P H A R M A C O L O GY IN C L I N I C AL PRACTICE Richard Lancaster MA, BChir, MB, FRCP, PhD Consultant Physician and Honorary Senior Lecturer, Clinical Pharmacology, St Mary's Hospital and Medical School, London WILLIAM HEINEMANN MEDICAL BOOKS LTD LONDON First published 1980 © Richard Lancaster, 1980 ISBN 0 433 19052 3 Text set in 10/12 pt VIP Plantin, printed and bound in Great Britain at The Pitman Press, Bath Preface This book is aimed primarily at medical undergraduates during their clinical years, but it is hoped that it will also be of value to all doctors in clinical practice and to whom drugs are an essential therapeutic tool. The book is divided into two parts. The objective behind Part I (Chapters 1-9) is to provide a bridge between basic pharmacology and clinical pharmacol- ogy. Thus it contains both brief summaries of important areas of basic pharmacology including mechanisms of drug action, drug distribution, metabolism and excretion and slightly more detailed chapters on aspects of pharmacology that are particularly important in clinical practice, such as pharmacokinetics and clinical trials. The main part of the book, Part II (Chapters 10-42), covers the clinical pharmacology of the most important and widely used groups of drugs in clinical practice. Each drug or group of drugs is considered under the four main headings of drug action, drug fate, adverse effects and clinical use, so as to provide students with an invariable frame within which to consider the information concerning any drug. This book is not intended as a book on therapeutics. Therapeutics is concerned with all aspects of treatment and hence must be concerned with more than drug therapy. However, as drugs are probably the most widely used tool in therapeutics it is hoped that the information on drugs contained in the book will facilitate therapeutic decision-making and benefit thereby the patient. Acknowledgements I would like to express sincere thanks to the following for their comments and criticisms of various chapters of the book:- D. R. Bevan, N. M. Bleehen, G. Bryan, D. S. Davies, M. Feiwell, P. F. Heffron, H. S. Jacobs, A. B. Kurtz, P. S. Lewis, A. C. Maddocks, E. A. Nieman, P. S. Sever, R. S. Smith, J. G. Walker and C. S. Wikox. To Frans Hobbiger, Professor of Pharmacology at The Middlesex Hospital, I offer special thanks, for his guidance and help during the time when I was a lecturer in his Department and for his criticisms of various aspects of the book. His dedication to all aspects of Pharmacology and to its teaching in particular has always been an inspiration to me. Lastly I thank Susan Gould for her excellent typing of the first draft, Tim Sloan and Jeffrey Idle for their help with chemical problems and Carol Dorrington-Ward and Jeffrey Idle for their help in correcting the proofs. Chapter 1 Drug Actions The study of drugs may be divided into pharmacodynamics, which is the study of drug actions and modes of action, and pharmacokinetics, which is the study of the fate of drugs in the body. In this chapter pharmacodynamic aspects of drugs and their relevance to clinical pharmacology will be discussed. Pharmacodynamics For drugs that reach their sites of action from the blood stream, there are four steps linking drug administration to drug effect. 1. Transfer of drug from site of absorption to plasma water. 2. Transfer of drug from plasma water to receptor compartment. 3. Drug-receptor interaction. 4. Production of drug effect. Steps 1 and 2, the transference steps, are the concern of pharmacokinetics and are considered in Chapter 4. Pharmacodynamics therefore starts with a study of drug-receptor interactions. Drug receptors In most instances, the initial event in the sequence that culminates in a drug-induced effect is the interaction between a drug molecule and a 'receptor' molecule or area located on the surface of the 'target' organ. Exceptions to this rule include chelating agents (Chapter 41) which interact directly with a particular cation and drugs whose actions are a consequence of their physical properties, e.g. bulk laxatives, osmotic diuretics and topical cooling agents. Receptors are macro molecules and in a few instances they have been isolated and their physico-chemical characteristics determined. In most of these the receptor is an enzyme that is stable in vitro, e.g. carbonic anhydrase, acetylcholinesterase, monoamine oxidase. Most receptors thus far characterised have been proteins located on cell surfaces, but this is not always the case; e.g. RNA is the receptor for the cytotoxic agent actinomycin D (Chapter 38) and ergesterol, a sterol component of the fungal cell membrane, for the antifungal agent nystatin (Chapter 35). For drugs whose receptors cannot be isolated, the nature of the drug-receptor relationship has derived from studies using indirect methods such as analysis of the dose-effect relationship and structure-action relationships. On such evi- dence receptors may be classified in terms of their specificity for drugs. Receptors with a low degree of specificity do not discriminate between optical isomers or between drugs of very similar but not identical structure. They occupy a relatively large area of the surface of the target organ and drug effects are only produced at relatively high drug concentrations. The receptors have a low affinity for the drugs with which they interact and their actions cannot be 4 Pharmacology in Clinical Practice antagonised by other drugs that compete for and occupy the same receptors. Examples of drugs whose receptors have a low degree of specificity include local and general anaesthetics (Chapter 12 and the surface-active antibacterial agents, polymyxin and bacitracin (Chapter 35). Receptors with a high degree of specificity are mostly those that are receptors for chemical transmitter