Classification of antiplatelet agents

The figure below shows how antiplatelet drugs can be classified according to their mechanism of action. Drug classes include: ADP antagonists (Thienopyridines), COX-1 inhibitors (the only member of this class is aspirin), phosphodiestherase inhibitors and GPIIb/IIIa antagonists.

Classification of antiplatelet agents

Aspirin
Mechanism of action As shown in the figure, aspirin inhibits platelet cyclooxygenase, a key enzyme in thromboxane A2 (TXA2) generation. Thromboxane A2 triggers reactions that lead to platelet activation and aggregation, aspirin acts as a potent antiplatelet agent by inhibiting generation of this mediator. These effects last for the life of the anucleate platelet, approximately 7 to 10 days.

Aspirin inhibition of COX-1 decreases TXA2 production. Source: Gasparyan, A. Y. et al. J Am Coll Cardiol 2008;51:1829-1843 Therapeutic considerations Aspirin is indicated as prophylaxis against transient ischemic attacks, myocardial infarction and thromboembolic disorders. It is also used for the treatment of acute coronary syndromes and in the prevention of reoclusion in coronary revascularization procedures. Since side effects such as GI bleeding and acute renal insufficiency are dose dependent, the recommended antiplatelet dose ranges from 75 mg to 325 mg. A related post in this blog reviews some relevant aspects about aspirin pharmacokinetics.

ADP-receptor blockers: thienopyridines

Mechanism of action

Thienopyridines block ADP receptors. Source:Harvey, R; Champe, P Lippincott illustrated reviews: Pharmacology, 4th edition. LWW: 2009. Thienopyridines act by inhibiting the ADP-dependent pathway of platelet activation. These drugs have no direct effect on prostaglandin metabolism. Therapeutics Ticlopidine is the oldest thienopyridine currently available. It is approved for secondary prevention of thrombotic strokes in patients intolerant of aspirin and for prevention of stent thrombosis in combination with aspirin. Serious adverse effects of ticlopidine therapy are mainly hematologic and include: neutropenia, thrombocytopenia and thrombotic thrombocytopenic purpura. Clopidogrel is approved for prevention of atherosclerotic events following recent myocardial infarction, stroke or established peripheral arterial disease. It is also approved for use in acute coronary syndromes that are treated with either PCI or coronary artery bypass grafting. It has a better safety profile than ticlopidine. Recent studies have shown that PPIs interact with clopidogrel, leading to a reduced effectiveness of the latter. New antiplatelet drugs: Prasugrel is a recently approved ( July 2009) agent in this class. Like ticlopidine and clopidogrel, prasugrel requires a loading dose to achieve a maximal antiplatelet effect rapidly.

Phosphodiesterase inhibitors
Dipyridamole is acts as vasodilator and antiplatelet agent. It inhibits adenosine uptake and cyclic GMP phosphodiesterase activity, this decreases platelet aggregability. Dipyridamole alone has little antiplatelet effect, it is currently used in combination with aspirin or warfarin in the

prophylaxis of thromboembolic disorders. It is also used in stress testing for myocardial perfusion imaging.

GPIIb/IIIa inhibitors
The glycoprotein IIb/IIIa inhibitors are used parenterally in patients with acute coronary syndromes by specialists, this class of drugs is not used in an outpatient setting by nonspecialists. Mechanism of action

IIb/IIIa receptor binding to fibrinogen. Source: www.integrilin.com Platelet membrane GPIIb-IIa receptors constitute the final common pathway of platelet aggregation, the integrin GPIIb/IIIa antagonists prevent cross-linking of platelets. Their action is independent of the aggregation-inducing stimulus. Therapeutic considerations Abciximab is a chimeric human-murine monoclonal antibody directed against GPIIb/IIIa, current indications include unstable angina that does not respond to conventional therapy in patients that undergo percutaneous coronary intervention. The peptide derivatives, eptifibatide and tirofiban are more selective towards the GPIIb/IIIa receptor and have a shorter effect than abciximab.

The most serious adverse effects of GPIIB-IIIa antagonists include major bleeding, intracerebral hemorrhage and thrombocytopenia.

Plasmin (rongshuan jiaonans) is a medicine from China - which has gone through a high technology of biochemical extraction - with thrombolytic effect that has been proven in vitro and in vivo. Plasmin contains many enzymes such as collagenase, plasminogen activator, and plasmin. Not only antithrombolytic, pharmacologically plasmin also has fibrinolytic, anticoagulant, antiplatelet and antiinflamation effect. Plasmin can decrease blood viscocity and increase erythrocyte deformabulity in animal model. Study in healthy population shows that plasmin is safe. Some preliminary studies show that plasmin is effective in ischemic stroke, angina pectoris, diabetes neuropathy, and other peripheral vessel disorders.