A group of investigators examined the effects of different muscarinic agonists and antagonists on the bladder musculature. The curves presented below were constructed after application of different agents. Curve A represents the effect of bethanechol, a pure cholinergic agonist. Which of the curves most likely represents the effect of bethanechol after application of a reversible competitive antagonist?

Question

A group of investigators examined the effects of different muscarinic agonists and antagonists on the bladder musculature.  The curves presented below were constructed after application of different agents.  Curve A represents the effect of bethanechol, a pure cholinergic agonist.  Which of the curves most likely represents the effect of bethanechol after application of a reversible competitive antagonist?

Quizplus · Accepted Answer

Antagonists are agents that bind to but do not activate receptors. Antagonists can be either competitive or noncompetitive. Competitive antagonists bind to the exact same receptor binding sites as endogenous or exogenous agonists, thereby preventing agonist binding and activation of the receptor. Competitive antagonism can be reversible (ionic bond) or irreversible (covalent bond). The effect of a reversible competitive antagonist can be overcome by high concentrations of agonist, which cause displacement of the antagonist from the receptors by mass action. Noncompetitive antagonists, on the other hand, bind to receptors at a site other than the primary agonist binding site, thereby causing a conformational (allosteric) change in the receptor protein that modifies the agonist binding site and prevents agonist binding. By binding to a different site than the agonist, noncompetitive antagonists are able to remain bound to the receptor even when high concentrations of agonist are present because the agonist is unable to displace noncompetitive antagonists from the receptor. The question has asked how the curve for bethanechol (Curve A) would be affected by the introduction of a reversible competitive antagonist. A reversible competitive antagonist is expected to require higher doses of the full agonist (bethanechol) to be present to achieve the same effect at each point along the curve. If enough of the original substrate is added, the reaction can still reach the same maximum effect. Thus, the log dose-response curve for a full agonist combined with a reversible competitive antagonist will exhibit a parallel shift to the right in the log-dose response curve, with an increase in the ED₅₀ and no change in the maximum effect (E_max). (Choice A) Curve A is the dose-response curve for the original agonist drug in the absence of modifiers such as antagonists. (Choices B and C) Both Curves B and C represent the effect of adding a noncompetitive antagonist to the agonist. Note that the ED₅₀ is unchanged (i.e. the ED₅₀ for Curves A, B and C occur at the exact same log drug concentration). This is a distinguishing characteristic of noncompetitive antagonism. The maximum effect (E_max) of Curves B and C are reduced because the noncompetitive antagonist has effectively reduced the number of receptors available for binding. The decrease in E_max will depend on the dose of noncompetitive antagonist present and is illustrated by the difference between Curves B and C, where a higher concentration of antagonist is present in Curve C than in Curve B. (Choice D) Curve D illustrates a rightward shift in the dose-response relationship, but the shift is not a parallel shift because the shape of the curve differs from that of Curve A, with changes in both E_max and ED₅₀. This curve is not characteristic of any single antagonist effect and may be the result of adding multiple types of antagonists. Educational Objective: The changes in the log dose-response curve expected for the effect of a reversible competitive antagonist added to a full agonist are: 1) a parallel shift to the right in the log-dose response curve, illustrating an increase in the ED₅₀, and 2) no change in the maximum effect (E_max). * Competitive=change ED₅₀=shift right; noncompetitive=change E_max=shift down.

A Group of Investigators Examined the Effects of Different Muscarinic