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Acetaminophen (N-acetyl-p-aminophenol or paracetamol) is the most popular over-the-counter analgesic and is one of the most common toxic exposures reported to poison centers. Acetaminophen is available as a sole agent or combined with a variety of other medications prepared in many different forms, such as tablets, capsules, gels, and liquids. Poisonings often occur because of the erroneous belief that this medication is benign or because the victim was unaware that acetaminophen was an ingredient in the ingested preparation. During 2008, the American Association of Poison Control Centers received reports of 71,328 exposures to acetaminophen combinations and 80,845 exposures to acetaminophen alone.1 There were 53 deaths attributed to isolated ingestion of acetaminophen combinations and 69 deaths attributed to isolated acetaminophen ingestions.1 The potential of an acetaminophen overdose is indicated by the observation that acetaminophen (alone and in combination) accounts for about 15% of the observed fatalities seen with isolated ingestions of the top 25 categories associated with a fatal outcome.1 Combining ED, hospital, and poisoning databases, an estimated 450 deaths occur each year in the U.S. due to acetaminophen overdoses, and approximately 100 of them are unintentional.2

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The recommended dosing of acetaminophen is 650 to 1000 milligrams in adults and 10 to 15 milligrams/kg in children, every 4 to 6 hours. The recommended maximum total daily dose is 4 grams in adults and 75 milligrams/kg in children. After ingestion of therapeutic doses, acetaminophen is rapidly absorbed from the GI tract, and peak serum levels are usually achieved within 30 minutes to 2 hours. In an overdose, peak serum levels are usually achieved within 2 hours, but delayed absorption of acetaminophen is reported following overdoses of preparations in which acetaminophen is combined with propoxyphene or diphenhydramine, as well as those with altered release kinetics such as extended-release preparations. In therapeutic amounts, acetaminophen has virtually 100% bioavailability, is approximately 20% bound to serum proteins, has a volume of distribution of around 0.85 L/kg, and an elimination half-life of approximately 2.5 hours. The therapeutic level for the antipyretic effect of acetaminophen is between 10 to 20 micrograms/mL, whereas the therapeutic level for the analgesic level is not established.

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In therapeutic amounts, acetaminophen is primarily metabolized by the liver through sulfation (20% to 46%) and glucuronidation (40% to 67%), with <5% undergoing direct renal elimination. Normally, a small percentage is also oxidized by the cytochrome P-450 system to a reactive metabolite N-acetyl-p-benzoquinoneimine (NAPQI), which is quickly detoxified by hepatic glutathione to a nontoxic acetaminophen-mercapturate compound that is renally eliminated (Figure 184-1).

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Figure 184-1.
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Acetaminophen metabolism. A. After ingestion of therapeutic amounts, predominant metabolism is via glucuronidation and sulfation. The small amount of N-acetyl-p-benzoquinoneimine (NAPQI) generated is metabolized by adequate glutathione stores to a nontoxic compound. B. After ingestion of large amounts, glucuronidation and sulfation are saturated, and an increased amount of NAPQI ...

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