A text-book of pharmacology and therapeutics : or, the action of drugs in health and disease

Front matter

THE LIBRARY

OF

TEXTBOOK

Preface To The Fourth Edition

THE revision of the United States Pharmacopoeia has necessitated the issue of a new edition of this text-book, and the opportunity has been taken to record such advances in the subjects of Pharmacology and Therapeutics as have been made in the last two years. In order to permit of this being done, and, in particular, to admit of references to the newer literature of the subject, some of the older bibliography has been curtailed. As a general rule, the new authors quoted have given references to their predecessors, but in some instances it may be necessary to refer to the earlier editions in order to complete the bibliography. The changes made in the text are too numerous to be detailed here, but perhaps attention may be called to the new features brought out by Embley and others in regard to the action of chloroform and its dangers, and to the change in the views held as to the effects of wood -alcohol in man.

The index of drugs, classified according to their therapeutic uses, has been retained in view of its manifest usefulness.

I have to express again my appreciation of the kindness of many friends who have aided me by suggestions, and to record my indebtedness to Dr. W. J. McNeal for reading the proofs of this edition.

A. E. C.

PREFACE TO THE FffiST EDITION

THE following pages were written to supply a want which I have felt keenly in teaching the subject of pharmacology to students who have completed the purely scientific branches of medicine and are beginning their clinical studies. My object has been to bridge over the hiatus which exists between the phenomena occurring in the normal organism and those which are elicited in the therapeutic use of drugs, to show how far the clinical effects of remedies may be explained by their action on the normal body, and how these may in turn be correlated with physiological phenomena. It necessarily follows that the subject is treated from the experimental standpoint, and that the results of the laboratory investigator are made the basis of almost every statement. Where these fail to elucidate the therapeutic effects or even to suggest a possible explanation, I have preferred to leave the question undiscussed rather than to call on such occult del ex machina as alterative or tonic actions.

Two great difficulties present themselves at the outset to the writer on pharmacology who is not satisfied to take his statements at second hand, or to formulate explanations from his unaided inner consciousness ; these are the overwhelming literature on the subject, and the wide limits of the field of study. As regards the first, I have read, as far as was in my power, the original papers of importance, and in order to facilitate the work of others who may wish to follow this, the only satisfactory method of study, have appended a bibliography to each chapter. It was impossible within the limits of a textbook to make this complete, or even to enumerate more than a few of the works consulted, and I have accordingly selected those which appeared most important, and those which were furnished with the most complete bibliography.

As regards the scope of the work, I have attempted to give the present standpoint of knowledge of such bodies as are of therapeutic or toxicological interest, and also of those which, possessing in themselves no immediate interest in practical medicine, have thrown important light on biological problems, and are accordingly likely to be referred to in scientific literature.

•8 PREFACE.

Unfortunately, a writer on this subject cannot as yet restrict his attention to these classes, but must refer at more or less length to many drugs which possess little interest either from a therapeutic or a scientific point of view. It is true that the more advanced teachers of medicine have very properly abbreviated their lists of remedies, until those generally employed may be enumerated in units where they were once counted in scores, but the student on going into practice meets numbers of drugs previously unknown to him, and not appreciating that these have already been tried and discarded by his teachers, is tempted to fall into the slough of unreasoning empiricism. There is still a tendency even among the educated to ascribe therapeutic virtues to every new weed and every new product of chemical industry, and the teacher of pharmacology must not only point out the good, but has the more ungrateful task of condemning the worthless. The period of constructive pharmacology has scarcely dawned ; at present its chief function is destructive and critical.

In dealing with each drug, I have attempted to unify the whole action by using the most distinctive feature as a centre around which to group the less important symptoms. Where, as is often the case, there is a divergence of views among authorities, I have generally presented only one side of the question, except in very important subjects. This dogmatic method has of course , its drawbacks, but is, I think, preferable to involving the student in a labyrinth of arguments and counter-arguments, the respective weight of which he is quite unable to estimate.

The preparations enumerated are those included in the United States and the British Pharmacopoeias, and such others as seemed of sufficient importance. I have attempted to indicate by special type (small capitals) those that are more generally used.

Some explanation may seem necessary for the introduction of the word " therapeutics " in the title, in view of the fact that pharmacology is stated in the introduction to embrace all that part of therapeutics which can be treated of apart from clinical lectures. This definition is not universally used, however, and it has been felt advisable to indicate more distinctly the scope of the work by adding the more familiar term.

