P2Y12 receptor antagonists: a rapidly expanding group of antiplatelet agents.

Adenosine-50-diphosphate (ADP) plays a key role in platelet function, because, although ADP itself is a weak platelet agonist, when secreted from the platelet dense granules where it is stored, it amplifies the platelet responses induced by other platelet agonists. The transduction of the ADP signal involves both a transient rise in free cytoplasmic calcium mediated by the Gq-coupled P2Y1 receptor, and inhibition of adenylyl cyclase mediated by the Gi-coupled P2Y12 receptor. Concomitant activation of both the Gq and Gi pathways by ADP is necessary to elicit normal ADP-induced platelet aggregation. Activation of the Gq pathway through P2Y1 leads to platelet shape change and rapidly reversible aggregation, whereas the activation of the Gi pathway through P2Y12 elicits a slow progressive and sustained platelet aggregation not preceded by shape change. In addition to its role in ADP-induced platelet aggregation, P2Y12 mediates the potentiation of platelet secretion induced by strong agonists and the stabilization of thrombin-induced platelet aggregates. P2Y12 has a more selective tissue distribution than P2Y1, making it an attractive molecular target for therapeutic intervention. Indeed, P2Y12 is the target of efficacious antithrombotic agents like ticlopidine and clopidogrel, which are already used in clinical practice either alone or in combination with other antithrombotic drugs. Ticlopidine and clopidogrel are structurally related compounds, belonging to the thienopyridine family of ADP receptor antagonists; they are pro-drugs that are inactive in vitro and need to be metabolized in vivo by the hepatic cytochrome P-450 1A enzymatic pathway to active metabolites, which have very short half-lives. They irreversibly and specifically inhibit the function of the platelet P2Y12 receptor, reproducing the platelet function abnormalities that are observed in patients who are congenitally deficient in P2Y12 and in P2Y12 knock-out mice. 1,2 The ability of thienopyridines to inhibit platelet aggregation induced by several platelet agonists (such as thromboxane A2 analogues, collagen, and low concentrations of thrombin) is accounted for by the suppression of the amplifying effect on platelet aggregation of ADP secreted from platelet dense granules. Treatment with these thienopyridines renders the thrombin-induced platelet aggregates more susceptible to deaggregation and inhibits shear-induced platelet aggregation. The use of ticlopidine and clopidogrel in the clinical setting, despite their proven antithrombotic activity, has some drawbacks. (i) The need for their metabolism to active metabolites accounts for their delayed antiplatelet effects: a maximum plateau of inhibition of ADP-induced platelet aggregation is observed 4–5 days after daily oral administration of 500 mg ticlopidine or 75 mg clopidogrel. It should be noted, however, that the delayed onset of action of clopidogrel can be reduced to about 2–5 h by a loading dose of 300–600 mg. (ii) As a consequence of the irreversible inhibition of P2Y12 function, the inhibitory effect of thienopyridines on circulating platelets lasts for approximately 10 days, which corresponds to the lifespan of a circulating platelet. Although the ability of thienopyridines to inhibit irreversibly P2Y12 with their short-lived metabolites has theoretical advantages, it may represent a problem for patients who need to undergo coronary bypass surgery, because treatment with clopidogrel within 4–5 days of the procedure is associated with increased blood loss, reoperation for bleeding, increased transfusion requirements, and prolonged intensive care unit and hospital length of stay. (iii) Finally, there is a substantial interindividual variability in platelet inhibition by ticlopidine and clopidogrel, which is mostly because of the interindividual differences to the extent of metabolism of the pro-drug to the active metabolite. Preliminary, small-sized studies demonstrated an association between insufficient platelet function inhibition by clopidogrel and heightened incidence of vascular events. Increasing the dose of clopidogrel might reduce the number of poor responders. However, the safety issues should caution against this policy, as severe toxic effects of the drug such as bone marrow aplasia and microangiopathic thrombocytopenia, which might be dosedependent, have been described, albeit less frequently that with ticlopidine. The above limitations of ticlopidine