Nonsteroidal antiinflammatory drugs and their effects.
New information about the mechanisms of action of nonsteroidal antiinflammatory drugs (NSAIDs) offers potential opportunities to minimize the complications of these commonly used drugs. Traditionally, the accepted mode of action of the NSAIDs has been the inhibition of prostaglandin synthesis through either reversible or irreversible binding to cyclooxygenase (COX). However, drugs that are weak prostaglandin synthesis inhibitors in vitro have been demonstrated to be equally as effective in vivo as other "stronger" COX inhibitors in treating inflammatory diseases, suggesting the importance of other actions of these drugs. Various NSAIDs have been used for years to palliate pain and inflammation in many different disease processes; unfortunately, they have not been demonstrated to alter the natural history of disease such as rheumatoid arthritis. Perhaps that is because prostaglandins do not play a large role in most inflammatory diseases; alternatively, it might be attributable to the inability of NSAIDs to exert their full effects because of their potential toxic reactions.An understanding of the effects of cyclooxygenase inhibition has been further complicated by the recently described second isoenzyme of prostaglandin synthase. One form of cyclooxygenase appears to be important in the maintenance of normal physiologic functions (COX-1), whereas the other form is induced primarily in sites of inflammation (COX-2). Even if inhibition of cyclooxygenase is only one mechanism of action for these drugs, with only some of the potential toxic effects modulated by the inhibition of prostaglandin synthesis such as inhibition of COX-1, an understanding of the actions of the two isoforms of cyclooxygenase is an important step in further delineating the inflammatory cascade. Ideally, the treatment of inflammation could be improved by inhibiting the effects of COX-2 without inhibiting COX-1 activity. Thus, some potential side effects of the NSAIDs might be alleviated. The presently available NSAIDs all affect both COX-1 and COX-2, although not equally. There are also data describing some of the NSAIDs as less toxic to the gastrointestinal mucosa because of their chemical composition. These data are typically based on in vitro experiments that use varying methodologies, making it difficult to compare the effects of any one NSAID between studies.This paper presents a brief review of several of the newly described effects of the NSAIDs and concentrates on the possible implications of the experimentally observed COX-2-selective effects of these clinically useful antiinflammatory agents.
Simon
L S
LS
Harvard Medical School, Deaconess Hospital, and Massachusetts General Hospital, Boston, Massachusetts.