NSAIDs & COX Inhibitors

NSAIDs & COX Inhibitors

1. Definition & overview

• NSAIDs (nonsteroidal anti-inflammatory drugs) are a chemically diverse class of weak organic acids (or pro-drugs of organic acids) that have analgesic, antipyretic and anti-inflammatory actions in varying measure, acting principally by inhibition of the prostaglandin (PG) G/H synthase (cyclooxygenase, COX) enzymes (G&G 14e Ch.42, pp.829–831).
• Also termed non-narcotic / non-opioid / aspirin-like analgesics: unlike morphine they do not depress the CNS, do not produce physical dependence, have no abuse liability, and are particularly effective in inflammatory pain (KDT 8e Ch.14, p.209).
• They act primarily on peripheral pain mechanisms (reversal of PG-mediated nociceptor sensitization) but also centrally in spinal cord and brain to raise the pain threshold (G&G 14e Ch.42, p.830; KDT 8e Ch.14, p.210).
• The landmark mechanistic insight: Vane and coworkers (1971) showed aspirin and NSAIDs block PG generation — now recognised as the major mechanism of action (KDT 8e Ch.14, p.210).
• Acetaminophen (paracetamol) is grouped with the NSAIDs but is a special case — effective antipyretic/analgesic with only weak anti-inflammatory activity at usual doses (G&G 14e Ch.42, p.829).
• NSAIDs provide only symptomatic relief; they do not retard progression of joint deformity in rheumatoid arthritis, osteoarthritis or rheumatic fever (G&G 14e Ch.42, p.847; KDT 8e Ch.14, p.213).

Historical perspective

• Willow bark (Salix alba) and meadowsweet (Spiraea ulmaria — origin of the name "aspirin") were folk antipyretics; salicin crystallized 1829 (Leroux), salicylic acid isolated 1836 (Piria), synthesized 1859 (Kolbe) (G&G 14e Ch.42, p.829).
• Hoffmann (Bayer, 1897–99) acetylated salicylic acid to give acetylsalicylic acid (ASA) — better tolerated; aspirin marketed 1899 (G&G 14e Ch.42, p.829).
• Acetanilide (antifebrin, 1886) and phenacetin (1887) were early para-aminophenol antipyretics; phenacetin withdrawn (analgesic-abuse nephropathy, haemolytic anaemia, bladder cancer). Acetaminophen — the active metabolite of both — popularised after 1949 (G&G 14e Ch.42, p.829; KDT 8e Ch.14, p.223).
• Phenylbutazone (1949) was the first agent for which the term "NSAID" was coined; indomethacin introduced 1963; ibuprofen (propionic acid) 1969; selective COX-2 inhibitors (coxibs) from the late 1990s (KDT 8e Ch.14, pp.209–210).