Pharmacology of the New P2Y12 Receptor Inhibitors: Insights on Pharmacokinetic and Pharmacodynamic Properties

Abstract

The P2Y(12) receptor is a key player in platelet activation and represents an effective pharmacological target for the inhibition of platelet aggregation and prevention of atherothrombotic events. Indeed, the clinical use of the P2Y(12) receptor inhibitor clopidogrel is an effective strategy for inhibiting platelet activity in patients with acute coronary syndrome, and for preventing thrombotic events in those undergoing percutaneous coronary intervention with stenting. However, clopidogrel has several drawbacks, which include delayed onset of action, large inter-individual variability in platelet response, genetic polymorphism of the metabolizing enzyme, drug-drug interactions (DDIs), and the two-step activation process catalyzed by a series of cytochrome P450 (CYP) isoenzymes. For these reasons, new P2Y(12) receptor inhibitors have been developed in an attempt to improve on the pharmacological and clinical profile of clopidogrel. Three new P2Y(12) receptor inhibitors--prasugrel, cangrelor, and ticagrelor--have arrived, and more are coming into clinical use. Each of these antagonists has individual properties and, according to their mechanism of inhibition, can be divided into irreversible (prasugrel) and reversible inhibitors (ticagrelor, cangrelor). These agents also have different metabolic pathways: prasugrel is a prodrug that requires metabolic activation through a cytochrome-dependent pathway, while ticagrelor and cangrelor do not require metabolic conversion. However, ticagrelor is a CYP3A4 substrate/inhibitor and thus it can be involved in DDIs. Indeed, ticagrelor significantly increases the plasma levels of CYP3A4 substrates such as statins. Moreover, concomitant use with strong CYP3A4 inhibitors (such as ketoconazole, itraconazole, clarithromycin, ritonavir, telithromycin, etc.) is contraindicated, while the co-administration of ticagrelor with potent CYP3A inducers (carbamazepine, rifampicin, phenytoin, phenobarbital) is discouraged. Prasugrel and ticagrelor determine a faster, greater, and more consistent adenosine diphosphate (ADP)-receptor inhibition than clopidogrel, with a near complete inhibition of platelet aggregation between 1-2 h after administration of an oral loading dose, while cangrelor shows a rapid and potent platelet inhibitory effect with intravenous infusion. Thus, the different pharmacokinetic and pharmacodynamic characteristics of the P2Y(12) receptor inhibitors enable clinicians to personalize therapy according to patient-specific medical requirements for better prevention of atherothrombotic events. In the present review, we describe the pharmacological properties, the pharmacokinetic and pharmacodynamic differences, and the clinical efficacy of the currently available P2Y(12) receptor inhibitors.

Ticagrelor Compared with Clopidogrel Increased Adenosine and Cyclic Adenosine Monophosphate Plasma Concentration in Acute Coronary Syndrome Patients

“…The main mechanism of the pathophysiology of ACS was platelet aggregation [20]. Ticagrelor had a potential inhibition on ADP-induced platelet aggregation by antagonizing P2Y 12 receptor. In addition, many present studies demonstrated that ticagrelor had a pleiotropic property that might be mediated by adenosine.…”

“…The P2Y 12 receptor antagonists play an important role in the inhibition of platelet aggregation and prevention of atherothrombotic events for the patients with acute coronary syndromes (ACSs) [1]. Ticagrelor, a new kind of P2Y 12 receptor antagonist, produced a faster, greater and more consistent antiplatelet effect than clopidogrel [2].…”

“…Ticagrelor, a new kind of P2Y 12 receptor antagonist, produced a faster, greater and more consistent antiplatelet effect than clopidogrel [2]. In the PLATO study, ticagrelor reduced the major adverse cardiac and cerebrovascular events (MACCE) compared with the standard treatment with clopidogrel [3].…”

“…However, ventricular pauses and dyspnoea were observed in patients treated with ticagrelor. These findings led to the hypothesis that the new P2Y 12 receptor antagonist ticagrelor may have a pleiotropic property.…”

New antithrombotic therapies and complementary and alternative medicine (CAM): Chartering into unknown territory

“…Following inactivation by metabolism, which occurs primarily by CYP3A and CYP2B6, prasugrel active metabolite and other metabolites are excreted in the urine (70%) and faeces (30%). On oral administration, prasugrel has a rapid and nearly complete (>80%) gastrointestinal absorption, with peak maximal platelet inhibition occurring within 1 hour and a half-life of 7 hours [47,48]. Preclinical and clinical studies have revealed that prasugrel has been demonstrated to have a faster onset of action, increased potency and less response variability with respect to platelet inhibitory activity as compared with clopidogrel [44] Ticagrelor (Brillinta®) Ticagrelor is an orally administered nonthienopyridine, which directly and reversibly inhibits the P2Y 12 receptor.…”