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HISTORY AND EPIDEMIOLOGY

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In the late 1800s, acetylsalicylic acid, aspirin, was shown to have antiinflammatory properties similar to those of corticosteroids when used in high doses in patients with rheumatoid arthritis. In a quest to develop a compound with antiinflammatory properties equivalent to corticosteroids but chemically nonsteroidal, Dr. Stewart Adams discovered and developed 2-(4-isobutylphenyl) propionic acid, now known as ibuprofen, and in the process created a new class of drugs designated as nonsteroidal antiinflammatory drugs (NSAIDs).35 Ibuprofen was initially marketed in the United Kingdom in 1969 and was introduced to the US market in 1974. Ibuprofen became available without a prescription in the United States in 1984.

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In addition to the numerous 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 developed, and in 1999, the first selective COX-2 inhibitor, rofecoxib, was approved by the US Food and Drug Administration (FDA), but it was withdrawn from the market in 2004 after postmarketing surveillance concluded an increase in myocardial infarctions and cerebrovascular accidents were associated with its use.

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NSAIDs are considered among the most commonly used and prescribed medications in the world.10,72 An estimated one in seven patients with rheumatologic diseases is given a prescription for NSAIDs, and another one in five people in the United States use NSAIDs for acute common complaints.94

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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.62

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The American Association of Poison Control Centers (AAPCC) compiles data regarding potentially toxic exposures called into participating poison centers throughout the United States using the National Poison Data System (NPDS) (Chap. 136). Beginning in 2006, a list of substances associated with the largest number of fatalities was reported annually, and since then NSAIDs have consistently been included in the top 25 substances.

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The term NSAID used in this chapter does not refer to salicylates, which are unique members of the NSAID class and are covered in Chap. 39.

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PHARMACOLOGY

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These chemically heterogeneous compounds can be divided into carboxylic acid and enolic acid derivatives and COX-2 selective inhibitors (Table 37–1). They all share the ability to inhibit prostaglandin (PG) synthesis. PG synthesis begins with the activation of phospholipases (commonly, phospholipase A2) that cleave phospholipids in the cell membrane to form arachidonic acid (AA). AA is metabolized by PG endoperoxide G/H synthase, otherwise known as COX, to form many eicosanoids, including PGs and the prostanoids, prostacyclin (PGI2) and thromboxane A2 (TXA2). AA can also be metabolized by lipoxygenase (LOX) ...

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