The Use And Misuse Of Nonsteroidal Anti-inflammatory Drugs (nsaids)

USES AND MECHANISM OF ACTION OF NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
1.    ANTIINFLAMMATION
Inhibition of Prostaglandin Biosynthesis by NSAIDs. The principal therapeutic effects of NSAIDs derive from their ability to inhibit prostaglandin production. The first enzyme in the prostaglandin synthetic pathway is prostaglandin G/H synthase, also known as cyclooxygenase or COX. This enzyme converts arachidonic acid (AA) to the unstable intermediates PGG2 and PGH2 and leads to the production of thromboxane A2 (TXA2) and a variety of prostaglandins.
Therapeutic doses of aspirin and other NSAIDs reduce prostaglandin biosynthesis and there is a reasonably good correlation between the potency of these drugs as cyclooxygenase inhibitors and their antiinflammatory activity. Further support linking cyclooxygenase inhibition to antiinflammatory activity is the high degree of stereoselectivity among several pairs of enantiomers of a-methyl arylacetic acids for inhibition of cyclooxygenase and suppression of inflammation; in each instance the d or (+) isomer is more potent in inhibiting cyclooxygenase and suppressing inflammation. G&G
There are two forms of cyclooxygenase, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The COX-1 is a primarily constitutive isoform found in most normal cells and tissues, while cytokines and inflammatory mediators that accompany inflammation induce COX-2 production (Seibert et al., 1997. However, COX-2 also is constitutively expressed in certain areas of kidney and brain (Breder et al., 1995) and is induced in endothelial cells by laminar shear forces (Topper et al., 1996). Importantly, COX-1, but not COX-2, is expressed as the dominant, constitutive isoform in gastric epithelial cells and is the major source of cytoprotective prostaglandin formation. Inhibition of COX-1 at this site is thought to account largely for the gastric adverse events that complicate therapy with tNSAIDs, thus providing the rationale for the development of NSAIDs specific for inhibition of COX-2 (FitzGerald and Patrono, 2001).