substances, e.g. cholinergic, adrenergic, dopaminergic and 5-hydroxytriptaminergic receptors or receptors for hormones. These dis- criminate between minor differences in chemical structure and between optical isomers. They occupy a tiny fraction of the cell surface, have a high affinity for specific drugs which are therefore active at very low concentrations. Dose-effect relationship Most of the concepts derived from studies on the dose-effect relationship have come from studies on the effects of drugs on smooth muscle in vitro. Such studies have shown that the dose-effect curve is 100 r 75 μ max 50 response H 25 0 Log dose FIG. 1 Log dose-response relationship. hyperbolic and if the intensity of effect, expressed as a percentage of the maximal response that the drug is capable of eliciting, is plotted against the log of the dose, the curve becomes sigmoid, the points between 25% and 75% maximal response falling along strait line (Fig. 1). A. J. Clarke (1933) applied the law of mass action to interpret the log dose-effect relationship. He assumed that one drug molecule reacted with one receptor molecule. ki R+A * = ^ RA k 2 R = a free receptor; A = a drug molecule; RA = an occupied receptor. Drug Actions 5 Assuming that the number of drug molecules is far greater than that of receptors, then at equilibrium: CA PA = CA+KA PA = fraction of the total number of receptors occupied, CA = concentration of drug A; KA = dissociation constant (k /k!) 2 Clarke assumed that receptors did not interact and that a 100% response is only achieved when 100% of receptors is occupied. The theory that the intensity of response to a drug is proportional to the number of receptors occupied by drug molecules is known as the Occupancy theory'. 100 r % max 75 tissue 50 h response 25 U Log dose A full agonist Β partial agonist FIG. 2 Comparison of full agonist and partial agonist in log dose- response relationship. A = full agonist; Β = partial agonist. The log dose-response relationship could also be accounted for if particular receptors varied in their affinity for specific drugs and if this variability was normally distributed over the target organ. Studies on isolated receptors have, thus far, failed to show variations in receptor affinity for specific drugs. The occupancy theory has been modified to account for the fact that different agonists, that are assumed to act on the same receptors, do not always produce the same maximal response. Such differences have been explained on the basis of a hypothetical drug characteristic 'intrinsic activity' or 'efficacy'. Thus drugs with a high degree of 'intrinsic activity' or 'efficacy' are capable of causing the maximal response of which the tissue is capable (full agonists) while drugs with a low degree of 'intrinsic activity' or 'efficacy' cause a less than maximal response at a maximally effective dose (partial agonists) (Fig. 2). 6 Pharmacology in Clinical Practice For the most part, drug effects are thought to be the consequence of conformational changes induced in receptor structures. It is notional that partial agonists, when occupying or interacting with a receptor, do not induce the same degree of conformational change in receptor structure as do full agonists. Antagonists occupy receptors but produce no tissue response. They therefore have negligible 'intrinsic activity' or 'efficacy'. They are described as being 'competitive' if they cause a shift to the right in the dose-response curve, but do not reduce the maximal response to an agonist (Fig. 3). In the presence of a full agonist, a partial agonist acts as a partial antagonist as it occupies a proportion of receptors and the intensity of response resulting is less than that caused by that proportion of receptors interacting with the full agonist. A A+C Log dose Log dose FIG. 3 and 4 Log dose-response curves: A = agonist; Β = competi- tive agonist; C = antagonist that irreversibly binds to receptors and hence inactivates them. C has not caused a shift to the right in the log dose-response curve, indicating that the tissue does not possess spare receptors for A. If an antagonist binds irreversibly to receptors, then its effect is to reduce the maximal response of the tissue to a given agonist (Fig. 4). However, it has become apparent that many tissues possess 'spare' receptors in that full agonists are capable of producing a maximal response, while interacting with only a small fraction of receptors. In tissues in which there are spare receptors for a given agonist, the agonist may produce a maximal tissue response even in the presence of an irreversible antagonist. The latter then only causes a fall in the maximal response in concentrations sufficient to reduce the numbers of receptors available to below that necessary for the agonist to produce a maximal effect. An alternative interpretation of drug-receptor interactions is that the intensity of response to a drug is proportional to the rate of drug-receptor interactions, i.e. the number of interactions/unit of time. According to this 'rate theory' the factor that determines the difference between an agonist and antagonist is the dissociation rate constant k (see equation 1) which describes the rate a drug 2 leaves its receptor. The greater the rate of dissociation the greater the rate of drug-receptor interaction. Agonists, therefore, have a high rate of dissociation Drug Actions 7 and antagonists a low rate of dissociation. As yet, there is too little data on the k 2 values of drugs to evaluate the general applicability of this theory. Production of drug effects The consequence of drug-receptor interaction and the conformational changes in receptors that result depends on the physiological role of receptor molecules and the organs of which they are part. Most drug receptors are located on cells. This is not always the case since, for