Chapter: Modern Pharmacology with Clinical Applications: Mechanisms of Drug Action

Drug Antagonism

The terms agonist and antagonist have already been in-troduced. The several types of antagonism can be classi-fied as follows 1. Chemical antagonism 2. Functional antagonism 3. Competitive antagonism a. Equilibrium competitive b. Nonequilibrium competitive 4. Noncompetitive antagonism


The terms agonist and antagonist have already been in-troduced. The several types of antagonism can be classi-fied as follows

1.           Chemical antagonism

2.           Functional antagonism

3.           Competitive antagonism

a.           Equilibrium competitive

b.          Nonequilibrium competitive

4.           Noncompetitive antagonism

Chemical Antagonism

Chemical antagonism involves a direct chemical interac-tion between the agonist and antagonist in such a way as to render the agonist pharmacologically inactive. A good example is the use of chelating agents to assist in the biological inactivation and removal from the body of toxic metals. Chelation involves a particular type of two-pronged attachment of the antagonist to a metal (the agonist). One chemical chelator, dimercaprol, is used in the treatment of toxicity from mercury, arsenic, and gold. After complexing with the dimercaprol, mer-cury is biologically inactive and the complex is excreted in the urine.

Functional Antagonism

Functional antagonism is a term used to represent the interaction of two agonists that act independently of each other but happen to cause opposite effects. Thus, indirectly, each tends to cancel out or reduce the effect of the other. A classic example is acetylcholine and epi-nephrine. These agonists have opposite effects on sev-eral body functions. Acetylcholine slows the heart, and epinephrine accelerates it. Acetylcholine stimulates intestinal movement, and epinephrine inhibits it. Acetylcholine constricts the pupil, and epinephrine di-lates it; and so on.

Competitive Antagonism

Competitive antagonism is the most frequently encoun-tered type of drug antagonism in clinical practice. The antagonist combines with the same site on the receptor as does the agonist, but unlike the agonist, does not induce a response; that is, the antagonist has little or no efficacy. The antagonist competes with the agonist for its binding site on the receptor. Competitive antagonists can fall into either of two subtypes, depending on the type of bond formed between the antagonist and the receptor. If the bond is a loose one, the antagonism is called equi-librium competitive or reversibly competitive. If the bond is covalent, however, the combination of the an-tagonist with the receptor is not readily reversible, and the antagonism is termed nonequilibrium competitive or irreversibly competitive.

If the antagonism is of the equilibrium type, the an-tagonism increases as the concentration of the antago-nist increases. Conversely, the antagonism can be over-come (surmounted) if the concentration of the agonist in the biophase (the region of the receptors) is increased. 

This relationship can best be appreciated by ex-amining 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 an-tagonist. The curves are parallel, and the maximum ef-fects 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 ag-onist are required. If the amount of the antagonist is in-creased, the dose–response curve is shifted farther to the right (curve c), still with no decrease in the maxi-mum effect of the agonist. However, the amount of ag-onist 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 antag-onist is increased assumes that very large amounts of the agonist can be achieved in the biophase. This is gen-erally 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 sup-ply of the agonist may be quite limited. In that case, in-creasing 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 illus-trated in Figure 2.6. As the dose of nonequilibrium an-tagonist is increased, the slope of the agonist curve and the maximum response achieved are progressively de-pressed. When the amount of antagonist is adequate (curve d), no amount of agonist can produce any re-sponse. The haloalkylamines, such as phenoxybenza-mine, which form covalent bonds with receptors, are ex-amples of nonequilibrium-competitive antagonists .

Noncompetitive Antagonism

In noncompetitive antagonism, the antagonist acts at a site beyond the receptor for the agonist. The difference between a competitive and a noncompetitive antagonist can be appreciated from the following scheme, in which two agonists, A and B, interact with totally different re-ceptor systems, RA and RB, to initiate a chain of events leading to contraction of a vascular smooth muscle cell. X is a competitive antagonist, and Y is a noncompetitive antagonist.

Antagonist X (competitive) has an affinity for RB but not RA. Thus, it specifically antagonizes agonist B. It does not antagonize agonist A. Antagonist Y acts on a receptor associated with the cellular translocation of calcium and inhibits the increase in intracellular free calcium. It will therefore antagonize the effects of both A and B, since they both ultimately depend on calcium movement to cause contraction.

The effect of a noncompetitive antagonist on the dose–response curve for an agonist would be the same as the effect of a non–equilibrium-competitive antagonist (Fig. 2.6). The practical difference between a noncompet-itive antagonist and a nonequilibrium-competitive an-tagonist is specificity. The noncompetitive antagonist antagonizes agonists acting through more than one re-ceptor system; the nonequilibrium-competitive antago-nist antagonizes only agonists acting through one recep-tor system. The antihypertensive drug diazoxide is one of the few examples of therapeutically useful noncompeti-tive antagonists .

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