SLOWPROCESSES 9The relationship between the concentration of a competi-
tive antagonist [B], and the dose ratio (r) was worked out by
Gaddum and by Schildt, and is:
r 1 [B]/KB,where KB is the dissociation equilibrium constant of the
reversible reaction of the antagonist with its receptor. KBhas
units of concentration and is the concentration of antagonist
needed to occupy half the receptors in the absence of agonist.
The lower the value of KB, the more potent is the drug. If sev-
eral concentrations of a competitive antagonist are studied
and the dose ratio is measured at each concentration, a plot of
(r1) against [B] yields a straight line through the origin with
a slope of 1/KB(Figure 2.6a). Such measurements provided
the means of classifying and subdividing receptors in terms of
the relative potencies of different antagonists.
PARTIAL AGONISTS
Some drugs combine with receptors and activate them, but are
incapable of eliciting a maximal response, no matter how high
their concentration may be. These are known as partial agonists,
and are said to have low efficacy. Several partial agonists are
used in therapeutics, including buprenorphine(a partial agonist
at morphine μ-receptors, Chapter 25) and oxprenolol(partial
agonist at β-adrenoceptors).
Full agonists can elicit a maximal response when only a
small proportion of the receptors is occupied (underlying the
concept of ‘spare’ receptors), but this is not the case with par-
tial agonists, where a substantial proportion of the receptors
need to be occupied to cause a response. This has two clinical
consequences. First, partial agonists antagonize the effect of a
full agonist, because most of the receptors are occupied with
low-efficacy partial agonist with which the full agonist must
compete. Second, it is more difficult to reverse the effects of a
partial agonist, such as buprenorphine, with a competitive
antagonist such as naloxone, than it is to reverse the effects of
a full agonist such as morphine. A larger fraction of the recep-
tors is occupied by buprenorphinethan by morphine, and a
much higher concentration of naloxoneis required to compete
successfully and displace buprenorphinefrom the receptors.SLOW PROCESSES
Prolonged exposure of receptors to agonists, as frequently
occurs in therapeutic use, can cause down-regulation or
desensitization. Desensitization is sometimes specific for a
particular agonist (when it is referred to as ‘homologous
desensitization’), or there may be cross-desensitization to dif-
ferent agonists (‘heterologous desensitization’). Membrane
receptors may become internalized. Alternatively, G-protein-
mediated linkage between receptors and effector enzymes
(e.g. adenylyl cyclase) may be disrupted. Since G-proteins link
several distinct receptors to the same effector molecule, this
can give rise to heterologous desensitization. Desensitization
is probably involved in the tolerance that occurs during
prolonged administration of drugs, such as morphine or
benzodiazepines (see Chapters 18 and 25).
Therapeutic effects sometimes depend on induction of tol-
erance. For example, analogues of gonadotrophin-releasing
hormone (GnRH), such as goserelinorbuserelin, are used to
treat patients with metastatic prostate cancer (Chapter 48).
Gonadotrophin-releasing hormone is released physiologically
in a pulsatile manner. During continuous treatment with
buserelin, there is initial stimulation of luteinizing hormone
(LH) and follicle-stimulating hormone (FSH) release, followed
by receptor desensitization and suppression of LH and FSH
release. This results in regression of the hormone-sensitive
tumour.100500
10 ^95 10 ^910 ^8
[Antagonist]→Slope 1/KB
Dose ratio –(a) log[Antagonist]→ 9 8 7pA 2Slope 1
log (dose ratio) –210(b)Figure 2.6:Competitive antagonism. (a) A plot of antagonist concentration vs. (dose ratio 1) gives a straight line through the origin.
(b) A log–log plot (a Schildt plot) gives a straight line of unit slope. The potency of the antagonist (pA 2 ) is determined from the intercept
of the Schildt plot.