifth nerve through the lacrimal nerve. Drugs Affecting the Gland. — ^The atropin group — paralyzing; the pilocarpin-eserin group — stimulation ; epinephrin — stimulating. According to the rule, atropin paralyzes the parasympathetic nerve-endings. Eserin and pilocarpin stimulate the parasympathetic nerve- endings. Epinephrin stimulates the sympathetic. The gland may also be stimulated reflexly over the parasympathetics through the second and seventh nerves. INTESTINAL SECRETION 179 Salivary Glands. — Nerves. — Sympathetics through the superior cervical ganglion and parasympathetics — through the chorda tym- pani, a branch of the seventh cranial. Function of the Glands. — To provide fluid to moisten the buccal cavity, the food, and to secrete a digestive enzyme, ptyalin. The nerves also supply fibers to the vessels of the gland; the s\Tripathetic are constrictors and the parasympathetic are dilators. Methods of Actiiig on Glands. — 1. Directly. 2. Reflexly: Taste, smell, movements, chewing, acids and pungent tasting substances. Direct Stiimdation. — 1. Through the Chorda. — Pilocarpin, eserin, muscarin, cholin. 2. Through the Sympathetic. — Epinephrin, cocain. Depression. — 3. Through the Chorda. — The atropin group. Depression. — 4. Through the Sympathetic. — Morphin — central action. Stimulation through action on all ganglion cells — nicotin, lobelin. Elimination of Drugs by the Salivary Glands. — Drugs are excreted in small amounts by the salivary glands. The following have been found: Iodides, bromides, hexamethyl- enamin, mercurial and lead compounds, quinin and some other alkaloids, sulphocyanides. Gastric Secretion. — Function of the gastric glands — secretion of digestive and diluting fluids. Nerves. — The stomach receives both motor and inhibitory fibers from the vagus. The finer anatomy of these is not known. It is probable that there are sympathetic fibers mixed with the para- sympathetic. The parasympathetic are motor; the sympathetic, inhibitory. The secretion of gastric juice is influenced by drugs, similarly to salivary secretion, but to a lesser degree. The pilocarpin group stimulates secretion. The atropin group diminishes it. From a practical standpoint the action of these drugs on the stomach in diseased condition is of little value, because they act on nerve-endings, and in most diseases where stimulation is needed the gland cell is involved or destroyed. In cases of hypersecretion the atropin grouj) of drugs are of value. Intestinal Secretion. — The secretion of intestinal juice is somewhat influenced \)y mechanical, chemical and thermal stimulation, but the extent of this and the mechaiiistri has been but little investi- gated. The amount of succiis entericus secreted by the small intestine has been estimated by Pn'gl at 3()()() c.c. j)er day. The juice was 180 PHARMACOLOGY OF THE GLANDS collected from a Thiry-Vella fistula and the total amount estimated. Succus entericus contains the following enzymes : 1. Enterokinase, which activates trypsin. 2. Erepsin. 3. Inverting or hydrolytic enzymes. 4. Nuclease, also secretin and prosecretin. The nervous control of the secretion has not been sufficiently investigated and there is practically no known pharmacology of intestinal secretion. Most investigations of the intestine have been confined to movement, absorption and excretion. When absorbed or given h\T)odermically the following drugs are excreted into the intestine, probably by the intestinal juice : 1. Ca, phosphates, sulphates, heavy metals, such as Fe, Cu, Zn, Bi, Hg. Mn, etc., morphin and other alkaloids, resinous cathartics, toxins, etc. Pancreatic Secretion. — ^Function of the pancreas — the secretion of digestive juices, probably also an internal secretion. Nerves. — ^\^agus and sympathetic splanchnic. The gland may be stimulated — chemically as by hormones, and through the nerves. 1. Stimulation by Parasympathetics. — ^The pilocarpin group of drugs, stimulate these nerves. 2. Inhibition through the Parasympathetics. — The atropin group, in small doses; large doses, in some way not understood, cause increased flow of juice. 3. Stimulated reflexly by mustard, spices, etc., acting on the duodenum. 4. Stimulated chemically through the blood by secretin, a sub- stance found in the duodenum and which may be prepared by grinds ing the duodenal mucous membrane with dilute hydrochloric acid. The two secretions — the chemical and the nervous, are different. The chemical secretion (due to secretin) is clear, watery, rich in alkali and poor in protein or organic matter, and. contains. but little ferment. It occurs after the administration of atropin. The nervous secretion is thick, opalescent, rich in ferments and poor in alkali. The normal relation of the two secretions is not well understood. Regarding the internal secretion of the pancreas, there is no phar- macology. No drugs are known which influence it. chapter xvii. phar:macology of the kidneys. The pharmacology of the kidney"is so important that the student is referred to the monograph on the "Secretion of the Urine," by Cushny/ for established facts, and Fischer's "Edema and Nephritis"- for suggestions. 1. Nerves. — So far as we know there are no secretory nerves to the kidney. This leaves the pharmacology a matter of circulation and direct action on the secreting cell. In all cases the act of secre- tion tends to dilate the vessels, and unless a drug which stimulates the secretory epithelium also constricts the vessels, it will act as a diuretic. 2. Blood-pressure. — Unless there is a blood-pressure of 40 mm. of Hg or more, practically no urine is secreted. After an essential pressure is established, the volume of urine secreted depends on the ^■olume of blood going through the kidneys. Theories of Diuresis. — Drugs can act only to modify the normal function of the kidney. This function is the secretion and excretion of urine. The mechanism of secretion is not satisfactorily under- stood. The student is advised to review the theories of secretion. 1. The Ludwig — filtration or physical theory. 2. Bowman — Heidenhain or secretory theory. 3. The modern view of theory which is more or less a combination of the first two, with modifications. Important Factors Modifying the Secretion of Urine .^1. The blood- pressure: To secrete at all the general blood-pressure must be 4(J mm. of mercury or over. 2. Free water must exist in the blood. Most of the water in the blood is in a colloidal or combined form. Some is being continu- ously absorbed and some excreted. The volume probably depends on the metabolic rate. Acids or acidosis increase the capacity of the proteins to hold water and lessens diuresis. Alkalies, salts, etc., lessen the water-holding capacity of the tissues and so increase diuresis. Man^- experimental facts support this theory. 3. Ab.sorption from the tubules seems an important factor in governing the amount of urine excreted. It may be assumed that • Longmans, Green & Co., 1917. ' Wiley & Sons. 182 PHARMACOLOGY OF THE KIDNEYS on passage through the tubules some of the secretion water may be reabsorbed, just as it would be on passage through the intestine: Diuretic salts then, may act by preventing reabsorption from the tubules just as cathartics act by preventing absorption from the intestines. In both cases there may also be a direct stimulating action on the parenchj^matous tissues. 4. Vasodilation. — Almost all substances on passage through the kidneys cause a vasodilation. If such substances do not injure the parenchymatous tissues they act as diuretics. Some substances which have a decided diuretic effect in minute amounts, are very harmful in slightly greater concentrations. Cantharidin and mer- cury are examples. Nerves of the Kidney. — The kidney is innervated by the vagus and by the splanchnics, through the celiac ganglion. These nerves, however, are not secretory but govern the vessels. The splanchnic is the chief motor nerve of the kidney and each is dis- tributed to the kidney of the same side. Diuretics.^ — Since there are no secretory nerves to the kidney, diiu-etics must act, either: 1. By increasing the volume of blood through the kidney. 2. By direct stimulation of the secreting cells. 3. By lessened absorption from the tubules. 4. By liberation of colloidal water from the tissue cells. 5. By a combination of all or any of these possibilities. Give the evidence for and against each of these possible mechanisms. The chief diuretics are: , 1. Caffein compounds. 2. The digitalis groups — in some conditions — edema. 3. Pituitary extract — not used for this purpose. 4. Salines — especially alkaline and absorbable salts. 5. Alkaline iodides. 6. Mercurials — especially when there is little catharsis. Antidiuretics. — All substances that increase sweating without the introduction of fluid: 1. Pilocarpin. 2. Arecolin. 3. Antipyretics. 4. Heat. 5. Camphor. 6. Large doses of opium. 7. Ammonium acetate and citrate. TLATE VII CAFFEINE An alkaloid existing iu cofiFee, tea, guarana, and cola nut. Classified as : Cerebral stimulant. Cardiac stimulant. Respiratory stimukint. Diuretic. Physiologic action : Kervous System. Cerebrum. Stimulates cortex, increasing the ac- tivity of psychic func- tions. Medulla. Stimulates res- piratory center and vaso- motor center. Vagus cen- ter may be stimulated, but the eflect masked by the direct effect upon the lieart. Muscular System. Initability tissue increased. Vagus Center Vaso Motor Center Cervical Sympathetic Voluntary Muscle and —Solar Plexus Circulation. Arterial pressure increased by vasomotor activity. Heart. Stiinulate> heart muscle, producing acceleration of the pulse. Capillary area. Contracts arterioles by stimulation of va.so- niDtor centev in the me i;cr cent, cafl'ein in water into the anterior lymph sac and make observations every few minutes. Notice the changes in irritability 186 PHARMACOLOGY OF THE KIDNEYS ■ — muscle cramps and a final paralysis. (Note the solubility of this alkaloid in water.) Compare the actions of caffein, strychnin and picrotoxin. Experiment IV. — Action of Caffein on the Frog's Heart. — Pith a frog and take heart tracings by the suspension method. Isolate and stimulate the vagus. Drop 1 per cent, of caffein solution slowly on the heart; take tracings and note whether or not there is any change in the vagus action. Continue the tracing until definite action is obtained. Fig. 40. — Method of arranging muscle for recording fatigue contractions. Experiment V. — Action of Caffein on the Turtle Heart. — Pith a turtle, expose vagi and take a record of the heart by the suspension method. Test irritability of both vagi. Irrigate the heart with 0.5 per cent, caffein by dropping the solution directly on the heart. Determine whether or not there is any change in the irritability of the vagi. Experiment VI. — The Action of Caffein on Turtle Heart Strips. — Prepare and take tracings of a ventricle strip suspended in 0.8 per cent, saline. When a good record is being obtained add sufficient 2 per cent, caffein in the same solution so that the concentration of the liquid in which the strip beats is 0.1 per cent, caffein. After thirty minutes change the concentration to 0.5 per cent, caffein; continue this until definite action is obtained. Experiment VII. — Action of Caffein on the Reflex Time of Frogs. — ■ Pith the animal and prepare for reflex time as under alcohol either by Tiirck's method or by electrical stimulation. Determine the average time of five reflexes. Then inject 1 c.c. of 0.5 per cent. SALINE DIURETICS 187 caffein in water into the anterior lymph sac and after fifteen minutes again determine the reflex time. Take average of at least five determinations. Experiment VIII. — Action of Caffein on Respiration. — Anesthetize a small dog with ether and prepare to measure blood-pressure, and respiratory volume with a spirometer. Place a cannula in the femoral vein for injection. Take a normal tracing and measure the expired air in minute intervals. Measure volume per minute and respiratory rate. Also make record of the respiration on the drum from the chest movements. This can be done by a rubber tube around the chest to which a tambour is attached. When normal tracings and volume measurements ar^ obtained, inject 1 c.c. of 3 per cent, morphin slowly into the femoral vein and note the changes in respiration every five minutes for fifteen minutes. Then inject intravenously 0.5 c.c. per kilo of 1 per cent, solution of caffein and again measure as before. Repeat injections if necessar}'. Tabulate results. Experiment DC. — Repeat Experiment IX under cocain, page 148, but use 1 c.c. 0.5 per cent, caffein. SALINE DIURETICS. All salts which are eliminated by the kidney are diuretics. In class experiments, sodium sulphate is often used and given intra- venously. However, when sulphates are given by mouth they are so slightly absorbed that little diuresis results. This is especially true if they produce catharsis. One must distinguish carefully between the theoretical and practical value of such procedures. Only salts that are absorbed and are excreted by the kidneys are practical diuretics. KNO3 is diuretic when given by mouth; if it is given intravenously, the potassium is so depressant that the action of the potassium may be so great that it will injure the heart. Potassium or sodium acetates are the most used. They have a double action, first the salt action, and second the alkaline reaction. They are oxidized to carbonates in the body. Salts may act as diuretics in three ways: 1. By direct action on the kidney. 