SECTION

SECTIONTHREE
ONE

GENERAL PRINCIPLES

1
1
How drugs act: general principles
Drugs in medicine 2 ignored what appear to be easily ascertainable facts. Thus,
The binding of drug molecules to cells 3
Protein targets for drug binding 3
A note on terminology 4
Drug specificity 4
Receptor classification 5
Quantitative aspects of drug–receptor interactions 6
—Agonist concentration–effect curves 6
—Competitive antagonism 7
—Partial agonists and the concept of efficacy 8
Direct measurement of drug binding to receptors 11
Drug antagonism 13
Desensitisation and tachyphylaxis 16
Pharmacology can be defined as the study of the manner
in which the function of living systems is affected by
chemical agents. It is a rather young science, having first
achieved independent recognition at the end of the 19th
century in Germany. Long before this, of course, herbal
remedies were widely used, but there was a surprising
reluctance to apply anything resembling scientific prin-
ciples to therapeutics. Even Robert Boyle, who laid the
scientific foundations of chemistry in the middle of the
17th century, was content, when dealing with therapeutics
(A Collection of Choice Remedies, 1692), to recommend
concoctions of worms, dung, urine and the moss from a
dead man’s skull. Indeed, therapeutics only began to be
influenced by science in the mid-19th century, at which
time Virchow dismissed the subject thus: ‘Therapeutics
is in an empirical stage cared for by practical doctors
and clinicians, and it is by means of a combination with
physiology that it must rise to be a science, which today
it is not.’ At that time, knowledge of the normal and
abnormal functioning of the body was too rudimentary
to provide even a rough basis for understanding drug
effects; at the same time disease and death were regarded
as semi-sacred subjects, appropriately dealt with by
authoritarian, rather than scientific, doctrines. Clinical
practice often displayed an obedience to authority, and
2
cinchona bark was recognised as a specific and effective
treatment for malaria, and a sound protocol for its use was
laid down by Lind in 1765. In 1804, however, Johnson
declared it to be unsafe until the fever had subsided, and
he recommended instead the use of large doses of calomel
in the early stages—a murderous piece of advice, which
was nonetheless generally followed for the next 40 years.
DRUGS IN MEDICINE
Repeated attempts were made to construct systems of
therapeutics, many of which produced even worse results
than pure empiricism. One of these was allopathy,
espoused by James Gregory (1735–1821). The favoured
remedies included blood-letting, emetics and purgatives,
used until the dominant symptoms of the disease were
suppressed. Many patients died from such treatment, and
it was in reaction against it that Hahnemann introduced
the practice of homoeopathy in the early 19th century.
The guiding principles of homoeopathy are:
• like cures like
• activity can be enhanced by dilution.
The system rapidly drifted into absurdity: for example,
Hahnemann recommended the use of drugs at dilutions
of 1 : 1060, equivalent to 1 molecule in a sphere the size
of the orbit of Neptune.
Many other systems of therapeutics have come and
gone, and the variety of dogmatic principles that they
embodied have tended to hinder rather than advance
scientific progress.*
*Therapeutic systems whose basis lies outside the domain of
science are, of course, very much alive today, and they are even
gaining ground under the general banner of ‘alternative’ or ‘holistic’
medicine. Mostly they reject the ‘medical model’ which attributes
disease to an underlying derangement of normal function that can

