Aspirin inhibits the cyclooxygenase enzyme, preventing the production of prostaglandin and thromboxane A2 (TXA2) from arachidonic acid. TXA2 activates the GP IIb/IIIa binding site on the platelet, allowing fibrinogen to bind (Physician's Desk Reference, 2004)(Aggrenox® PI). Aspirin inhibits platelet aggregation by irreversible inhibition of platelet cyclooxygenase and thus inhibits the generation of TXA2, a powerful inducer of platelet aggregation and vasoconstriction. Paradoxically, aspirin blocks synthesis of prostacyclin by endothelial cells, resulting in an effect that promotes platelet aggregation.
Aspirin is rapidly hydrolyzed in plasma to salicylic acid, with a half-life of 20 minutes. Salicylic acid is primarily conjugated in the liver to form salicyluric acid, a phenolic glucuronide, an acyl glucuronide, and a number of minor metabolites. Salicylate metabolism is saturable and total body clearance decreases at higher serum concentrations due to the limited ability of the liver to form both salicyluric acid and phenolic glucuronide. Following toxic doses (10 to 20 g), the plasma half-life may be increased to more than 20 hours (Physician's Desk Reference, 2004; Aggrenox® PI).
Clopidogrel is a potent, noncompetitive inhibitor of ADP-induced platelet aggregation (Plavix® PI). Clopidogrel inhibits the binding of ADP to platelet membrane receptors. The effect of clopidogrel on ADP binding is irreversible and lasts for the duration of platelet life, about seven to ten days. The inhibition is specific and does not significantly affect cyclooxygenase or arachidonic acid metabolism.
The mechanism of action of clopidogrel is different from that of aspirin. Clopidogrel is extensively metabolized by the liver. The main circulating metabolite is the carboxylic acid derivative, which has no effect on platelet aggregation. It represents about 85% of the circulating drug-related compounds in plasma. The elimination half-life of the main circulating metabolite was eight hours after single and repeated administration. Covalent binding to platelets accounted for 2% of radiolabel with a half-life of 11 days.
Both low- and high-affinity ADP receptors are present on platelets, and the active metabolite of clopidogrel binds to the low-affinity receptors. ADP binding to this site is necessary for activation of the GP IIb/IIIa receptor, which is the binding site for fibrinogen. Fibrinogen links different platelets together to form the platelet aggregate. Clopidogrel thus ultimately inhibits the activation of the GP IIb/IIIa receptor and its binding with fibrinogen (Figure 2).
Dipyridamole has been suggested to act as an antiplatelet drug by several possible mechanisms (Aggrenox® PI). It directly stimulates prostacyclin synthesis, potentiates the platelet inhibitory actions of prostacyclin, and inhibits phosphodiesterase to raise platelet cyclic AMP levels. However, these effects may not occur at therapeutic levels of the drug; hence, the mechanism of action of dipyridamole remains to be elucidated. Dipyridamole is metabolized in the liver, primarily by conjugation with glucuronic acid, of which monoglucuronide (which has low pharmacodynamic activity) is the primary metabolite. In plasma, about 80% of the total amount is present as parent compound and 20% as monoglucuronide. Most of the glucuronide metabolite (about 95%) is excreted via bile into the feces, with some evidence of enterohepatic circulation. Due to the extended absorption phase of the dipyridamole component, only the terminal phase is apparent from oral treatment with aspirin/extended-release dipyridamole, which is 13.6 hours.
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