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 actionAs 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 considerationsAspirin 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.

TherapeuticsTiclopidine 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 non-

specialists.

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 considerationsAbciximab 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 anti-inflamation 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.