2. By lessening the water-holding capacity of the body colloids. 3. By increasing the alkalinity, as in the case of the acetates.- Acidosis decreases the urinary flow by increasing the water-holding capacity of the body colloids. 188 PHARMACOLOGY OF THE KIDNEYS Experiment I. — Prepare a dog for measurement of blood-pressure, respiration and urine flow. Inject intravenously 5 per cent, of the animal's weight of 0.85 per cent, of NaCl solution. 1. Measure urine flow for thirty minutes. 2. Inject slowly 20 c.c. of ^ acid (HCl). Watch carefully that the injection does not kill the animal. Measure the urine for thirty minutes. 3. Inject 40 c.c. j-q of Na2C03 slowly and measure the urine for thirty minutes. 4. Inject slowly 3 per cent, of KNO3 until the heart shows symp- toms of depression. Measure the urine for thirty minutes. 5. Inject 30 c.c. of 10 per cent. Na2S04 and measure the urine for thirty minutes. 6. Inject 10 c.c. of y^ HCl and note the influence on the flow of urine. 7. Inject 10 c.c. of y^ Na2C03 and note the effect for thirty minutes. Experiment II. — Diuretic Action of Caffein on the Normal Animal. — 1. Select a male rabbit. Catheterize until the bladder is empty. 2. At the end of an hour catheterize again and measure the amount of urine. 3. Inject subcutaneously 10 mg. per kilo of body weight of citrate cafi^ein in water. 4. At the end of an hour catheterize again and measure the volume of urine. 5. Compare and discuss the results. What do you conclude as to the diuretic action of caffein. Experiment III, — 1. A group of from ten to twenty students should work together. Each one should empty the bladder com- pletely at the beginning of the experiment. 2. Then each one should drink 300 c.c. of water. 3. At the end of an hour empty the bladder and measure the volume of the urine. 4. Then each person should drink 300 c.c. of water, one-third of the students taking 2.5 grains of caffein, one-third 5 grains and one- third 10 grains.^ 5. At the end of one hour empty the bladder and measure the volume of urine. 6. Compare results and discuss briefly the diuretic action of the caffein. 7. A second group should carry through this same experiment but without drinking any water. PHENOLSULPHONEPHTHALEIN 189 PHENOLSULPHONEPHTHALEIN. Kidney Function. — This drug is not used in therapeutics, but as a diagnostic test of kidney function. When the kidneys are normal, about 60 to 80 per cent, of this is excreted within two hours after the h>i^odermic injection. Experiment I. — Take seven rabbits and place each in a separate clean metabolism cage. Two days before the experiment inject — 1. With 2 c.c. per kilo of 1 per cent, arsenious acid, AS2O3, subcu- taneously. 2. With 1 c.c. per kilo of 10 per cent, potassium bichromate. 3. Each day for three days preceding the experiment, 1 c.c. per kilo of 0.5 per cent, uranium nitrate. 4. Mercuric chloride, 5 c.c. per kilo of 0.2 per cent, for two days preceding the experiment. 5. Five c.c. per kilo of 5 per cent, ammonium oxalate. 6 and 7. Controls. Empty the bladder of each and inject hypodermically 2 c.c. of a 6 mg. per cubic centimeter solution of phenolsulphonephthalein. Also give each one 20 c.c. of 0.9 per cent. NaCl. In two hours empty the bladder of each one and determine how much of the phenol- sulphonephthalein has been excreted. Compare with the controls. What is the condition of the animals at this time? Experiment II. — Anesthetize each of the animals with ether. Insert a bladder cannula for collection of urine and a cannula in the jugular vein for injection of solutions. Wait ten minutes between each injection and measure the urine for each period. 1. Inject 20 c.c. of 0.19 per cent. NaCl. 2. Inject 5 c.c. of 2 per cent, sodium citrate. ;3. Inject 2 c.c. of 0.05 per cent, citrated caffein. 4. Inject 10 c.c. of 0.5 per cent, theobromine sodium salicylate. 5. Inject 2 c.c. of 0.5 per cent, calomel in 1 per cent, sodium thiosulphate. Make a chart showing the efl'ect of each drug on each animal and compare with the normal animals. Experiment m. — Inject subcutaneously with aseptic precautions 2 c.c. of a 0.5 mg. solution containing per cubic centimeter of phenolsulphonephthalein into 10 students. In one or two hours determine the amount excreted. If a colorimeter is not available the amount of coloring material can be determined as follows: (a) Place the urine in a 500 c.c. or 190 PHARMACOLOGY OF THE KIDNEYS 1000 c.c. graduate; add sufficient NaOH to color. Make up to 100 c.c. or 200 c.c. mark. (6) Place 0.5 mg. per cubic centimeter of phenolsulphonephtha- lein or the amount injected subcutaneously in another graduate of the same size. Alkalinize with NaOH and dilute until the color matches the urine. From the degree of dilution of the standard required to match the urine the percentage excreted can be determined. CHAPTER XVIII. PHARIVIACOLOGY OF SWEAT-GLANDS. Function. — The sweat-glands are excretory organs for salts and water mainly. There is some nitrogenous matter also, but not of sufficient amount to reckon in metabolic experiments. In cases of uremic poisoning and other pathologic states the nitrogen elimina- tion by the sweat-glands may be increased. Distribution of the Glands. — 1. In man and horses the whole surface of the skin contains sweat-glands. 2. In dogs and cats sweat-glands are found on the feet only. 3. Rabbits, rats and mice have no sweat-glands. Innervation. — The sweat-glands are under the direct control of sjVTnpathetic nerves and the drugs acting on the secretion of sweat act mainly on the nerve-endings, although there are centrally acting diaphoretics. We do not know that any drugs act directly on the glands. The striking peculiarity of the nerves to the sweat-glands is that although sympathetic they are stimulated by pilocarpin and paralyzed by atropin in a manner similar to autonomic nerves; likewise epinephrin is without influence on them. They provide the one great exception to the rule that epinephrin stimulates sympathetic nerve-endings and pilocarpin stimulates autonomic endings. Drugs that act on the nerves governing the secretion of sweat may act (1) centrally and (2) peripherally. The drugs acting on the sweat centers are ammonium salts, picrotoxin, camphor and strychnin to some extent. The proof that they act centrally is that they fail to act after section of the nerve to the part or after high section of the cord. The location of the sweat center is not definitely known. It is, however, above the fifth spinal segment, because cases in the human are known in which fractures at this level, with injury to the cord, stopped sweating below the injury, not above. The center is prob- ably located in the medulla. In the cat, in addition, it has been established that there are at least two spinal sweat centers, one for the forelimbs in the lower cervical and another for the hindlimbs in the dorsal region. Diaphcjretics acting on the nerve endings are pilocarpin, muscarin, eserin, and arecolin. 192 PHARMACOLOGY OF SWEAT-GLANDS Proof that the action is peripheral, is that they act after section of the nerves. Other drugs and agents acting centrally. Most drugs that exert an antipyretic effect act centrally and in large doses cause sweating. The sudorific glands are affected in the same way as the sweat- glands, but have not been so carefully studied. ENDOCRINAL PHARMACOLOGY. Concerning the pharmacology of the endocrinal glands, we must say that more numerous experiments have been made in feeding glands and extracts and some definite results on blood-pressure, respiration, etc., have been gotten, but regarding the modification of the function of each of these glands by drugs or otherwise, little has been learned. Those glands like the adrenals that have a nervous mechanism, can be stimulated by drugs like nicotin and perhaps depressed by general depressants, but little of anything definite has yet been learned. CHAPTER XIX. PH.\RMACOLOGY OF THE LIVER, MAMMARY GLANDS, UTERUS AND BLADDER. PHARMACOLOGY OF THE LIVER. Main Functions of the Liver. 1. Secretion of bile. 2. Carbohydrate transformations. 3. Sympathetic functions. 4. Interrelative functions with other organs. Secretion of Bile. — This is controlled by the vagus and splanchnic nerves. Drugs Influencing the Formation of Bile are Termed Clwla- gogues. — The bile stimulants are: 1. Bile itself. 2. Bile salts. 3. Soaps. 4. Albuminoses. 5. Dilute HCl. 6. Salicylates and benzoates. 7. Calomel. Drugs Stimulating movement of the Gall-bladder. — Pilocarpin. Drugs Lessening Movement of Gall-bladder. — Atropin. Atropin is frequently used in gall-stone colic because of this property. Excretion of Drugs by the Bile. — Cu, Pb, Hg, menthol, methylene blue, am}'l alcohol, hexamethylenamin and other drugs have been reported in the bile. They occur, however, only in traces, except hexamethylenamin, which is said to be excreted in quantities sufficient to sterilize the bile. The Glycogenic Function of the Liver. — This is influenced by a large number (;f drugs, but tlie action may be indirect. In fact, while it is well known that the liver is exceedingly important in carbo- hydrate metabolism, the mechanism of the action is little under- stood, and while the action of many drugs on this metabolism has been studied to some extent, it is the liarmful action that has been most studied. \'ery little is known of drugs that have a beneficial 13 194 PHARMACOLOGY OF THE MAMMARY GLANDS effect on the glycogenic function of the liver. The harmful effect is usually manifested by an increase in the sugar content of the blood and by glycosuria, though a hypoglycemia may also occur. Drugs Influencing the Carbohydrate Metabolism of the Liver. — 1. Epinephrin is necessary for the normal process; in large amounts hypodermically it causes glycosuria. 2. Salts injected intravenously cause hyperglycemia and glyco- suria. 3. It may be influenced in the same way by many drugs acting on the nervous system, as strychnin, caffein and others. 