Drugs have, for many years, been the most widely used
form of therapeutic intervention available to doctors.
Reliance on natural products, mainly from plants, pre-
dominated until, in the 1920s, synthetic chemicals were
first introduced, and the modern pharmaceutical industry
began to develop.* Natural products remain an important
source of new drugs, but most are now synthetic chemicals.
Scientific understanding of drug action—the kind of
understanding that enables us to predict the pharmaco-
logical effects of a novel chemical substance, or to design
a chemical that will produce a specified therapeutic
effect—is growing rapidly, but is still far from complete.
Even so, certain generalisations are possible, and these
are discussed in this chapter.
To begin with, we should gratefully acknowledge Paul
Ehrlich for insisting early in this century that drug action
should be understood in terms of conventional chemical
interactions between drugs and tissues, and for dispelling
the idea that the remarkable potency and specificity of
action of some drugs put them somehow out of reach
of chemistry and physics and required the intervention of
magical ‘vital forces’. Although it is the case that many
drugs produce actions in doses and concentrations so
small that the dimensions assume an almost astronomical
remoteness, low concentrations still involve very large
numbers of molecules. Thus one drop of a solution of
a drug at only 10−10 mol/l still contains about 1010 drug-
molecules, so there is no mystery in the fact that it may
be defined in biochemical or structural terms, detected by objective
means, and influenced beneficially by appropriate chemical or
physical interventions. They focus instead mainly on subjective
malaise, which may be disease-associated or not. Abandoning
objectivity in defining and measuring disease goes along with a
similar departure from scientific principles in assessing therapeutic
efficacy, with the result that principles and practices can gain
acceptance without satisfying any of the criteria of validity that
would convince a critical scientist, and that are required by law to
be satisfied before a new drug can be introduced into therapy.
Public acceptance, alas, has little to do with demonstrable efficacy.
*In recent years, biotechnology has emerged as a major source of
new therapeutic agents in the form of antibodies, enzymes and
various regulatory proteins, including hormones, growth factors and
cytokines (see Buckel 1996). Though such biotechnology products
are generally produced in a very different way from conventional
drugs, the pharmacological principles are essentially the same.
Gene therapy and cell-based therapies (see Ch. 50), though still in
their infancy, will take therapeutics into a new domain. The
principles governing the design, delivery and control of functioning
artificial genes introduced into cells, or of engineered cells
introduced into the body, are very different from those of drug-
based therapeutics, and will require a different conceptual
framework, which texts such as this will increasingly need to
embrace if they are to stay abreast of modern medical treatment.
HOW DRUGS ACT: GENERAL PRINCIPLES 1
produce an obvious pharmacological response. Some
bacterial toxins (e.g. diphtheria toxin) act with such
precision that a single molecule taken up by a target cell
is sufficient to kill it.
THE BINDING OF DRUG MOLECULES TO CELLS
One of the basic tenets of pharmacology is that drug
molecules must exert some chemical influence on one or
more constituents of cells in order to produce a pharma-
cological response. In other words, drug molecules must
get so close to these constituent cellular molecules that
their function is altered. Of course, the molecules in the
organism vastly outnumber the drug molecules and if
the drug molecules were merely distributed at random,
the chance of interaction with any particular class of
cellular molecule would be negligible. Pharmacological
effects therefore require, in general, the non-uniform
distribution of the drug molecule within the body or
tissue, which is the same as saying that drug molecules
must be ‘bound’ to particular constituents of cells and
tissues in order to produce an effect. Ehrlich summed it
up thus: ‘Corpora non agunt nisi fixata’ (in this context,
‘A drug will not work unless it is bound’).**
Understanding the nature of these binding sites, and
the mechanisms by which the association of a drug
molecule with a binding site leads to a physiological
response, constitutes the major thrust of pharmacological
research. Most drugs produce their effects by binding,
in the first instance, to protein molecules. Even apparent
exceptions, such as general anaesthetics (see Ch. 32),
which have long been thought to produce their effects
by an interaction with membrane lipid, now appear to
interact mainly with membrane proteins (see Franks &
Lieb 1994). The only important exception to proteins as
target sites is DNA, on which a number of antitumour and
antimicrobial drugs act (Ch. 41), as well as mutagenic
and carcinogenic agents (Ch. 49).
PROTEIN TARGETS FOR DRUG BINDING
Four kinds of regulatory proteins are commonly involved
as primary drug targets, namely:
• enzymes
• carrier molecules
**There are, if one looks hard enough, exceptions to Ehrlich’s
dictum, drugs which act without being bound to any tissue
constituent (for example osmotic diuretics, osmotic purgatives,
antacids, heavy metal chelating agents). Nonetheless, the principle
remains true for the great majority.
3
1 GENERAL PRINCIPLES
• ion channels
• receptors.
A few other types of protein (e.g. structural proteins such
as tubulin, which specifically binds colchicine; Ch. 13)
are known to function as drug targets, and it must be
remembered that there exist many drugs whose sites of
action are not yet known. Furthermore, many drugs are
known to bind (in addition to their primary targets) to
plasma proteins (see Ch. 4), as well as to cellular con-
stituents, without producing any obvious physiological
effect. Nevertheless, the generalisation that most drugs
act on one or other of the four types of protein listed
above serves as a good starting point.
Further discussion of the mechanisms by which such
binding leads to cellular responses is given in Chapter 2.
A NOTE ON TERMINOLOGY
The term receptor tends to be used loosely, and can cause
confusion. Some authors use it to mean any target mole-
cule with which a drug molecule has to combine in order
to elicit its specific effect, which can include any of the
four types listed. Thus, the voltage-sensitive sodium
channel of excitable membranes is sometimes referred
to as the ‘receptor’ for local anaesthetics (see Ch. 40), or
the enzyme dihydrofolate reductase as the ‘receptor’ for
methotrexate (Ch. 42). In each case the drug molecule
combines with and incapacitates the protein molecule,
thus producing its effect. This is different from the situa-
tion where, for example, adrenaline acts on a receptor in
the heart (see Ch. 8). In this case, the primary function of
the receptor molecule is to serve as a recognition site for
catecholamines. When adrenaline binds to the receptor,
a train of reactions is initiated (see Ch. 2), leading to an
increase in force and rate of the heartbeat. The receptor
produces an effect only when adrenaline is bound; other-
wise it is functionally silent.* This, in general, is true
of all receptors for endogenous mediators (hormones,
neurotransmitters, cytokines, etc.). There is a distinction
between agonists, which ‘activate’ the receptors, and
antagonists, which may combine at the same site without
causing activation. Receptors of this type form a key part
of the system of chemical communication that all multi-
cellular organisms use to coordinate the activities of their
cells and organs. Without them we would be no better
than a bucketful of amoebae. The distinction between
agonists and antagonists only exists for receptors with
*Actually some receptors, such as the benzodiazepine receptor
(Ch. 33) show resting activity, which can be either increased or
decreased when a ligand molecule binds (see p. 10).
4
this type of physiological regulatory role; we cannot
usefully speak of ‘agonists’ for the noradrenaline carrier
or for the voltage-sensitive sodium channel or for
dihydrofolate reductase. In pharmacology it is best to
reserve the term ‘receptor’ for interactions of the regula-
tory type, where the small molecule (ligand) may func-
tion either as an agonist or as an antagonist; in practice
this limits use of the term to receptors which have a
physiological regulatory function, and this usage will
be observed in this book.** More details about the mole-
cular nature of receptors, and the ways in which they
influence cell function, are given in Chapter 2.
DRUG SPECIFICITY
For a drug to be useful as either a therapeutic or a
scientific tool, it must act selectively on particular cells
and tissues. In other words it must show a high degree
of binding-site specificity. Conversely, proteins that
function as drug targets generally show a high degree of
ligand specificity; they will recognise only ligands of a
certain precise type, and ignore closely related molecules.
These principles of binding-site and ligand specificity
can be clearly recognised in the actions of a mediator
such as angiotensin (Ch. 15). This peptide acts strongly
on vascular smooth muscle, and on the kidney tubule,
but has very little effect on other kinds of smooth muscle,
or on the intestinal epithelium. Other mediators affect a
quite different spectrum of cells and tissues, the pattern
in each case being determined by the specific pattern
of expression of the protein receptors for the various
mediators. On the other hand, a small chemical change,
such as conversion of one of the amino acids in angio-
tensin from L- to D-form, or removal of one amino acid
from the chain, can inactivate the molecule altogether,
since the receptor fails to bind the altered form. The
complementary specificity of ligands and binding sites,
which gives rise to the very exact molecular recognition
properties of proteins, is central to explaining many of
the phenomena of pharmacology. It is no exaggeration
to say that the ability of proteins to interact in a highly
selective way with other molecules—including other
proteins—is the basis of living machines. Its relevance
to the understanding of drug action will be a recurring
theme in this book.
Finally, it must be emphasised that no drug acts with
**We break our own rule in Chapter 16 by referring to the ‘LDL
receptor’, a term in common usage to describe a macromolecule—
not strictly a receptor according to our definition—which plays a
key role in lipoprotein metabolism.

