Handbook of pharmacology

Front matter

Class Book.

OopightN .

COPYRIGHT DEPOSIT.

Preface

The time has arrived in the differentiation of the teaching of medicine when the demarcation line should be more sharply drawn between those courses presenting to the student the scientific principles underlying the action of medicinal agencies and that phase of his training which deals with the practical use of medicaments in the alleviation of diseases. A parallel, illustrating the matter, can be drawn from the relations- of the subjects of Physiology and Pathology. Physiology undertakes to present the underlying principles governing the reactions of the normal living body. Pathology deals with the reactions of the living body, but under conditions which we loosely classify as diseased, i.e., the reactions of the body when out of normal relations. Both treat of functions, but the two subjects are separated by the inherent nature which classifies one as normal functions, the other as pathological, a line which, of course, cannot be sharply drawn. Just so is it with the broad subject which deals with the reactions of the living body to drugs. The principles underlying this field are best presented from the standpoint of the reactions of the normal body to drugs and drug agents, which is the peculiar province of Pharmacology. The term Therapeutics, in the restricted sense, ought to apply only to that phase of the subject which deals with the reactions of the diseased body to drugs and drug agencies. These two phases of the broad field of Pharmacology and Therapeutics are, of course, intimately related, just as are Physiology and Pathology. And in the pedagogy of medical education they should be kept in their proper sequence, but should be presented in distinct and consecutive courses, as in the instance of Physiology and Pathology. Medical students should have placed in their hands a Textbook on Pharmacology without being burdened and confused by a mass of matter on practical Materia Medica and Therapeutics while they are getting the principles of the subject of Pharmacology.

The desire to carry forward this idea in meeting an organization which has already been well established in the medical curricula of our best schools has led to the presentation of this Textbook.

Courses in Pharmacology have been organized along two lines: One represented by that splendid old Textbook on Therapeutics and

PREFACE

Pharmacology, by George B. Wood, which ran so many editions in the hands of his descendants. This is typical of the group which classifies the drugs primarily according to the physiological symptoms they induce in the body. This classification, which characterizes a number of pharmacologies of the present, has in an introductory course the pedagogical disadvantage of presenting a confusing array of new facts to the student each time he shifts from one general topic to another. For example, under the chapter on Cardiac Stimulants, the student is suddenly brought face to face, not only with the great number of drugs, new and strange to him, which have this characteristic action on the cardiac apparatus, but he must correlate their actions throughout other parts of the body, making the problem doubly complicated.

The other type of Textbook, of which Cushny's classical Pharmacology and Therapeutics is our best example, bases the organization on the twofold nature of pharmacological agencies, viz., the chemical relations of the drugs and the characteristic physiological reactions of particular groups. No method can be strictly logical in presenting such a wide range of facts without involving wasteful repetition. But Cushny 's method has the pedagogical advantage which may be illustrated by the subject of strychnine. Here the student is presented with the characteristic actions of a single new drug typical of a group. But he is asked to trace the reactions over the entire body with the physiology of which he is assumed to be familiar. In short, the student is asked to establish the scientific relations of a new substance or a group of substances within an organism with which physiology has already given him a working acquaintance.

In gathering the material for this book, use has been made of the literature of physiology, pharmacology, and therapeutics to the extent called for in the presentation of the underlying principles of the subject. Recognizing that even the most elementary student often desires fuller detail of some phase of the subject, and that the teacher needs a ready reference to sources in the literature used to support given principles, a few references to original sources have been inserted as footnotes. The articles so referred to are, in the main, those which present reviews of the literature or through which the literature may become available. No attempt has been made to give exhaustive reference lists. Free use has been made of the standard textbooks and encyclopedias of the subject, to the authors of which the writer expresses his particular obligation.

It is hoped that the number of figures introduced from the litera-

PREFACE v

ture and from experiments in our own laboratories will be of special aid to both the student and the teacher. They are presented as standards for comparisons in laboratory experimental work as well as for the purpose of elucidating the subject matter of the text itself. For many of these illustrations I am especially indebted to my own students, to whom I here make grateful acknowledgment.

Chas. W. Greexe.

Columbia, Missouri.

September 10, 1914.

