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Australian Journal of Pharmacy : March 2005
pharmacy ed counselling casebook including prostacyclin (PGI2) and nitric oxide. Disruption to the endothelium (for example, due to vascular injury or rupture of atherosclerotic plaques) exposes prothrombic surfaces (for example, collagen) and stimulates three important platelet processes. • Platelet adhesion to the exposed sub-endothelium through specific receptor interactions between glycoprotein (GP) and von Willebrand factor (VWF), and between GPIa and collagen; • Platelet activation through a cascade of intracellular processes triggered by platelet adhesion and other stimuli (including thrombin and shear stress). A number of preformed sub- stances such as adenosine diphosphate (ADP) are released from platelets and the formation of free arachidonic acid is induced. Arachidonic acid is converted by the cyclo-oxyge- nase enzyme (COX) to prostaglandin (PG) endoperoxides, which are further metabolised in platelets to thromboxane A2 (TXA2), and in endothelium to PGI2 released ADP and TXA2 cause local vasoconstriction and exert positive feedback effects that amplify the platelet activation process (for example, acti- vation of other platelets). Platelet activation also initiates the expression of glycoprotein receptors particularly for GPIIb/IIIa, on the platelet surface; and • Platelet aggregation , through interaction between GPIIb/IIIa and von Willebrand factor, to form a haemostatic plug at the site of vascular damage.4–6 Antiplatelet drugs Aspirin (low dose) inhibits platelet aggregation by irreversibly inhibiting platelet cyclo-oxygenase, reducing the synthesis of thromboxane A2 (an inducer of platelet aggregation) for the life of the platelet. Low dose aspirin is recommended for the pre- vention of serious vascular events, including myocardial infarc- tion and stroke, in patients at high risk (for example, acute and post-myocardial infarction, angina, peripheral arterial disease, stroke, atrial fibrillation). In patients with no previous cardio- vascular disease, benefit in terms of cardiovascular prevention should be weighed against risk of GI and intracranial bleeding.4–8 Dipyridamole is a vasodilator which inhibits platelet func- tion by inhibiting phosphodiesterase, increasing platelet cAMP. It is used with warfarin for the prevention of thromboembolism Figure One: Events leading to aggregation of platelets and site of action of anti-platelet drugs3–6 Ruptured atherosclerotic plaque (disruption of endothelium) ? Adhesion of platelets to thrombogenic surface (GPIb to VWF) ? Activation of platelets ? Aspirin ?? Release of ADP etc. Clopidogrel ?? Ticlopidine ?? Arachidonate activation ? Production of cyclic endoperoxides ? ? ?Thromboxane A2 antagonists ?Synthesis of thromboxane A2 ? ?cAMP production Expression of ? ? GPIIb/IIIa receptors ? ? ? Antagonists of GPIIb/IIIa receptors ? (abciximab. eptifatide, tirofiban) Linkage of adjacent platelets by fibrinogen binding to GPIIb/IIIa receptors ? cAMP production AGGREGATION ??Epoprostenol of platelets ? = inhibition of that pathway; TXA2 = thromboxane A2; GP = glycoprotein; VWF = von Willebrand factor; cAMP = cylic adenodine monophosphate; ADP = adenosine diphosphate 204 ? THE AUSTRALIAN JOURNAL OF PHARMACY VOL.86 MARCH 2005 ?? ?Thromboxane A2 antagonists ??Phospodiesterase enzyme ? ? Dipyradamol