Adverse effects of nonsteroidal anti-inflammatory drugs on the gastrointestinal system

Two enzymes, cyclo-oxygenase (COX) and 5-lipoxygenase, act upon arachidonic acids to produce prostaglandins and leukotrienes. Inhibition of COX-2 by non-steroidal anti-inflammatory drugs (NSAIDs) lowers synthesis of proinflammatory prostaglandins and produces analgesia. COX-2 is highly inducible by endotoxin, IL-1, hypoxia, epidermal growth factor (EGF), benzo[a]pyrene, and transforming growth factor beta 1(TGF-beta 1). COX-1 in constitutively expressed. Conventional NSAIDs also inhibit the synthesis of cytoprotective prostaglandins by COX-1 in the gastrointestinal tract. Surplus arachidonic acids accumulate and enhance the generation of leukotrienes via the lipoxygenase pathway inducing neutrophil adhesion to endothelium and vasoconstriction. The NSAIDs harboring a carboxyl group also inhibit oxidative phosphorylation (OXPHOS) lowering adenosine-triphosphate (ATP) generation leading to loss of mucosal cell tight junctions and increased mucosal permeability. Administration of NSAIDs that do not interfere with OXPHOS, and concomitant use of prostaglandin analogues to restore cytoprotection reduces complications of NSAID use. However, no NSAID that lacks potential for serious gastrointestinal toxicity is currently available. Selective inhibitors of COX-2 and 5-lipoxygenase are newer, promising drugs. Surprisingly, COX-2 null mice are able to mount an inflammatory response, suffering however, from kidney dysfunction and a shortened life span. Results of clinical studies on the long-term use of NSAID drugs such as selective inhibitors are still pending.

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