Effects
P2Y12 antagonists are antiplatelet agents and prevent the formation of blood clots. The effects are due to binding to the adenosine diphosphate receptor P2Y12 on platelets. This receptor plays a central role in glycoprotein (GP)-IIb/IIa activation and platelet aggregation. The continuous binding of adenosine diphosphate (ADP) to P2Y12 is an important prerequisite for thrombus formation. The thienopyridines clopidogrel and prasugrel bind irreversibly to the receptor via a disulfide bond and exert their effects throughout platelet life. The drugs therefore act for up to 7-10 days after discontinuation, which is a disadvantage if surgery is required because of the risk of bleeding. In contrast, ticagrelor, a new drug approved in 2011, is a competitive and thus reversible inhibitor that can be discontinued rapidly.
Structure and Metabolimus
Clopidogrel and prasugrel are thienopyridines. Both agents are prodrugs and must be metabolically converted to the active drug via ester hydrolysis and cytochromes P450. Clopidogrel is susceptible to drug-drug interactions and efficacy may be limited by genetic differences. This results in a relevant proportion of patients responding inadequately to treatment. Clopidogrel is biotransformed to the active metabolite by CYP2C19. The results of various studies indicate that concomitant administration of the commonly prescribed proton pump inhibitors (especially omeprazole) reduces the pharmacologic effect of clopidogrel. Omeprazole is an inhibitor of CYP2C19 and reduces biotransformation. Activation of prasugrel does not occur via CYP2C19 or CYP2C9, which is an advantage in terms of interactions and genetic variability. The metabolite is formed more rapidly, the onset of action is faster, and prasugrel inhibits platelet aggregation more potently than clopidogrel. Ticagrelor is a direct antagonist with a rapid onset of action that does not require metabolic activation. It is a cyclopentyltriazolopyrimidine without a thienopyridine structure. Ticagrelor is metabolized primarily by CYP3A4. It is a substrate as well as a mild inhibitor of P-glycoprotein. Cangrelor is also a direct antagonist, has a rapid onset of action, and is readily controlled due to its short half-life. It is not a prodrug and does not have a thienopyridine structure.
Active Ingredients
1st generation:
- Ticlopidine (Ticlid, off-label).
2nd generation:
3rd generation:
- Ticagrelor (Brilique, 2011).
- Cangrelor (Kengrexal, 2015)
Indications
For prevention of atherothrombotic events such as myocardial infarction and stroke in patients with acute coronary syndrome and percutaneous coronary intervention. P2Y12 antagonists are often administered in combination with acetylsalicylic acid (Aspirin cardio) because of their synergistic effects. Fixed combinations are also commercially available for this purpose (eg, DuoPlavin).
Dosage
According to the drug label. For clopidogrel and prasugrel, once-daily dosing is sufficient for maintenance dosing. Ticagrelor must be taken twice daily, which may pose a problem for treatment adherence. Cangrelor is administered as an infusion.
Adverse effects
The most common potential adverse effects include bleeding in various organs.
