Mechanism of action of nonsteroidal anti-inflammatory drugs.

After more than a century of use, pharmacologists thought they had discovered the mechanism of action of nonsteroidal anti-inflammatory drugs (NSAIDs) when their inhibitory action on the production of prostaglandins was described. This action was located at the inhibition of the enzyme responsible for the conversion of arachidonic acid to prostaglandins, namely cyclo-oxygenase. More recently, it has been recognized that more than one isoform of the enzyme exists. The two forms of cyclo-oxygenase described are widely different in their location, activity, and role, especially because the COX-1 isoenzyme seems to be mainly a constitutive enzyme whereas the COX-2 isoenzyme is inducible. This separation of activity appears to be correlated with the separation of function of the various prostaglandins, whereas the constitutive form is associated with "physiologic" functions and the inducible form with inflammatory responses. Recent advances have included the development of drugs with a high specificity toward the inducible enzyme (COX-2) to focus on the anti-inflammatory actions, because many of the unwanted side effects of NSAIDs have been associated with inhibition of the constitutive isoform (COX-1). Other recent developments in studies of the NSAIDs have included potential therapeutic actions in other degenerative conditions.