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The chapter describes the nonsteroidal anti-inflammatory drugs (NSAIDs) used to treat inflammation, pain, and fever and the drugs used for hyperuricemia and gout. The NSAIDS are first considered by class, then by groups of chemically similar agents described in more detail. Many of the basic properties of these drugs are summarized in Tables 34–2, 34–3, and 34–4. 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. Aspirin irreversibly acetylates COX; several structural subclasses of tNSAIDs, including propionic acid derivatives (ibuprofen, naproxen), acetic acid derivatives (indomethacin), and enolic acids (piroxicam) compete in a reversible manner with arachidonic acid (AA) at the active site of COX-1 and COX-2. Acetaminophen (paracetamol) is effective as an antipyretic and analgesic agent at typical doses that partly inhibit COXs, has only weak anti-inflammatory activity, and exhibits fewer GI side effects than the tNSAIDs.
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INFLAMMATION, PAIN, AND FEVER
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INFLAMMATION. The inflammatory process is the response to an injurious stimulus. It can be evoked by noxious agents, infections, antibodies, physical injuries. The ability to mount an inflammatory response is essential for survival in the face of environmental pathogens and injury; in some situations and diseases, the inflammatory response may be exaggerated and sustained without apparent benefit and even with severe adverse consequences. The inflammatory response is characterized mechanistically by:
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Transient local vasodilation and increased capillary permeability
Infiltration of leukocytes and phagocytic cells
Tissue degeneration and fibrosis
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Many molecules are involved in the promotion and resolution of the inflammatory process. Histamine, bradykinin, 5-HT, prostanoids, leukotrienes (LTs), and platelet-activating factor are important mediators of inflammation (see Chapter 33).
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Prostanoid biosynthesis is significantly increased in inflamed tissue. Inhibitors of the COXs, which depress prostanoid formation, are effective and widely used anti-inflammatory agents. Prostaglandin E2 (PGE2) and prostacyclin (PGI2) are the primary prostanoids that mediate inflammation. They increase local blood flow, vascular permeability, and leukocyte infiltration through activation of their respective receptors, EP2 and IP. PGD2, a major product of mast cells, contributes to inflammation in allergic responses, particularly in the lung.
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Activation of endothelial cells plays a key role in "targeting" circulating cells to inflammatory sites. Endothelial activation results in leukocyte adhesion as the leukocytes recognize newly expressed L- and P-selectin and E-selectin with sialylated Lewis X and other glycoproteins on the leukocyte surface and endothelial intercellular adhesion molecule-1 (ICAM-1) with leukocyte integrins.
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The recruitment of inflammatory cells to sites of ...