instance, the anticoagulant heparin induces conformational changes in a recep- tor molecule antithrombin III which is free in the plasma. This conformational change increases the affinity of antithrombin III for its substrate thrombin and the plasma concentration of free thrombin falls in consequence. Drugs may affect many aspects of cell function, e.g. membrane permeability to cations, active transport systems, the availability of cyclic nucleotides that modulate intracellular metabolic events, etc. In general, their primary effect is to inhibit or impair biochemical processes. They are more effective at impairing energy requiring (i.e. active) rather than passive processes and if they inhibit a particular metabolic sequence, they are most effective when inhibiting the rate limiting step. Drug effects on cells cause changes in the function of the organs of which they are a part. These changes may be localised to the organ itself or they may trigger off a physiological response to the change in function of the target organ. For example, the primary effect of the hypotensive drug hydralazine is vasodilata- tion of resistance vessels. This causes a fall in peripheral resistance which is sensed by baro-receptors in the aortic arch and carotid body and results in an increase in sympathetic tone, causing an increase in heart rate and cardiac output. The net effect on the BP of hypertensive subjects depends on the balance between these opposing primary and secondary effects. The actions of drugs therefore may be considered at the molecular level (drug-receptor interactions), the cellular level, the organ or tissue level, and at the level of the whole animal. Clinical pharmacology is concerned with the use of drugs in man in both health and disease, a further consideration being drug actions in particular disease states. In clinical practice a detailed analysis of drug actions at all levels is frequently unnecessary and attention is focused on actions that may be of benefit (i.e. therapeutic) in particular conditions and actions that may be detrimental (i.e. adverse). In this text, the mode of action of drugs will be described briefly and related, where possible, to what is known of the pathophysiology of the condition for which it is being prescribed. The relevance of the mode of action of drugs to clinical pharmacology Clin- ical pharmacology often seems to be concerned with pharmacokinetic aspects of drugs at the expense of pharmacodynamic aspects, whereas knowledge of the latter is just as often of value in the clinical usage of drugs. Drug-receptor interactions Knowledge of the nature of the binding of drugs to their receptors is essential for the interpretation of pharmacokinetic data. For 8 Pharmacology in Clinical Practice drugs that bind reversibly to receptors there is generally a close correlation between the concentration of drug in plasma water and the intensity of drug effect. For drugs that bind irreversibly (covalently) to receptors on the other hand or that induce irreversible changes, the response is often proportional to the peak plasma concentration but thereafter the relationship between plasma concentration and response is poor. Drug interactions Pharmacodynamic drug interactions can often be predicted from knowledge of the mode of action of drugs that are administered concomit- antly (Chapter 9). Drug potency The potency of a drug refers to two separate characteristics: 1. The more potent a drug, the lower the dose necessary to produce a given effect. The absolute weight of a drug prescribed is only occasionally of relevance in therapeutics. If the dose is large, it may be inconvenient to take and the compliance with drug-taking instructions may fall off; e.g. in tuberculosis, paraminosalicylic acid is prescribed in 10-15 g dose/day. Its bulk is inconvenient and causes a proportion of patients to stop taking it and this encourages the emergence of resistant organisms. 2. The size of the maximal effect. If two drugs produce the same effect, e.g. the'diuretics frusemide and bendrofluazide, but the maximal effect of the one (frusemide) is greater than that of the other (bendrofluazide), then the one with the greater effect is described as the more potent, irrespective of the size of their maximally effective doses. Therapeutic index In animals, the ratio of the dose that is lethal to 50% of a group of animals (LD50) to the dose that produces a given effect in 50% (ED50) is described as the therapeutic index or ratio. In clinical pharmacology there can be no such simple expression relating what is desirable about a drug (therapeutic) to what is undesirable (adverse) for a variety of reasons. 1. A drug effect may be described as 'adverse' in one set of circumstances but therapeutic in another; e.g. the hypotensive effect of L-dopa in parkinsonism is often the dose-limiting adverse effect but it is the 'therapeutic' effect of alpha methyldopa in hypertension. 2. Drugs usually produce a number of effects some of which are therapeutic and some adverse. The dose-response curves for all these effects may differ considerably in slope and shape so that no single ratio can relate what is therapeutic to what is adverse. Furthermore, adverse effects often vary enorm- ously in severity between those on the one hand that decrease the quality of life without serious consequences, e.g. drowsiness, nausea, dizziness, etc., and those on the other that are life-threatening, e.g. bone marrow depression, hepatocellu- lar damage, etc. Knowledge of the relationship of both to the therapeutic dose range is necessary for effective use of drugs. 3. It is seldom possible to construct log-dose response curves in man for therapeutic effects of drugs and this is hardly ever possible for adverse effects. The relationship between therapeutic and adverse effects of a drug in a