4. Certain other drugs which greatly depress the animal, like hydrazins, peptons, etc., given intravenously, may cause hypo- glycemia. The other chemical functions of the liver, liKe the formation of urea, its action in fat metabolism, its function in blood coagulation, etc., are markedly influenced by the internal secretions of other glands like the thyroid, adrenals, etc., and also by chemical agents. The actions of phosphorus, hydrazin, arsenic, etc., on the liver are striking. PHARMACOLOGY OF THE MAMMARY GLANDS. The fimction of these is milk secretion. They are markedly influenced by the internal secretion of the ovaries, and probably they give off an internal secretion, but distinct evidence of this has not been presented. Drugs theoretically might stimulate or decrease the volume of milk secreted. As a matter of fact, however, drugs have little influence on milk secretion. Nerves.^ — Experimental investigation shows that the mammary gland is little, if at all, under the direct influence of the nervous system. That such nerves exist, however, is unquestionable, as shown by the marked influence of emotional states on milk secretion. Mackenzie,^ from an investigation of the mechanism of milk secretion, concludes that: 1. The secretory activity of the gland is not under the influence of the nervous system. 2. Agents that modify the secretion reach the gland by the blood. 3. Extracts of the pituitary, corpus luteum, pineal body, the uterus and the mammary gland itself stimulate secretion. 4. The pituitary gland is the most active stimulant. 5. Inhibitory hormones are produced by the fetus and placenta. 1 Quart. Jour, of Exp. Physiol., 1911, iv, 305. PHARMACOLOGY OF THE UTERUS 195 6. Drugs such as pilocarpin and atropin that influence the secretion of most glands are without effect. 7. Because of the ineffectiveness of the drugs mentioned in (6) it is conchided there are no demonstrable secretory nerves to these glands. This is supported by electrical stimulation of nerves going to the glands. Lactagog^ues. — Practically there are none. The secretion of milk is said to be lessened by the administration of KI and by the local application of belladonna. In the latter case the analgesic action on the sensory nerves, may be confused with an action on the secretory mechanism. Elimination of Drugs in the Milk. — Iodides, bromides, salicylates antipATin, arsenic, mercury, hexamethylenamin, morphin, atropin, etc., have been found in the milk of animals. PHARMACOLOGY OF THE UTERUS. The uterus, like the intestine, is in more or less continuous movement. These movements are automatic, that is not initiated by nerve impulses, but controlled by the nerves. The motor nerves are autonomic, from the nervus pelvicus (Erigen's) and inhibitory from the sympathetic from the hypo- gastric plexus. Drugs modifying uterine movements, may act: 1. On the muscle directly, (a) Hypophysis extracts, (6) barium salts and (c) ergot. Hypophysis acts directly on the muscle and causes maximal con- traction. Barium also acts directly on the muscle and stimulates it. 2. On the ganglion cells, (a) Nicotin: The result of nicotin varies, depending on the species of animal and the predominating ganglion cells, much in the same way as epinephrin. 3. On the nerve-endings. Epinephrin. — The uterus receives sympathetic nerves from the hypogastric plexus. The action of epinephrin is identical with stimulation of this plexus, but it differs in different animals. The uterus receives through the sympathetic both motor and inhibitory fibers. The predominating action varies with the animal and with the condition of the animal. Thus, stimulation of the hypogastric nerves of the non-pregnant cat causes inhibition. In the pregnant state it causes contraction. In the rabbit the usual result in all cases is contraction. In the dog, contraction is followed by inhibi- tion. Epinephrin acts similarly to stimulation of this plexus. 196 PHARMACOLOGY OF THE UTERUS Atropin. — In small doses atropin may increase the action, but in larger amounts always inhibition. This is the usual atropin action on autonomic nerves, except the primary stimulation which in most regions is absent. ' Physostigmin and PUocarpin. — These drugs exert their usual action on autonomic nerve ends — stimulation. Ergot. — The fluidextract of ergot is the principal preparation used in medicine. The recent work of Dale has simplified greatly the knowledge of ergot action. It contains three active ingredients : ergotoxin, tyramin and ergamin. cl Ergotoxin and tyramin act like epinephrin and stimulate the myo- neural junction of the true sympathetic nerves. There are some differences, however, between the action of epinephrin and these. The action and differences are as follows: 1. Epinephrin acts on both motor and inhibitory nerves, and under special conditions, therefore, may cause a fall of blood- pressure. 2. Ergotoxin stimulates the vasoconstrictors only. Large doses may paralyze these, so that after ergotoxin, epinephrin may cause a fall in bloodrpressure. 3. Tyramin acts on both motor and inhibitory nerves, but only to a small extent on the inhibitory. 4. Ergamin does not act on the nerve-endings at all, but on the non-striated muscle directly. 5. Different samples of ergot may differ in action, depending on the relative amounts of these bases present. Also in pregnant animals when there is a development of sympathetic nerves the action varies from that in the non-pregnant animal. Study these actions in detail from the text. Experiment I. — Action on the frog; take three frogs; give one 0.5 c.c. of fluidextract ergotse. Give the second 1 c.c. and the third 2 c.c. Inject into the abdominal lymph sac. Experiment II. — Action of Ergot on the Arterioles. — (a) Place a frog on the boards and examine the capillary circulation of the web of the foot. Make a sketch of the field and give the animal 0.5 c.c. fluidextract ergotse and repeat observations at five-minute intervals. (b) Repeat (a), using 1 c.c. of the fluidextract. (c) Repeat (1) and (2), using the mesentery instead of the foot for observations. Experiment III. — Action of Ergot on the Blood-pressure, Respira- tion, Pupil and Vagus Tone. — Prepare a dog for blood-pressure and respiratory tracings. Insert a cannula in the femoral vein for injec- PHARMACOLOGY OF THE UTERUS 197 tion. Isolate a loop of the intestine for observation of the action on the capillaries. Make normal tracings and inject the fliiidextract of ergot, 0.5 c.c. at a time, and repeat every five minutes until the animal dies. Note the action on the heart, respiration, pupil and intestines. A tracing of the intestinal movements may be taken by one of the methods under epinephrin. Experiment IV. — Action of Ergot on the Heart Stri2)s. — Prepare a heart strip, and when it is beating regularly add fluidextract of ergot gradually until the bath contains 10 per cent, of the fluidextract. Fig. 41.- -Frog on cork plate to show method of preparation for studying the circula- tion in the web of the foot. Experiment V. — Action of Ergot on the Uterus. — Take segments of the uterus of a guinea-pig, cat or rabbit and arrange for tracing as with a heart strip. Keep the bath at 40° C. When it is contract- ing rhythmically, add, drop by drop, some fluidextract of ergot. In the preparation of uterine strips certain precautions are necessary to get results. 1. An anesthetic if used in removing the uterus acts to prevent the rhythmical movements. 2. Shock or brutal manipulations have the same effect. It is best to remove the head of the animal quickly with a pair of large scissors or a sharp knife Then the uterus is removed quickly, using 198 PHARMACOLOGY OF THE UTERUS a forceps and scissors — do not handle — and place in well-aerated warm (40° C.) saline, and always handle with these precautions in mind. Experiment VI. — Study the effect of ergot on the uterus when injected intravenously by Barbour's method. Fig. 42. — Method of examination of circulation in the web of a frog's foot, apparatus consists of a cork plate with a hole in it. The Experiment VII. — Standardization of Ergot. — No satisfactory method is available. Three more or less satisfactory methods are used: 1. Blood-pressure method. 2. Cock's-comb method. 3. The uterine method: (a) Isolated Uterus: Experiment V; (b) in situ: Experiment VI. The blood-pressure method is the easiest and perhaps the most reliable. 0.08 c.c. of the fluidextract per kilo of body weight should cause a rise in blood-pressure of 30 mm. Hg. in the dog. PHARMACOLOGY OF THE UTERUS 199 Anesthetize a dog with ether. Keep the anesthetic regular and prepare for blood-pressure and respiratory tracings. Prepare for injection into the femoral vein. Then proceed as follows: 1. Take normal tracing of about three inches on the drum. Then stop driun. 2. Inject 0.04 c.c. per kilo body weight of the fluidextract and wait five minutes. 3. Take a three-inch tracing on the drum. Stop drum and wait five minutes. 4. Then take another tracing. Keep this up until three or four tracings are taken. The blood-pressure of each will be different. If the first injection causes a fall in pressure of more than 35 mm. Hg. or a rise of more than 50 mm. Hg., the dose should be reduced one-half. If the fall is less than 25 mm. or the rise less than 24 mm. the dose should be doubled. 5. The same animal may be used for three or four injections if one allows sixty minutes to elapse between injections. Experiment VDI. — The Cock's-comb Method. — ^This method is used by some manufacturers to determine the strength of an unknown quantity of ergot by comparing its effects with the effects of an equal quantity of standardized ergot. Leghorn cocks with large combs and wattles are advised; they are used in preference to the others because the common barnyard fowl varies too greatly in its reaction. The cock to be used must not be fed for twenty-four hours previously. Examine the color, temperature and general appearance of the comb and wattles. Then with a hypodermic syringe inject deep into the breast muscles 5 c.c. of a first-class preparation of fluid- extract of ergot. The drug may also be given into the crop with a soft-rubber catheter. Place the animal in ar quiet place and observe it carefully, from time to time, for at least one or two hours. Do you note any change in the appearance of the comb and wattles? If so, at what time after the injection is the change at its maximum? If you had a stan- dardized preparation and a non-standardized preparation of the fluidextract of ergot, could you compare the relative strengths of these two solutions by their relative actions in the same sized doses on roosters of approximately the same size, age and sensitivity to the drug? Note the action on the intestine. The method is not very satisfactory. 200 PHARMACOLOGY OF THE BLADDER PHARMACOLOGY OP THE BLADDER. The bladder is merely a reservoir. The muscular coat is strengthened at the cervix by a circular coat, which acts as the sphincter vesicae internus, while around the urethra on the outside of the bladder is the sphinctei- vesicae externus. When the urine accumulates to a certain extent the pressure reflexly stimulates the sphincters. Nerves. — The bladder receives motor fibers from the second to the third sacral nerves — autonomic — through the N. Erigentes from the hypogastric plexus. It also receives sympathetic fibers from the second to the fifth lumbar nerves, reaching the bladder through the inferior mesenteric ganglion. Local application of epinephrin will usually cause a relaxation. Atropin is given in cases of enuresis to inhibit the urinary reflex by an action on the auto- nomic nerve-ends. The small amounts that escape in the urine in therapeutic doses could scarcely exert this influence. Antisepsis. — Various drugs are given in cystitis, etc., with the idea of disinfecting the urine. Among these are (1) hexamethylenamin, which acts only in acid reaction; (2) sodium benzoate and salicy- late, (3) various volatile oils such as copaiba, cubeb, oleum santali. A study of these comes more directly under antiseptics, than under the dynamics of the bladder. CHAPTER XX. PHARMACOLOGY OF THE MUSCLES. The muscles are divided into two great groups: L Voluntary: Mastication. Respiration. Locomotion. 