complete specificity. Thus histamine antagonists (Ch. 13),
although they can be shown to have a higher affinity for
histamine receptors than for other sites, produce many
effects, such as sedation and prevention of vomiting,
which do not appear to depend on histamine antagonism.
In general, the lower the potency of a drug, and the higher
the dose needed, the more likely it is that sites of action
other than the primary one will assume significance. In
clinical terms, this is often associated with the appearance
of unwanted side-effects, of which no drug is free.
A major aim of pharmacological research is to identify
and characterise, in molecular terms, the protein targets
of many different types of drug. This has revealed the
mode of action of many drugs, such as opiate analgesics
(Ch. 37), cannabinoids (Ch. 39), and benzodiazepine
tranquillisers (Ch. 33), whose actions were described
in exhaustive detail for many years without yielding any
clues about the molecular basis of their effects. All have
now been shown to target well-defined receptors, which
have been fully characterised by gene-cloning techniques
(see Ch. 2).
RECEPTOR CLASSIFICATION
Where the action of a drug can be associated with a parti-
cular receptor, this provides a valuable means for classi-
fication and refinement in drug design. For example,
pharmacological analysis of the actions of histamine (see
Ch. 12) showed that some of its effects (the H1 effects,
such as smooth muscle contraction) were strongly antag-
onised by the competitive histamine antagonists then
known. Black and his colleagues, in 1970, suggested that
the remaining actions of histamine, which included its
stimulant effect on gastric secretion, might represent a
second class of histamine receptor (H2). Testing a number
Targets for drug action
¡ A drug is a chemical that affects physiological function
in a specific way.
¡ Most drugs are effective because they bind to particular
target proteins, namely:
—enzymes
—carriers
—ion channels
—receptors.
¡ Specificity is reciprocal: individual classes of drug bind
only to certain targets, and individual targets recognise
only certain classes of drug.
¡ No drugs are completely specific in their actions. In many
cases, increasing the dose of a drug will cause it to affect
targets other than the principal one, and lead to side-effects.
HOW DRUGS ACT: GENERAL PRINCIPLES 1
of histamine analogues, they found that some were
selective in producing H2 effects, with little H1 activity.
By analysing which parts of the histamine molecule
conferred this type of specificity, they were able to
develop selective antagonists, which proved to be potent
in blocking gastric acid secretion, a development of
major therapeutic significance (Ch. 21). A third type of
histamine receptor (H3) has recently been defined.
This example illustrates the principle of receptor classi-
fication based on pharmacological criteria—receptors
being classified on the basis of the effects of particular
drugs—which continues to be a valuable and widely-used
approach. Newer experimental approaches have subse-
quently revealed several different criteria on which to
base receptor classification. The first of these was the
direct measurement of ligand binding to receptors (see
p. 11), which allowed many new receptor subclasses to
be defined—subclasses only very dimly discernible from
studies of drug effects. More recently, molecular cloning
has revealed the amino acid sequence of many receptors
(see Ch. 2), providing a completely new basis for classi-
fication at a much finer level of detail than can be reached
through pharmacological analysis. Finally, analysis of
the biochemical pathways that are activated in response
to receptor activation (see Ch. 2) shows patterns that
provide yet another basis for classification. The result of
this data explosion has been that receptor classification
has suddenly become very much more detailed, with a
proliferation of receptor subtypes for all of the main types
of ligand; more worryingly, alternative molecular and
biochemical classifications began to spring up which
were incompatible with the accepted pharmacologically
defined receptor classes. Responding to this growing
confusion, the International Union of Pharmacological
Sciences (IUPHAR) has set up various expert working
groups to produce agreed receptor classifications for the
major types, taking into account the pharmacological,
molecular and biochemical information available.* These
wise men have a hard task; their conclusions will be
neither perfect nor final, but are essential to ensure a
consistent terminology. To the student, this may seem an
arcane exercise in taxonomy, generating much detail but
little illumination; the tedious lists of drug names, actions
and side-effects that used to burden the subject are in
danger of being replaced by exhaustive tables of recep-
tors, ligands and transduction pathways. In this book, we
have tried to avoid detail for its own sake, and include
only such information on receptor classification as seems
*Published as The IUPHAR compendium of receptor
characterization and classification 1998. IUPHAR Media, London.
5
1 GENERAL PRINCIPLES
interesting in its own right, or is helpful in explaining the
actions of important drugs. A useful summary of known
receptor classes is now published annually (Trends in
Pharmacological Sciences, Receptor Supplement).
QUANTITATIVE ASPECTS OF DRUG–RECEPTOR
INTERACTIONS
The first step in drug action on specific receptors is
the formation of a reversible drug–receptor complex, the
reactions being governed by the Law of Mass Action.
Suppose that a piece of tissue, such as heart muscle or
smooth muscle, contains a total number of receptors Ntot,
for an agonist such as adrenaline. When the tissue is
exposed to adrenaline at concentration xA and allowed
to come to equilibrium, a certain number NA of the
receptors will become occupied, and the number of
vacant receptors will be reduced to Ntot − NA. Normally
the number of adrenaline molecules applied to the tissue
in solution greatly exceeds Ntot, so that the binding
reaction does not appreciably reduce xA. The magnitude
of the response produced by the adrenaline will be related
(even if we do not know exactly how) to the number
of receptors occupied, so it is useful to consider what
quantitative relationship is predicted between NA and xA.
The reaction can be represented by:
k+1
A + R AR
drug free receptor k–1 complex
(xA) (Ntot – NA) (NA)
The Law of Mass Action (which states that the rate of
a chemical reaction is proportional to the product of
the concentrations of reactants) can be applied to this
reaction.
Rate of forward reaction = k+1xA(Ntot – NA) (1.1)
Rate of backward reaction = k–1NA (1.2)
At equilibrium the two rates are equal:
k+1xA(Ntot – NA) = k–1NA (1.3)
The proportion of receptors occupied or ‘occupancy’,
pA = NA/Ntot, which is independent of Ntot, is:
xA
pA = (1.4)
xA + k–1/k+1
Defining the equilibrium constant for the binding reaction,
KA = k−1/k+1, equation (1.4) can be written:
xA xA/KA
pA = ———— or pA = ———— (1.5)
xA + KA xA/KA + 1
6
A
1.0
Fractional occupancy
0.5
KA = 1.0
0
0 5 10
Concentration (linear scale)
B
1.0
Fractional occupancy
0.5
KA = 1.0
0
0.1 1.0 10.0
Concentration (log scale)
Fig. 1.1 Theoretical relationship between occupancy
and ligand concentration, plotted according to equation
(1.5). A Plotted with a linear concentration scale, this curve
is a rectangular hyperbola. B Plotted with a logarithmic
concentration scale, it is a symmetrical sigmoid curve.
This important result is known as the Hill–Langmuir
equation.*
The equilibrium constant, KA, is a characteristic of the
drug and of the receptor; it has the dimensions of concen-
tration and is numerically equal to the concentration of
drug required to occupy 50% of the sites at equilibrium.
(Verify from equation (1.5) that when xA = KA, PA = 0.5.)
The higher the affinity of the drug for the receptors,
the lower will be KA. Equation (1.5) describes the rela-
tionship between occupancy and drug concentration, and
generates a characteristic curve known as a rectangular
hyperbola, as shown in Figure 1.1A. It is common in
pharmacological work to use a logarithmic scale of con-
centration; this converts the hyperbola to a symmetrical
sigmoid curve (Fig. 1.1B).
AGONIST CONCENTRATION–EFFECT CURVES
The binding of drugs to their receptors in tissues can be
measured directly (see p. 11) and shown to obey equation
*A. V. Hill first published it in 1909, when he was still a medical
student. Langmuir, a physical chemist working on gas adsorption,
derived it independently in 1916. Both subsequently won Nobel
prizes. Until recently, it was known to pharmacologists as the
Langmuir equation, even though Hill deserves the credit.

