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Competitive antagonists increase the ED50 while the Emax remains the same. Irreversible antagonists do not change the ED50 while decreases the Emax.

Katzung pharmacology, says that the irreversible antagonist may change the ED50 when spare receptors are present. How is that? What difference would it make? Could anyone explain the change graphically?

Spare receptors are said to be present when the Kd (dissociation constant, from the drug-receptor binding curve) is more than the ED50 (from the dose-response curve). This may happen due to

  1. prolonged effect of a drug-receptor interaction or
  2. when the receptors are actually in excess of the drug

ED50 = effective dose at 50% of maximum effect, Kd = Dissociation constant.

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Irreversible antagonism is like removing receptors.

If there are spare receptors, maximum effect, or any effect level, can be recovered with more ligand (because displacing the irreversible ligand is not necessary, when there are other sites to fill).

$$K_D = \frac{R*L}{RL}$$

A given effect level corresponds to a given $RL$, but with less receptor $R$ available, more ligand $L$ is needed. That is by definition a change in ED50.

If you have no spare receptor (or there is enough antagonist to prevent full effect even with spare receptors), then maximum effect cannot be recovered. There is a new Emax, lower than without antagonist; but without shifting the dose-response curve to the right.

Here is an example in Rang&Dale (8th ed., p. 12, fig 2.6). Curves are labelled with time of incubation with a given quantity of irreversible inhibitor, that is equivalent to varying concentration of irreversible inhibitor at steady state. First two show the situation with spare receptors, and last two show what happens when the original Emax cannot be reached because there are not enough receptors left to elicit maximum response.

enter image description here

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