2, Involuntary: Cardiac. Smooth. The function of muscles is contraction. This results in motion, oxidation, reduction, etc., with consequent formation of heat and chemical changes. Stimulation may result in: 1. Greater contraction. 2. More prolonged contraction. 3. The ability to do more work. 4. Greater chemical activity. Drugs may cause stimulation or depression (1) by acting directly on the muscle; (2) indirectly through the nerve; (3) indirectly through the circulation. VOLUNTARY MUSCLES. Why one group, the voluntary, should be under the control of the will and another, the involuntary, should be beyond the control of the will cannot be answered. The fact that in one case, volun- tary, the mcjtor nerves arise in the brain anterior to the fissure of Rolando and that the effector neurone goes direct from the anterior portifni of the cord to the muscle, does not explain the control of this group. As far as we know, one set should be as much under the control as the other. Again, why one set may be paralyzed by curara and another by atropin, or why one set should be stimulated by epincphriii and another by acetyl cholin or pilocari)iii, is beyond our grasp at the present time. It is probably due to chcnnical (iifl'iT cent, calcium. What is the efl'ect? Rabbits are very easily killed by air embolism. 212 PHARMACOLOGY OF MUSCLES Experiment IV. — Prepare several turtle heart strips. Place 1 (a) in normal saline. When it is beating rhythmically add a sufficient quantity of barium chloride to make the solution 0.01 per cent. (b) To number (2) in the same way add sufficient CaCl2 to make it 0.03 per cent. When there is marked action on the beat exchange (a) and (6). If an exchange cannot be made conveniently change the solution in both. CHAPTER XXI. PHARMACOLOGY OF THE LYMPHATICS. Lymph is the colorless fluid which fills the lymphatic vessels and surrounds the tissue elements. The movement is from the tissue to the veins and this movement is due to (1) the difference in pres- sure of the lymph at its origin and the pressure in the larger veins, (2) to the movement of the muscles, etc., (3) to the movements of respiration, and (4) in certain animals, notably the frog, it is due to the rhythmic action of lymph hearts. Fig. 45. — Po.sterior lymph hearts in the frog. The beating of these hearts will facilitate the spread of a drug in the frog after the blood heart has been removed, L, posterior lymph hearts; GL, gluteus muscles; 7C', iliococcygeus; P, pyriformis; R. rectus; VE, va.stus externus. (After Ecker.) The physiology of lymph formation is not settled, therefore the pharmacology must be somewhat incomplete. Certain facts are definite, but depending on whether we consider the lymph a secre- tion or a filtration the exjjlaiiation will vary. Ludwig taught that lymph is formed by filtration, and in minor degree by dill'usion. Heidenhain believed that lymph is secreted by the cai)illary epithelium. Drugs that cause a flow of lynijih are called lyinj)hagogues. Heidenhain classifies these: 214 PHARMACOLOGY OF THE LYMPHATICS Class I: Peptone. Leech extract. Extract of crayfish muscle. Egg albumen. Protein substances, these increase the amount, specific gravity and the total solids of the lymph — probably due to injury of the vessels — inflammation. Class II : Salts, sugar, etc. Crystalline substances that increase the volume but cause a more watery lymph. Experiment I. — Anesthetize a dog and record arterial pressure, insert a cannula into the thoracic duct and measure the flow of lymph. Now inject slowly 5 c.c. of a 5 per cent, peptone solution and note the changes in lymph flow and blood-pressure. Repeat until definite action is obtained. Experiment II. — Repeat Experiment I, using potassium iodide sugar, etc. Test the lymph for presence of the drugs used. Experiment III. — ^Test the effect of pilocarpin and atropin on the flow of lymph as in the previous experiment. An extract from the lymph glands of animals has been employed in exophthalmic goiter, lymphadenoma and other glandular swell- ings, but the results are not thought to be of any permanent value. From a practical standpoint the flow of lymph must be influenced through the factors that are most concerned in its circulation, viz. : 1. The circulation of the blood. 2. The condition of the muscles. 3. Respiration. The fact that the atropin or pilocarpin have no influence on the flow of lymph, indicates that it is not a secretion. CHAPTER XXII. GENERAL PROTOPLASM POISONS AND MISCELLANEOUS. HYDROCYANIC ACID. Hydrocyanic acid is a general protoplasmic poison. It is classi- fied by Loew a "substituting" poison because it reacts with the aldehyde group forming substitution products. The nature of the combination is so strong that it is fatal. It is for this reason a gen- eral protoplasmic poison. The main actions of the cyanides are: 1. A destructive action on enzymes. 2. Primary stimulation and paralysis of the nerve and medullary centers. 3. A paralysis of the oxidative processes in the muscle. 4. An action on the blood-formation of methemoglobin and cyanhemoglobin? (See Fig. 55, page 239.) Experiment I. — Drop 1 c.c. of 5 per cent. KCN solution into the mouth of a small cat. Note carefully the symptoms. Experiment II. — Count the heart-beat and respiration of a dog and inject intravenously 1 c.c. of 1 per cent. XaCN or KCN. Record results. Experiment in. — Action of the Cyanides on Respiration, Blood- pressure, and Blood and Oxycjen Consumption. — (a) Give a dog a hypodermic injection of 2 c.c. of 3 per cent, morphin sulphate. (6) In thirty minutes anesthetize with ether and prepare for blood- pressure and respiration tracings and measure the exhaled air with a spirometer. Place a cannula in the femoral vein for injections. (c) Take normal tracings and measurements. id) Inject 1 c.c. of 0.1 per cent, sodium cv'anide per kilo. If there is a noticeable effect, measure the change in the ex])ire(l air. (e) Repeat with double the dose of the cyanide. (j) When aspliyxial symptoms become marked, examine the blood microscopi(;ally and with the spectroscope. ig) Take 0.5 c.c. of blood and test its action on hydrogen peroxide as in the Ix'ginning f)f the experiment. ill) llydrocsiuiic acid is siij)j)ose(i to com})ine with loosely-bouiid sulphur ill proteins to form IISCX, which is not nearly so toxic 216 GENERAL PROTOPLASM POISONS AND MISCELLANEOUS as HCN. For this reason sulphides have been advised as antidotes in cyanide poisoning. (i) When the symptoms of asphyxiation are marked, run into the femoral vein 1 c.c. of 5 per cent, sodium sulphide or calcium sul- phide. Run this in slowly as sulphides are also toxic. Repeat the sulphide injection if necessary. (j) If the animal shows a return toward normal, make complete records. (k) Repeat the sulphide injection if it is thought advisable. Collect urine at the end of each experiment with the cyanides and test for sugar. ACIDS, ALKALIES AND CORROSIVES. Experiment I. — Prepare an animal for blood-pressure and respira- tion tracings. Insert a cannula in the femoral vein for injection from a burette. (a) Take normal tracing. (6) Inject slowly until symptoms of marked depression are apparent, ^g- HCl or any other acid. (c) When respiration or heart shows signs of collapse, quickly inject the same amount of y^ Na2C03. (d) Repeat (6) and (c). If animal is still living, use for one of the following experiments. Experiment II. — Corrosire Action of Acids and Alkalies. — These experiments should be carried out on animals that have been used for some other work, as it is not necessary to waste animals for these experiments alone. Respiration and blood-pressure tracings should be taken at the same time. The animals should be deeply anesthetized. Inject 50 c.c. of the following solutions through a stomach tube, and after thirty to sixty minutes remove the stomach with the esophagus and the upper part of the small intestine. Spread on a white paper or plate for comparison. (a) 50 c.c. NaOH, 40 per cent. (b) 50 c.c. NH4OH, concentrated. (c) 50 c.c. HNO3, concentrated. (d) 50 c.c. HCl, concentrated. (e) 50 c.c. H2SO4, concentrated. (/) 50 c.c. phenol, 95 per cent. (g) 50 c.c. phenol plus 95 to 100 c.c. glycerin. (h) 50 c.c. cresol. SULPHIDES 217 (0 50 c.c. picric acid concentrated in water. (j) 50 c.c. acetic glacial. (A') 50 c.c. phosphoric, 50 per cent. (/) 50 c.c. HgCla, 0.1 per cent. Experiment III. — Set up four fermentation tubes with 10 per cent, glucose. Inoculate with yeast. Keep: 1. For control. 2. Make slightly acid with HCl. 3. Make weakly alkaline with NaaCOs. 4. Make strongly alkaline with NaOH. Compare the rate of fermentation at 40° C. Experiment IV. — Put about 10 grams of muscle or glandular tissue in each of seven test-tubes and cover with: 1. Concentrated H2SO4. 2. Concentrated HCl. 3. Concentrated NaOH. 4. Concentrated acetic acid. 5. Phenol 95 per cent. 6. Concentrated HNO4. 7. Tincture iodin. After fifteen minutes wash off the chemical and compare with the original. SULPHIDES. The sulphides are readily absorbed and excreted by the lungs. Experiment I. — Compare this with ammonia. Anesthetize a dog. Insert a tracheal cannula. Take blood-pressure tracing from the carotid and respiratory tracing from the abdomen. Inject slowly 1 per cent, sodium sulphide or ammonium sulphide into the femoral vein and hold a piece of paper moistened with silver nitrate or lead acetate at the tracheal cannula. Note the time necessary to detect the excretion of the sulphide. Experiment 11. — Repeat with calcium sulphide. Determine the toxic dose and the cause of death. This has been advised in mercuric chloride poisoning. Experiment III. — Action of Sulj)hides on Yeast Fermentation. — In a series of fermentation tubes containing 10 ])er cent, cane sugar containing yeast add: 1. 0.01 per cent, sodium or potassiinn sulphide. 2. 0.05 per cent, sodium or potassium sulphide. 3. 0.1 per cent, sodium or potassium sul})hide. 4. Control. What is the effect ou fermentation at 40° C? 218 GENERAL PROTOPLASM POLSONS AND MISCELLANEOUS Experiment IV. — Coat the hairy surface of the arm with a layer of CaS, prepared by rmuiing HoS into milk of lime, and in a few minutes scrape it off with a scalpel. What is the result? Experiment V. — Examme the chest of an anesthetized animal with a stethoscope. Allow to mhale the fumes of dilute H2S. Continue the inhalation until symptoms of edema take place. State findings and give explanation. OXALATES AND FLUORmES. Experiment I. — (a) Put a pinch of powdered sodium or potassium oxalate into a test-tube. Add 5 c.c. of blood and shake. Compare the clotting time of oxalated blood with normal blood. (b) Use potassium or sodium fluoride as m (a). Experiment II. — (a) Anesthetize a dog and prepare for blood- pressure and respiratory tracings. Inject slowly into the femoral vein 0.1 per cent, sodium oxalate. When depression is marked inject 1 per cent, calcium chloride slowly. Oxalates are general protoplasmic poisons, because they precipitate calcium salts and calcium is necessary to the life of protoplasm. (b) Use 0.1 per cent, potassium fluoride as in («). IODIDES. 