(1.5). Usually, however, it is a biological response, such
as a rise in blood pressure, contraction or relaxation of
a strip of smooth muscle in an organ bath, or the acti-
vation of an enzyme, that is actually measured and plotted
as a concentration–effect or dose–response curve, as in
Figure 1.2. Though they look similar to the theoretical
concentration–occupancy curves in Figure 1.1B, they
cannot be used to measure the affinity of agonist drugs
for their receptors, since the physiological response pro-
duced is not, as a rule, directly proportional to occupancy.
For an integrated physiological response, such as a rise
in arterial blood pressure produced by adrenaline, many
factors interact. Adrenaline (see Ch. 8) increases cardiac
output and constricts some blood vessels while dilating
others, and the change in arterial pressure itself evokes
a reflex response which modifies the primary response
to the drug. It is obviously unrealistic to expect that the
final effect will be directly proportional to occupancy in
this instance, and the same is true of most drug-induced
effects.
A second difficulty in drawing inferences about
agonist affinity from concentration–effect curves is that
the concentration of the drug at the receptors is often
not known, even though the concentration in the organ
bath is simple to calculate. Thus agonists may be subject
to rapid enzymic degradation or uptake by cells as they
diffuse from the surface towards their site of action, and
a steady state can be reached in which the agonist concen-
tration at the receptors is very much less than the concen-
100
Histamine
(guinea pig heart)
Response (% max)
Acetylcholine
(frog rectus muscle)
50
0
-7 -6 -5 -4 -3
10 10 10 10 10
Concentration (mol/I)
Fig. 1.2 Experimentally observed concentration–effect
curves. Though the lines, drawn according to the binding
equation (1.5), fit the points well, such curves do not give
correct estimates of the affinity of drugs for receptors. This is
because the relationship between receptor occupancy and
response is usually non-linear.
HOW DRUGS ACT: GENERAL PRINCIPLES 1
Binding of drugs to receptors
¡ Binding of drugs to receptors necessarily obeys the Law
of Mass Action.
¡ At equilibrium, receptor occupancy is related to drug
concentration by the Hill–Langmuir equation.
¡ The higher the affinity of the drug for the receptor, the
lower the concentration at which it produces a given level
of occupancy.
¡ The same principles apply when two or more drugs
compete for the same receptors; each has the effect of
reducing the apparent affinity for the other.
tration in the bath. In the case of acetylcholine, for
example, which is hydrolysed by cholinesterase present
in most tissues (see Ch. 7), the concentration reaching the
receptors can be less than 1% of that in the bath, and an
even bigger difference has been found with noradrenaline,
which is avidly taken up by sympathetic nerve terminals
in many tissues (see Ch. 8). Thus, even if the concentration–
effect curve looks just like a facsimile of the binding
curve, as in Figure 1.2, it cannot be used directly to
determine the affinity of the agonist for the receptors.
COMPETITIVE ANTAGONISM
Equation (1.5) describes the relationship between concen-
tration and occupancy when a single drug is present.
The treatment can easily be extended to describe the
situation when two or more competing drugs are present.
‘Competing’ means that the receptor can bind only one
drug molecule at a time. Applying the same Mass Action
rules as before, the occupancy equation becomes:
xA/KA
pA = (1.6)
xA/KA + xB/KB + 1
Comparing this result with equation (1.5) shows that
adding drug B (the competitive antagonist), as expected,
reduces the occupancy by drug A, if the concentration
of A is kept the same. Alternatively, the concentration
of A may be increased (to xA′ say) so as to restore pA, to
the value reached in the absence of the antagonist, the
-2 ratio r (= xA′/xA), by which the concentration will need to
10
be increased, is given (from equations 1.5 and 1.6) by:
xB
r= +1 (1.7)
KB
If it is assumed that the response of the test system
depends only on the agonist occupancy pA′, then it is
predicted from the theory given above that the effect
of the competitive antagonist on the response can also
7
1 GENERAL PRINCIPLES
100
80
Response (%max)
60
40
20
0 0
-11 -10 -9 -8 -7 -6
10 10 10 10 10 10 10
A Isoprenaline concentration (mol/I)
Fig. 1.3 Competitive antagonism of isoprenaline by propranolol measured on isolated guinea-pig atria. A Concentration–
effect curves at various propranolol concentrations (indicated on the curves). Note the progressive shift to the right without a change of
slope or maximum. B Schild plot (equation 1.8). The equilibrium constant (K) for propranolol is given by the abscissal intercept
2.2 × 10−9 mol/l. (Results from: Potter L T 1967 J Pharmacol 155: 91)
be overcome by increasing the agonist concentration
r-fold. Equation (1.7) is therefore useful experimentally,
because it should apply to measurements of biological
responses as well as to direct measurements of agonist
binding. Equation (1.7), which is often known as the
Schild equation after its originator, predicts two charac-
teristic properties of competitive antagonism:
• The dose ratio r depends only on the concentration
and equilibrium constant of the antagonist, and not
on the size of response that is chosen as a reference
point for the measurements, nor on the equilibrium
constant for the agonist. On a semi-logarithmic plot
of effect against concentration, therefore, the effect of
the competitive antagonist will be to shift the curve
to the right without changing its slope or maximum, a
characteristic that can easily be tested experimentally.
• The dose ratio achieved should increase linearly with
xB, and the slope of a plot of (r − 1) against xB is equal
to 1/KB.* This relationship, being independent of the
characteristics of the agonist, should be the same for
all agonists that act on the same population of receptors.
These equations have been verified for many examples of
competitive antagonism (Fig. 1.3).
PARTIAL AGONISTS AND THE CONCEPT OF EFFICACY
So far, we have considered drugs either as agonists,
which in some way ‘activate’ the receptor when they
8
5
4
-9
KB =2.2 x 10 mol/I
3
log (r-1)
2
1
-5 -4 -9 -8 -7 -6
10 10 10 10 10
B Propranolol concentration (mol/I)
occupy it, or as antagonists, which cause no activation.
However, the ability of a drug molecule to activate the
receptor is actually a graded, rather than an all-or-
nothing, property. If a series of chemically related agonist
drugs acting on the same receptors is tested on a given
biological system, it is often found that the maximal
response (the largest response that can be produced by
that drug in high concentration) differs from one drug to
another. Some compounds (known as full agonists) can
produce a maximal response (the largest response that
the tissue is capable of giving), whereas others (partial
agonists) can only produce a submaximal response
(Fig. 1.4). The difference between full and partial agonists
lies in the relationship between occupancy and response.
Figure 1.5 shows the relationship between occupancy
and concentration for drugs whose equilibrium constant
is 1.0 µmol/l. Drug a is a full agonist, producing a
*Equation (1.7) can be expressed logarithmically in the form:
log(r – 1) = log xB – log KB (1.8)
Thus a plot of log(r − 1) against log xB, usually called a Schild plot,
should give a straight line with unit slope and an abscissal intercept
equal to log KB. Following the pH and pK notation, antagonist
potency can be expressed as a pA2 value; under conditions of
competitive antagonism pA2 = − log KB. Numerically, pA2 is defined
as the negative logarithm of the molar concentration of antagonist
required to produce an agonist dose ratio equal to 2. As with pH
notation, its principal advantage is that it produces simple
numbers, a pA2 of 6.5 being equivalent to KB = 3.2 × 10−7 mol/l.
 HOW DRUGS ACT: GENERAL PRINCIPLES 1

Competitive antagonism 100

¡ Reversible competitive antagonism is the commonest
and most important type of antagonism, and has two R=Me
main characteristics: 80
— in the presence of the antagonist, the agonist log-

Response (%max)
concentration–effect curve is shifted to the right
without change in slope or maximum, the extent of the 60
shift being a measure of the dose ratio
— the dose ratio increases linearly with antagonist
concentration; the slope of this line is a measure of Et
40
the affinity of the antagonist for the receptor.
¡ Antagonist affinity, measured in this way, is widely used
as a basis for receptor classification.
20
iPr

nPr-nDec
0
maximal response at about 0.2 µmol/l, the relationship
-6 -5 -4
10 10 10
between response and occupancy is shown by the steep Concentration (mol/I)
curve in B. Comparable plots for a partial agonist are Fig. 1.4 Partial agonists. Concentration–effect curves for
shown as the shallow curves in A and B, the essential substituted methonium compounds on frog rectus abdominis
difference being that the response at any given occupancy muscle. The compounds were members of the
is much smaller for the partial agonist, which cannot decamethonium series (Ch. 7), R Me2 N+(CH2)10 N+ Me2 R.
produce a maximal response even at 100% occupancy. The maximum response obtainable decreases (i.e. efficacy
decreases) as the size of R is increased. With R = nPr or
This can be expressed quantitatively in terms of efficacy,
larger, the compounds cause no response, and are pure
a parameter originally defined by Stephenson (1956) antagonists. (Results from: Van Rossum J M 1958
which describes the ‘strength’ of a single drug–receptor Pharmacodynamics of cholinometic and cholinolytic drugs.
complex in evoking a response of the tissue. Subse- St Catherine’s Press, Bruges)
quently, it was appreciated that characteristics of the

100 1.0 100

a a
Response Full agonist
(full agonist)
Fractional occupancy

Response (%max)
Response (%max)

Occupancy
(both drugs)
50 0.5 50
b b
Partial agonist
Response
(partial agonist)

0 0 0
0.01 0.1 1.0 10.0 0 0.5 1.0
A
A Concentration (m mol/I) B
B Occupancy

Fig. 1.5 Theoretical occupancy and response curves for full and partial agonists. A The occupancy curve is for both drugs,
the response curves a and b are for full and partial agonist respectively. B The relationship between response and occupancy for full
and partial agonist, corresponding to the response curves in A. Note that curve a produces maximal response at about 20%
occupancy, while curve b produces only a submaximal response even at 100% occupancy.

