Pharmacology in Clinical Practice

604 Pages·1980·10.527 MB·English

by  Richard Lancaster (Auth.)

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