1. Excretion. — Take 0.5 gram KI in a capsule. After fifteen minutes collect about 5 c.c. saliva, add a few drops of H2SO4 and an equal volume of 1 per cent, sodium nitrite and shake with 5 c.c. of cliloroform. If I is present it will dissolve the chloroform with a violet color. Repeat every five minutes until I is detected. Then again m twenty-four hours. Test the urine in the same way. 2. Twelve students in groups of six each should study the absorp- tion of iodides from the gastro-intestinal tract as follows: Six study the time of absorption and excretion on an empty stomach, i. e., 11 A.M. or 4 P.M., and the other six immediately after a midday meal. Compare the average time of absorption as manifested by the above tests. The results with the iodides will, in general, hold good for the other drugs. What is the philosophy of giving drugs sometimes before, sometimes after meals? 3. Many of the uses and supposed benefits of the iodides can be studied only in clinical cases. Their mode of action is still obscure. HEAVY METALS 219 HEAVY METALS. These have a local and a general action. The local action is due to their combining with the proteins. The general action appears only after absorption and is manifest mainly on the kidney, circulation, and central nervous system. 1. Test the action of a few drops of 5 per cent. AgNOa, HgCb, Fe2Cl6, CuS04, Pb (€211302)2 and ZnS04 on a solution of egg white or blood serum. 2. Give a dog 5 mg. per kilo of mercuric chloride. Watch this animal for several days or until he dies. Note especially heart-rate, nervous symptoms and the action on the kidneys as manifested by the urine and by the postmortem. 3. Action on yeast: Shake a cake of yeast in 500 c.c. of 2 per cent, dextrose. Fill a series of fermentation tubes. Keep one for control and to the others add 0.1 c.c. and 1 c.c. of the solution in Experi- ment I. Note the results in thirty minutes and in twenty-four hours. Local Action. — Heavy metals unite with proteins to form pro- teinates. The proteins may play the part either of acid or base. These salts are not true chemical compounds, i. e., they are not of definite composition. The amount of the heavy metal in the precipitate varies. The precipitating action on proteins causes the heavy metals to act as astringents, and it also explains the vomiting caused by the heavy metals. As astringents they may act in three ways: 1. By the formation of albuminates, with the liberation of free acids, and the acid also causing some astringent action. 2. The metal may be absorbed locally and so constrict the local vessels. 3. The insoluble salts, like bismuth subnitrate, may cover and protect the surface mechanically. General Action. — The general action of the heavy metals is seen only after prolonged ingestion. The general symptoms and actions of the heavy metals differ mainly in the rate of absorption. There is little difference in the toxicity of arsenic and iron when injected into the blood. Mercur}' is the only heavy metal which is absorbed from the alimentary canal in sufficient quantity to produce acute poisoning other than corrosive. Chronic poisoning arises because excretion is slower than ab.sorption. 220 GENERAL PROTOPLASM POISONS AND MISCELLANEOUS Symptoms of Metallic Poisoning. — G astro-intestinal. — Loss of appetite, pain and discomfort, nausea, vomiting, purging, hemor- rhages and congestion. Ulcers may occur if the animal lives long enough. Lead and some others may induce constipation and griping, but they may also elicit purging. Kidney. — Irritation, inflammation, cirrhosis, etc. Circulation. — ^Little direct action; late in poisoning some action may result from disorders of nutrition. Some dilation of the vessels of the intestines and fall of blood- pressure. In the case of lead the vessels may be constricted and pressure high. The blood, as a rule, less alkaline, is due to the increase of lactic acid. Central Nervous System. — As a general rule, stimulation of some parts and depression of others. Delirium, hallucinations, mania, stupor, coma. Convulsions indicating that the motor areas, basal ganglia and spinal cord are affected. The different types of convul- sions may occur. Lesions of the brain have been found. Peripheral neuritis, especially with lead and antimony. This neuritis does not differ from that caused by alcohol or toxins. Metabolism. — Some of them may in small amounts produce changes similar to that produced by phosphorus. Colloidal Heavy Metals. — Copper, platinum, silver, etc., are some- times used in medicine. The basis for their use is the action of minute amounts of copper on infusoria and other unicellular organisms. POTASSIUM SALTS. Experiment I. — Absorption arid Excretion. — (a) Take 0.5 gram KI in a capsule and test the saliva every ten minutes for the presence of the salt, as follows: Place the saliva in a test-tube or on a white tile and acidify with a drop of nitric acid, then add a few drops of 1 per cent, starch paste. A blue color indicates the presence of iodin. (6) Collect the urine every fifteen minutes; add a few drops of nitric acid and a few drops of the starch paste. Experiment 11. — Action of Potassium Salts on the Heart and Vessels. — Prepare a turtle heart strip, and when it beats rhythmically in saline, add KCl so that the fluid contains 0.01 per cent KCl, 0.02, 0.04, 0.08 and 1 per cent. When depression is marked, replace the solution with 0.9 per cent. NaCl solution. Experiment III.^ — Action of Potassium on Reflex Time. — Pith a frog and study the reflex time by Tiirck's method. Inject 0.5 c.c. of AMMONIUM 221 potassium bromide and determine the change in reflex time after thirty minutes. Experiment IV. — Anesthetize a dog and take blood-pressure and respiration tracings; inject 1 per cent, of KCl slowly until the heart is markedly depressed. Then inject 10 c.c. of 1 per cent. CaCl2. Repeat with KCl. AMMONIUM. Experiment I. — Give a dog 2 c.c. of 3 per cent, morphin sulphate hypodermically; after thirty minutes count the heart and respira- tion-rate. Now inject 5 c.c. of 2 per cent, ammonium chloride per kilo and note the changes in the rate of the heart and respiration. Anesthetize the animal; prepare for blood-pressure and respiration tracings and for injection into the femoral vein. Slowly inject 1 per cent, ammonium chloride until spasms develop. Notice the character of these and compare with strychnin. Finally, give sufficient strychnin to produce tetanus. Experiment II. — Inhalation of Ammonia. — Give a dog 2 c.c. of 3 per cent, morphin h^T^odermically. In thirty minutes anesthetize with ether. Prepare for blood-pressure and respiratory tracings. Isolate the vagi, but do not cut When the animal is well anesthe- tized let him inhale a 10 per cent, solution of NH4OH. What is the result? Now cut the vagi and continue the inhalation. If spasms do not develop soon, let him inhale 20 per cent, ammonia. Note the strength of the solution. If allowed to inhale a weak solution the absorption is so slow that spasms do not develop readily. Note the condition of the lungs at the end of the experiment. Experiment m. — (\)unt the pulse and respiration of a rabbit. Hold a piece of cotton with ammonia to the nose of the animal or blow the ammonia vapor into the nostrils. Stoppage of the respiration or slowing or temporary arrest of the heart follows. Trigeminal vagus reflex. Experiment IV.— In a series of frogs inject into the abdominal lymph sac: 1. 0.2 c.c. of 5 per cent, ammonium chloride. 2. 0.5 c.c. of 5 3. l.Oc.c. of 5 4. 2.0 c.c. of 5 If convulsions develop, note the type. Pith or destroy the brain and the incdulla. How does the action of ammonia dift'er from strychnin '! 222 GENERAL PROTOPLASM POISONS AND MISCELLANEOUS EXPERIMENTAL GLYCOSUEIA. This may be caused by: 1. Lesions of the nervous system. 2. Asphyxia. 3. The intravenous injection of salts and drugs. 4. By the subcutaneous, intravenous or intraperitoneal adminis- tration of epinephrin. 5. By the action of phloridzin. 6. Excessive use or administration of sugar. The mechanism of the action in any case is not well understood. Experiment I. — Inject 1 or 2 c.c. of 1 to 1000 epinephrin subcu- taneously into a rabbit. In two hours catheterize and test the urine for sugar. Too large a dose of epinephrin administered may kill the animal. Experiment II. — Give a rabbit I gram of phloridzin dissolved in 5 c.c. of olive oil subcutaneously. In an hour catheterize and test the urine for sugar. Experiment III. — Draw blood from the femoral or jugular vein of a dog and determine the amount of sugar by the Benedict method (page 242). Inject into the abdominal cavity 1 gram of phloridzin dissolved in about 7 c.c. of olive oil. In one or two hours catheterize and test the urine for sugar. The amount may also be determined. Test the sugar concentration of the blood when the sugar appears in the urine. Give a rabbit a hypodermic injection of 3 c.c. of 3 per cent, morphin. Collect the urine after two hours and test for sugar. Is there any change in the type of respiration? Is Cheyne-Stokes type manifest? Morphin causes glycosuria by asphyxia. Experiment IV. — Anesthetize a cat and inject a molecular length of the solution of sodium sulphate slowly into the femoral or jugular vein. Cats are easily killed by the injection of sulphates if it is made too rapidly. Collect the urine and test for sugar frequently. Experiment V. — Give a dog or cat 1 gram of potassium cyanide by mouth in 50 c.c. of water. When death occurs collect the urine and test for sugar with Fehling's solution. BERNARD'S METHOD OF PUNCTURING THE FLOOR OF THE FOURTH VENTRICLE (PIQURE). The instrument he used is shown in the figure (Fig. 46). The end of the instrument is thin and chisel-like and fashioned for boring. A BERXARD'S METHOD OF PUXCTURING THE FLOOR 223 very thin central point, about 1 mm. long, and needle-like, extends beyond the fluted end. This sharp point punctures the floor of the Fig. -10. — The instrument to make the puncture (piqilre). Fig. 47. — Occipital bone of the rabbit, showing landmarks for piqure as described by Bernard. On the head of the rabbit the finger is run along the central line until one feels the tuberosity, .4, which corresponds to the .superior occipital process B. Immediately behind this process (B) the needle or drill is worked through the bone C, C, auditory tubes. 'PUNGURm INSTRUMENT. •6EREBELLUM. AUDITORY TUBE^ MEDULLA ORim OF 5EVENTH NERVE. Fig. 48. — Outline of the rabbit's head, to .show the course of the needle in piriurc. (After Bernard.) fourth vcntric-Ic l)et\veen acoustic and piicumogastric nerves. To accomplish this the animal's head is held in the left hand, witlian assistant holding the feet. The finger of the right hand is |)assed over 224 GENERAL PROTOPLASM POISONS AND MISCELLANEOUS the skull until one feels the tuberosity figure (Fig. 47). Just posterior to this tuberosity the instrument is inserted between the spongy tissue and the bone. By a boring pressing movement the instru- ment is forced through the bone into the cranial cavity. The instrument is then directed obliquely to the middle point between the angles of the animal's lower jaw (Fig. 48) or to cross a line which extends from one ear to the other. During this operation the least movement of the animal may cause a fatal laceration of the respiratory center. The attenuated end or needle of the instrument touches the bacilaire when the instrument is withdrawn. If the operation is properly done the animal suffers very little incon- venience. There is no convulsion or great disturbance of respira- tion. The prolonged point of the instrument touches the bone and prevents a fatal compression of the nervous tissue by the thicker part of the instrument. The animal is a little stunned for the moment, but rapidly recovers. In one or two hours sugar appears in the urine. TUBtRCLE OF WtHZEL. <- LOBE OF CEREBELLUM. FLOOR OF FOURTH VEHTRICLL ORm OF VAGUS tiERVE POINT OF CALAMUS •SCRIPTORIUS. Fig. 49. — -Showing the fourth ventricle of a rabbit. (After Bernard.) Practice is necessary for this operation, and it may first be done on the dead animal and a postmortem performed to locate the site of the puncture. The second animal may be anesthetized, and if a dental drill or other suitable instrument is at hand the skull may be entered by that means. A very light hat-pin will suffice for the puncture needle. Diuretic puncture: A similar puncture to that described, but slightly higher in the calamus results in a polyuria without glyco- suria. This polyuria may last as long as forty-eight hours. FERMENTS, ENZYMES AND DIGESTANTS 225 FERMENTS, ENZYMES AND DIGESTANTS. All focxl is digested by ferments. Indigestion is one of the most common causes of sickness. It is natural to think, therefore, that the pharmacology of digestion or fermentation would be highly important; however, such is not the case. The study is full of interest, but of little value so far as the practice of medicine is con- cerned. Digestants are prescribed liberally, but are almost certainly useless, and the practice has fallen off much in recent years. Besides being prescribed as digestants, enzymes such as trypsin and papain have been injected into pathological tissues with the idea of digesting them, and so acting as caustics. The most important enzymes in pharmacology may be classified as follows: 1. Coagulating — thrombin and rennet. 