Mechanism Of Gastric Mucosal Toxicity

Aspirin and the other NSAIDs exert their antiinflammatory effect through inhibition of the enzyme cyclo-oxygenase (COX) (see Chapter 15). This enzyme is present in two isoforms. COX-1 is involved in the formation of prostaglandins, which protect the gastric mucosa, while COX-2 is induced in response to inflammatory stimuli and is involved in the formation of cell-damaging cytokines. Most NSAIDs inhibit both isoforms so the beneficial anti-inflammatory effect is offset by the potential for gastric mucosal injury by depletion of prostaglandins. The latter leads to deleterious effects including reduction of mucosal blood flow and a reduced capacity to secrete protective mucus and bicarbonate ion. Aspirin is particularly potent in this respect, perhaps due to the fact that it inhibits COX irreversibly, unlike the other NSAIDs where inhibition is reversible and concentration dependent. Gastrointestinal bleeding can complicate use of low-dose aspirin.

NSAIDs are weak organic acids and the acid milieu of the stomach facilitates their nonionic diffusion into gastric mucosal cells. Here the neutral intracellular pH causes the drugs to become ionised and they accumulate in the mucosa because they cannot diffuse out in this form. Nabumetone differs from other NSAIDs in that it is nonacidic, and therefore is not so avidly concentrated in gastric mucosa, which may partially explain why this drug has less tendency to produce peptic ulceration.

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