Chapter I.— GENERAL CONSIDERATION: PAGE

Introduction and Definition — The Nature of the Action of Drugs — Relation of Pharmacological Action to Chemical Composition — Physiological Factors Modifying Pharmacological Responses — Nature of the Change Induced by Drugs in the Pharmacological Actions of the Body — The Method of Application of Drugs as Modifying the Changes in Pharmacological Activity — Changes Produced in the Reactive Power of the Individual by the Continued Application of the Drug — Summation and Tolerance — Pharmacologic versus Therapeutic Action — The Fate of Drugs in the Body 1-18

Part I. Organic Drugs

A. General Depressant Series.

Chapter II.— THE ALCOHOL GROUP

Introductory and Chemical — Alcohol as a Local Irritant : on the skin ; on the mucous membrane of the mouth and stomach; the action of alcohol on the central nervous system; explanation of the nervous symptoms; action on the nervous system of lower animals; duration of the effects on the central nervous system; action on the muscular tissue, on the heart and circulatory system, the respiratory system, on the digestive tract; the liver in relation to alcohol oxidations; alcohol on metabolism; the elimination of alcohol; the effects of the repeated use of alcohol on the germ-plasm and fertility; alcohol habit and disease — Summary 19-38

THE ANESTHETICS.

THE ETHER-CHLOROFORM GROUP.

Chapter III.— ETHER

Historical — Outline of the General Action of Ether: stages of anesthetic effects — Details of the Action of Ether: on the central nervous system, on the respiratory center, on the circulatory system and blood-pressure, on voluntary muscle, on the alimentary canal; the absorption, distribution, and execretion of ether — Summary . :}0-49

Chapter IV.— CHLOROFORM

Details of the Action of Chloroform: stages of anesthetic effects: on the central nervous system, on the circulatory system, on the heari ; chloroform on the voluntary muscles, on the alimentary canal; tinabsorption of chloroform; the execretion of chloroform — Sum mary 50-57

Chapter V.— NITROUS OXIDE: Historical and General — Nitrous Oxide on the General Activities of

the Body — The Administration of Nitrous Oxide ... 58-62

vii viii CONTENTS

Chapter VI.— CHLORAL HYDRATE: PAGE

Historical and Chemical — Pharmacological Action : the general symptoms; chloral hydrate on the nervous system 63-65

Chapter VII.— MORPHINE AND THE OPIUM SERIES

Historical and Chemical — Outline of Pharmacological Action — Details of Action: on the central nervous system, the circulatory system; reactions of the heart and its nervous mechanism; normal movements of the stomach and of the intestine; action of morphine on the stomach and intestine; morphine on the eye, on the frog; morphine on metabolism — Action of Codeine, Papaverine, Thebaine, and Heroin — Excretion of the Morphine Group — The Abuse of Opium — Summary 66-83

Chapter VIII.— APOMORPHINE AND APOCODEINE

Historical and Chemical — Outline of Action — Details of Action : on the central nervous system; depressant action on muscular tissue; apocodeine on nervous structures, on the alimentary canal and urinary motor system; apocodeine in support of pharmacological investigation — Irritant Emetics 84-88

B. General Stimulating Series.

Chapter IX.— THE CAFFEINE GROUP

Historical and Chemical — Outline of Pharmacological Effects — Details of effects of caffeine: on the central nervous system, the spinal cord, the medulla; action on skeletal muscle, on the circulation: the cardiac mechanism; the vasomotor apparatus; on the respiratory mechanism; caffeine on metabolism; diuretic action; absorption and excretion — Summary 89-95

Chapter X.— THE STRYCHNINE GROUP

Chemical and Historical — Outline of Action — Details of Action: on the spinal cord, the medulla, on respiration, on the circulation, on skeletal muscle; action on the special sense organs, on the alimentary canal, on metabolism; excretion — Strychnine Poisoning — Brucine — Summary 96-106

C. Drugs with Specific Action for Peripheral Parts of the Xcrrous System.

Chapter XI.— THE CURARE GROUP

Historical and Chemical — Outline of Action — Details of Action: on the motor nerve endings, on peripheral ganglia; absorption from the stomach — Comparison with Related Drugs .... 107-111

Chapter XII.— THE ATROPINE SERIES

Historical and Chemical — Outline of Pharmacological Action — Details of Action: general symptoms; action on the central nervous system: specific action on the eye; specific action on glands, on the circulatory system, on the alimentary canal, the stomach, and the intestine, on the bladder and uro-genital apparatus; excretion — Summary 112-121

CONTEXTS ix

Chapter XIII.— THE PILOCARPINE, MUSCARINE, PHYSOSTIG- MINE GROUP

I. PILOCARPIXE. pAGE

Historical and Chemical — Outline of Action — Details of Pharmacological Action : on glands, on the circulatory apparatus, the heart, the blood-vessels, on the respiratory tract, on the central nervous system, the alimentary tract; action of pilocarpine on the iris and the ciliary mechanism of the eye — Summary.

