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Nonsteroidal antiinflammatory drugs (NSAIDs) comprise a class of xenobiotics with analgesic, antipyretic, and antiinflammatory properties. These desirable clinical effects account for the extensive list of approved clinical uses, including the treatment of pain, inflammation, and fever, as well as the management of connective tissue, immunologic, and rheumatologic diseases.55 In addition to the countless benefits of NSAIDs, some deleterious and life-threatening effects are associated with both their therapeutic use and overdose. In an attempt to circumvent some of these adverse effects, selective cyclooxygenase-2 (COX-2) inhibitors were introduced to the market but one was withdrawn because of their own toxicity profiles. The term NSAID used in this chapter does not refer to salicylates, which are unique members of the NSAID class and are covered in Chapter 35.

The discovery of NSAIDs began with the creation of acetyl salicylic acid (aspirin) by Felix Hoffman in 1897.59 Searching for an antirheumatic xenobiotic with less adverse gastrointestinal (GI) effect than aspirin, Stewart Adams and John Nicholson discovered and developed 2-(4-isobutylphenyl) propionic acid, now known as ibuprofen, in 1961. Ibuprofen was initially marketed under the trade name Brufen in the United Kingdom in 1969 and was introduced to the U.S. market in 1974. Ibuprofen became available without a prescription in the United States by 1984. More than a decade later, in 1999, the first selective COX-2 inhibitor, rofecoxib, was approved by the U.S. Food and Drug Administration (FDA), but it was withdrawn in 2004 after increased myocardial infarctions and cerebrovascular accidents were associated with its use.

The American Association of Poison Control Centers (AAPCC) compiles data from participating poison centers throughout the United States using the National Poison Data System (NPDS), formerly known as the Toxic Exposure Surveillance System (TESS). Approximately 4% of all human exposures reported to the AAPCC from 2003 to 2007 were to NSAIDs (including COX-2 inhibitors, ibuprofen, ibuprofen with hydrocodone, indomethacin, ketoprofen, naproxen, and others), which translates to about 90,000 to 100,000 calls annually. In 2006, the AAPCC introduced a Fatality Review Team, which attempts to determine the relationship between exposure and death. The 2006 and 2007 annual reports assigned five deaths and 107 life-threatening manifestations to NSAID exposure (see Chap. 135).

Ibuprofen, naproxen, and ketoprofen are currently the only nonprescription NSAIDs in the United States. NSAIDs are also contained in cough and cold preparations and in prescription combination drugs (eg, ibuprofen with hydrocodone) and have occasionally been found as adulterants in herbal preparations.64

NSAIDs are considered among the most commonly used and prescribed medications in the world.10,75 An estimated one in seven patients with rheumatologic diseases is given a prescription for NSAIDs, and another one in five U.S. citizens uses NSAIDs for acute common complaints.99

These chemically heterogeneous compounds can be divided into carboxylic acid and enolic acid derivatives and COX-2 selective inhibition (Table 36–1). They all share the ability to ...

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