To those acquainted with the Grundriss der Arzndmittellehre of Schmiedeberg, it is unnecessary to state that this volume has been largely inspired by that classical work. Some chapters may in fact be regarded as merely expansions of those issued from the Strassburg laboratory, but this must necessarily be the case in any work which

PREFACE. 9

pretends to treat the subject from the experimental standpoint. The use of such a model naturally exposes the writer to the criticism that he has fallen short of the original standard, especially when such divergences are made from it as occur in this work. But if I have departed from the letter in some respects, I hope that at least the spirit of the Grundriss has been preserved in these pages. . I must acknowledge my indebtedness for references to papers which might have otherwise escaped my notice to the following textbooks : Kobert's Lehrbuch der Intoxicationen, Lewin's Nebenwirkungen der Arzneimittel, Husemann's Pflanzenstoffe, Harnack's Arzneimittettehre, H. C. Wood's Therapeutics, its Principles and Practices and Stokvis' Leqons de Pharmacotherapie.

Finally, I have much pleasure in acknowledging the assistance of my colleagues in the preparation of this work, particularly that of Professor Huber, who furnished several of the illustrations. Dr. G. B. Wallace has put me under lasting obligations through the patience and care which he has bestowed on the tedious task of proof-correction, and I must thank Dr. W. Mogk also for his assistance in this part of the work.

Contents

PAGE.

Introduction. 17

Mode of action of drugs, stimulation, depression, irritation . . 20 Elective affinity of drugs, protoplasm poisons .... 22

Introduction

PHARMACOLOGY is the study of the changes induced in living organisms by the administration in a state of minute division of such unorganized substances as do not act merely as foods. Many of the best known of these substances are used to counteract the effects of disease, or to reinforce the tissues in their struggle to maintain their functions, when these are rendered abnormal. These substances are known 'as drugs, and the art of applying drugs in disease, is Therapeutics. Other substances are of little or no value in disease, but are of importance because they act as poisons, that is, cause dangerous or fatal symptoms in man or animals, when they are ingested in quantity. The practical study of the effects of these poisons in man — the diagnosis and the treatment of poisoning, and the methods of detecting the poison — is termed Toxicology. But the explanation of the symptoms induced by chemical substances, and their study, as apart from their practical applications, belong to the field of pharmacology, which includes not only the effects of drugs and poisons, but those of any substance which induces changes in the living organism, whether those changes are of benefit to it, injurious, or quite indifferent.1

The substances must, of course, conform to the requirements of the definition. Thus, a needle introduced into the tissues induces effects which are outside the field of pharmacological investigation, because it is not in a state of minute division. But the iron of the needle may be reduced to a fine powder and induce changes in the body which are then the legitimate subject of research. Similarly the drug must be introduced from without, for many active agents are formed within the body, but their study belongs rather to the departments of physiology and pathology ; and the effects of organized bodies introduced from without are now studied under bacteriology. Pharmacology is really a department of biology, very closely related to the other sciences included by that term. Thus, as physiology is the study of the life of the normal organism, pharmacology is the study of the organism rendered abnormal by drugs, while in pathology the phenomena of life under disease are examined. All three subjects may be pursued without reference to the practical needs of medicine, and all three are closely interconnected and mutually dependent, for, in many instances, the normal condition of an organ can be recognized only by considering the results of its destruction by disease (pathology), or of its paralysis or stimulation by chemical agents

1 It is quite impossible to distinguish between drugs and poisons. Almost all remedies given in excess cause dangerous or fatal symptoms, while many poisons are valuable remedies in small doses. Some bodies may in fact be remedies, foods, or poisons according to the quantity ingested and the method of application. 2 17

(pharmacology). Similarly, many of the features of disease are now recognized to be due to the presence of unorganized poisons formed in and by the tissues, and it accordingly becomes difficult to accurately define the limits of pathology and pharmacology. Thus, the toxines formed by microbes resemble in their action some of the ordinary drugs or poisons, and might be considered along with these. But the study of these toxines is so closely bound up with that of the microbes from which they originate, that it has been thought better to leave them to be treated by special text-books on bacteriology. For a similar reason the antitoxines, which play so prominent a role in modern therapeutics, may be excluded from treatises on pharmacology, for the present at any rate.

