It seems appropriate to review briefly the unique features of aspirin’s pharmacokinetics (PK) and pharmacodynamics (PD) in inhibiting platelet function.

The drug permanently inactivates the cyclooxygenase (COX) activity of the platelet enzyme, prostaglandin (PG)G/H-synthase-1 (also referred to colloquially as COX-1), responsible for the first committed step in prostanoid biosynthesis.
In human platelets, this results in dose- and time-dependent inhibition of thromboxane (TX)A2 formation. Platelet TXA2 production represents an important amplification mechanism of platelet activation, by virtue of its being triggered in response to any platelet agonist and in turn inducing further platelet recruitment and aggregation.

In healthy subjects, inhibition of platelet TXA2 production by aspirin is cumulative upon repeated daily dosing and saturable at low doses (?30 mg) because of its irreversible nature.

In contrast to the uniform effectiveness of low-dose aspirin in blocking platelet COX-1 activity in healthy individuals,some clinical conditions are associated with suboptimal antiplatelet effects of aspirin. These include patients following coronary artery bypass surgery, patients with essential thrombocythaemia, patients with coronary artery disease who have metabolic syndrome (independently of diabetes mellitus), and type 2 diabetes mellitus.

The mechanisms of suboptimal aspirin effect in these conditions are likely related to the fact that they all are associated with increased in vivo platelet activation.

Thus, impaired acetylation of platelet COX-1 could result from accelerated platelet turnover, or from platelet activation-induced generation of hydroperoxides that are known to impair the acetylation of COX-isozymes by aspirin.

Given the short half-life (?20 min) of aspirin in the human circulation, the long-lasting duration of its antiplatelet effect is ensured by acetylation of COX-1 in bone-marrow megakaryocytes and limited de novo protein synthesis in blood platelets.

These factors typically allow a once daily regimen of aspirin administration, when the drug is used as an antiplatelet agent. However, changes in the systemic bioavailability of the drug, as may occur with some enteric-coated formulations and in association with obesity,or faster renewal of the drug target, as may occur in association with altered megakaryopoiesis, may limit the duration of its antiplatelet effect and require a different (e.g. bid) dosing regimen.

G Mohan.