Acetaminophen
Acetaminophen (Anacin-3, Liquiprin, Panadol, Paracetamol, Tempra, Tylenol, and many other brands) is a widely used drug found in many over-the-counter and prescription analgesics and cold remedies. When it is combined with another drug, such as diphenhydramine, codeine, hydrocodone, oxycodone, dextromethorphan, or propoxyphene, the more dramatic acute symptoms caused by the other drug may mask the mild and nonspecific symptoms of early acetaminophen toxicity, resulting in a missed diagnosis or delayed antidotal treatment. Common combination products containing acetaminophen include the following: Darvocet, Excedrin ES, Lorcet, Norco, NyQuil, Percocet, Unisom Dual Relief Formula, Sominex 2, Tylenol with Codeine, Tylenol PM, Tylox, Vicks Formula 44-D, and Vicodin.
Mechanism of toxicity
Hepatic injury. One of the products of normal metabolism of acetaminophen by cytochrome P-450 (CYP) mixed-function oxidase enzymes is highly toxic; normally this reactive metabolite (NAPQI) is detoxified rapidly by glutathione in liver cells. However, in an overdose, production of NAPQI exceeds glutathione capacity and the metabolite reacts directly with hepatic macromolecules, causing liver injury.
Renal damage may occur by the same mechanism, owing to renal CYP metabolism.
Overdose during pregnancy has been associated with fetal death and spontaneous abortion.
Very high levels of acetaminophen can cause lactic acidosis and altered mental status by uncertain mechanisms, probably involving mitochondrial dysfunction.
Pharmacokinetics. Acetaminophen is rapidly absorbed, with peak levels usually reached within 30–120 minutes. (Note: Absorption may be delayed after ingestion of sustained-release products [Tylenol Extended Release, Tylenol Arthritis] or with co-ingestion of opioids or anticholinergics.) Volume of distribution (Vd) = 0.8 to 1 L/kg. Elimination is mainly by liver conjugation (90%) to nontoxic glucuronides or sulfates; mixed-function oxidase (CYP2E1, CYP1A2) accounts for only about 3–8% but produces a toxic intermediate (see Item A above). The elimination half-life is 1–3 hours after a therapeutic dose but may be greater than 12 hours after an overdose (see also Table II–61).
Toxic dose
Acute ingestion of more than 200 mg/kg in children or 6–7 g in adults is potentially hepatotoxic.
Children younger than 10–12 years of age appear to be less susceptible to hepatotoxicity because of the smaller contribution of CYP to acetaminophen metabolism.
In contrast, the margin of safety may be lower in patients with induced CYP microsomal enzymes because more of the toxic metabolite may be produced. High-risk patients include alcoholics and patients taking inducers of CYP2E1, such as isoniazid. Fasting and malnutrition may also increase the risk for hepatotoxicity, presumably by lowering cellular glutathione stores.
Chronic toxicity has been reported after daily consumption of supratherapeutic doses. A consensus guideline from the American Association of Poison Control Centers (AAPCC) recommends medical evaluation if more than 150 mg/kg/d (or 6 g/d) has been ingested for 2 days or longer. One study reported elevated transaminases in more than one-third of healthy volunteers given doses of 4 g/d for several days.
Children have developed toxicity after receiving as little as 100–150 mg/kg/d for 2–8 days. The AAPCC guideline recommends medical evaluation for doses of more than 150 mg/kg/d for 2 days or 100 mg/kg/d for 3 days or more. There is a single case report of hepatotoxicity in an infant receiving 72 mg/kg/d for 10 days.
As with acute overdose, the risk for injury from chronic use may be greater in alcoholic patients and persons taking isoniazid and other drugs that induce CYP2E1.
Clinical presentation.
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