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2. Aspirin and the older nonselective NSAIDs inhibit both cyclooxygenase isoforms and thereby decrease prostaglandin and thromboxane synthesis throughout the body. Prostaglandins necessary for normal cell function are depleted, as well as prostaglandins involved in inflammation. 3. Aspirin: Aspirin has three therapeutic dose ranges: the low range (< 300 mg/d) is effective in reducing platelet aggregation; intermediate doses (300-2400 mg/d) have antipyretic and analgesic effects; and high doses (2400-4000 mg/d) are used for their anti-inflammatory effect. Aspirin is readily absorbed and is hydrolyzed in blood and tissues to acetate and salicylic acid. Salicylate is a reversible nonselective inhibitor of cyclooxygenase. Elimination of salicylate is first-order at low-doses, with a half-life of 3-5 hours. At high (anti-inflammatory) doses, half-life increases to 15 hours or more and elimination becomes zero-order. Excretion is via the kidney. Other NSAIDs: The other NSAIDs are well absorbed after oral administration. Ibuprofen has a half-life of about 2 hours, is relatively safe, and is the least expensive of the older, and piroxicam are noteworthy because of their longer half-lives (12-24 hours), which permit less frequent dosing. These other NSAIDs are used for the treatment of mild to moderate painand especially the pain of inflammation such as that seen in rheumatoid arthritis and gout. COX-2 inhibitors are primarily used in inflammatory disorders. Selected NSAIDs are also used to treat other conditions, including dysmenorrheal, headache, and patent ductus arteriosus in premature infants. Ketorolac is notable as a drug used mainly as a systemic analgesic, not as an anti-inflammatory drug (though it has typical nonselective NSAID properties). It is the only NSAID available in a parenteral formulation. 4. COX-1 is primarily expressed in noninflammatory cells, whereas COX-2 is expresses in activated lymphocytes, polymorphonuclear cells, and other inflammatory cells.

5. Acetaminophen is an analgesic and antipyretic agent lacking anti-inflammatory or antiplatelet

effects. 6. Toxicity: In therapeutic dosages, acetaminophen has negligible toxicity in most individuals. However, when taken in overdose or by patients with severe liver impairment, the drug is a very dangerous hepatotoxin. The mechanism of toxicity requires oxidation to cytotoxic intermediates by phase I P450 enzymes. This occurs if substrates for phase II conjugation reactions (acetate and

glucuronide) are lacking. People who regularly consume three or more alcoholic drinks per day are at increased risk of acetaminophen-induced hepatotoxicity. 7. (1) reducing inflammation during acute attacks (with colchicines, NSAIDs, or glucocorticoids); (2) accelerating renal excretion of uric acid with uricosuric drugs (probenecid or sulfinpyrazone) and (3) reducing (with allopurinol) the conversion of purines to uric acid by xanthine oxidase. 8. Cytotoxic drugs (eg, methotrexate) probably act by reducing the numbers of immune cells available to maintain its mechanism in ulcerative colitissulfapyridine appears to be more important than the 5-aminosalycilic acid component. Hydroxychloroquine may interfere with the activity of T lymphocytes, decrease leukocyte chemotaxis, stabilize lysosomal membranes interfere with DNA and RNA synthesis, and trap free radicals. Penicillamine appears to have anti-inflammatory effects similar to those of hydroxychloroquine. Organic gold compounds alter the activity of macrophages, cells that play a central role in inflammation, especially that of arthritis, and suppress phagocytic activity by polymorphonuclear leukocytes.