Figure

Idealized dose-response curves of an agonist in the absence (a) and the presence (b, c, d) of increasing doses of an equilibrium-competitive antagonist.

creased. This relationship can best be appreciated by examining dose-response curves, as in Figure 2.5. Curve a is obtained in the absence of the antagonist. Curve b is obtained in the presence of a modest amount of the antagonist. The curves are parallel, and the maximum effects are equal. The antagonist has shifted the dose-response curve of the agonist to the right. Any level of response is still possible, but greater amounts of the agonist are required. If the amount of the antagonist is increased, the dose-response curve is shifted farther to the right (curve c), still with no decrease in the maximum effect of the agonist. However, the amount of agonist required to achieve maximum response is greater with each increase in the amount of antagonist. Examples of equilibrium-competitive antagonists are atropine, d-tubocurarine phentolamine, and naloxone.

Of course, this continual shift of the curve to the right with no change in maximum as the dose of antagonist is increased assumes that very large amounts of the agonist can be achieved in the biophase. This is generally true when the agonist is a drug being added from outside the biological system. However, if the agonist is a naturally occurring substance released from within the biological system (e.g., a neurotransmitter), the supply of the agonist may be quite limited. In that case, increasing the amount of antagonist ultimately abolishes all response.

The effect of a nonequilibrium antagonist on the dose-response curve of an agonist is quite different from the effect of an equilibrium antagonist, as illustrated in Figure 2.6. As the dose of nonequilibrium antagonist is increased, the slope of the agonist curve and the maximum response achieved are progressively depressed. When the amount of antagonist is adequate (curve d), no amount of agonist can produce any response. The haloalkylamines, such as phenoxybenza-mine, which form covalent bonds with receptors, are examples of nonequilibrium-competitive antagonists (see Chapter 11).

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