NSAIDS AND GI INJURY .1. EPIDEMIOLOGY AND PATHOGENESIS

The widespread use of NSAIDs, due to their vast prescription and over- the-counter market, has drawn attention to the potential for adverse e vents associated with this otherwise effective class of drugs. Althoug h the majority of NSAID users tolerate NSAID exposure without clinical ly important toxicity, given the large number of patients exposed, NSA ID-induced GI injury represents the most frequent adverse drug event i n the United States. NSAID-induced toxicity can range from symptoms su ch as nausea and dyspepsia (up to 60% of users) to serious adverse GI events such as bleeding and perforation (estimated to aff ect up to 2- 4% of users/year). Risk factors for NSAID-related complications includ e advanced age, history of previous ulcer disease or GI bleeding, conc omitant corticosteroids or anticoagulant use, use of high doses or mul tiple NSAIDs and the presence of certain other chronic diseases. NSAID ulcers develop as a consequence of the reduction in prostaglandin-med iated defensive factors and local irritative effects of the drugs, whi ch combine to render the mucosa of the stomach and duodenum vulnerable to acid. NSAIDs may also cause injury to the small and large intestin e. Two isoenzymes of cyclooxygenase (COX) have been identified, a cons titutive form important for GI and platelet function (COX-1) and an in ducible form (COX-2) at sites of inflammation. The potency and duratio n of COX-1 inhibition of currently marketed NSAIDs correlates with the ir ulcer risk. It is anticipated that highly selective COX-2 inhibitor s will be associated with a marked reduction in ulcer risk.