P2Y12 inhibitors

The P2Y12 receptor is a Gi-coupled receptor on the platelet surface that, when activated by ADP, inhibits adenylyl cyclase (lowering cAMP) and promotes platelet activation, shape change, degranulation, and GPIIb/IIIa receptor activation leading to aggregation. P2Y12 inhibitors block this receptor, reducing platelet aggregation and thrombus formation.

Mechanism/Classes: - Thienopyridines (irreversible inhibitors): Clopidogrel, Prasugrel, Ticlopidine — these are prodrugs requiring hepatic activation (clopidogrel via CYP2C19, making it susceptible to genetic polymorphisms and drug interactions like omeprazole). - Non-thienopyridines (reversible inhibitors): Ticagrelor (oral), Cangrelor (IV) — do not require hepatic activation, have faster onset/offset.

Clinical Uses: - Acute coronary syndrome (STEMI/NSTEMI) - often combined with aspirin (dual antiplatelet therapy, DAPT) - Percutaneous coronary intervention (PCI) with stent placement - prevents stent thrombosis - Secondary prevention of ischemic stroke/TIA - Peripheral arterial disease

Key Comparisons: - Clopidogrel: Most widely used, CYP2C19 polymorphisms cause variable efficacy (poor metabolizers have reduced effect) - Prasugrel: More potent, faster onset, but higher bleeding risk; contraindicated in prior stroke/TIA, age >75, low body weight - Ticagrelor: Reversible, requires twice-daily dosing, can cause dyspnea as a side effect (non-platelet mechanism) - Cangrelor: IV, ultra-short acting, used during PCI for rapid onset/offset

Adverse Effects: Bleeding (most common), thrombotic thrombocytopenic purpura (TTP) - rare but classically associated with ticlopidine/clopidogrel, neutropenia (ticlopidine).

High-Yield Points: Know that clopidogrel is a prodrug requiring CYP2C19 activation; PPIs (especially omeprazole) can reduce its efficacy by inhibiting CYP2C19. Aspirin + P2Y12 inhibitor (DAPT) is standard after stent placement to prevent stent thrombosis, typically for 6-12 months depending on stent type and bleeding risk.