Mechanisms of gastric and duodenal damage and protection

Abstract

By binding to the cyclooxygenase enzyme, non-steroidal, anti-inflammatory drugs (NSAIDs) inhibit synthesis of prostanoids characteristic of the cell under consideration. For the gastric mucosa, the main products are prostaglandin (PG) E2 or PGI2; for platelets the main product is thromboxane. Aspirin irreversibly acetylates the cyclooxygenase enzyme. Consequently, it has more prolonged effects, particularly in cells like platelets, which are not rapidly turned over. Prostaglandin-dependent protective actions in the stomach and duodenum which are inhibited by NSAIDs include mucous and bicarbonate secretion, surface epithelial cell hydrophobicity and mucosal blood flow. Prostaglandins are also protective of the microvasculature and can increase the flux of water from serosa to mucosa, with possible dilution of injurious substances. Abrogation of these properties renders the mucosa more vulnerable to injury. In addition, salicylates have topical irritant properties. A number of repair mechanisms, including epithelial cell division and possibly angiogenesis, are prostaglandin dependent. As a consequence of these actions, acute damage and ulcers develop more easily and ulcers heal more slowly when individuals take NSAIDs. In some cases the anti-hemostatic effects of NSAIDs may be partly instrumental, and data in model systems have shown that aspirin and possibly piroxicam can enhance intragastric bleeding separately from their effects of mucosal injury. Smoking, which predisposes to peptic ulceration, also appears to reduce mucosal prostaglandin synthesis. Other predisposing factors such as age, sex and the ulcer diathesis have little effect. Some have found Helicobacter pylori to enhance leukotriene synthesis. We have shown that NSAIDs are also associated with increased leukotriene B4 as well as reduced prostaglandin synthesis in patients taking NSAIDs long term.