Mechanisms of nonsteroidal anti-inflammatory drug-induced gastric damage. Actions of therapeutic agents.

All nonsteroidal anti-inflammatory drugs (NSAIDs) used in the treatment of rheumatic diseases may cause gastric mucosal damage. Although the best-studied agent is aspirin, the mechanisms by which it damages the gastric mucosa are not fully understood. However, it is thought that the drug impairs mucosal defenses by penetrating the protective mucous and bicarbonate layers and damaging the epithelial lining cells. In turn, gastric acid is permitted to pour through the breached defenses. This "back-diffusion" of acid further injures cells and destroys capillaries and venules. This local damaging effect is pH dependent and is contributed to by the acid secretion of the stomach. Other mechanisms by which aspirin may induce or contribute to mucosal injury include inhibition of mucosal prostaglandin synthesis, reduction and alteration of mucus secretion, reduction of bicarbonate secretion, interference with cell turnover, as well as systemic effects such as platelet dysfunction. The mechanism by which nonaspirin NSAIDs cause gastrointestinal damage is uncertain. All are known to inhibit prostaglandin synthesis, which could contribute to their toxicity since prostaglandins found in the stomach both inhibit acid secretion and have mucosal defensive effects. Partial protections against aspirin-induced or other NSAID-induced gastric mucosal damage has been demonstrated, at least in some studies, by sucralfate, prostaglandins, omeprazole and histamine (H2)-receptor antagonists. Sucralfate appears to act primarily on local defensive mechanisms; its antisecretory effects are minimal. Prostaglandins exert a protective effect at both antisecretory and nonantisecretory (cytoprotective) doses, indicating that either or both mechanisms may be involved. The most recently studied agent, omeprazole, is the most potent of all acid inhibitors; it may also be cytoprotective, possibly as a result of its effects on sulfhydryl groups. Prostaglandins and omeprazole are not available in the United States and their potential side effects may limit their use in patients with chronic rheumatic diseases. Protection by H2-receptor antagonists is mostly related to reduction of acid secretion, though a cytoprotective effect may occur.