II. MUSCARINE.

Historical and Chemical — Outline of Action — Details of Action : on the heart and circulatory system, on blood-pressure, on the glands and the alimentary tract, on the eye.

III. PHYSOSTIGMIXE OP ESERINE.

Historical and Chemical — Outline of Pharmacological Action — Details of Action: on the eye, on the circulatory apparatus, on striped muscle; physostigmine on the muscles of the stomach and intestines, on the central nervous system — Summary: comparison of the pilocarpine group 122-135

Chapter XIV.— THE NICOTINE SERIES

Historical and Chemical — Outline of Pharmacological Action — Details of Pharmacological Symptoms — Action: on the central nervous system, the cerebral cortex and medulla, the spinal cord; nicotine on peripheral ganglia, on the circulatory system, on cardiac muscle; the local nervous apparatus of the heart; the vasomotor system; on the glandular apparatus; the action of nicotine on the eye, on the alimentary canal; excretion — The Xicotine Habit: tolerance . 136-146

Chapter XV.— THE CONIINE, SPARTEINE GROUP

I. CONIINE.

Historical and Chemical — Outline of Action — Action: on the central nervous system, on the autonomic nervous system, on voluntary motor nerve endings, on the circulatory apparatus, on the respirator}* movements; excretion of coniine.

II. PYRIDINE AXD PIPERID1XE; III. LOBELINE; IV. GELSEM- IXIXE; V. SPARTEINE ... 147-151

Chapter XVI.— EPINEPHRINE

Historical and Chemical — Outline of Pharmacological Action — Details of Action: on the nervous system: epinephrine on blood-pressure, on the heart, the salivary glands, on gastric and intestinal movements, on the eve; adrenaline on the urogenital apparatus, on the

eye; glycosuria — General Discussion of Epinephrine — Summary 152-164

Chapter XVII.— THE ERGOT SERIES

Eistorical and Chemical — Outline of Action — Details of Pharmacological Action of chemically pure principles; ergotoxine; isoamylamine; parahydroxy phenylethylamine ; extracts of ergot; ergol on the uterus, on the circulatory Bystem. the heart, on the alimentary canal; effect of ergot on other physiological mechanisms . 166 17:> x CONTENTS

D. Drugs with Primary Activity on Smooth Muscle.

Chapter XVIII.— BARIUM CHLORIDE: PAGE

Outline of Pharmacological Action — Action: on the circulatory system, on the heart, on the peripheral arterioles, on other smooth muscle, skeletal muscle, the central nervous system; local action of barium salts; therapeutic indications 174-177

Chapter XIX.— THE NITRITES AND THE NITRO-GLYCERINES

Chemical — Outline of Action — Action : on the circulatory system, the heart, on the respiratory apparatus ; formation of methemoglobin — Summary 178-180

E. Glucosides of the Digitalis Series.

Chapter XX.— THE DIGITALIS GROUP

Historical and Chemical — Outline of Action — Details of Action: on the circulatory system, the heart, on the peripheral arterioles; digitalis on the central nervous axis, as a diuretic; local irritating effect — Cumulative Action — Summary.