Even when these limitations are accepted, pharmacology has an enormous field to cover, and one which has been only very partially explored at the present day, in spite of the unremitting industry of many investigators. But a small part of the subject has been sufficiently developed to admit of text-book treatment, that namely, which is concerned with drugs used in therapeutics and with the commoner poisons. The slow advance of pharmacology is partly due to its position midway between the biological sciences and practical therapeutics, for while the biologist confounds it with clinical study, the clinician regards it as an experimental science. Its relation to biology has already been mentioned and its relation to practical therapeutics is no less close, for the effects of drugs in disease are as much a part of pharmacology as is their action in the nonnal organism. The aim's of the pharmacologist and the clinician are not identical, however. The former seeks to solve the problem how the drug acts in a given case, while the primary object of the latter is to remedy the condition by any means in his power. Thus, in a case of heart weakness, the clinician prescribes some remedy which he has found of benefit in other similar cases, and regards only as of secondary interest the question which to the pharmacologist is the absorbing one, namely, whether the drug acts on the heart directly or through some other organ. Of course the results are of mutual advantage, for the physician supplies the experimental investigator with new facts and with new fields of inquiry, while the latter may indicate more exactly the conditions in which the drug is likely to be of benefit in the future by defining the method in which it acts. It is, therefore, much to be regretted that differences of opinion so often arise between these two classes of observers, for these can only retard the progress of both the science and the practical art. Doubtless there are often faults on both sides. The scientist sometimes insists too strongly on inductions drawn from a limited number of animal experiments, and refuses to admit results which have been obtained in thousands of cases of disease by competent observers. On the other hand, the therapeutist often lays too little weight on the general principles governing the interaction of the drug and the organism. Both often exceed the limits of their provinces, the scientist in refusing to admit effects of which he has perforce but a small experience, the clinician in attempting to refute deductions founded on experiments which he has no opportunity of performing. An example may render the relation of these allied subjects

PHAEMA COLOG Y. 19

clearer, and one has been recently offered in the discussion regarding the effects of iron. This metal has been used for many years in a form of anaemia, and its curative properties are attested by many thousands of cases and by whole generations of practical physicians. A pharmacologist, therefore, exceeds his province when he expresses doubt regarding this clinical fact simply because he is unable to explain it, but he is within his rights in discussing the means by which iron acts as a remedy. The clinician, on the other hand, enters on a pharmacological question when he attempts to determine whether iron acts by absorption or by its presence in the bowel, and must base his arguments on scientific experiment and not on his clinical experience of the curative effects of the metal. Fortunately for the progress of medicine and pharmacology, the scientific clinician is imbued with the desire to ascertain the methods in which drugs act as well as to cure disease, and thus unites clinical observation with pharmacological research. It is to be anticipated that the results of the practical physician and of the experimental investigator will come into more complete accord as more exact methods of clinical research are used by the former, and a wider laboratory experience is attained by the latter. But both methods are necessary to the complete knowledge of the action of a drug. Animal experiment cannot be dispensed with, for only thus can the action of drugs be ascertained in detail and expeditiously, and at the present time, when a new remedy appears almost every week, it is impossible to await the verdict of the clinics to separate the useful from the worthless, even if it were permissible to apply to the human subject drugs of unknown action and potency.

Pharmacology is one of the most recent developments of medical and biological science. It is true that from the earliest times attempts have been made to explain the effects of drugs on the then prevailing theories of pathology, but the objective study of the action of drugs on the organism has been a development of the nineteenth century, or it might almost be said, of the second half of it. During this period the same methods of research have been adopted as had earlier proved so fruitful in physiology and pathology, and with equally happy results. The study of drugs was termed Materia Medica up to this time, and comprised an examination of their botanical and chemical properties along with some account of the diseases in which they had proved of value. This descriptive rather than experimental study has been continued under the name of Pharmacognosy, but is now pursued by pharmacists chiefly. Undoubtedly the student of medicine ought to know those characters of drugs which are of importance as modifying their action and application, but it is undesirable that his valuable time should be occupied in the detailed description of crude substances, which he may probably never have an opportunity of seeing in his future practice.

Another subject which now occupies a much less prominent position in medical study than formerly, is Pharmacy, or the art of preparing drugs for therapeutic use. Some general knowledge of the methods used is no doubt indispensable to the educated physician, but the details may be left to the pharmacist. Pharmacy will probably occupy a still more subordinate position in medical education as the tendency to include only one or two drugs in a prescription becomes more widespread. As long as a dozen or more components went to make one mixture, it was of importance to know their solubility and their interactions, but with the decay of the complex prescription the study of pharmacy by medical students has certainly become less imperative.

MODE OF ACTION OF DRUGS. STIMULATION, DEPRESSION AND IRRITATION.

A small number of drugs affect the organism only through their physical properties, as when an inert oily body is applied to an abraded surface and promotes its healing by protecting it from irritation and from the evaporation of fluid, or when common salt absorbed into the blood changes its osmotic tension, and thus alters the distribution of fluids in the tissues.

