Competitive & Irreversible Antagonist

Reseptor antagonist bind to receptors but do not activate them. The primary action of antagonist
is to prevent agonist (other drugs or endogenous regulatory molecules) from activating receptors.
Some antagonists (socalled “inverse agonists”), also reduce receptor activity below basal levels
observed in the absence of bound ligand. Antagonists are divided into two classes depending on
whether or not they reversible compete with agonists for binding to receptors.
In the presence of a fixed concentration of agonist, increasing concentrations of a reversible
competitive antagonist progressively inhibit the agonist response: high antagonist
concentrations prevent response completely. Conversely, sufficiently high concentrations of
agonist can completely surmount the effect of a give concentration of the antagonist; that is, the
Eₘₐₓ for the agonist remains the same for any fixed concentration of antagonist (Figure 2-3A).
Because the antagonism is competitive, the presence of antagonist increases the agonist
concetration required for given degree of response, and so the agonist concentration-effect curve
is shifted to the right.
FIGURE 2-3
GAMBAR KURVA
Some receptor antagonists bind to the the receptor in an irreversible or nearly irreversible
fashion, either by form a covalent bond with the receptor or by binding so tightly that, for
practical purposes, the receptor is unavailab for binding of agonist. After occupancy of some
proportion of receptors by such as an antagonist, the number of remaining unoccupied receptors
may be too low for the agonist (event at high concentrations) to elicit a respons comparable to
the previous maximal response (Figure 2-3B). If spare receptors are present, however, a lower
dose of an irreversibke antagonist may leave enough receptors unoccupied to allow achievement
of maximum response to agonist, although a higher agonist concentration will be required
(Figures 2-2B and C; see Receptors, Effector Coupling and spare Receptors, above).
Therapeutically, irreversible antagonist present distinctive advantages and disadvantages. Once
the irreversible antagonist has occupied the receptor, it need not be present in unbound form to
inhibit agonist responses. Consequently, the duration of action of such an irreversible antagonist
is relatively independent of its own rate elimination and more dependent on the rate of turnover
of receptor molecules.
Phenoxybenzamine, an irreversible α-adrenoreceptor antagonist, is used to control the
hypertension caused by