Bufonine and Buf otaline — Chemical — Action : on the frog's heart, on

the mammal, on blood-pressure and the pulse .... 181-104

Chapter XXI.— THE SAPONIN AND SAPOTOXIN GROUP: Historical and Chemical — Sapotoxin: as an irritant; toxic systemic

effects; general saponin symptoms; solanin 195-196

F. Drugs, Chiefly Alkaloids, that Primarily Influence General Metabolism.

Chapter XXIL— HYDROCYANIC ACID:

Chemical — Outline of Action — Details of Action: on the central nervous system, on respiration, the circulatory system; metabolism 197-200

Chapter XXVI.— EMETINE: Chemical — Details of Action — Systemic Actions 212

COXTEXTS xi

G. Drugs Poisonous to General Protoplasm.

Chapter XXVIL— COCAINE: PAGE

Historical and Chemical — Outline of Pharmacological Action — x^ction : on the central nervous system; cocaine on the circulatory system, the peripheral blood-vessels, on the heart, on skeletal muscle; cocaine on the eye; elimination of cocaine; local and anesthetic action; the cocaine habit — Substances which produce anesthesia similar to cocaine: tropacocaine, eucaine, stovaine, holocaine, novocaine — Summary 213-221

Chapter XXVIII.— QUININE

Historical and Chemical — Outline of Action — Details of Systemic Action: action on undifferentiated protoplasm; quinine as an antipyretic; action on muscle, on the digestive tract and digestion, the liver, the central nervous system ; elimination of quinine — Summary 222-230

H. The Coal Tar Series.

A.

Chapter XXIX.— THE COAL TAR ANTIPYRETICS

Historical and Chemical: the general antipyretic action; action of the antipyretics on the central nervous system, on the circulation; variations in susceptibility; comparison of acetanilide, antipyrine, and acetphenetidine 231-236

B.

Chapter XXX.— THE COAL TAR ANTISEPTICS

Historical and Chemical — Outline of Pharmacological Action of the Coal Tar Antiseptics.

I. THE PHENOLS.

Toxicity to protoplasm: on the central nervous system, the circulatory system; the excretion of carbolic acid; toxicology; summary.

II. SALICYLIC ACID AND THE SALICYLATES.

Toxicity to general protoplasm; action on the central nervous system, on the circulatory system, on the alimentary canal; antipyretic action; acetyl-salicylic acid; summary 237-247

I. Internal Secretions.

Chapter XXXI.— THE THYROIDS AND PARATHYROIDS

General Introduction — Internal Secretions of the Thyroid and Parathyroid Glands.

A.— THE THYROID AND THYROIODIN.

Historical and Chemical — Outline of Action: effects of the removal of the thyroids; engrafting of thyroid and parathyroid tissue; interrelationship of the thyroids and the parathyroids; feeding of the thyroid tissue and of thyroiodin.

B.— PARATHYROIDS.

Systemic phenomena following removal of parathyroids; metabolism after parathyroidectomy; theoretical 24 xii CONTENTS

Chapter XXXII.— THE PITUITARY GLAND AND THE HYPOPH- YSIS: PAGE

Anatomical — Outline of Pharmacological Action — Details of Pharmacological Action.

A.— PITUITARY GLAND.

Changes in metabolism following removal of the pituitary; administration of pituitary; clinical evidences from atrophy and hypertrophy of the pituitary; interrelation of the pituitary and other organs.'

B.— HYPOPHYSIS.

Influence of the hypophysis on the functions of nerve structures, the

heart, on smooth muscular structures; hypophysin . . . 255-258

J. Irritants and Counter Irritants.

General Introduction.

Chapter XXXIIL— THE BACTERIAL TOXINS:

Historical and Introductory: nature of the irritant action; the inflammatory process a physiological response to irritant action; action of bacteria and bacterial toxins; characteristics of toxins; type of toxin action; antitoxins; specificity of toxins .... 259-267

Chapter XXXIV.— IRRITANTS OF THE EXTERNAL SKIN

Introductory — Outline of Action : permeability of the skin to certain irritants; acute inflammation; action of the volatile oils; toxic glucosides of the mustard series; cantharidin .... 26S-273

Chapter XXXV.— THE VEGETABLE CATHARTICS. IRRITANTS AFFECTING THE ALIMENTARY CANAL

Introduction — Outline of Pharmacological Action : nature of the reaction by which the vegetable purgatives produce catharsis; action at the point of contact; action after absorption; the anthracene group; the jalap group; the neutral oil series . . 274-281

Chapter XXXIX.— ISOTONIC PHYSIOLOGICAL SOLUTIONS: PAGE

Physiological saline; perfusions of physiological salines; Ringer's solution; Locke's solution; sera and lymphs; summary . . . 297-303

L. Detailed Action of Salts Normal to the Body Pluids and of Their Chemical

Relatives.

Chapter XL.— THE SODIUM-POTASSIUM GROUP, INCLUDING THE CHLORIDES, BROMIDES, IODIDES, SULPHATES, NI- TRATES, ETC.:

The Sodium Salts: sodium chloride, the bromides, iodides, sodium nitrate, sodium sulphate, sodium phosphate — Potassium Salts — Ammonium Salts: on secretion; on the nervous system; excretion — Lithium, Rubidium, and Cesium Salts 304-309

Chapter XLL— THE SALTS OF THE CALCIUM-MAGNESIUM GROUP, IN COMBINATION WITH VARIOUS ANIONS:

Calcium Salts: in relation to the heart; in the coagulation of blood; on nerve tissue; on metabolism; excretion — Magnesium Salts — Barium and Strontium 310-314

Chapter XLIL— THE SALINE CATHARTICS:

Nature of the Action of the Saline Cathartics: sodium sulphate; sodium potassium tartrate; magnetism sulphate; the saline cathartics as enemas 315-323

Chapter XLIII.— ALKALIS AND ACIDS:

Alkalis: the cauterizing action of the alkalis; the physiological action

of the alkalis — Acids: the action of dilute acids .... 324-328

Chapter XLIV.— OXIDIZING AGENTS, OXYGEN, PEROXIDE, ETC.:

Oxygen : effects of increase of oxygen — The Peroxides . . . 329-332

Chapter XLV.— THE SALTS OF THE HEAVY METALS:

The general reactions of salts of heavy metals; absorption of salts of heavy metals; distribution and excretion of the heavy metals in the body 333-337

Chapter XLVL— IRON:

The normal relations of iron in the body; absorption of iron; iron-protein compounds; astringent action 338-340

Chapter XLVIL— SULPHUR AND THE SULPHUR COMPOUNDS:

Action of sulphur, sulphides, sulphates; the organic sulphur compounds 341-342

Chapter XLVIII.— PHOSPHORUS AND THE PHOSPHORUS COM- POUNDS:

Historical — Outline of Pharmacological Action — Action: <»t' phosphorus as a genera] protoplasmic poison; fatly degeneration after phosphorus poisoning; action on the skeletal structures; the inorganic phosphates; organic phosphorus compounds . 343-349 xiv CONTENTS

Chapter XLIX.— ARSENIC AND ANTIMONY: PAGE

A. Absenic. — Introductory — Outline of Action: general toxicity of

arsenic compounds; on the circulatory system; arsenic on the alimentary tract; metabolism; excretion of arsenic — Organic and Synthetic Arsenic Compounds: the arsanilates; salvarsan.

B. Antimony. — The irritant action of antimony 350-356

Chapter L.— LEAD SALTS:

Historical and Chemical — Outline of Action: the general toxic action of lead salts; chronic lead poisoning; lead on the digestive tract; excretion of the lead by glands; excretion of lead by the kidneys: reaction on the circulatory system, on the nervous system; muscular effect 357-363

Chapter LL— ZINC SALTS:

General toxic and disinfectant action of copper salts; the local action;

the systemic action of zinc 364-365

Chapter LIL— THE SALTS OF COPPER:

General toxic and disinfectant action of copper salts; systemic action

of copper; the elimination of copper salts 366-367

Chapter LIIL— THE MERCURY SALTS:

Chemical — Outline of Pharmacological Action — Details of Action: the absorption of mercury; action on bacteria, on differentiated animal protoplasm, on the alimentary tract, on the central nervous system, on the circulatory and respiratory systems; mercury on the kidney; excretion of mercury; chronic poisoning . . . 368-375

Chapter LIV.— SALTS OF SILVER:

The local and antiseptic action of silver salts; the toxic action; systemic effects "376-377

Chapter LV.— SALTS OF BISMUTH:

The action of soluble bismuth compounds; the action of insoluble

bismuth salts 378-380

APPENDIX 381-386

Chapter I. Pharmacological Factors Of General

BEARING

Introduction

Pharmacology is the science which treats of changes in the physiological actions of normal living organisms induced by chemical or physical-chemical agencies. It must be understood that the word has often received a wider range of application in the literature, especially by the older writers. The term Pharmacology has been used synonymously with the term Materia Medica in its broader sense, also to designate the broad field of actions induced in pathological as well as in normal organisms. The present tendency in these days of specialization is to restrict the boundary of the field. In this book the term pharmacology is used in the restricted sense expressed by the definition just given.

