Pathogenesis Of Nsaid Toxicity Ulceration

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The complex elements that defend the gastroduodenal mucosa from damage are largely dependent on endogenous prostaglandins synthesized in the upper GI mucosa. COX is the rate-limiting catalytic step in prostaglandin production. At least two isoforms of COX have been identified. COX-1 is constitutively expressed in the GI tract and plays an important role in the maintenance of normal gastric and duodenal physiology. COX-2 is an inducible form, which is upregulated in areas of injury (10). However, COX-2 is also regulated in response to physiologic stimuli in numerous tissues, including the kidney, brain, and reproductive tract. NSAIDs, in general, nonspecifically inhibit COX isoforms, leading to both beneficial (antiinflammatory) and toxic (GI bleeding) outcomes.

The stomach and duodenum are covered by a mucus-bicarbonate barrier that provides a primary defense against the strongly acidic gastric lumen. Production of the components of this barrier is regulated by COX-1-derived prostaglandins. The surface epithelium provides the second line of gastroduodenal defense. Regeneration, the process by which larger epithelial defects (e.g., ulcers) heal, requires cellular proliferation, which is at least partly dependent on prostaglandins and growth factors (11). Although very little COX-2 is present in the intact stomach, prostaglandins derived from COX-2 induced in the damaged stomach play an important role in ulcer healing, particularly related to angiogenesis stimulated by growth factors (12). Another key factor preventing mucosal injury is maintenance of microvascular blood flow, which is also regulated by COX-1-derived prostaglandins.

The mechanisms by which NSAIDs cause ulcers remain incompletely understood; they involve both topical injury and systemic effects mediated by depletion of endogenous prostaglandins. Analogous to Helicobacter pylori-associated ulcer disease (large exposure risk with low absolute ulcer risk), the biologic basis for those individuals at increased risk for NSAID-related ulcers remains unknown.

Aspirin and most NSAIDs undergo ion trapping within the proximal GI mucosa, causing direct cellular injury. NSAIDs also directly attenuate the hydrophobic or nonwettable properties of the mucus barrier independently of prostaglandin-mediated actions (13). Although topical effects can be largely prevented by administering enteric-coated NSAID formulations or prodrugs, the failure of these approaches to reduce the incidence of symptomatic NSAID-induced ulcers demonstrates that topical injury is not the critical determinant of NSAID-induced injury. For example, parenteral administration of an NSAID such as ketorolac may lead to ulcer complications (14). Certain NSAIDs, such as indomethacin, piroxicam, oxaprozin, and ketorolac, also undergo an extensive enterohepatic recirculation, resulting in repeated exposure to the GI mucosa and increased toxicity (11).

The clinically important adverse effects of NSAIDS—ulcers with an increased risk of complications—appear to be largely owing to their systemic actions. Inhibition of COX-1, with a resultant decrease in endogenous prostaglandins critical to mucosal defense, is thought to be the most important mechanism of action. Platelet COX-1 is also inhibited irreversibly by aspirin and for as long as 18 hours by other NSAIDs. The impaired platelet function may potentiate GI bleeding from both the upper and lower GI tract.

COX-1 inhibition leads to not only quantitative but also qualitative decreases in mucus barrier function. Since prostaglandin deficiency impairs regenerative responses, erosions created by direct topical injury are exposed to acid in a vulnerable condition. Ulcerations occur in areas of decreased blood flow, and NSAIDs induce microvascular ischemia partly by causing neutrophil adherence in the microcirculation. The role of nitric oxide (NO) in the maintenance of epithelial integrity is related to its ability to maintain mucosal blood flow. In animal models, inhibition of NO synthesis exacerbates NSAID injury, and NO donors reduce NSAID toxicity (15). NO-releasing aspirin/NSAIDs, which are not currently available in clinical practice, cause little damage despite marked inhibition of prostaglandin levels. This may be of greatest value when aspirin therapy is needed, allowing the utilization of a nonulcero-genic antiplatelet agent; clinical trials supporting the animal data are anxiously awaited.

Finally, acid plays an important secondary role in NSAID-induced ulceration. Recent data demonstrating the efficacy of high-dose H2 blockers and proton pump inhibitors in the treatment and prevention of NSAID damage support this concept. This suggests that topical injury is the first step in NSAID ulceration; then acid, in concert with prostaglandin depletion, synergizes for the development of clinically important ulceration. Finally, the discovery of two distinct COX isoforms has further illuminated the mechanisms of NSAID-induced injury. Traditional NSAIDs inhibit both isoforms of COX (dual inhibitors) and therefore produce both beneficial (antiinflammatory) and toxic (GI injury) effects, whereas the COX-2-specific inhibitors (COXIBs) appear to spare the GI mucosa from injury.

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