Aines

PARt

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MoDALities oF tHeRAPy in RHeUMAtiC DiseAse

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Nonsteroidal Anti-inflammatory Drugs
LesLie R. BaLLou • Benjamin W. e. Wang pharmacologic factors are likely involved. The inhibition of PG production occurs at the molecular level by inhibiting the enzyme involved in PG biosynthesis, PGH synthase, more commonly referred to as cyclooxygenase (COX). COX exists in at least twoisoforms, COX-1 and COX-2 (for a complete review, see Simmons and colleagues1). The discovery of the second COX isoform (COX-2) increased understanding of the many, varied clinical effects elicited by the NSAIDs. The COX-2 isoform, whose expression is primarily increased during inflammation, has enabled better understanding of the PG biosynthetic pathway in the context of two, independently regulatedCOX isoforms: COX-1, a constitutively active isoform, and COX-2, an inducible isoform most commonly expressed in response to inflammatory stimuli. The development of COX-2-selective NSAIDs (coxibs) facilitated inhibition of PG production during inflammation in certain tissues, while leaving intact the ability of COX-1 to produce PGs in the tissues not directly involved in inflammation, most notablyplatelets and gastroduodenal mucosa. The therapeutic and adverse effects of the nonselective NSAIDs compared with the coxibs could be directly linked to the biosynthesis and biologic actions of PGs produced by two distinct COX isoforms. COX-2 also is constitutively expressed in some tissues (e.g., brain, kidney, and endothelium), and its inhibition therein may underlie at least some of the adverseeffects of coxib use. NSAIDs are in widespread use in treating patients with rheumatoid arthritis (RA) or osteoarthritis, and they are extensively used to treat the symptoms of a variety of other rheumatic diseases most often characterized by chronic musculoskeletal pain and a wide range of acute pain manifestations, such as headache, dysmenorrhea, injury, and postoperative pain. Millions ofpeople currently use aspirin (acetylsalicylic acid [ASA]) for the prevention of cardiovascular thrombosis. The potential uses of NSAIDs as chemopreventive agents against diseases ranging from Alzheimer’s disease to cancer are currently under intense investigation. Because the use of NSAIDs has become so widespread for the treatment of common diseases and ailments directly associated with the agingpopulation, it is crucial to understand their underlying mechanisms of action, potential for adverse reactions, and interactions with other drugs. This chapter discusses the class-specific characteristics of the traditional, nonselective NSAIDs and newer COX-2-selective
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Key Points
Nonsteroidal anti-inflammatory drugs (NSAIDs) and coxibs are effective anti-inflammatory, antipyretic, andanalgesic compounds. Evidence suggests that there is little difference in the efficacy of the various NSAIDs and COX-2 inhibitors in the treatment of pain and inflammation. Awareness of patient risk factors for gastrointestinal ulceration is crucial to minimize ulcer complications resulting from NSAID or coxib therapy. Rates of gastrointestinal ulceration may be reduced with the use of acyclooxygenase-2 selective inhibitor or the concomitant use of an NSAID with a proton-pump inhibitor. There is evidence that all currently available NSAIDs and coxibs are associated with an increased incidence of cardiovascular disease. Awareness of cardiovascular risk factors is crucial to minimize cardiovascular adverse effects resulting from NSAIDs and coxibs. Periodic monitoring of blood pressure, renalfunction, and liver enzymes should be considered in all patients taking NSAIDs and coxibs. Practitioners should be aware of the shared toxicities of all drugs in this class. Practitioners must approach simultaneous use of NSAIDs or coxibs with other antiplatelet agents, anticoagulants, and corticosteroids with caution. The incidence of adverse effects increases in the elderly. This population...