108. Pharmacology | Pharmacodynamics Part 2: Quantifying Agonism and Antagonism and Pharmacodynamic Variability in Individuals and Populations

A patient taking a high-dose irreversible active-site antagonist for a pituitary tumor shows no reduction in agonist Emax during the first several days of treatment. After one week, however, Emax progressively decreases even though the antagonist dose is unchanged.
Which explanation best accounts for the initial preservation and later loss of Emax?

A. Receptor supersensitivity followed by desensitization
B. Spare receptors initially maintain response until they are depleted
C. Downregulation of antagonist concentration over time
D. Competitive agonist displacement of the antagonist
E. Tachyphylaxis to the antagonist itself

B

A. Supersensitivity involves antagonist exposure, not irreversible antagonists.
B. Correct. Spare receptors allow full Emax initially despite receptor blockade; once enough receptors are permanently inactivated, Emax falls.
C. Irreversible antagonists do not get “downregulated,” and the dose is unchanged.
D. Irreversible antagonists cannot be displaced.
E. Tachyphylaxis is an acute loss of response to agonists, not antagonists.

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