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.
Acetaminophen is administered orally. Absorption is related to the rate of gastric emptying, and peak blood concentrations are usually reached in 30–60 minutes. Acetaminophen is slightlybound to plasma proteins and is partially metabolized by hepatic microsomal enzymes and converted to acetaminophen sulfate and glucuronide, which are pharmacologically inactive (see Figure 4–5). Less than 5% is excreted unchanged. A minor but highly reactive metabolite (N-acetyl-p-benzoquinone) is impor-tant in large doses because it is toxic to both liver and kidney . 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.
Although said to be equivalent to aspirin as an analgesic and antipyretic agent, acetaminophen differs in that it lacks anti-inflammatory properties. It does not affect uric acid levels and lacks platelet-inhibiting effects. The drug is useful in mild to moder-ate pain such as headache, myalgia, postpartum pain, and other cir-cumstances in which aspirin is an effective analgesic. Acetaminophen alone is inadequate therapy for inflammatory conditions such as rheumatoid arthritis, although it may be used as an analgesic adjunct to anti-inflammatory therapy. For mild analgesia, acetaminophen is the preferred drug in patients allergic to aspirin or when salicylates are poorly tolerated. It is preferable to aspirin in patients with hemo-philia or a history of peptic ulcer and in those in whom bronchos-pasm is precipitated by aspirin. Unlike aspirin, acetaminophen does not antagonize the effects of uricosuric agents; it may be used con-comitantly with probenecid in the treatment of gout. It is preferred to aspirin in children with viral infections.
In therapeutic doses, a mild increase in hepatic enzymes may occa-sionally occur in the absence of jaundice; this is reversible when the drug is withdrawn. 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 centri-lobular necrosis, sometimes associated with acute renal tubular necrosis. Present data indicate that 4–6 g acetaminophen is associated with increased liver function test abnormalities. Doses greater than 4 g/d are not usually recom-mended and a history of alcoholism contraindicates even this dose. Early symptoms of hepatic damage include nausea, vomiting, diar-rhea, and abdominal pain. Cases of renal damage without hepatic damage have occurred, even after usual doses of acetaminophen. Therapy is much less satisfactory than for aspirin overdose. In addi-tion to supportive therapy, the measure that has proved most useful is the provision of sulfhydryl groups in the form of acetylcysteine to neutralize the toxic metabolites .
Hemolytic anemia and methemoglobinemia are very rare adverse events. Interstitial nephritis and papillary necrosis—serious compli-cations of phenacetin—have not occurred nor has GI bleeding. Caution is necessary in patients with any type of liver disease.
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.