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Acetaminophen (paracetamol in the United Kingdom, Europe) is a common analgesic found in many nonprescription and prescription products. After absorption, it is metabolized mainly by glucuronidation and sulfation, with a small fraction metabolized via the P450 mixed-function oxidase system (2E1) to a highly toxic reactive intermediate. This toxic intermediate is normally detoxified by cellular glutathione. With acute acetaminophen overdose (greater than 150–200 mg/kg, or 8–10 g in an average adult), hepatocellular glutathione is depleted and the reactive intermediate attacks other cell proteins, causing necrosis. Patients with enhanced P450 2E1 activity, such as patients who have alcohol use disorder and patients taking INH, are at increased risk for developing hepatotoxicity. Hepatic toxicity may also occur after overuse of acetaminophen—eg, as a result of taking two or three acetaminophen-containing products concurrently or exceeding the recommended maximum dose of 4 g/day for several days. The amount of acetaminophen in US oral prescription combination products (eg, hydrocodone/acetaminophen) is limited by the FDA to no more than 325 mg per tablet.


Shortly after ingestion, patients may have nausea or vomiting, but there are usually no other signs of toxicity until 24–48 hours after ingestion, when hepatic aminotransferase levels begin to increase. With severe poisoning, fulminant hepatic necrosis may occur, resulting in jaundice, hepatic encephalopathy, AKI, and death. Rarely, massive ingestion (eg, serum levels greater than 500–1000 mg/L [33–66 mmol/L]) can cause early onset of acute coma, seizures, hypotension, and metabolic acidosis unrelated to hepatic injury.

The diagnosis after acute overdose is based on measurement of the serum acetaminophen level. Plot the serum level versus the time since ingestion on the acetaminophen nomogram shown in Figure 38–1. Ingestion of sustained-release products or coingestion of an anticholinergic agent, salicylate, or opioid drug may cause delayed elevation of serum levels, which can make it difficult to interpret the nomogram. In addition, the nomogram cannot be used after chronic or staggered overdose.

Figure 38–1.

Nomogram for prediction of acetaminophen hepatotoxicity following acute overdosage. Patients with serum levels above the line after acute overdose should receive antidotal treatment. (Reproduced with permission from Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA; Panel of Australian and New Zealand clinical toxicologists. Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres. Med J Aust. 2008;188(5):296–301.)


A. Emergency and Supportive Measures

Administer activated charcoal if it can be given within 1–2 hours of the ingestion. Although charcoal may interfere with absorption of the oral preparation of the antidote acetylcysteine, this is not considered clinically significant.

B. Specific Treatment

If the serum or plasma acetaminophen level falls above the line on the nomogram ...

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