Pharmacology, from this point of view, is not limited by any question of utility or application in the art of healing. It is quite immaterial whether a given agency be destructive of life, or of aid in maintaining life. If the agency is one that primarily influences the otherwise normal physiological processes, inducing reactions that are characteristic and constant, then it belongs to the field of pharmacology.

No sharp and all-inclusive boundary can be set around pharmacological agencies. Schmiedeberg has given a classical definition in which he specifically excludes substances capable of assimilation. Yet many recognized food materials have a decided influence on the normal reactions of the living body. They may be primarily nutritive, yet at the same time they produce changes in the physiological functions over and above those of simple nutrition, hence to that extent are pharmacological in nature. Also, many chemical agencies, which are well recognized as of the pharmacological group, for example alcohol or strychnine, are oxidized in the body and thus yield energy, and are to that extent nutritive, therefore foods. Nutritive processes and those of the type indicated as pharmacological shade from the one to the other so that no sharp dividing line can be drawn.

Pharmacological agencies are, for the chief part, chemicals, i.e., drugs. Many of these chemicals are of practical value in disease. The art of the application of drugs in the modification of the processes of disease with the purpose of recovering the normal functions is known as therapeutics. This term also is used with widely varying meanings by different writers. Occasionally the word therapeutics is given the meaning which includes pharmacology as outlined above and vice versa. The term drugs should be restricted to designate chemicals of therapeutic value. In the restricted interpretation of the relations of this field pharmacology deals with the physiological action of chemicals on the normal body while therapeutics deals with the action of drugs on the diseased body. In therapeutics chemical agencies are used for the purpose of recovering the normal, i.e., in the art of healing. In pharmacology, on the other hand, the whole intent of investigations and procedures is for the scientific purpose of unfolding the reactions induced. That the net results of pharmacological investigation may or may not yield a body of facts of positive utility is wholly a secondary consideration, though in presenting the subject from the standpoint of the undergraduate medical student it is the commendable practice to choose those materials and drugs which are of most importance in the practice of the art of healing.

If the action of the drug is destructive of the living organism it is said to be a poison. The science which deals with the limited field of drugs with poisonous action is termed toxicology. It is a subdivision of pharmacology.

Formerly much attention was given to the source and preparation of drugs. These subjects are now of primary interest, chiefly to the manufacturer and professional pharmacist. The present tendency is to eliminate them from other than secondary consideration under the subject of pharmacology. However, the definitions and limitations of these subjects may be given here for the sake of a fuller understanding of the general field. Materia Medica deals with the origin, preparation, and composition of drugs. As many of the active drugs are derived from plant tissues, the special field of the study of drug-producing plants is recognized under the title pharmacognosy. The art of preparing and compounding drugs is known as pharmacy. and the skilled druggist who does the compounding is called the pharmacist. With the present great development in the manufacture and preparation of drugs and drug principles we arc rapidly dispens-

NATURE OF THE ACTIOX OF DRUGS 3

ing with the services of the pharmacist, who formerly played so large and important a part in the preparation of medicinal agencies.

A study of pharmacology assumes a wide and intimate knowledge of the subject of physiology. It is only on the basis of such knowledge that one can build the science of pharmacology. Physiology deals with the intricate and complicated reactions of the living body to every change either in the internal or external environment. These changes are constantly shifting throughout the life cycle of the individual organism and these shifting reactions make up the sum total of the physiological life itself. When pharmacological agencies are introduced into the body or brought into contact with living protoplasm by whatever device, the living tissue or organism responds to their presence. In other words, the presence of the special agency is only one of the numerous factors which induce response in the living protoplasm. The study of drug action is, therefore, only a restricted portion of the field of physiology.

Modern science has taken up the questions of pharmacology with the same vigor and spirit of investigation which has characterized the development of physiological knowledge during the last threequarters of a century. In this spirit scientists have studied the details of the changes induced by drugs, thus establishing the facts on a strictly scientific observational basis. This method and the results are in direct opposition to the old empiricism. The findings have been seized upon by the clinician and therapeutist, since they enable him to proceed in the light of definite and known pharmacological actions of the agent. On the assumption that a given drug, which has been proved to induce a change of a certain nature in the normal organism will induce a change in the same direction in the diseased or pathological organism, the clinician can apply a given drug with a definite knowledge of what effects may be expected. This is the rational treatment in opposition to the empirical. Modern medicine and modern therapeutics look to the science of pharmacology for the basic facts for a rational procedure.