9
1 GENERAL PRINCIPLES
tissue (e.g. the number of receptors that it possesses and
the nature of the coupling between the receptor and the
response; see Ch. 2), as well as of the drug itself, were
important, and the concept of intrinsic efficacy was
developed (see Jenkinson 1996, Kenakin 1993). The
relationship between occupancy and response can thus
be represented:
Characteristics of tissue
εNtot xA
Response = f
( xA + KA ) result in their constitutive activation (Bond et al. 1995),
Characteristics of drug
In this equation, f represents the transducer function
which describes the characteristics of the responding
system; ε is the intrinsic efficacy, which is a characteristic
of the drug–receptor complex. The importance of this
formal representation is that it explains how differences
in the transducer function and the density of receptors in
different tissues can result in the same agonist, acting on
the same receptor, appearing as a full agonist in one tissue
and as a partial agonist in another. By the same token, the
relative potencies of two agonists may be different in
different tissues, even though the receptor is the same.
For a more detailed discussion of drug–receptor inter-
actions, see Kenakin (1993), Jenkinson (1996).
It would be nice to be able to give a more concrete
account of what efficacy means in physical terms, and
to understand why one drug may be an agonist while
another, chemically very similar, is an antagonist. As
yet this cannot be done, but the simple scheme known as
the two-state model (see Colquhoun 1973, Leff 1995)
shown in Figure 1.6 provides a starting point. It is en-
visaged that the receptor can exist in two states, ‘resting’
(R) and ‘activated’ (R*), either of which can bind a drug
molecule, the equilibrium constants being K and K*
respectively. A shift in the equilibrium between these two
states in favour of R* initiates the response (see Ch. 2).
Normally, when no ligand is present, the equilibrium
favours the resting state. For binding of a drug molecule
to shift the equilibrium in favour of R* (in other words,
for a drug to be an agonist), the necessary condition is
that the drug should have a higher affinity for R* than
for R (K > K*). The larger the ratio K/K*, the greater
the drug’s efficacy. If K = K*, binding will leave the
conformational equilibrium undisturbed, and the drug
will be a pure competitive antagonist. This formalism is
undoubtedly too simple, especially for receptors that
act through more complex transduction machinery (see
Ch. 2); more elaborate models are discussed by Kenakin
(1993).
10
For some receptors, we now realise, an appreciable
level of activation exists even when no ligand is present.
Examples include the benzodiazepine receptor (see Ch. 33)
and the dihydropyridine receptor (Ch. 15). Furthermore,
receptor mutations occur, either spontaneously, in some
disease states, or experimentally created (see Ch. 2),
which result in appreciable activation in the absence of
any ligand (constitutive activation). Recently, it has been
found that simply over-expressing β-adrenoceptors can
a result that may prove to have major pathophysiological
implications. Under these conditions, a ligand which
binds preferentially to the inactivated state (i.e. K* > K)
can shift the equilibrium towards this state. Such com-
pounds are known as inverse agonists, since they reduce
the level of constitutive activation (Fig. 1.7). Like cats,
however, most receptors have a strong preference for the
inactive state; for these, there is no practical difference
between a competitive antagonist and an inverse agonist.
Constitutive activation is a relatively recent discovery,
however, and may prove to be of greater pharmacological
significance than is realised at present (see Milligan et al.
1995).
Whatever its theoretical status, efficacy is a concept
of great practical importance, since the ability of a drug
to act as an agonist or antagonist on a particular type
of receptor is often crucial for its therapeutic use.
Stephenson (1956), studying the actions of acetyl-
choline analogues in isolated tissues, found that many full
agonists were capable of eliciting maximal responses
at very low occupancies, often less than 1%. If a full
Agonists, antagonists and efficacy
¡ Drugs acting on receptors may be agonists or antagonists.
¡ Agonists initiate changes in cell function, producing
effects of various types; antagonists bind to receptors
without initiating such changes.
¡ Agonist potency depends on two parameters: affinity (i.e.
tendency to bind to receptors) and efficacy (i.e. ability,
once bound, to initiate changes which lead to effects).
¡ For antagonists, efficacy is zero.
¡ Full agonists (which can produce maximal effects) have
high efficacy; partial agonists (which can produce only
submaximal effects) have intermediate efficacy.
¡ According to the two-state model, efficacy reflects the
relative affinity of the compound for the resting and
activated states of the receptor. Agonists show selectivitiy
for the activated state; antagonists show no selectivity.
¡ Inverse agonists show selectivity for the resting state of
the receptor, this being of significance only in unusual
situations where the receptors show constitutive activity.

Resting state
R R*
No ligand
Equilibrium favours R
Full agonist — strong preference for R*
Equilibrium strongly shifted to R*
Partial agonist — weak preference for R*
Equilibrium partially shifted to R*
Antagonist — no preference
Equilibrium not shifted
response can occur when only a small fraction of the
receptors is occupied, the system may be said to possess
spare receptors, or a receptor reserve. This is common
with drugs that elicit smooth muscle contraction, but less
so for other types of receptor-mediated response, such
as secretion, smooth muscle relaxation or cardiac stimu-
lation, where the effect is more nearly proportional to
receptor occupancy. The existence of spare receptors
does not imply any actual subdivision of the receptor
pool, but merely that the pool is larger than the number
needed to evoke a full response. This surplus of receptors
over the number actually needed might seem to be a
somewhat profligate biological arrangement. It means,
HOW DRUGS ACT: GENERAL PRINCIPLES 1
Activated state
Fig. 1.6 Schematic representation of
effects of ligands on receptor
activation. In the resting state (no
ligand) the equilibrium normally favours
the resting state. A full agonist binds
preferentially to the activated state, and
shifts the equilibrium towards activation.
A partial agonist shows a weaker
preference, and shifts the equilibrium to
a smaller extent, even when the
receptors are fully occupied. An
antagonist shows no preference, and
does not shift the equilibrium, though it
reduces the effect of an agonist by
preventing the agonist from binding to
the receptors.
however, that a given number of agonist–receptor com-
plexes, corresponding to a given level of biological
response, can be reached with a lower concentration of
hormone or neurotransmitter than would be the case if
fewer receptors were provided. Economy of hormone
or transmitter secretion is thus achieved at the expense
of providing more receptors.
DIRECT MEASUREMENT OF DRUG BINDING TO
RECEPTORS
The binding of drugs to receptors can often be measured
directly by the use of radioactive drug molecules (usually
11
1 GENERAL PRINCIPLES

