Clopidogrel is a prodrug requiring CYP2C19 activation to its active thiol metabolite. A patient who is a CYP2C19 poor metabolizer (e.g., carrying two loss-of-function alleles *2/*2) would best be switched to which antiplatelet agent that does NOT require hepatic bioactivation?

• A Prasugrel, noting it is still a prodrug but activated by CYP3A4 and CYP2B6 rather than CYP2C19
• B Aspirin, which does not require CYP2C19 activation for antiplatelet effect
• C Vorapaxar, a PAR-1 antagonist used as primary antiplatelet in ACS
• D Ticagrelor, a reversible direct P2Y12 receptor antagonist not requiring metabolic activation ✓

Explanation

Ticagrelor is a cyclopentyl-triazolo-pyrimidine (CPTP) class direct P2Y12 receptor antagonist. Unlike clopidogrel (thienopyridine, requiring CYP2C19 activation) and prasugrel (also a thienopyridine prodrug, activated by intestinal esterases then CYP3A4/2B6), ticagrelor is an active drug administered in its final form with no hepatic bioactivation required. This makes it fully effective regardless of CYP2C19 genotype — an important clinical advantage in poor metabolizers who are at risk of stent thrombosis on clopidogrel. Ticagrelor also binds P2Y12 reversibly (unlike the irreversible thienopyridines). Vorapaxar is used as add-on therapy, not as a primary antiplatelet switch for this indication.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.