Irreversible Antagonism — FRCA Primary MCQ

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ModeratePharmacology - General PrinciplesIrreversible AntagonismFRCA Primary

Following exposure of an isolated tissue to an orthosteric antagonist, extensive washing does not reverse the blockade. Once sufficient receptors have been inactivated, increasing the agonist concentration cannot restore the original maximum response. The antagonist forms stable covalent bonds with the receptors. Which type of drug–receptor interaction is present?

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Correct answer: E — Irreversible antagonism

The correct answer is E. Irreversible antagonists commonly form stable covalent bonds with receptors, so blockade persists after the free drug has been removed and is not surmounted by increasing agonist concentration. Once receptor reserve is exhausted, the agonist maximum response decreases. With spare receptors, limited irreversible receptor occupation may initially produce a rightward shift without reducing the maximum, so a reduced maximum is not inevitable at every antagonist concentration. Phenoxybenzamine is the classic example: its prolonged alpha-adrenoceptor blockade is attributed to stable covalent bonding. Competitive antagonism is reversible and surmountable. Physiological antagonists act through different receptors, while allosteric modulators bind outside the orthosteric site. A partial agonist activates the receptor but has lower efficacy than a full agonist.

Reference: ADVANZ Pharma. Phenoxybenzamine 10 mg Capsules, Summary of Product Characteristics, sections 5.1–5.2. Updated 2023. https://www.medicines.org.uk/emc/product/6036/smpc