100 100
Change in level of receptor activation (%)

Change in level of receptor activation (%)

Agonist Antagonist in presence
of agonist

Agonist in presence of
antagonist
50 50

Constitutive level of Antagonist alone

receptor activation
0 0
Inverse agonist
in presence of
Inverse agonist antagonist
Antagonist in presence
of inverse agonist

-50 -50
-10 -8 -6 -4 -10 -8 -6 -4
10 10 10 10 10 10 10 10
Ligand concentration (M) Antagonist concentration (M)
A
A B
B

Fig. 1.7 The interaction of a competitive antagonist with normal and inverse agonists in a system that shows receptor
activation in the absence of any added ligands (constitutive activation). A The degree of receptor activation (vertical scale)
increases in the presence of an agonist (open squares), and decreases in the presence of an inverse agonist (open circles). Addition
of a competitive antagonist shifts both curves to the right (closed symbols). B The antagonist on its own does not alter the level of
constitutive activity (open symbols), since it has equal affinity for the active and inactive states of the receptor. In the presence of an
agonist (closed squares) or an inverse agonist (closed circles), the antagonist restores the system towards the constitutive level of
activity. These data (reproduced with permission from Newman-Tancredi A et al. 1997 Br J Pharmacol 120: 737–739) were obtained
with cloned human 5-HT receptors expressed in a cell line. (Agonist: 5-carboxamidotryptamine; inverse agonist: spiperone; antagonist:
WAY 100635; see Ch. 9 for information on 5-HT receptor pharmacology.)

with 3H, 14C or 125I). The main requirements are that the receptors, leaving behind the non-specific component.
radioactive ligand (which may be an agonist or antag- This is then subtracted from the total binding to give an
onist) must bind with high affinity and specificity, and estimate of specific binding (Fig. 1.8).
can be labelled to a sufficient specific radioactivity to If the specific binding follows the Hill–Langmuir
enable minute amounts of binding to be measured. equation (equation 1.5), the relationship between the
The usual procedure is to incubate samples of the tissue amount bound (B) and ligand concentration (x) should
(or membrane fragments) with various concentrations be:
of radioactive drug until equilibrium is reached. The
tissue is then removed, or the membrane fragments Bmaxx
B= (1.9)
separated by filtration or centrifugation, and dissolved x+K
in scintillation fluid for measurement of its radioactive
Bmax is the total number of binding sites in the preparation
content.
(often expressed as pmol/mg protein) and K is the
In such experiments there is invariably a certain amount
equilibrium constant (see equation 1.5). To display the
of ‘non-specific binding’ (i.e. drug taken up by structures
results in linear form, equation (1.9) may be rearranged
other than receptors) which obscures the specific com-
to:
ponent, and needs to be kept to a minimum. The amount
of non-specific binding is estimated by measuring the B Bmax B
radioactivity taken up in the presence of a saturating — = —— – — (1.10)
x K K
concentration of a (non-radioactive) ligand that inhibits
completely the binding of the radioactive drug to the A plot of B/x against B (known as a Scatchard plot;

12
 HOW DRUGS ACT: GENERAL PRINCIPLES 1

A B C Scatchard plot
300 100 150

Specifically bound (fmol/mg)

Total bound (fmol/mg)

Bmax = 91 fmol/mg

Bound/free (m l/mg)
Total

K = 0.66 nM
Non-specific

0 0 0
0 20 0 20 0 100
Concentration (nmol/I) Bound (fmol/mg)

Fig. 1.8 Measurement of receptor binding (β-adrenoceptors in cardiac cell membranes). The ligand was 3H-cyanopindolol, a
derivative of pindolol (see Ch. 8). A Measurements of total and non-specific binding at equilibrium. Non-specific binding is measured
in the presence of a saturating concentration of a non-radioactive β-receptor agonist, which prevents the radioactive ligand from
binding to β-receptors. The difference between the two lines (light blue) represents specific binding. B Specific binding plotted against
concentration. The curve is a rectangular hyperbola (equation 1.9). C Scatchard plot (equation 1.10). This gives a straight line from
which the binding parameters K and Bmax can be calculated.

Fig. 1.8) gives a straight line from which both Bmax and to decrease in number if it is in excess, a process of adap-
K can be estimated. Statistically, this procedure is not tation which produces gradual changes in responsiveness
without problems, and it is now usual to estimate to drugs or hormones with continued administration
these parameters from the untransformed binding valves (see p. 16).
by an iterative non-linear curve-fitting procedure. Binding curves with agonists are more difficult to
Autoradiography can also be used to investigate the interpret than those with antagonists, since they often
distribution of receptors in structures such as the brain, reveal an apparent heterogeneity among receptors. For
and direct labelling with ligands containing positron- example, agonist binding to muscarinic receptors (Ch. 7)
emitting isotopes is now used to obtain images by and also to β-adrenoceptors (Ch. 8) suggests at least
positron-emission tomography (PET) of receptor dis- two populations of binding sites with different affinities.
tribution in humans. This technique has been used, for This may be due to the fact that receptors can exist either
example, with schizophrenic patients, to measure the unattached or coupled within the membrane to another
degree of dopamine receptor blockade produced by anti- macromolecule, the G-protein (see Ch. 2), which consti-
psychotic drugs under clinical conditions (see Ch. 34). tutes part of the transduction system through which the
When combined with pharmacological studies, binding receptor exerts its regulatory effect. Antagonist binding
measurements have proved very valuable. It has, for does not show this complexity, probably because antag-
example, been confirmed that the spare receptor hypo- onists, by their nature, do not lead to the secondary event
thesis for muscarinic receptors in smooth muscle is of G-protein coupling. Agonist affinity has, indeed, proved
correct; agonists are found to bind, in general, with to be a very elusive parameter to measure, a fact which
rather low affinity, and a maximal biological effect has generated an algebraic paperchase in the pharmaco-
occurs at low receptor occupancy. It has also been shown, logical literature, with many enthusiastic followers.
in skeletal muscle and other tissues, that denervation
leads to an increase in the number of receptors in the
target cell, a finding that accounts, at least in part, for DRUG ANTAGONISM
the phenomenon of denervation supersensitivity. More
generally, it appears that receptors tend to increase in Frequently, the effect of one drug is diminished or com-
number, usually over the course of a few days, if the pletely abolished in the presence of another. One mech-
relevant hormone or transmitter is absent or scarce, and anism, competitive antagonism, was discussed earlier;

