Page 36 - Basic _ Clinical Pharmacology ( PDFDrive )

22 SECTION I Basic Principles

A 1.0 B 1.0

E max B max
Drug effect (E) 0.5 Receptor-bound drug (B) 0.5

EC 50 K d

Drug concentration (C) Drug concentration (C)
FIGURE 2–1 Relations between drug concentration and drug effect (A) or receptor-bound drug (B). The drug concentrations at which
effect or receptor occupancy is half-maximal are denoted by EC 50 and K d , respectively.

transformation is convenient because it expands the scale of Receptor-Effector Coupling & Spare
the concentration axis at low concentrations (where the effect Receptors
is changing rapidly) and compresses it at high concentrations When an agonist occupies a receptor, conformational changes
(where the effect is changing slowly), but otherwise has no bio- occur in the receptor protein that represent the fundamental basis
logic or pharmacologic significance.
of receptor activation and the first of often many steps required
to produce a pharmacologic response. The overall transduction
process that links drug occupancy of receptors and pharmacologic
response is called coupling. The relative efficiency of occupancy-
response coupling is determined, in part, at the receptor itself; full
agonists tend to shift the conformational equilibrium of receptors
more strongly than partial agonists (described in the text that fol-
A B C lows). Coupling is also determined by “downstream” biochemical
events that transduce receptor occupancy into cellular response.
Agonist effect 0.5 tionship between drug occupancy and response can be simple
D
For some receptors, such as ligand-gated ion channels, the rela-
because the ion current produced by a drug is often directly pro-
portional to the number of receptors (ion channels) bound. For
other receptors, such as those linked to enzymatic signal transduc-
E
tion cascades, the occupancy-response relationship is often more
complex because the biologic response reaches a maximum before
full receptor occupancy is achieved.
Many factors can contribute to nonlinear occupancy-response
coupling, and often these factors are only partially understood. A
EC (A) EC (B) EC (C) EC (D,E) K d
50
50
50
50
useful concept for thinking about this is that of receptor reserve
Agonist concentration (C) (log scale)
or spare receptors. Receptors are said to be “spare” for a given
FIGURE 2–2 Logarithmic transformation of the dose axis and pharmacologic response if it is possible to elicit a maximal bio-
experimental demonstration of spare receptors, using different logic response at a concentration of agonist that does not result in
concentrations of an irreversible antagonist. Curve A shows ago- occupancy of all of the available receptors. Experimentally, spare
nist response in the absence of antagonist. After treatment with a receptors may be demonstrated by using irreversible antagonists
low concentration of antagonist (curve B), the curve is shifted to to prevent binding of agonist to a proportion of available recep-
the right. Maximal responsiveness is preserved, however, because tors and showing that high concentrations of agonist can still
the remaining available receptors are still in excess of the number produce an undiminished maximal response (Figure 2–2). For
required. In curve C, produced after treatment with a larger concen- example, the same maximal inotropic response of heart muscle to
tration of antagonist, the available receptors are no longer “spare”; catecholamines can be elicited even when 90% of β adrenoceptors
instead, they are just sufficient to mediate an undiminished maximal
response. Still higher concentrations of antagonist (curves D and E) to which they bind are occupied by a quasi-irreversible antagonist.
reduce the number of available receptors to the point that maximal Accordingly, myocardial cells are said to contain a large proportion
response is diminished. The apparent EC 50 of the agonist in curves D of spare β adrenoceptors.
and E may approximate the K d that characterizes the binding affinity What accounts for the phenomenon of spare receptors? In
of the agonist for the receptor. some cases, receptors may be simply spare in number relative to