2. Amidases — ptyalin and amylopsin. 3. Pepsin. 4. Tr\'psin. 5. Erepsin. 6. Catalases or those that liberate oxygen from hydrogen peroxide. The general properties of these need not be rehearsed. We know nothing of their structure, as they are colloids of unknown composi- tion, and as such are killed by heat, antiseptics, etc. When injected intra^•enously they produce toxic symptoms resembling albumoses and peptones; but this may be due to adhering albuminoid mate- rial. Powders like kaolin or charcoal when shaken with solutions of ferments absorb the ferment. In the same way, and perhaps to a greater extent, ferments are absorbed by the material upon which they act probably because of electrical attraction. (For a detailed account of enzymes, see Biochemical Catalysts in Life and Industry, Effront and Prescott, also Oppenheimer, Die Fermente.) Experiment I. — In a series of test-tubes place 5 c.c. of milk, 5 c.c. of reiniin and 5 c.c. of the following solutions: 1. Water. 2. Physiological saline. 3. Formaldehyde 1 to KKK). 4. Mercuric chhjride 1 to lOOO. 5. Pancreatin, 0.1 per cent. 6. Phenol, 1.1 percent. • 7. AgN():i, 0.1 per cent. 8. KOI I, 0.1 i)er cent. 0. IICI, 0.1 jRT cent. 226 GENERAL PROTOPLASM POISONS AND MISCELLANEOUS Experiment II. — Repeat Experiment I, using 5 c.c. of 1 per cent, starch, 5 c.c. of saliva, diluted one-half and filtered, and 5 c.c. of the above solutions. Experiment III. — Repeat Experiment I, using 5 c.c. of 1 per cent, trypsin, 5 grams of washed fibrin and 5 c.c. of the solutions in Experiment I. Experiment IV. — ^Run about 10 c.c. of blood from an artery into 3 c.c. of the following solutions: 1. Water. 2. Liquor sodii chloridi physiologicus. 3. 5 per cent, peptone. 4. Saturated magnesium sulphate. 5. 1 per cent, potassium oxalate. 6. 1 per cent, hirudin. 7. 0.1 per cent. KOH. 8. 0.1 per cent. HCl. 9. 1 per cent, sodium citrate. 10. 1 per cent, sodium carbonate. Discuss results in each case. CHAPTER XXIII. PHARMACOLOGY OF THE BLOOD. Function. Volume. Relative I'ulumes of Corpuscles and Serum. Viscosity. Clotting. — Calcium, adrenalin, gelatin, hirudin, peptone, oxalates, fluorides, etc. Alkalinity, Acidosis. Distribution in Tissues. Drugs and Conditions Changing J^olume and Distribution. Laking. Composition. Sugar, content of. Glycolysis. Detoxicating, action of. '' Blood-pressure: Muscle, nerves, heart. FUNCTIONS OF THE BLOOD. The Functions of the blood are: 1. To carry nutritive and energy-yielding material to the tissues. 2. To carry waste products from the tissues. 3. It is the medium of transmission of the internal secretions. 4. It aids in regulating the temperature of the body. 5. It carries oxygen from the linigs to the tissues and carbon dioxide from the tissues to the lungs, to the respiratory center and wherever needed. ' These functions relate blood closely to every tissue in the body, and changes in the blood must modify the function of each tissue; but the physiology or pharmacology of the blood itself may be studied without reference to any other tissue. To perf(;rm its functions normally, blood has certain qualities or properties and drugs may modify tliese, quantitatively only: I. Vohirne.— 'rhv amount of l)]()od in the vessels is normally one-thirteenth to oiic-fourteciith of the body weight, and serious 228 OUTLINE FOR PHARMACOLOGY OF THE BLOOD consequences follow any marked variation in the total volume or its distribution. 2. Distribution. — The distribution of this among the various organs in the rabbit is given by Ranke as follows ■} Per cent. Spleen 0.23 Brain and cord 1 . 24 Kidneys 1.63 Skin 2.10 Intestines 6.30 Bones 8.24 Heart, lungs, large vessels 22.76 Resting muscles 29.20 Liver 29.30 There is little occasion to attempt a reduction of the volume of the blood by drugs, though in cases of plethora it might be bene- ficial. As a matter of fact, however, it is not a very successful undertaking. Diaphoresis, diuresis, catharsis and the withholding of fluids from the food or drink may lessen the volume somewhat, but the object of such treatment is usually to remove toxins or other poisonous material or to favor the absorption of pleural, peritoneal exudates or edematous fluid rather than to reduce the volume of the blood primarily. VOLUME OF THE BLOOD. The volume may be increased by excessive drinking; the result, however, is very temporary. Anything that causes a dilation of the vessels, as the nitrites, may cause a very transient increase. Usually, however, the increase in volume is local, because drugs that dilate the vessels usually do so locally and not generally. Increasing the volume of the blood is a more frequent and suc- cessful undertaking. After cases of severe hemorrhage a trans- fusion of blood is 6ften made. Similarly, after operation or shock the blood-pressure may be raised by increasing the blood volume either by transfusion or by the injection of saline. In cases of chlorosis or anemias, iron and other drugs may increase the blood volume by increasing or building up red corpuscles. Hygienic and dietetic treatment may yield similar results. VISCOSITY. A certain viscosity seems necessary for blood to perform its proper function. If there be deficient colloidal matter to which the 1 Howell, p. 458. VISCOSITY 229 viscosity is due, the fluid tends to leave the vessels and to accumu- late in the tissues. This is the cause of the relative failure of saline injection in cases of low blood-pressure due to shock or hemorrhage. It has been found in these cases, if saline alone be injected, that the rise in blood-pressure may be relatively short, because the fluid leaves the vessels either by way of the kidney or into the tissues to cause an edema. For this reason the addition of gum arabic or some other colloid, or the transfusion of blood, has been advocated. Diminished viscosity also permits certain crystalloids like sugar to pass through the kidneys and perhaps also into the tissues. This can easily be shown by comparing the rate of dialysis in whole blood and serum. Sugar will dialyze from serum much more readily than from the whole blood. Adrenalin and calcium salts increase the clotting of the blood and perhaps also its viscosity, while oxalates, potassium iodide and fluoride, organic substances, such as peptone, pepsin, snake venom or hirudin, lessen viscosity. Anything that lessens the amount of protein in the blood or the volume of the corpuscles may lessen viscosity. Normally, the protein of the blood is about 8 per cent. The volume of the corpuscles, however, is about one-half the total volume. Consequently, we should expect the blood to be of much greater viscosity than water. The proteins are hydrophyllic colloids. Changes in acidity or alkalinity markedly modify the water-holding capacity of the pro- teins and consequently change the viscosity. This viscid character is the most striking distinction of the organic and inorganic colloids. An 8 per cent, solution of blood has 4.4 to 5.5 times the viscosity of water. The viscosity of the blood is greater than serum, although the serum volume for volume con- tains almost twice as much protein as the blood, GO to 39. The viscosity bears a close relation to the number of corpuscles, as shown by the following table :^ Number of corpuscles Viscosity of serum per cubic millimeter. plus corpuscles. 1.9 3.2 times 10« 3.3 6.3 " 10" 4.9 12.6 " 10" 15.6 Increase in temperature reduces the viscosity, since at 37° it is 10 per cent, less than at 17°. An increase of 5° in fever • Mathews: Physiological Chemistry, p. .'512. 230 OUTLINE FOB PHARMACOLOGY OF THE BLOOD may reduce the viscosity 4 per cent. Increase in the hydrogen ion concentration of the blood increases the viscosity. Since CO2 increases the hydrogen ion content, venous blood has a greater viscosity than arterial. Dyspnea increases it; hunger, salts, diminish it, while a meat diet increases viscosity. There are many condi- tions in the practice of medicine when the heart requires rest and relief from overwork and the viscosity of the blood is important, since the greater the viscosity the more work is placed on the heart to keep it circulating. CLOTTING OF THE BLOOD. Clotting is another mechanism for increasing the viscosity, but the phenomenon is so striking that it is generally considered by itself. However, the mechanism may be an extreme case of protein swelling due to absorption of water, such as occurs when an acid is added to gelatin. It is rendered more hydrophyllic, swells, and has a greater viscosity. This is an important fundamental property of the blood, since if it were not present, everyone would be a hemophilic, or rather none would survive. It is a property essential to life. The real nature of it is not fully understood and probably will not be until we know more of the nature of matter. It is generally accepted that the fibrin formed during the clotting is derived from fibrinogen. This substance can be prepared in solution free from other proteins. The mechanism of the clotting has been presented by Howell in his Physiology. He prepares fibrinogen as follows: Collect horses' or cats' blood by allowing it to escape from the vessel without coming in contact with the wounded surface or tissue into a solution of sodium oxalate of such strength that the final volume contains 0.1 per cent, oxalate. Centrifuge and obtain clear plasma and add an equal volume of saturated sodium chloride. This precipitates fibrinogen, centrifuge and remove the supernatant liquid. Wash with a half-saturated solution of NaCl and then dissolve with stirring in a 2 per cent, solution of NaCl and filter. This is precipitated again by half- saturation with NaCl, centrifugalized, washed and the process repeated a third time, and the washed precipitate dissolved in a 1 per cent, solution of NaCl. It is sometimes necessary to add a few drops of a 0.5 per cent, solution of sodium bicarbonate to get this last precipitate into solution. CLOTTING OF THE BLOOD 231 The solution so prepared will not clot except on the addition of blood serum containing the so-called fibrin ferment thrombin. If instead of thrombin Ca salts be added, and some sodium bicar- bonate about the same concentration as in Ringer's solution, a clot may be formed, but very slowly. This, Howell thinks, is due to the fibrinogen containing a ti-ace of thrombinogen, the antecedent of thrombin. Thrombin may be prepared as follows: Allow blood to clot, remove the serum and precipitate with 20 volumes of alcohol, let stand for a week and then filter. Dry the precipitate, grind it and extract it with water. The aqueous solution contains thrombin in addition to other proteins. A solution made in this way will cause the precipitation of fibrinogen. That thrombin is not present in normal blood, however, is shown by the fact that blood led directly from the artery into alcohol and extracted in the same manner as above will not yield a clot. Calcium is necessary for normal clotting. This was shown by Arthus and Pages by adding sodium oxalate to plasma, so that the concentration was 0.1 per cent. It was then dialyzed until the excess of oxalate was removed. Dialyzed plasma will remain unclotted indefinitely, but clots immediately if a little calcium be added. The role of calcium in clotting is in the conversion of prothrombin into thrombin, because it has been shown by Hammarsten that dialyzed oxalated plasma is readily clotted if some thrombin solu- tion free from calcium be added to it. The process of clotting may be represented as follows: Ca + thrombinogen = thrombin. Thrombin + fibrinogen = fibrin. Since blood that comes in contact with tissues clots much more quickly than blood drawn without touching tissue, it is generally accepted that the tissues furnish an activator or kinase — thrombo- kinase that hastens clotting. To illustrate this properly the following formula is used : Cellular elements = thrombokinase. Thrombokinase + calcium + thrombinogen = thrombin. Thrombin + fibrinogen = fibrin. The pharmacology of clotting is concerned with any changes in the bkjod or its environment that alter the rate or nature of clotting. Means of Hastening or Retarding Clotting.