Medical Therapy of Ulcerative Colitis by Gary R. Lichtenstein

Author:Gary R. Lichtenstein
Language: eng
Format: epub
Publisher: Springer New York, New York, NY

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

NSAIDs are one of the most commonly used medications worldwide and have been implicated as a cause of flares secondary to an inhibitory effect on prostaglandins and through uncoupling mitochondrial oxidative phosphorylation [61]. The association between NSAIDs and IBD flares has not been clearly established, though several studies have examined this relationship [62–68]. In the United States, more than 70 million NSAID prescriptions and 30 billion over-the-counter preparations are sold every year [69]. Although NSAID use has typically been associated with the development of gastroduodenal injury, evidence implicating these agents in inducing and exacerbating damage in the distal gastrointestinal tract is also mounting. Colonic injury ranging from colitis resembling inflammatory bowel disease to colonic perforation and bleeding has been described [65, 70, 71].

More than 80 % of patients with IBD interviewed in one study reported use of NSAIDs within the previous month, and approximately one-third of these patients thought that there was an association between their IBD symptoms and NSAID use. In contrast, only 2 % of the IBS population used as a control group reported worsening symptoms following NSAID use [64, 66]. Most studies are case series or case reports and have reported an association between NSAIDs and IBD, though given the methodological shortcomings, causality cannot be established [62, 63, 67, 68]. For example, in new cases of IBD, there was a significant self-reported exposure to NSAIDs/salicylates within 3 months prior to presentation when compared to sex-matched community controls (OR = 9.1, 95 % CI:4.5–21.9) [68]. Some studies did not find a relationship between NSAIDs and IBD activity though these had significant limitations [64–66].

The exact mechanism by which NSAIDs can lead to exacerbations of IBD is not fully understood, though some speculate that small bowel mitochondrial dysfunction and colonic effects of prostaglandin are central. The key enzyme in the inhibition of colonic prostaglandin (PG) synthesis is cyclooxygenase (COX), which exists in two isoforms, COX-1, the constitutive enzyme involved in maintaining mucosal integrity in the GI tract, and COX-2, an inducible enzyme that is expressed at sites of inflammation [72]. COX-2 expression is significantly increased in the colonic mucosa of patients with active IBD when compared to inactive disease or healthy controls [73]. COX-2 appears to have a beneficial effect in healing experimental colitis, and in theory, COX-2 inhibition might impair colitis healing [72]. Alternatively, NSAIDs uncouple mitochondrial oxidative phosphorylation and reduce ATP levels, which can lead to increased permeability because of dysfunction at the mucosal tight junctions [74].

Because of the evidence suggesting that COX-2-specific inhibitors are less toxic to the gastrointestinal tract than traditional NSAIDs, patients and physicians have hoped that selective inhibition of COX-2 would result in anti-inflammatory and analgesic effects without exacerbating IBD. However, cases of IBD flares associated with the use of COX-2 inhibitors have been reported in the literature [75–77]. In a series of 33 patients with IBD who were prescribed with celecoxib or rofecoxib, 39 % experienced exacerbation of their disease [78]. A multicenter, randomized, double-blinded, placebo-controlled trial that enrolled 222 subjects with

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