II. The Nature of the Action of Drugs

The chemical substances that produce pharmacological reactions in the body by virtue of chemical combinations with constituents of the body are properly called drugs. The term is an old and convenient one, though its application is often vague and indefinite. The character of the change in the reactions depends upon many environmental conditions, of which one of the most important is the manner in which the drug is brought into contact with the tissues of the organism. On this basis the drug actions may be either local or general.

i. Local actions. — A certain class of changes produced in the body by drugs is dependent upon the fact that the chemical is brought into contact with only a restricted part of the body, hence the restricted action is purely local and for purely mechanical reasons. For example, if strong sulphuric acid comes in contact with the skin it will produce chemical destruction of the tissue of that local spot. While sulphuric acid is generally destructive to protoplasm, in this instance it can act only locally in the same sense that a hot piece of iron will sear only that portion of the body which it touches.

2. General actions. — On the other hand, when chemical agents are introduced into the body in such manner that they are distributed throughout its extent by means of the circulation, then the reactions that occur are characterized by two general types.

The drug may be one capable of inducing change in the physiological activities of the body whatever the nature and function of the organs or parts considered. If so, it is said to have a general action. An example is found in alcohol. "When alcohol is absorbed into the circulation and distributed throughout the organism it induces a change in function in all parts of the body.

Most of the drugs used in practical medicine belong to this class. It cannot be said that the chemicals produce exactly the same change in every type of protoplasm, yet the parts of the body affected are so numerous and widely distributed that the general functions are thrown out of balance, hence the action of the drug is said to be general in its nature. The majority of the physical-chemical changes induced in the body are of this class, especially the purer examples of salt action.

3. Specific actions. — In sharp contrast with these drugs of general action is a different class, namely, the specific drugs. In this class, although the drug may be brought in contact with all the tissues of the body still it shows especial affinity for certain tissues only and not for others. Nicotine is an example of such a drug. This alkaloid picks out especially the nervous tissue. Its specific action is still more detailed in that it forms compounds with that differentiation in nerve tissue represented by the link between the pro- and post-

NATURE OF THE ACTION OF DRUGS 5

ganglionic neurons of the autonomic system. While nicotine does enter into reaction to some extent with other portions of the nervous tissue and with the muscular tissues, still the intensity of the action is so much stronger at the particular sjmapsis that the other reactions are overshadowed, thrown into the background as it were. Hence this nicotine reaction is said to be specific. Numerous illustrations of this action can be given. Pilocarpine, acting at the same point, would be antagonistic to atropine, the characteristic curare action on peripheral motor nerve endings, the action of strychnine on certain synapses in the central nerve axis, and of caffeine on muscle and on nerve, particularly the nerve structures of the higher centers are examples. The behavior of such drugs in the body is always in sharp contrast with those reacting generally throughout the body such as the general protoplasmic poisons. The latter class are characterized by the changes which they induce in the physiological responses of general, i.e., undifferentiated, protoplasm. The specific drugs are characterized by the selective action on highly differentiated points in the structure of the animal body.

4. Indirect action of drugs. — Drugs also induce many changes in the normal functions of the body as indirect actions. That is to say, as a result of the primary action of the drug in the body the balance that exists among the coordinated physiological mechanisms is upset, hence there will follow a chain of effects induced by the shifting in the function of that tissue especially influenced by the drug. These purely secondary effects are physiological rather than pharmacological. Nevertheless they must be understood by the pharmacologist, and especially by the therapeutist who makes a rational application of the drug in disease. A simple illustration of this kind of secondary effect is found in the change of the heart rate produced by atropine. This drug paralyzes the endings of the vagus in the heart, thus eliminating the tonic control of the vagus. As a result the heart rate is greatly increased, not due to any direct effect of the drug, but purely secondary to the action of the drug in eliminating the inhibitory function of the vagus nerve. In like manner many drugs which produce profound changes in the circulatory system are accompanied by secondary effects on the respiratory mechanism or the renal system. Most so-called " tonics " induce their favorable changes in nutrition and metabolism in a purely indirect or secondary way.