Antiplatelet agents: mechanisms of action and general overview

This post is an overview on antiplatelet drugs, we will focus on the classification of agents and  their mechanism of action. The most relevant facts related to therapeutics will also be discussed here,  followed by a video review by  K.G. Paul, M.D.

A related article explores the pharmacology of thrombolytic agents.

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

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.

Source: Gasparyan, A. Y. et al. J Am Coll Cardiol 2008;51:1829-1843

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

Source:Harvey, R; Champe, P “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

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 non-specialists.

Mechanism of action

Source: www.integrilin.com

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.

Video review on antiplatelet drugs

Dr. Paul, from www.usmlevideos.net reviews antiplatelet therapy, focusing on ticlopidine and clopidogrel.

References and further reading on antiplatelet therapy

Golan, David E (editor). “Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy”, 2nd edition. LWW: 2008.

Harvey, R; Champe, P (series editors). “Lippincott illustrated reviews: Pharmacology”, 4th edition. LWW: 2009.

Brunton, L.B., Lazo, J.S., & Parker, K.L. (Eds.). “Goodman & Gilman’s the pharmacological basis of therapeutics“, 11th edition. New York: McGraw-Hill:2005.

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