ADVERSE-EFFECTS OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS ON THE GASTROINTESTINAL SYSTEM

Two enzymes, cyclo-oxygenase (COX) and 5-lipoxygenase, act upon arachi donic acids to produce prostaglandins and leukotrienes. Inhibition of COX-2 by nonsteroidal anti-inflammatory drugs (NSAIDs) lowers synthesi s of proinflammatory prostaglandins and produces analgesia. COX-2 is h ighly inducible by endotoxin, IL-1, hypoxia, epidermal growth factor ( EGF), benzo[a]pyrene, and transforming growth factor beta 1(TGF-beta 1 ). COX-1 is constitutively expressed. Conventional NSAIDs also inhibit the synthesis of cytoprotective prostaglandins by COX-1 in the gastro intestinal tract. Surplus arachidonic acids accumulate and enhance the generation of leukotrienes via the lipoxygenase pathway inducing neut rophil adhesion to endothelium and vasoconstriction. The NSAIDs harbor ing a carboxyl group also inhibit oxidative phosphorylation (OXPHOS) l owering adenosine-triphosphate (ATP) generation leading to loss of muc osal cell tight junctions and increased mucosal permeability. Administ ration of NSAIDs that do not interfere with OXPHOS, and concomitant us e of prostaglandin analogues to restore cytoprotection reduces complic ations of NSAID use. However, no NSAID that lacks potential for seriou s gastrointestinal toxicity is currently available. Selective inhibito rs of COX-2 and 5-lipoxygenase are newer, promising drugs. Surprisingl y, COX-2 null mice are able to mount an inflammatory response, sufferi ng however, from kidney dysfunction and a shortened life span. Results of clinical studies on the long-term use of NSAID drugs such as selec tive inhibitors are still pending.