NSAIDS and Aspirin: Recent Advances and Implications for Clinical Management

Abstract

Acetylsalicylic acid (aspirin) is unique—it contains two active moieties within one and the same molecule: the reactive acetyl group of the unmetabolized aspirin and the salicylate metabolite. Both have different pharmacokinetics and pharmacodynamics. Aspirin is rapidly hydrolyzed into inactive acetate and salicylate by aspirin “esterases,” preferentially in the intestinal epithelium, liver, and blood. The half-life of unmetabolized aspirin in blood is 20–30 min, the half-life of salicylate at analgesic doses of 1–2 g about 3 h. Different galenic preparations of aspirin are available with different pharmacokinetics, most notable a disintegrating formulation with markedly increased systemic bioavailability of unmetabolized aspirin. Pharmacological actions of aspirin, i.e., anti-inflammatory, analgesic, and antipyretic effects, are largely due to acetylation. This action is irreversible, i.e., the duration of action is determined by the turnover rate of the protein and not by the short half-life of aspirin in blood. The most important protein targets are the prostaglandin cyclooxygenases-1 (COX-1) and COX-2. Both enzymes are inhibited in vitro at comparable potency. In vivo; the inhibition of COX-2 is less pronounced, probably because of the rapid protein turnover rate of the enzyme and the short half-life of aspirin. In addition, acetylation of COX-2 allows for generation of15-(R)HETE and subsequent formation of “aspirin-triggered lipoxin” (ATL) by interaction with white cell lipoxygenases. In the cardiovascular system, aspirin also acetylates eNOS with subsequent upregulation of NO formation and enhanced expression of the antioxidant heme-oxygenase-1. Salicylate has some actions by its own, notably uncoupling of oxidative phosphorylation at low millimolar concentrations. This will contribute to the anti-inflammatory and, perhaps, antipyretic effects of aspirin.