But the great majority of drugs act through their chemical affinity for certain forms of living matter. They probably form temporary combinations with some forms of protoplasm, and alter the function of all cells, which contain these forms. At least this is the only explanation of their affecting certain organs while others escape their influence. To take an example, the cells of the spinal cord normally receive sensory impressions from the exterior and send out motor impulses. But under strychnine the motor impulses are much more violent than usual, and this may be expressed by saying that the combination of strychnine and cord protoplasm functions more powerfully than unaltered cord protoplasm. The activity is changed, however, only in degree and not in kind ; the reflex movement may be more powerful or less powerful than normally, but it remains a reflex movement and cannot under any circumstances partake of the nature of a voluntary movement. In other words, the action of drugs is quantitative and not qualitative, the activity of living matter may be changed, but the form which the activity assumes is unchangeable.

In recent years much attention has been paid to a series of natural phenomena occurring in the border-land between physics and chemistry and the application of the results of " physical chemistry " to pharmacology has proved of great value already and promises to elucidate in the future many problems which have hitherto been unapproachable. Examples of such applications will be met in the Meyer- Overton theory of narcosis and in the chapters on salt action. The tendency of study in this direction is to reduce the class of reactions which have hitherto been ascribed to special chemical affinity between drugs and protoplasm and to attribute many of the changes induced by drugs to the physical structure of the living cell rather than to its chemical constitution.

Drugs which increase the activity of any organ or function are said to stimulate it, while those which lessen the activity are said to depress

MODE OF ACTION OF DRUGS. 21

it. Another condition induced by drugs is irritation, for although this term is often applied loosely as a synonym for stimulation, the two conditions are not identical. Stimulation is properly used to indicate an increase in the specialized function of a cell, producing, for instance, in the spinal cord an increase in the reflex excitability. Irritation, on the other hand, is used rather in reference to the changes in the conditions common to all forms of living matter, that is, it indicates a change in the nutrition and growth of the cell, rather than in the specialized functions. Irritation may thus be induced in all kinds of tissues and is the commonest change caused by drugs in the less differentiated forms such as the connective tissues and ordinary epithelia ; while stimulation is met with in the more highly specialized cells, such as those of the heart, nervous system, or secretory glands. In many instances the irritant action of drugs may be explained by their known reactions with the proteids of the cell ; for example, substances which dissolve proteids, or precipitate them, or withdraw fluid from them, all tend to cause irritation when they are applied to living tissues. In other cases irritation appears to be induced through some chemical action the nature of which is quite unknown.

When stimulation is prolonged or excessive, the protoplasm generally becomes depressed and finally loses its activity entirely (paralysis). Some authorities have asserted that depression is invariably preceded by stimulation, and that stimulation sufficiently prolonged invariably leads to depression and paralysis. Both statements are too absolute, although they are true in the great majority of cases. For example, the action of atropine on the terminations of the cardiac inhibitory nerves is purely depressant. Even the most minute quantities of this alkaloid never increase the activity of these terminations, for if a quantity too small to paralyze them is ingested, it has apparently no effects whatever, and as the dose is increased, the first effect is paralysis.

Depression, whether induced directly, or following on stimulation, has been shown in several instances to resemble the fatigue induced by the prolonged exercise of the normal organ, and it is probably true that depression and fatigue are, in all instances, identical in appearance, although not necessarily identical in cause. For example, the phenomena of fatigue of the terminations of the motor nerves in muscle resemble exactly those induced by curara, but in the former the cause may be that the conducting substance of the nerve ends has been used up by the repeated passage of impulses, while in the latter the conducting substance is so changed that it becomes incapable of transmitting stimuli to the muscles. The final result is, of course, the same ; there being no available conducting substance, impulses fail to reach the muscle. But the fatigued terminations rapidly recover, as conducting substance is reformed, while the curarized recover only when the poison is eliminated.

In most cases an excessive dose of a stimulating poison leads to depression and paralysis. The cell becomes functionally dead, but if the failure of its function does not involve the death of the organism, it

22 INTE OD UCTION.

may recover and reassume its ordinary function as if no stage of inactivity had intervened. Excessive irritation, on the other hand, leads to actual death and disintegration, from which there is no recovery. For example, the cells of the spinal cord are first stimulated, and later paralyzed by a large dose of strychnine, but this is not fatal to cold-blooded animals, and after a few days the spinal cord regains its normal function, as the poison is eliminated. On the other hand, the injection of an irritant into the subcutaneous tissues causes dilatation of the vessels, effusion of fluid, and increased growth and rapid division of the cells. If only a small quantity be injected, this condition is recovered from, although it generally leaves evidence of its presence in the form of an increase in the fibrous tissue. But if the irritation be intense, the cells undergo degeneration and die, and an abscess is formed. The cells thus destroyed can never recover as the paralyzed ones do. They are either absorbed, or removed by the opening of the abscess, and their room is filled by the overgrowth of the neighboring tissues.

