Acetaminophen (Tylenol) is the active metabolite of both phenacetin and acetanilide but has fewer toxic ef-fects than either precursor. Phenacetin and acetanilide are no longer used therapeutically because they have been linked to methemoglobinemia.
Acetaminophen, with a pKa of 9.5, is rapidly absorbed from the GI tract following oral administration. Peak plasma concentrations are observed within 30 minutes to 2 hours. Absorption is nearly complete following oral administration but varies with suppository forms of the drug. Acetaminophen is less plasma protein bound than the salicylates, although the amount bound varies from 20 to 50%. Following the use of normal therapeutic doses of acetaminophen, metabolism and conjugation to sulfate or glucuronides occurs, and clearance of these metabolites occurs in the kidney. A minor toxic metabo-lite is generated by the metabolism of acetaminophen via the P450 mixed-function oxidase system. This toxic metabolite is normally conjugated to glutathione in the liver and excreted via the kidney as conjugated cysteine and mercapturic acid. However, with the depletion of glutathione in certain disease states, such as liver cir-rhosis and necrosis, and following chronic use of high doses of acetaminophen, this toxic reactive metabolite can accumulate and induce liver damage.
Acetaminophen is a weak inhibitor of peripheral COX. Its analgesic effects may arise from inhibition of prostanoid synthesis in the CNS or other centrally me-diated effects yet to be elucidated. The antipyretic ef- fects of acetaminophen are similar to those of aspirin in that it acts at the level of the hypothalamus to reduce pyrogen-initiated alterations in body temperature by in-hibiting prostaglandin synthesis.
Acetaminophen is similar to salicylates in that it is a useful analgesic for mild to moderate pain, with equal efficacy to aspirin, and like aspirin, it is antipyretic. However, acetaminophen exerts little if any effects on platelet aggregation and is not antiinflammatory. Thus, it is not useful for patients with arthritis or other inflam-matory diseases. It is also not useful as an antithrombotic agent in the prevention of myocardial infarction or tran-sient ischemic attacks. Acetaminophen does not produce the gastric ulceration that can occur with aspirin and is useful in patients who are salicylate sensitive or who have a history of ulcers or other gastric ulcerations.
Toxicity from overdose with acetaminophen differs in time course and mechanism from that observed with the salicylates.The onset of toxicity may not occur for several days, and the predominant damage is to the liver. The ini-tial signs of toxicity occur within 12 to 24 hours and in-clude nausea and vomiting. Signs of hepatotoxicity occur within 72 hours. In addition to hepatotoxic effects, renal necrosis and myocardial damage may occur. Oral N-acetylcysteine is used to treat acetaminophen toxicity, al-though many patients are hypersensitive to such treat-ment. In addition, gastric lavage with activated charcoal can be used immediately after ingestion of the drug to decrease acetaminophen absorption from the stomach.
Acetaminophen is contraindicated in late-stage alco-holism, since chronic alcohol consumption can induce the P450 system, leading to increased production of the toxic metabolite of acetaminophen, hence to liver necro-sis. In addition, barbiturates and phenytoin induce the liver P450 system and may decrease the effectiveness of acetaminophen. Acetaminophen crosses the placenta but is nonetheless used in pregnant women with few side effects for the mother or the fetus. Although the drug has been shown to be present in breast milk, no conclu-sive evidence links the drug to abnormalities associated with consumption of breast milk by the newborn.
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