ticlopidine

MECHANISM: Ticlopidine is a prodrug. Hepatic CYP metabolism (CYP2C19, CYP2B6) converts it to an active metabolite. The metabolite irreversibly binds the P2Y12 subtype of the ADP receptor on platelets. This prevents ADP-mediated activation of the GPIIb/IIIa complex (the fibrinogen receptor), so fibrinogen cross-linking and platelet aggregation are reduced. Because the binding is irreversible, the effect lasts the platelet lifespan (7-10 days). Onset is delayed (days) unless a loading dose is given. Platelet function returns only as new platelets are made.

CLASS: Thienopyridines include ticlopidine (1st generation), clopidogrel (2nd), and prasugrel (3rd). Ticagrelor and cangrelor are non-thienopyridine, reversible P2Y12 inhibitors. Ticagrelor is not a prodrug.

INDICATIONS (historical): (1) Secondary prevention of stroke/TIA in patients who are intolerant of or fail aspirin. (2) Prevention of subacute stent thrombosis after coronary stenting, combined with aspirin. Clopidogrel has replaced it in both uses.

ADVERSE EFFECTS (high-yield): - Neutropenia/agranulocytosis: usually within the first 3 months. This required CBC monitoring every 2 weeks during that period. - Thrombotic thrombocytopenic purpura (TTP): pentad of microangiopathic hemolytic anemia, thrombocytopenia, fever, renal dysfunction, and neurologic changes. It is related to ADAMTS13 deficiency/inhibition. Clopidogrel has a much lower risk but a rare association. - Aplastic anemia. - GI upset and diarrhea (common). - Hypercholesterolemia (raised total cholesterol and triglycerides). - Bleeding and rash.

CLINICAL PEARLS: - The hematologic toxicity is the key reason clopidogrel is preferred. Clopidogrel has a better safety profile and a faster onset. - Do not confuse with: - Clopidogrel: CYP2C19 prodrug. Reduced efficacy in CYP2C19 loss-of-function polymorphisms and with omeprazole/esomeprazole. - Dipyridamole: PDE inhibitor and adenosine reuptake inhibitor that prevents platelet aggregation. - Cilostazol: PDE3 inhibitor used for claudication. It is contraindicated in heart failure. - Abciximab, eptifibatide, tirofiban: directly block GPIIb/IIIa. - Drug-induced TTP can also be caused by ticlopidine, clopidogrel, cyclosporine, and quinine. - Mnemonic: "TICLopidine = TICKLISH marrow" (neutropenia, TTP, aplastic anemia). Thienopyridines work on the ADP receptor (P2Y12), so they are the "ADP receptor inhibitors." - Platelet-inhibitor comparison: Aspirin irreversibly inhibits COX-1, reducing TXA2. ADP receptor inhibitors reduce GPIIb/IIIa expression. GPIIb/IIIa antagonists block the final common pathway. Platelet transfusion can partially reverse effects, though the drug's active metabolite may inactivate transfused platelets if given too soon.