Dual Antiplatelet Therapy for Prevention of Recurrent Ischemic Events

Jean Nappi, PharmD, Fccp, Bcps; Robert Talbert, PharmD, Fccp, Bcps


Am J Health Syst Pharm. 2002;59(18) 

In This Article

Mechanism of Action of Oral Antiplatelet Agents

The oral antiplatelet agents currently available target one or more pathways in the hemostatic cascade (Figure 1).[23,24] Aspirin's actions are mediated by irreversibly acetylating the enzyme cyclooxygenase (COX).[25,26] COX has two isoforms: COX-1 and COX-2. Aspirin selectively inhibits COX-1 over COX-2 by 166-fold.[27] The antithrombotic action of aspirin is mainly due to inhibition of platelet COX-1, which prevents the synthesis of thromboxane A2.[26] COX-2 is induced by inflammatory stimuli and results in the production of prostaglandins that contribute to the inflammatory response. Inhibition would promote platelet aggregation; however, COX-2 remains essentially unaffected at aspirin doses of less than or equal to 300 mg.[25,26]

Figure 1.

Platelet interactions with agonists and antagonists of platelet aggregation, the vessel wall, other platelets, and adhesive macromolecules. Agents in parentheses prevent the formation or inhibit the function of the adjacent agonists of platelet aggregation. ADP = adenosine diphosphate, VWF = von Willebrand factor, cAMP = cyclic adenosine monophosphate, GP = glycoprotein. Adapted, with permission, from reference 24.

Dipyridamole and cilostazol increase concentrations of cyclic adenosine monophosphate (cAMP) in the platelet by inhibiting phosphodiesterase,[28] stimulating prostacyclin production,[29] and reducing cellular uptake of adenosine.[30] Dipyridamole may also directly enhance prostacyclin-mediated platelet inhibition and inhibit thromboxane A2.[31,32] Cilostazol and its active metabolites inhibit phosphodiesterase activity and suppress degradation of cAMP, resulting in an increase in cAMP in platelets and blood vessels. It reversibly inhibits platelet aggregation induced by ADP, collagen, arachidonic acid, epinephrine, thromboxane A2, platelet-activating factor, and shear stress.

The ADP receptor antagonists clopidogrel and ticlopidine inhibit ADP activity by preventing its binding to the platelet receptor.[21,33] ADP stimulates expression of the GP IIb/ IIIa receptor[21] and may mediate release of other aggregation agonists and enhance platelet binding of von Willebrand factor.[33] Hence, the end result of ADP inhibition is impairment of platelet aggregation and fibrinogen-mediated platelet crosslinking.[21] The GP IIb/IIIa receptor antagonists block the final common pathway in platelet activation.[34] The intravenous GP IIb/IIIa receptor antagonists are effective in the management of ischemic events related to percutaneous interventions and in patients hospitalized for unstable angina and non-ST-segment elevation myocardial infarction (NSTEMI).[35,36] However, results of clinical studies of the oral GP IIb/IIIa receptor antagonists (orbofiban, sibrafiban, xemilofiban, and lotrafiban) have been disappointing. The oral agents increased mortality by 31% (p = 0.001),[37] showed a similar trend for recurrent coronary events compared with placebo,[37,38,39,40,41,42] and were associated with more frequent bleeding complications.[39,40,42,43]


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