Acetaminophen is one of the most important drugs used in the treatment of mild to moderate pain when an anti-inflammatory effect is not necessary. Phenacetin, a prodrug that is metabolized to acetaminophen, is more toxic and should not be used.
Acetaminophen is the active metabolite of phenacetin and is responsible for its analgesic effect. It is a weak COX-1 and COX-2 inhibitor in peripheral tissues and possesses no significant anti-inflammatory effects.
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Pharmacokinetics: Acetaminophen is administered orally. Peak blood concentrations are usually reached in 30–60 minutes. Acetaminophen is poorly bound to plasma proteins and is partially metabolized by hepatic microsomal enzymes to the inactive sulfate and glucuronide (see Figure 4–5). Less than 5% is excreted unchanged. In large doses, a minor but highly reactive metabolite (N-acetyl-p-benzoquinone) is important because it is toxic to both liver and kidney (see Chapter 4). The half-life of acetaminophen is 2–3 hours and is relatively unaffected by renal function. With toxic doses or liver disease, the half-life may be increased twofold or more.
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Indications: Although said to be equivalent to aspirin as an analgesic and antipyretic agent, acetaminophen lacks anti-inflammatory properties. It does not affect uric acid levels and lacks platelet-inhibiting effects. The drug is useful in mild to moderate pain such as headache, myalgia, postpartum pain, and other circumstances in which aspirin is an effective analgesic. Acetaminophen alone is inadequate therapy for inflammatory conditions such as RA. For mild analgesia, acetaminophen is the preferred drug in patients allergic to aspirin, when salicylates are poorly tolerated. It is preferable to aspirin in patients with hemophilia, in those with a history of peptic ulcer, and in those in whom bronchospasm is precipitated by aspirin. Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents.
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Adverse Effects: In therapeutic doses, a mild reversible increase in hepatic enzymes may occasionally occur. With larger doses, dizziness, excitement, and disorientation may occur. Ingestion of 15 g of acetaminophen may be fatal, death being caused by severe hepatotoxicity with centrilobular necrosis, sometimes associated with acute renal tubular necrosis (see Chapters 4 and 58).
4.
Present data indicate that even 4 g acetaminophen is associated with increased liver function test abnormalities. Doses greater than 4 g/d are not usually recommended, and a history of alcoholism contraindicates even this dose. Early symptoms of hepatic damage include nausea, vomiting, diarrhea, and abdominal pain. Cases of renal damage without hepatic damage have occurred, even after usual doses of acetaminophen. Therapy for overdose is much less satisfactory than that for aspirin overdose. In addition to supportive therapy, one should provide sulfhydryl groups in the form of acetylcysteine to neutralize the toxic metabolites (see Chapter 58).
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Hemolytic anemia and methemoglobinemia are very rare adverse events. Interstitial nephritis and papillary necrosis— serious complications of phenacetin—have not occurred, and GI bleeding also has not occurred. Caution is necessary in patients with any type of liver disease.
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Dosage: Acute pain and fever may be effectively treated with 325–500 mg four times daily and proportionately less for children. Dosing in adults is now recommended not to exceed 4 g/d, in most cases.