Pathogenesis of gastroduodenal injury due to nonsteroidal antiinflammatory drugs: implications for prevention and therapy.

ABSTRACT

Nonsteroidal antiinflammatory drugs (NSAIDs) initiate gastroduodenal ulceration and promote complications such as bleeding and perforation by interfering with the ability of the proximal gastrointestinal tract to maintain its defensive capabilities. Mucosal defense is composed of three critical components preepithelial, epithelial, and postepithelial. Preepithelial defense is composed of the mucous gel containing mucin, bicarbonate, and surface-active phospholipids. The epithelial component includes the surface cells, their apical tight junctions, and membrane transporters. Postepithelial defense is maintained by mucosal blood flow, which is essential for both defense and repair. NSAIDs interfere with each component of mucosal defense via direct toxic effects along with cyclooxygenase inhibition and depletion of endogenous prostaglandins. Although NSAID injury is dependent on luminal acid, attempts to prevent NSAID injury by acid suppression using H2-receptor antagonists in humans have had limited success, whereas complete inhibition of acid secretion with proton pump inhibition may have promise. Prostaglandins appear most effective for prevention of NSAID injury, sucralfate appears ineffective, and bismuth compounds have not been studied extensively. Recent evidence suggests that NSAID ulcers heal quickly with proton pump inhibitors compared with H2-receptor antagonists in patients who continue NSAID therapy.