13
1 GENERAL PRINCIPLES
a more complete classification includes the following
mechanisms:
• chemical antagonism
• pharmacokinetic antagonism
• antagonism by receptor block
• non-competitive antagonism, i.e. block of receptor–
effector linkage
• physiological antagonism.
Chemical antagonism
Chemical antagonism refers to the uncommon situation
where the two substances combine in solution, so that
the effect of the active drug is lost. Examples include
the use of chelating agents (e.g. dimercaprol) which bind
to heavy metals and thus reduce their toxicity, and the
use of neutralising antibodies against protein mediators,
such as cytokines and growth factors. The latter strategy
is currently limited to experimental use, but may be
developed for therapeutic use in the near future (see
Ch. 10).
Pharmacokinetic antagonism
Pharmacokinetic antagonism describes the situation in
which the ‘antagonist’ effectively reduces the concentration
of the active drug at its site of action. This can happen
in various ways. The rate of metabolic degradation of
the active drug may be increased (e.g. the reduction of
the anticoagulant effect of warfarin when an agent
that accelerates its hepatic metabolism, such as pheno-
barbitone, is given; see Chs 5 and 48). Alternatively,
the rate of absorption of the active drug from the gastro-
intestinal tract may be reduced, or the rate of renal
excretion may be increased. Interactions of this sort
are discussed in more detail in Chapter 48. They have a
tendency to occur unexpectedly in clinical situations, and
are a major preoccupation of clinical pharmacologists.
Antagonism by receptor block
Receptor-block antagonism involves two important
mechanisms:
• reversible competitive antagonism
• irreversible, or non-equilibrium, competitive
antagonism.
Reversible competitive antagonism has been discussed
in some detail earlier in this chapter. Its key features
are surmountability, expressed in the parallel shift of
the agonist log-concentration–effect curve without any
reduction in the maximal response, and the linear Schild
plot (see p. 8). These characteristics reflect the fact
14
that the rate of dissociation of the antagonist molecules is
sufficiently high that, on addition of the agonist, a new
equilibrium is rapidly established. In effect, the agonist
is able to displace the antagonist molecules from the
receptors, although it has, of course, no power to evict a
bound antagonist molecule, or vice versa. Displacement
occurs because, by occupying a proportion of the vacant
receptors, the agonist reduces the rate of association of
the antagonist molecules, so that the rate of dissociation
temporarily exceeds that of association, and the overall
antagonist occupancy falls.
Irreversible, or non-equilibrium, competitive antag-
onism occurs when the antagonist dissociates very slowly,
or not at all, from the receptors, with the result that no
change in the antagonist occupancy takes place when the
agonist is applied.*
The fractional occupancy by the agonist is thus reduced
in proportion to the fraction of receptors not occupied by
the antagonist. Thus, if the fraction of receptors blocked
by the antagonist is pB, the fraction accessible to the
agonist is reduced to (1 − pB).
The antagonism is non-surmountable because no
matter how high the agonist concentration, the agonist
occupancy cannot exceed (1 − pB). The effects of re-
versible and irreversible antagonists are compared in
Figure 1.9. In some cases (Fig. 1.10A), the theoretical
effect is accurately reproduced, but the distinction be-
tween reversible and irreversible competitive antagonism
(or even non-competitive antagonism; see p. 15) is not
always so clear. This is because of the phenomenon of
spare receptors (see p. 11); if the agonist occupancy
required to produce a maximal biological response is very
small (say 1% of the total receptor pool), then it is
possible to block irreversibly nearly 99% of the receptors
without reducing the maximal response. The effect of a
lesser degree of antagonist occupancy will be to produce
a parallel shift of the log-concentration–effect curve that
is indistinguishable from reversible competitive antago-
nism (Fig. 1.10B). In fact, it was the finding that an irre-
versible competitive antagonist of histamine was able to
reduce the sensitivity of a smooth muscle preparation to
histamine nearly 100-fold without reducing the maximal
response that first gave rise to the spare receptor hypo-
thesis. Irreversible competitive antagonism occurs with
drugs that possess reactive groups which form covalent
bonds with the receptor. These are mainly used as ex-
perimental tools for investigating receptor function, and
*Some authors refer to this type of antagonism as non-competitive,
but this term is best reserved for antagonism that does not involve
occupation of the receptor site (see p. 15).
 HOW DRUGS ACT: GENERAL PRINCIPLES 1

A.
A Reversible competitive antagonism

1.0
Fractional occupancy

Antagonist
0.5 0 1 10 100 1000
concentration

0
-2 -1 2 3 4 5
10 10 1 10 10 10 10 10
Agonist concentration

B.
B Irreversible competitive antagonism

1.0
0

Antagonist
Fractional occupancy

Fig. 1.9 Hypothetical agonist

concentration
concentration–occupancy curves
in the presence of reversible and
irreversible competitive 0.5 1
antagonists. The concentrations are
normalised with respect to the
equilibrium constants (i.e. 1.0
corresponds to a concentration equal 10
to K, and results in 50% occupancy). 100
0
A Reversible competitive -2 -1 2
10 10 1 10 10
antagonism. B Irreversible
competitive antagonism. Agonist concentration

few are used clinically. Irreversible enzyme inhibitors slope and maximum of the agonist log-concentration–
which act similarly are clinically used, however, and response curve as in Figure 1.10B though it is quite
include drugs such as aspirin (Ch. 13), omeprazole possible for some degree of rightward shift to occur as
(Ch. 21) and monoamine oxidase inhibitors (Ch. 35). well.

Non-competitive antagonism Physiological antagonism

Non-competitive antagonism describes the situation Physiological antagonism is a term used loosely to
where the antagonist blocks at some point the chain of describe the interaction of two drugs whose opposing
events that leads to the production of a response by actions in the body tend to cancel each other. For
the agonist. For example, drugs such as verapamil and example, histamine acts on receptors of the parietal cells
nifedipine prevent the influx of calcium ions through of the gastric mucosa to stimulate acid secretion, while
the cell membrane (see Ch. 15) and thus block non- omeprazole blocks this effect by inhibiting the proton
specifically the contraction of smooth muscle produced pump; the two drugs can be said to act as physiological
by other drugs. As a rule, the effect will be to reduce the antagonists.

15
1 GENERAL PRINCIPLES

100 Control 100 Control

20 min
5 min
15 min
Response (%max)

Response (%max)
30 min
50 50 40 min

60 min
120 min
60 min
0 0
-10 -9 -8 -7 -6 -5 -8 -7 -6 -5 -4 -3
10 10 10 10 10 10 10 10 10 10 10 10

A.
A 5-hydroxytryptamine concentration (mol/l) B.
B Carbachol concentration (mol/l)

Fig. 1.10 Effects of irreversible competitive antagonists on agonist concentration–effect curves. A Rat stomach smooth
muscle responding to 5-hydroxytryptamine at various times after addition of methysergide (10−9 mol/l). B Rabbit stomach responding
to carbachol at various times after addition of dibenamine (10−5 mol/l). (After: (A) Frankhuijsen A L, Bonta I L 1974 Eur J Pharmacol
26: 220; (B) Furchgott R F 1965 Adv Drug Res 3: 21)

mechanisms can give rise to this type of phenomenon.

