Chapter 35: Nonsteroidal Antiinflammatory Drugs

HISTORY AND EPIDEMIOLOGY

In the 1950s, the only treatment for rheumatoid arthritis included high-dose aspirin and gold therapy (chrysotherapy). While searching for new compounds that were chemically nonsteroidal and had antiinflammatory properties, Dr. Stewart Adams filed a patent for “Antiinflammatory Agents” in 1961. One of the compounds in this list was 2-(4-isobutylphenyl) propionic acid, which today we call ibuprofen. This discovery created a new class of drugs designated as nonsteroidal antiinflammatory drugs (NSAIDs).³⁶ 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.

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the first selective COX-2 inhibitor, rofecoxib, was approved by the US Food and Drug Administration (FDA), but it was withdrawn from the market in 2004 after postmarketing surveillance concluded that an increase in myocardial infarctions and cerebrovascular accidents were associated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

Nonsteroidal antiinflammatory drugs are considered among the most commonly used and prescribed nonprescription medications in the world.^12,72 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 uses NSAIDs for acute common complaints.⁹⁴

Ibuprofen, naproxen, and ketoprofen are currently the only nonprescription NSAIDs in the United States. Nonsteroidal antiinflammatory drugs are also contained in cough and cold preparations and in prescription combination drugs (eg, ibuprofen with hydrocodone) and are occasionally found as adulterants in herbal preparations.⁶¹

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. 130). The AAPCC Annual Report lists NSAIDs among the top 25 substances associated with the largest number of fatalities.

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. 37.

PHARMACOLOGY

These chemically heterogeneous compounds are divided into carboxylic acid and enolic acid derivatives and COX-2 selective inhibitors (Table 35–1). They all share the ability to inhibit prostaglandin (PG) synthesis. Prostaglandin synthesis begins with the activation of phospholipases (commonly, phospholipase A₂) that cleave phospholipids in the cell membrane to form arachidonic acid (AA). Arachidonic acid 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). Arachidonic acid is also metabolized by lipoxygenase (LOX) to form hydroperoxy eicosatetraenoic acid (HPETE), which ...