Chapter 34

### INTRODUCTION

This chapter describes the nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat inflammation, pain, and fever and the drugs used for hyperuricemia and gout.

Most currently available traditional NSAIDs (tNSAIDs) act by inhibiting the prostaglandin (PG) G/H synthase enzymes, colloquially known as the cyclooxygenases (COXs; see Chapter 33). The inhibition of cyclooxygenase-2 (COX-2) is thought to mediate, in large part, the antipyretic, analgesic, and anti-inflammatory actions of tNSAIDs, while the simultaneous inhibition of cyclooxygenase-1 (COX-1) largely but not exclusively accounts for unwanted adverse effects in the GI tract. Selective inhibitors of COX-2 (celecoxib, etoricoxib, lumiracoxib) are a subclass of NSAIDs that are also discussed. Aspirin, which irreversibly acetylates COX, is discussed, along with several structural subclasses of tNSAIDs, including propionic acid derivatives (ibuprofen, naproxen), acetic acid derivatives (indomethacin), and enolic acids (piroxicam), all of which compete in a reversible manner with the arachidonic acid (AA) substrate at the active site of COX-1 and COX-2. Acetaminophen (paracetamol) is a weak anti-inflammatory drug; it is effective as an antipyretic and analgesic agent at typical doses that partly inhibit COXs. Acetaminophen has fewer GI side effects than the tNSAIDs.

History. The history of aspirin provides an interesting example of the translation of a compound from the realm of herbal folklore to contemporary therapeutics. The use of willow bark and leaves to relieve fever has been attributed to Hippocrates but was most clearly documented by Edmund Stone in a 1763 letter to the president of The Royal Society. Similar properties were attributed to potions from meadowsweet (Spiraea ulmaria), from which the name aspirin is derived. Salicin was crystallized in 1829 by Leroux, and Pina isolated salicylic acid in 1836. In 1859, Kolbe synthesized salicylic acid, and by 1874, it was being produced industrially. It soon was being used for rheumatic fever, gout, and as a general antipyretic. However, its unpleasant taste and adverse GI effects made it difficult to tolerate for more than short periods. In 1899, Hoffmann, a chemist at Bayer Laboratories, sought to improve the adverse-effect profile of salicylic acid (which his father was taking with difficulty for arthritis). Hoffmann came across the earlier work of the French chemist, Gerhardt, who had acetylated salicylic acid in 1853, apparently ameliorating its adverse-effect profile, but without improving its efficacy, and therefore abandoned the project. Hoffmann resumed the quest, and Bayer began testing acetylsalicylic acid (ASA) in animals by 1899—the first time that a drug was tested on animals in an industrial setting—and proceeded soon thereafter to human studies and the marketing of aspirin.

Acetaminophen was first used in medicine by von Mering in 1893. However, it gained popularity only after 1949, when it was recognized as the major active metabolite of both acetanilide and phenacetin. Acetanilide is the parent member of this group of drugs. It was introduced into medicine in 1886 under the name antifebrin by Cahn and Hepp, who had discovered its antipyretic action accidentally. However, acetanilide ...

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