Pharmacology: Inhibitors of P2y12

Abstract

Dual antiplatelet treatment consisting of aspirin and a P2y12 inhibitor represents the cornerstone of treatment in patients with acute coronary syndrome (ACS) and those undergoing percutaneous coronary intervention. P2y12 inhibitors are broadly used worldwide to prevent and treat ischemic events in cardiac patients; however, understanding their pharmacokinetic and pharmacodynamic properties is important for accurate use in daily practice. Within the group of P2y12 inhibitors, thienopyridines such as ticlopidine, clopidogrel, and prasugrel are prodrugs that require hepatic metabolization and conversion to a pharmacologically active metabolite to exert the antiplatelet effect. Their active metabolites covalently and irreversibly bind to the P2y12 receptor for the entire life span of the platelet. Contrary, the cyclopentyltriazolopyrimidine-type P2y12 inhibitor, ticagrelor, and the intravenous P2y12 receptor inhibitor cangrelor are direct-acting P2y12 inhibitors that do not require metabolic activation and noncompetitively inhibit the P2y12 receptor by inducing a conformational change. Due to lower risk of hematological side effects, faster onset of action, and once-daily administration, ticlopidine was soon replaced by clopidogrel that has become the P2y12 inhibitor of choice for many years in patients with cardiovascular disease. However, the onset of the antiplatelet effect of clopidogrel was still relatively delayed for many ACS patients requiring urgent PCI. In addition, a relatively high rate (15-40 %) of patients did not reach adequately low levels of platelet reactivity with clopidogrel-as evaluated by ADP-induced platelet function testing-and was exposed to an increased risk of stent thrombosis, myocardial infarction, and mortality. Thus, novel oral P2y12 receptor inhibitors prasugrel and ticagrelor were developed to provide faster, more predictable, .