Nonsteroidal anti-inflammatory drugs (NSAIDs) are in use throughout the world (table 1). NSAIDs are popular because of their versatile effectiveness as analgesics, antipyretics, and as anti-inflammatory agents. Aspirin is also used in low doses as an anti-thrombotic agent. Unfortunately, aspirin and most other NSAIDs can injure the gastric and duodenal mucosa, with considerable morbidity and mortality.
The pathogenesis and clinical manifestations of gastroduodenal toxicity attributed to the use of NSAIDs and aspirin will be reviewed here. Other topics, such as other side effects, including injury to the small and large intestine, recommendations for the prevention and treatment of NSAID-induced gastroduodenal injury, and an overview of selective COX-2 inhibitors are discussed elsewhere. (See "NSAIDs: Adverse effects on the distal small bowel and colon" and "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs (including aspirin): Primary prevention of gastroduodenal toxicity" and "Overview of selective COX-2 inhibitors".)
SYSTEMIC VERSUS TOPICAL EFFECTS
Aspirin and many other nonsteroidal anti-inflammatory drugs (NSAIDs), (eg, ibuprofen, naproxen, indomethacin, and ketorolac) are carboxylic acids . As such, they are not ionized at the acidic pH found in the gastric lumen and thus can be absorbed across the gastric mucosa. Once the drug moves from the acidic environment of the gastric lumen into the pH–neutral mucosa, the drug ionizes and is trapped temporarily in epithelial cells where it may damage these cells.
However, this "topical" epithelial injury by many NSAIDs does not appear to be of prime importance in the pathogenesis of clinically important endpoints (symptomatic ulcers). The pathogenesis of symptomatic peptic ulcer disease caused by repeated exposure to NSAIDs is mainly a consequence of systemic (post-absorptive) inhibition of gastrointestinal mucosal cyclo-oxygenase (COX) activity. Even intravenous or intramuscular administration of aspirin or NSAIDs can cause gastric or duodenal ulcers in animals and humans [2-5].
THE CENTRAL ROLE OF CYCLO-OXYGENASE PRODUCTS (PROSTAGLANDINS)
Cyclo-oxygenase (COX), the rate-limiting enzyme in prostaglandin (PG) synthesis, converts the unsaturated fatty acid arachidonic acid (C20:4) (derived from phospholipids in cell membranes) into PGG2 and then to PGH2 (picture 1). The gastric and duodenal mucosa proceed to convert PGH2 to various prostanoids (prostaglandins and thromboxane A2) PGs such as PGE2 protect the mucosal lining from injury by luminal acid-pepsin.