Читать книгу Practical Cardiovascular Medicine - Elias B. Hanna - Страница 33

Typically, aspirin +/- one ADP-receptor antagonist (ticagrelor, clopidogrel) is started upon admission, upstream of catheterization.³⁶ In the current era of potent ADP-receptor antagonists and quick catheterization <24 hours, upstream therapy with those agents does not seem necessary, and initiation during catheterization appears sufficient (ACCOAST, ISAR-REACT-5 trials).^69,70 In fact, ESC guidelines recommend against routine pre-treatment with an ADP receptor antagonist (class III). Upstream IIb/IIIa inhibitor therapy is not beneficial.^60,71,72

Figure 1.4 Platelet receptors and antiplatelet mechanisms of action.

Cyclooxygenase 1 (COX-1) allows the synthesis of thromboxane A2 (TXA2), which acts on its platelet receptor, eventually activating the IIb/IIIa receptor. Aspirin irreversibly acetylates COX-1. While the pharmacokinetic half-life of aspirin is only ~20 min – 2 h, the pharmacodynamic effect of aspirin lasts the lifespan of the platelet (5–7 days).

The platelet ADP receptor eventually leads to conformational activation of the IIb/IIIa receptors. Clopidogrel and prasugrel (thienopyridines) are prodrugs that get metabolized into the same active metabolite. This active metabolite irreversibly binds to the P2Y12 ADP receptor, extending the pharmacodynamic effect of these drugs to 5–7 days despite a half-life of 6 h. The prodrugs are metabolized by cytochromes (CYP), particularly CYP2C19; only 15% of clopidogrel vs. 100% of prasugrel is actively metabolized. This explains why prasugrel is a much more potent inhibitor of platelet aggregation (~75% vs. ~35% inhibition of platelet aggregation).

Some patients have a CYP2C19 mutation that slows clopidogrel metabolism and preferentially increases its inactivation by esterases, translating into a poor or no response to clopidogrel. Prasugrel, on the other hand, has only one metabolic pathway, and will be metabolized by cytochromes regardless of how slow the metabolism is.

Ticagrelor directly binds to the P2Y12 ADP receptor and reversibly inhibits it (the effect clears as the drug clears from plasma). Despite being a reversible ADP antagonist, the very potent ADP blockade and the long half-life translate into an antiplatelet effect that lasts 3–4 days (half-life ~15 h). Since it directly acts on its receptor, the response to ticagrelor is consistent and potent (~75% platelet inhibition), including in clopidogrel non-responders.

Cangrelor is an intravenous ADP receptor antagonist that directly and reversibly binds to the ADP receptor. It inhibits 90% of the platelet aggregation. In contrast to ticagrelor, it has a short half-life of 5 min, which, in addition to the reversible receptor binding, leads to a very quick onset and offset of action.

Thrombin is also a potent activator of platelet aggregation. Vorapaxar blocks the thrombin receptor.

Cyclic AMP, promoted by cilostazol, inhibits platelet aggregation.

The IIb/IIIa receptor is the final common pathway of platelet aggregation and allows linking of the platelets through fibrinogen molecules.