— Ik'forc; nil operations the clotting tiinc is or should be dcterniiiicd. Normally, blood clots in from three to ten minutes. If for any reason clotting does not occur, or is long delayed, the operation may l)e contra-indicated. 232 OUTLINE FOR PHARMACOLOGY OF THE BLOOD Conditions Delaying or Preventing Clotting are: 1. Loiv Tempera' tiire. — This can best be shown with blood that normally is slow in coagulating. The blood of the horse, terrapin or birds coagulates slowly. If horse's blood be collected in narrow vessels surrounded by ice the clotting is so long delayed that the corpuscular elements, being of greater specific gravity than the plasma will sink gradually to the bottom and the clear yellow plasma can be pipetted off. Similarly, with the blood of all species, clotting is delayed, but in most cases coagulation even on cooling will be too rapid for the preparation of plasma. 2. Coagulation is delayed hy anything that precipitates or removes calcium as the oxalates or citrates. These remove the calcium in insoluble form, and prevent the formation of the ferment necessary for clotting. 3. Strong solutions of MgSOi, and of Na^SOi prevent clotting. The explanation of this is not well understood, but it is believed to be due, in a measure, to their preventing the disintegration of the cellu- lar elements, thus delaying or preventing the formation of thrombo- kinase. It is known that tissue products accelerate clotting and that blood within the veins does not readily clot. It may also be due to the precipitation of the calcium with these strong sulphate solutions. Similarly: 4. Sodium Fluoride prevents clotting, perhaps by precipitation of the calcium as fluorides. It may also lessen ferment action, and this would be an additional factor. 5. Certain organic substances, like pepsin, trypsin, peptone and hirudin, when injected, intravenously, prevent clotting. The mechanism of the action here is not understood, but it may be that these bodies cause an increase of antithrombin. Prevention of clotting is of use only in experimental work. It is never desired in medicine. Agents Hastening Clotting. — Much more important than delaying clotting is the hastening of it. This cannot be done in the best way until we understand normal clotting. Since calcium is neces- sary for clotting, one of the first methods employed to hasten clotting is the administration of calcium salts. The value of these is questionable. The intravenous injection of adrenalin also aids clotting. If this be given too quickly, however, there is danger from the increased blood-pressure. Pressure to a bleeding surface aids coagulation, and the presence THE ALKALINITY OF THE BLOOD AND ACIDOSIS 233 of gauze, sponges, or clothes, or other bodies also aids. Pressure by causing the liberation of thrombokinase and acting as a foreign body furnishes a nucleus for the deposit of fibrin crystals, and also aid in the rupture of blood platelets, etc., and in this way hasten coagulation. THE ALKALINITY OF THE BLOOD AND ACIDOSIS. One of the essentials of life is an alkaline reaction. The actual alkalinity, while near neutrality, is yet insured against this actual neutrality by a reserve or potential alkalinity that is available in case of necessity. An acid reaction is due to an excess of H ions; alkalinity is due to free OH ions. In water which is neutral in reaction, the H and OH ions are in equal numbers, H times OH=10-i^ The product of H and OH in any dilute solution is always equal to this figure, consequently, when we know one we can calculate the other. An increase of H ions means a diminution of OH ions and vice versa. Hydrogen Ion Concentration.- — By this expression we mean the concentration of dissociated H, in terms of a normal solution. For example, if one gram of hydrogen is dissociated in 10,000,000 liters of water the concentration is 10"^ normal. Method of Expressing H Ion Concentration. — It would obviously be cumbersome to express a dilution of one molecule of dissociated H in 10,000,000 liters of water by 0.0000001 and in biological work we are dealing mainly with these dilutions. A less cumbersome method of notation is therefore advisable. Consequently, the above dilution is written H = 10-^ At the present time the custom is to use the logarithm only and to avoid the negative sign. The reciprocal 7 is used so that 10^ really would mean 10"^ In order to save space and to express the concentration expli- citly, Sorensen has suggested a plan which is very widely adopted. He expresses the potential or concentration of the H ions as PHi, PH2, PH3, etc., where PHi = /o acid or H = 10-' PH« =TOfto'«oo acid or H = lO"" PH? = Neutrally or H = 10"' PHs = Tftooooo alkali or H = lO's PHh = xff alkali or H = 10"" PHu = r alkali or H = lO"'^ 234 OUTLINE FOR PHARMACOLOGY OF THE BLOOD This system is brief, but confusing until studied. Since the numbers refer to negative logarithms the higher the number the fewer H ions in a given volume, while the OH ions increase. This + is quite comprehensible when we remember that H times OH is always 14 or 10~^*. If PH is 14, it follows that OH must be zero, and if PHi is y^ acid P OHimust also be yq alkali. As now employed Sorensen's figures are the logarithms of the dilution in terms of normal solution. PHi4 is y alkali, and when H is PHi3 = P0Hi the solution is Yq alkali. Potential Alkalinity. — The weakly alkaline condition of the blood is guaranteed by a mixture of H2CO3, NaHCOs and NaH2P04. These are all very weakly dissociating substances and may be considered in the blood to be in a balanced state: H2CO3 ,^ J NaH2P04 = K and — ^ ^^ ^^ = K2 NaHCOs N2H PO4 When K and K2 are constants and the sum of these constants in terms of H ions is about PH, 7.1 to 7.8 and may be briefly repre- sented as: H2CO3 NaHCOs Ki If acid be added to this directly or indirectly, as in cases of acidosis, it liberates H2CO3. This will either break into CO2 and H2O and K, kept constant, or it will tend to act with Na2C03 if such be present and restore the constant in that way. If enough acid be added or developed the whole alkali reserve may be exhausted. The phosphates are balanced in the same way. According to Michaelis and Garmendia the ratio of NaH2P04 1 , , „^^ = -.r—^ molecules. Na2HP04 5.1 Since the normal blood always contains CO2, NaHC03 and Na2 HPO4 in this balanced state the H ion concentration at any one time cannot be determined by titration, because as fast as the actual alkalinity is removed the potential alkalinity is converted into actual. Consequently, the titration alkalinity is the sum of actual and potential. SPECIFIC GRAVITY OF BLOOD 235 This difference between the actual and total alkalinity of the blood is known as the "buffer" value and NaHCOa and Xa2 HPO4 are the buffers, XaHCOs especially. The value of this buffer is illustrated by comparing the effect of acid added to a liter of water and to a liter of XaHCOs. The reaction of a solution of pure X'aHCOs is very weakly alkaline. Water is neutral. A drop of acid added to a liter of water will definitely acidify it. When added to a solution of X'aHCOs, however, it will not change the actual alkalinity and will not exceed the acidity of CO2 until all of the X'aHCOs has been decomposed. The amount of acid required to do this will depend on the amount of the X'aHCOs in solution. In other words, on the buffer value of the solution. The carbonates are the chief biological buffers. Acidosis. The actual significance of this term varies in many minds. As generally accepted, a state of acidosis exists w^hen large amounts of acetone, aceto-acetic acid, and in the more severe cases, ^-oxybutyric acid, are excreted in the urine. This occurs frequently in diabetes. The actual alkalinity of the blood may not be changed for a long time, but these bodies as they are excreted combine with and exhaust the reserve alkalinity or buffer alkalinity. Normal adults excrete 3 to 15 mg. of combined acetone and aceto- acetic acid per day. Over 20 mg. is considered pathological. The amount may be increased by fasting, and by and by an exclusively carbohydrate diet, diabetes, intoxications of pregnancy and other diseases may cause an abnormal amount to develop. SPECIFIC GRAVITY OF BLOOD. The specific gravity of the blood has so far been no aid in diagnosis. Normally it varies between 1.045 to 1.075. The simplest method of determining the specific gravity is that of Hammerschlag, which consists of mixing CIICls, specific gravity 1.520, and benzol, specific gravity 0.090, until the mixture has the specific gravity of about 1.055 as y adding 20 grams of sodium chh^ride to the blood solution to raise tli(; boiliiig-j>oint. J)o not char the blood by direct heat. Test the distillate direct with ferric chloride or shake the distillate with ether; exajif^rate the ether and test the residue. 16 242 OUTLINE FOR PHARMACOLOGY OF THE BLOOD CARBON DIOXIDE. Experiment I. — Anesthetize a dog with ether and prepare for blood-pressure and respiratory tracings. Administer CO2 from a nitrous oxide apparatus. Study especially the action on the blood- pressure. Alternate with O2. Experiment II. — Remove the mask and allow the animal to return to normal. Now shut off the trachea with a clamp and take a tracing until the animal shows signs of impending death; then remove the clamp and resuscitate. Experiment HI. — Give curara until the respiratory muscles are paralyzed. Insert a tracheal catheter for intratracheal insufflation. Alternate with oxygen and carbon dioxide and observe the effect on the heart. Experiment IV. — Solid carbonic acid (carbonic acid snow) has been used as an irritant in chronic inflammatory conditions also as a local anesthetic, due to its freezing powers. It is also used for the preparation of histological sections. LEWIS-BENEDICT METHOD OF DETERMINING BLOOD SUGAR. Dissolve 36 grams of picric acid in 50 c.c. of 1 per cent. NaOH. Cool and dilute to 1000 c.c. Take 2 c.c. of blood and wash out into a test-tube with 4 c.c. water to lake. When laking is complete make up to 25 c.c. with the picrate solution. Shake and filter. Measure 8 c.c. into a tube graduated at 12.5 c.c. and 25 c.c. Add 1 c.c. of 20 per cent. Na2C03 and heat in a water-bath for fifteen minutes. Compare the color of this solution by means of a colorimeter with that of a 0.1 per cent, solution of dextrose in picrate solution which has been treated in exactly the same way as the blood. It makes little difference what volume of blood is taken provided the same volume of the standard solution is taken. The volumes given in the original method are for convenience in calculation where a permanent standard is used. I believe the better method is to make the standard new with each determination.