ELECTIVE AFFINITY OF DRUGS. PROTOPLASM POISONS.

Most drugs have an elective affinity for certain definite tissues. Thus, some attack the heart only, others the central nervous system and others the terminations of the motor nerves in muscle. Among the cardiac poisons again, some act on the ventricle, others on the auricle, and among the poisons of the central nervous system, some act primarily on the cortex, others on the medulla oblongata and others on the spinal cord. This elective affinity is not merely a question of degree, as is sometimes stated, for a drug which has a powerful action on the brain, may have no effect on the heart except when administered in such quantities as alter the physical characters of the blood. A drug may even alter different structures in diametrically opposite directions. Thus, atropine depresses certain nerve terminations, but stimulates the brain, and curara, which paralyzes the peripheral terminations of the motor nerves, stimulates the spinal cord. In some instances the immunity of a cell to the action of a drug may perhaps be explained by the latter failing to penetrate into its interior, but this is not true in the great majority of cases.

The fields of activity of different drugs vary greatly in extent. One may comprise only the terminations of the secretory fibres in the sweat glands (agaricin), while another, which affects these in the same way, may involve many other terminations in its action (atropine). Most poisons, however, while acting on a certain narrow area in small doses, extend the limits of their activity when larger quantities are ingested. Thus, a poison which acts in small doses on the medulla oblongata only, may, when exhibited in larger quantities, involve the spinal cord and the brain, and in still greater concentration may affect the heart and other organs. No poison is known that acts equally on all organs and tissues, but those which have a wide field of operation are often

REMOTE, LOCAL, AND GENERAL ACTION. 23

known as protoplasm poisons. These paralyze any form of living matter when they are brought in contact with it in sufficient quantity, but if they are injected into the blood and thus distributed equally throughout the body, they invariably select some special organ as the chief seat of their activity. This is exactly parallel to the behavior of chemical agents in the laboratory. For example, acetate of lead added to a solution of a chloride, or of a sulphate, precipitates it, but added to a mixture of the two, throws down more of the sulphate than of the chloride. Nitrate of silver, on the other hand, precipitates the chloride only. Acetate of lead may be compared to the protoplasm poisons, nitrate of silver to those with a less extensive field of action. As protoplasm poisons affect a large number of different forms of living matter it follows that they alter the nutrition rather than specialized functions. Many of them cause irritation ; others are used to destroy or retard the growth of microbes and are known as disinfectants or antiseptics.

REMOTE, LOCAL, AND GENERAL ACTION.

Drugs change directly only those organs and tissues with which they come into immediate contact. But the alteration of one part of the organism very often entails that of another to which the drug may not have access, or for which it has no special affinity, because impulses are transmitted through the nerves, or changes are induced in the circulation and nutrition. Thus irritation of the skin may alter the rate of the pulse by impressions being transmitted by the cutaneous nerves and reflected along the inhibitory nerves of the heart. Similarly a poison that weakens the heart may induce disorder of the respiration, from the circulation being deficient in the medulla oblongata ; and depression of the brain may lessen the oxidation in the muscles, because it leads to lessened movement. These secondary changes, which are not due to the direct action of the drug on the organs concerned, are known as remote or indirect effects.

The local action of a drug is that induced at the point of application before it enters the circulation, the general or systemic action is that due to its elective affinity for certain organs to which it is carried by the blood. The local effects are very often entirely different in nature from the general action, for a drug may act as an irritant at the point of application and as a depressant to the brain when it is carried to it in the blood. Local effects may be induced wherever the drug can be applied — in the skin, the alimentary tract, the respiratory passages, and the other mucous membranes. They also occur in the subcutaneous tissues when the poison is injected hypodermically, and in any of the deeper organs and tissues which can be reached by the needle of the syringe. Local remedies may cause irritation, or may protect the surface from irritation, may depress the sensory end-organs and cause local anaesthesia, or lessen secretion, or alter the functions at the point of application in many other ways. They may also have remote effects, as has been mentioned. Many drugs have only a local action, because they are not absorbed, are absorbed in inactive forms, or are excreted or deposited as rapidly as they pass into the circulation, so that enough is not present in the blood at any one time to induce general effects. On the other hand, many powerful poisons have little or no effect at the point of application, but possess an elective affinity only for some organ to which they are carried by the circulation.