DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

46 ligand-receptor complex, LR*. The ability of a drug to
activate a receptor and generate a cellular response is a
reflection of its efficacy. Historically, efficacy has
been treated as a proportionality constant that quantifies
the extent of functional change imparted to a
receptor-mediated response system on binding a drug.
Thus, a drug with high efficacy may be a full agonist,
eliciting, at some concentration, a full response. A drug
with a lower efficacy at the same receptor may not elicit
a full response at any dose (Figure 3–1). When it is possible
to describe the relative efficacy of drugs at a particular
receptor, a drug with a low intrinsic efficacy will
be a partial agonist. A drug that binds to a receptor and
exhibits zero efficacy is an antagonist. When the
response of an agonist is measured in a simple biological
system, the apparent dissociation constant, K app
, is
a macroscopic equilibrium constant that reflects both
the ligand binding equilibrium and the subsequent equilibrium
that results in the formation of the active receptor
LR*.
Quantifying Agonism. When the relative potency of two
agonists of equal efficacy is measured in the same biological
system, and downstream signaling events are the
same for both drugs, the comparison yields a relative
measure of the affinity and efficacy of the two agonists
(Figure 3–3). It is convenient to describe agonist
response by determining the half-maximally effective
concentration (EC 50
) for producing a given effect. Thus,
measuring agonist potency by comparison of EC 50
values
is one method of measuring the capability of different
agonists to induce a response in a test system and
for predicting comparable activity in another. Another
method of estimating agonist activity is to compare
maximal asymptotes in systems where the agonists do
not produce maximal response (Figure 3–3B). The
advantage of using maxima is that this property depends
solely on efficacy, whereas drug potency is a mixed
function of both affinity and efficacy.
SECTION I
GENERAL PRINCIPLES
Quantifying Antagonism. Characteristic patterns of
antagonism are associated with certain mechanisms of
blockade of receptors. One is straightforward competitive
antagonism, whereby a drug with affinity for a
receptor but lacking intrinsic efficacy competes with
the agonist for the primary binding site on the receptor
(Ariens, 1954; Gaddum, 1957). The characteristic pattern
of such antagonism is the concentration-dependent
production of a parallel shift to the right of the agonist
dose-response curve with no change in the maximal
response (Figure 3–4A). The magnitude of the rightward
shift of the curve depends on the concentration
of the antagonist and its affinity for the receptor
(Schild, 1957).
A partial agonist similarly can compete with a
“full” agonist for binding to the receptor. However,
increasing concentrations of a partial agonist will
inhibit response to a finite level characteristic of the
drug’s intrinsic efficacy; a competitive antagonist will
reduce the response to zero. Partial agonists thus can
be used therapeutically to buffer a response by inhibiting
excessive receptor stimulation without totally abolishing
receptor stimulation (for instance, pindolol, a
β antagonist with slight intrinsic agonist activity, will
prevent overstimulation of the heart by blocking effects
of endogenous catecholamines but will assure slight
receptor stimulation in patients overly sensitive to the
negative inotropic and negative chronotropic effects of
β blockade).
An antagonist may dissociate so slowly from the
receptor that its action is exceedingly prolonged, as with
the opiate partial agonist buprenorphine and the Ca 2+
channel blocker amlodipine. In the presence of a slowly
dissociating antagonist, the maximal response to the
agonist will be depressed at some antagonist concentrations
(Figure 3–4B). Operationally, this is referred
to as noncompetitive antagonism, although the molecular
mechanism of action really cannot be inferred
unequivocally from the effect. An antagonist may also
interact irreversibly (covalently) with a receptor, as do
the α adrenergic antagonist phenoxybenzamine and the
acetylcholinesterase inhibitor DFP (diisopropylfluorophosphate),
to produce relatively irreversible effects.
An irreversible antagonist competing for the same
binding site as the agonist can produce the pattern of
antagonism shown in Figure 3–4B. Noncompetitive
antagonism can also be produced by another type of
drug, referred to as an allosteric or allotopic antagonist.
This type of drug produces its effect by binding to
a site on the receptor distinct from that of the primary
agonist, thereby changing the affinity of the receptor
for the agonist. In the case of an allosteric antagonist,
the affinity of the receptor for the agonist is decreased
by the antagonist (Figure 3–4C). In contrast, a drug
binding at an allosteric site could potentiate the effects
of primary agonists (Figure 3–4D); such a drug would
be referred to as an allosteric agonist or co-agonist
(May et al., 2007).
The affinity of a competitive antagonist (K i
) for its receptor
can be determined in radioligand binding assays or by measuring
the functional response of a system to a drug in the presence of the
antagonist (Cheng, 2004; Cheng and Prusoff, 1973; Limbird, 2005).
Concentration curves are run with the agonist alone and with the