^ PHLORIDZIN. Experiment I. — Dissolve 0.25 gram of phloridzin in 4 c.c. of olive oil and inject subcutaneously into a rabbit. Collect the urine with a catheter every thirty minutes and test for sugar. 1 Jour. Biol. Chem., 1915, xx, 61; ibid., 1919, xxxvii, 503. SAPONINS 243 Experiment II. — Give a rabbit 2 c.c. of epinephrin, 1 to 1000 hypo- dermically. Collect the urine and test as in Experiment I. Experiment III. — Take a sample of blood from a dog and deter- mine the amount of sugar by the Benedict method. Dissolve 1 gram of phloridzin in 7 or 8 c.c. of olive oil and inject subcuta- neously or intraperitoneally. Collect the urine every two hours and test for sugar. When sugar appears, determine the amount and also the amount in the blood at the same time. Experiment IV. — Determine the blood-sugar in a dog's blood. Give it a h^1^odermic of 2 c.c. of epinephrin every fifteen minutes for five times. Collect the urine at the end of two hours. Determine the amount of sugar in the blood and compare with the phloridzin animal. SAPONINS. From a chemical standpoint most saponins are non-nitrogenous glucosides, but because of some striking ph^^sical actions in which they resemble soap they are called saponins. They foam when shaken in water and emulsify fats. They are not absorbed from the intact alimentary canal, but have a local irritating action. In small doses they are expectorants. Quillija, senega root and sarsaparilla owe their action to saponins. They are little used for this purpose and have a very limited use in medicine. If a solution of saponin is added to blood or injected into the circulation it causes a laking of the red corpuscles with free hemoglobin in the serum and urine. The laking is due to changes in the corpuscular envelope. The most toxic saponins are called sapotoxins. Experiment I. — Shake a few drops of tincture of soap bark with a little water. Xote results. Add about 2 c.c. tincture of soap bark to about 1 inch of cott(mseed oil in a test-tube and shake. Result? What is emulsification? Experiment II. — Shake a solution of saponin in water. Study the relation fjf sa])onin to surface tension by placing a little sulphur in water and comparing the effect with sulphur dusted on a 1 per cent, saponin solution. How would you detect saponin in plant extracts? Experiment III. — Laking of blood by saponin. (a) I'o .') c.c. of blood add 0.5 c.c. of 8 per cent, saponin solution in 0.9 i)er cent. Xa(^l. (h) As a control use 0.5 c.c. of 0.9 per cent. XaCl solution. Keep the mixtures at 40° C. Laking soon occurs in the saponin solution. 244 OUTLINE FOR PHARMACOLOGY OF THE BLOOD Experiment IV. — Cholesterin neutralizes the action of saponin. Prepare test-tubes as follows : 1. Five c.c. of 0.9 per cent. NaCl. 2. Five c.c. of 0.9 per cent. NaCl, containing 0.5 c.c. of 3 per cent, saponin. 3. Same as 2, but in addition add 0.2 of 1 per cent, solution of cholesterin in ether. 4. Five c.c. of blood plus 0.2 c.c, cholesterin in ether. 5. Five c.c. of distilled water. To each tube add 0.25 c.c. defibrinated blood and set in an incubator at 40° C. Observe in fifteen and thirty minutes. Which tubes can you read printed matter through? Experiment V. — Taste a 0.1 per cent, solution of saponin. Do not swallow more than 1 c.c. Experiment VI. — In the following experiments record changes in heart-rate, respiration and general symptoms. Give by mouth to a dog 10 c.c. of 0.1 per cent, solution of saponin per kilogram body weight. Note and record symptoms. Experiment VII. — Give a dog 2 c.c. per kilo of 0.1 per cent, solution of saponin hypodermically. Experiment VIII. — Give a dog 1 c.c. per kilo of 0.1 per cent, saponin intravenously. Experiment IX. — Take a tracing of a frog or turtle heart and per- fuse or irrigate it with 0.01 per cent, saponin in 0.8 per cent. NaCl. Compare result with digitalis. LIST OF STOCK SOLUTIONS. These solutions are kept for convenience and may be diluted when needed. They should be made up in 0.8 per cent. NaCl or in Ringer's solution. Adrenalin hydrochloride or other epinephrin solution, 1 to 1000. It is preferable to purchase this in tablet form of such strength that one tablet in 1 c.c. will make a 1 to 1000 solution. Aconitin, 0.1 per cent., also the tincture. Alcohol, various solutions . . . . 1 to 80 per cent. Amyl nitrite 1 per cent, and in 3 minim and 5 minim pearls. Atropin 0.1 and 1 per cent. Acacia 6 per cent, freshly made. Barium chloride 0. 01, 0. 1, 1 per cent. Caffein 0. 1, 0.5, 1, 2 per cent. Caffein citrate 0.1, 0.5, 1, 2 per cent. Caffein sodio-benzoate .... 0. 1, 0. 5, 2 per cent. Calcium chloride 0.1,0.3,0.5, 1 per cent. Carbolic acid 0.5, 1, 5 per cent. LIST OF STOCK SOLUTIONS 245 Chloral hydrate Chloroform . Cocaine, HCl . Codeine phosphate Curara . Digitalis Ergot, fluidextract, dilute as needed. Ether Hyoscyamin Morphin sulphate Nicotin . ;e as Nitioglj-cerin Physostigniin or physostigmin sali- cylate Pilocarpin nitrate Potassium chloride Potassium bromide ... Quinine, HCl . . .... Quinine bisulphate Sodium nitrate Sodium sulphate Strj-chnin, nitrate or sulphate Thebain Veratrin . 0. 1, 1, 2 per cent. 0.05, 0. 1, 0.5 per cent. 0.01, 0.2, 0.5, 1 per cent. 0.5, 1 per cent. 0.5, 1 per cent., slightly acidify with /g HCl. 0.0005, 0.001, 0.002, 0.1, 0.5 percent., also the tincture. 1, 2, 5 per cent. 1 per cent, of the hydrochloride and the hydrobromide, also the tincture. 0.3 per cent, make up as needed. 0.1, 1 per cent, with a little «__ HCl diluti needed. . 1 per cent. 0. 1 and 1 per cent. 0. 1, 1 per cent. 0.03, 0.1, 5 per cent. 0.03, 0.1, 5 per cent. 0.1,1 per cent. 0.1,1 per cent. 0.01, 0.05, 1 per cent. 1, 10 per cent. 0.01, 0. 1, 1 per cent. 0.5,1 per cent. 0. 05, 1 per cent. INDEX. Abducent nerves, 100 Absorption, 85 acceleration of, 85 drugs acting after, 91 from alimentary tract, 85 retardation of, 85 Accessory nerves, 104 Acetonitril, 164 Hunt's test for, 164 Acidosis, 233, 235 Acids, 216 hydrocyanic, 215 Aconitin, 117 bio-assay of, 119 main actions of, 117 Squibb's test for, 119 Acoustic nerves, 101 Adaptation, 58 Administration of drugs, method of, 24 Adrenalin, standardizing of, method of, 115 Affinity, elective, 23 Alcohol, 121 action of, antiseptic, 90 on heart, 121 on pupil, 121 on reflexes, 121 effect of, on student, 123 as a food, 92 group of drugs, action of, 91 reactif)n of, on student, 123 Alcohol-chloral grouj) of drugs, 121 action of, on heart, 121 Ahmentary tract, action of drugs on, 56 Alkalies, 216 AlkaUnity of blood, 233 potential, 233 Ammonium, 221 Anesthesia, 29, 124 chlon)fonn, symptoms of, 125 closed method of, 132 ether, 126 and chloroform, 124 8ymi)toiiis of, 124 for dogs, cats, rabbits, guinea- pigs, 31 local, 30 morphin-ether, 32 Anesthesia, nitrous-oxide, 132 specific action of, 133 symptoms of, 124 tests for, 31 Anesthetic action of cocain, 147 Anesthetics, action of, on central nervous system, 29 chief local, 57 effects of, on circulation, 129 on respiration, 129 on temperature, 129 Animals, care of, 29 Anodynes, local, 57 Antagonism, 163 chemical, 163 definition of, 163 physiological, 163 Anthelmintics, 84 classification of, 84 Antidiuretics, 182 Antipyi'esis, 173 Antipyretics, 173, 174 Antisepsis, 200 intestinal, 87, 89 Antiseptic action of alcohol, 90 dusting powders, 89 ] Antiseptics, 88 Areas of brain, motor, 93 exposure of, 93 I influence of drugs on, 93 Aromatic bitters, 71 Astringent bitters, 72 Astringents, 81 I classification of, 82 I Atropin, actions of, 152 on third nerve, 161 Atropin-pilocarpin group, 152 Autonomic drugs, 149, 152 system, classification of, 149 drugs acting on, 152 B Bakium salts, 211 Benedict's method of determining vis- cosity of sugar ill blood, 242 Bernard's experiment, 138 "sugar puncture," 222 Bitters, 71 ad ion of, 72 248 INDEX Bitters, aromatic, 71 astringent, 72 compound, 72 local action of, 72 principle, 71 therapeutic use of, 73 Bladder, pharmacology of, 200 Blood, alkahnity of, 233 clotting of, 230 agents hastening, 232 theories of, 231 corpuscles, fragiHty of, 238 permeability of red, 240 function of, 222 laking of, 235 agents causing, 236 pharmacology of, 227 specific gravity of, 235 sugar in, Benedict's method of determining viscosity of, 242 volume of, 228 Blood-pressure, factors concerned in maintenance of, 106 methods of increasing, 107 of lowering, 107 pharmacology of, 106 recording of, 51 Bloodvessels, action of nitrites on, 119 Brain, areas of, motor, 93 exposure of, 93 influence of drugs on, 93 Bromides, 133 actions of, 133 on central nervous system, 133 Burns, treatment of, 66 Caffein, 183 action of, on central nervous system, 183 on frog, 185 on heart, 184 on kidneys, 184 mechanism of, 184 on respiration, 184 Calcium salts, 211 Cannabis, 134 action of, on central nervous system, 135 assay of, 135 preparation of, 136 standard of, 136 Carbon dioxide, 242 Carminatives, 74 Cathartics, 78 classification of, 78 therapeutic, 79 definition of, 78 Caustic poisoning, 70 symptoms of, 70 treatment of, 70 Caustics, 69 Central nervous system, action of anesthetics on, 29 of bromides on, 133 of caffein on, 183 of cannabis on, 135 of curara on, 137 of morpliin on, 32 of picrotoxin on, 137 of strychnin on, 137 Cerebrum. See Central nervous sys- tem. Chloral-alcohol group of drugs, 121 Chloroform, 124 anesthesia, symptoms of, 125 CiUary muscle, action of, 161 Circulation, action of nitrites on, 118 effects of anesthetics on, 129 Clotting of blood, 230 agents hastening, 232 theories of, 231 Cocain, local anesthetic action of, 147 Concentration hydrogen ion, 233 Corpuscles, fragiHty of, 238 permeabiUty of red, 240 Corrosives, 216 Curara, action of, on central nervous system, 137 on mammals, 143 on motor nerve endings, 143 Cyanhemoglobin, 239 Demulcents, 62 Digestants, 225 Digitalis, 108 standardization of, one hour frog method, 178 standardizing of, gold fish method, 115 Hatcher's cat method, 114 Digitaloid drugs, action of, 109 Diuresis, theories of, 181, 183 Diuretics, action of, 182 method of, 187 chief, 182 saUne, 187 Doses, 23 Drugs, administration of, methods of, 24,44 definition of, 17 doses of, rules for, 23 fate of, in body, 25 Dusting powders, 64 antiseptic, 89 essentials of, 65 principal, 64 Emetics, 77 irritant, 67 INDEX 249 Emollients, principal, 63 use of, 63 Enzymes, 199, 225 of intestinal juice, 180 Epinephrin, 166 action of, diflfering from ergotoxin, 196 Ergot, 193 standardization of, 198 Ergotoxin, action of, differing from epinephrin, 196 Escharotics, 67 Eserin, action of, differing from pilo- carpin, 162 proof of, 160 Ether, 29, 124 anesthesia, 126 symptoms of, 124 Ether-morphin, 32 Eye, function of, 160 pharmacology of, 160 Facial nerves, 100 pharmacology of, 101 Fatigue, causes of, 19 Ferments, 225 Fluorides, 218 G Gastric glands, 179 Gastro-intestinal sedatives, 71 tract, 71 movements of, 71, 86 mechanism of, 86 pharmacology of, 71 Glands, classification of, 178 drugs affecting, 178 function of, 178 gastric, 179 intestinal, 179 mammary, i)harmacology of, 194 pharmacology of, 178 salivary, 179 sweat, 191 distribution of, 191 function of, 191 innervation of, 191 j)harmacology of, 191 Giossopharyngeai nerves, 101 Glycogen in liver, 193 (ilycf)