Drug antagonism
Drug antagonism occurs by various mechanisms:
¡ chemical antagonism (interaction in solution)
¡ pharmacokinetic antagonism (one drug affecting the
absorption, metabolism or excretion of the other)
¡ competitive antagonism (both drugs binding to the same
receptors); the antagonism may be reversible or
irreversible
¡ non-competitive antagonism (the antagonist interrupts
receptor–effector linkage)
¡ physiological antagonism (two agents producing
opposing physiological effects).
DESENSITISATION AND TACHYPHYLAXIS
Often, the effect of a drug gradually diminishes when it
is given continuously or repeatedly. Desensitisation and
tachyphylaxis are synonymous terms used to describe this
phenomenon which often develops in the course
of a few minutes. The term tolerance is conventionally
used to describe a more gradual decrease in respon-
siveness to a drug, taking days or weeks to develop, but
the distinction is not a sharp one. The term refractoriness
is also sometimes used, mainly in relation to a loss of
therapeutic efficacy. Drug resistance is a term used to
describe the loss of effectiveness of antimicrobial or
antitumour drugs (see Chs 41 and 43). Many different
They include:
• change in receptors
• loss of receptors
• exhaustion of mediators
• increased metabolic degradation
• physiological adaptation
• active extrusion of drug from cells (mainly relevant
in chemotherapy (see Chs 41 & 43).
Change in receptors
Among receptors directly coupled to ionic channels,
desensitisation is often rapid and pronounced. At the
neuromuscular junction (Fig. 1.11A), there is evidence
that the desensitised state is caused by a slow conforma-
tional change in the receptor, resulting in tight binding
of the agonist molecule without the opening of the ionic
channel (see Changeux et al. 1987). A similar change
has been described for the β-adrenoceptor (Fig. 1.11B),
which becomes, on desensitisation, unable to activate
adenylate cyclase, though it can still bind the agonist
molecule. It is believed that phosphorylation of specific
residues in the receptor protein is responsible for many
types of desensitisation (see Ch. 2).
Loss of receptors
Prolonged exposure to agonists often results in a gradual
decrease in the number of receptors as measured by

16

A
A
5 sec
10 mV
5 mV
B
B complication, but it can be exploited clinically. For
100
b -receptors
80
% of control
60
40
20 Response
0 amphetamine, which acts by releasing noradrenaline
0 4 8 24 56 88
Time (hours)
Fig. 1.11 Two kinds of receptor desensitisation.
A Acetylcholine (ACh) at the frog motor endplate. Brief
depolarisations (upward deflections) are produced by short
pulses of ACh delivered from a micropipette. A lung pulse
(horizontal line) causes the response to decline with a time-
course of about 20 seconds, owing to desensitisation, and it
recovers with a similar time-course. B β-adrenoceptors of rat
glioma cells in tissue culture. Isoprenaline (1 µM) was added
at time zero, and the adenylate cyclase response and β-
adrenoceptor density measured at intervals. During the early
uncoupling phase, the response (black line) declines with no
change in receptor density (dark blue line). Later, the
response declines further concomitantly with disappearance
of receptors from the membrane by internalisation. The grey
and light blue lines show the recovery of the response and
receptor density after the isoprenaline is washed out during
the early or late phase. (From: (A) Katz B, Thesleff S 1957 J
Physiol 138: 63; (B) Perkins J P 1981 Trends Pharmacol Sci
2: 326)
drug-binding studies. This occurs with β-adrenoceptors
(Fig. 1.11B) and appears to be a slower process than the
‘uncoupling’ from adenylate cyclase mentioned above. In
studies on cell cultures, the number of β-adrenoceptors
can fall to about 10% of normal in 8 hours in the presence
HOW DRUGS ACT: GENERAL PRINCIPLES 1
of a low concentration of isoprenaline. Recovery to
normal takes several days. Similar changes have been
described for other types of receptor, including those
for various peptides. It is believed that the vanishing
receptors are taken into the cell by endocytosis of patches
of the membrane. This type of adaptation is common for
hormone receptors, and has obvious relevance to the
effects produced when drugs are given for extended
periods. Receptor desensitisation is generally an unwanted
example, gonadotrophin-releasing hormone (see Ch. 26)
is used to treat endometriosis or prostatic cancer; given
continuously, this hormone paradoxically inhibits gonado-
trophin release (in contrast to the normal stimulatory
effect of the physiological secretion, which is pulsatile).
Exhaustion of mediators
In some cases, desensitisation is associated with deple-
tion of an essential intermediate substance. Drugs such as
and other amines from nerve terminals (see Chs 8 and
28), show marked tachyphylaxis because the releasable
stores of noradrenaline become depleted.
Increased metabolic degradation
Tolerance to some drugs, for example barbiturates
(Ch. 33) and ethanol (Ch. 39), occurs partly because
repeated administration of the same dose produces a
progressively lower plasma concentration. The degree
of tolerance that results is generally modest, and in both
of these examples other mechanisms contribute to the
substantial tolerance that actually occurs.
Physiological adaptation
Diminution of a drug’s effect may occur because it is
nullified by a homeostatic response. For example, the
blood pressure-lowering effect of thiazide diuretics is
limited because of a gradual activation of the renin–
angiotensin system (see Ch. 15). Such homeostatic mech-
anisms are very common, and if they occur slowly the
result will be a gradually developing tolerance. It is a
common experience that many side-effects of drugs, such
as nausea or sleepiness, tend to subside even though drug
administration is continued. We may assume that some
kind of physiological adaptation is occurring, though
little is known about the mechanisms involved.
17
1 GENERAL PRINCIPLES
REFERENCES AND FURTHER READING
Bond R A, Leff P, Johnson T D et al. 1995 Physiological effects
of inverse agonists in transgenic mice with myocardial
overexpression of the β2-adrenoceptor. Nature 374: 270–276
(A study with important clinical implications, showing that
overexpression of β-receptors results in constitutive receptor
activation)
Buckel P 1996 Recombinant proteins for therapy. Trends
Pharmacol Sci 17: 450–456 (Thoughtful review of the status of,
and prospects for, protein-based therapeutics)
Changeux J-P, Giraudat J, Dennis M 1987 The nicotinic
acetylcholine receptor: molecular architecture of a ligand-
regulated ion channel. Trends Pharmacol Sci 8: 459–465 (One
of the first descriptions of receptor action at the molecular
level)
Colquhoun D 1973 The relationship between classical and
cooperative models for drug action. In: H P Rang (ed) Drug
receptors. Macmillan, London (An excellent, and still relevant,
discussion of the relationship between ‘allostain’ and
‘classical’ models of agonist action)
Franks N P, Lieb W R 1994 Molecular and cellular mechanisms
of general anaesthesia. Nature 367: 607–614 (A review of new
ideas about the site of action of anaesthetic drugs)
Jenkinson D H 1996 Classical approaches to the study of
drug–receptor interactions. In: Foreman J C, Johansen T (eds)
Textbook of receptor pharmacology. CRC Press, Boca Raton
(Good account of pharmacological analysis of receptor-
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indicated effects)
Kenakin T 1993 Pharmacologic analysis of drug–receptor
interactions, 2nd edn. Raven Press, New York (Excellent and
detailed textbook, covering most of the material in this chapter
in greater depth)
Lauence D R (ed) 1998 A dictionary of pharmacology and allied
topics. Elsevier, Amsterdam (An excellent compendium,
strongly recommended. Incorporates fringe, as well as
mainstream terminology)
Leff P 1995 The two-state model of receptor activation. Trends
Pharmacol Sci 16: 89–97 (An update of the discussion by
Colquhoun (1972) taking into account discoveries at the
molecular level)
Milligan G, Bond R A, Lee M 1995 Inverse agonism:
pharmacological curiosity or potential therapeutic strategy?
Trends Pharmacol Sci 16: 10–13 (Excellent review of the
significance of constitutive receptor activation, and the effects
of inverse agonists)
Sibley D R, Lefkowitz R J 1985 Molecular mechanisms of
receptor desensitization using the β-adrenergic receptor-coupled
adenylate cyclase system as a model. Nature 317: 124–129
(Good discussion of the phenomenon and mechanisms of
receptor desensitization)
Stephenson R P 1956 A modification of receptor theory. Br J
Pharmacol 11: 379–393 (Classic analysis of receptor action,
introducing the concept of efficacy)