COX-1 and COX-2 inhibitors

Abstract

By inhibiting prostaglandin synthesis, non-steroidal anti-inflammatory drugs (NSAIDs) cause mucosal damage, ulceration and ulcer complication throughout the gastrointestinal tract. The recognition that there are two cyclo-oxygenase enzymes, one predominating at sites of inflammation (COX-2) and one constitutively expressed in the gastrointestinal tract (COX-1), has led to the important therapeutic development of COX-2 inhibitors. COX-2 is phylogenetically more primitive that COX-1 and, while very similar, has critical differences, particularly the existence of a small pocket half way down the active enzyme site. A number of drugs achieve selectivity by binding to this pocket, including presumptively rofecoxib and celecoxib. Others, such as meloxicam, may inhibit COX-2 by different mechanisms. Truly selective COX-2 inhibitors have been shown to have no effect on gastric mucosal prostaglandin synthesis, to cause no acute injury, and no chronic ulceration compared to placebo. Rofecoxib has, in a prospective systematic evaluation involving 8076 patients, been shown to reduce clinically significant ulcers, ulcer complications and gastrointestinal bleeding significantly compared to naproxen. Outcomes data for celecoxib have also been published although differences from the combined comparator agents (diclofenac and ibuprofen) did not reach statistical significance. Use of aspirin in the class study has shown that the benefits of COX-2 inhibitors may be reduced by aspirin use. The VIGOR study has raised the possibility that some NSAIDs, particularly naproxen, may protect against vascular disease compared to COX-2 inhibitors (or placebo).