NSAIDs (including aspirin): Pathogenesis of gastroduodenal toxicity
- Mark Feldman, MD, MACP, AGAF, FACG
Mark Feldman, MD, MACP, AGAF, FACG
- Section Editor — Acid Peptic Disease
- Texas Health Presbyterian Hospital Dallas
- Clinical Professor of Internal Medicine
- University of Texas Southwestern Medical School at Dallas
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 anti-inflammatory agents. Aspirin is also used in low doses as an anti-platelet agent. Unfortunately, aspirin (even in very low doses) and other NSAIDs can injure the gastric and duodenal mucosa, with considerable morbidity and mortality.
The pathogenesis and some clinical aspects 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 . Their pKa values range from 3.50 (aspirin) to 4.85 (ibuprofen). 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 these drugs move from the acidic environment of the gastric lumen into the pH–neutral mucosa, the drugs ionize and are 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 PROTECTIVE 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 (figure 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.
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- SYSTEMIC VERSUS TOPICAL EFFECTS
- THE CENTRAL PROTECTIVE ROLE OF CYCLO-OXYGENASE PRODUCTS (PROSTAGLANDINS)
- MECHANISMS OF GASTRODUODENAL PROTECTION BY ENDOGENOUS PROSTAGLANDINS
- ROLE OF NITRIC OXIDE
- SPECTRUM OF GASTRODUODENAL MUCOSAL INJURY
- Gastric damage
- Duodenal damage
- NSAID-INDUCED GASTRIC TOXICITY NOT MEDIATED THROUGH COX-1 INHIBITION
- ROLE OF HELICOBACTER PYLORI INFECTION
- RISK OF GASTROINTESTINAL COMPLICATIONS
- American College of Gastroenterology recommendations
- RELATIONSHIP BETWEEN DYSPEPTIC SYMPTOMS AND GASTRODUODENAL MUCOSAL INJURY
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS