Toxicology

Acetaminophen is consistently one of the most common toxic drug exposures.

In general, acute doses of 150 mg/kg or 7.5 g in adults and 200 mg/kg in children are considered toxic.

It is recommended that doses exceeding this threshold be managed in a health care facility.

The mechanism of toxicity is caused by the active metabolite N-acetyl-p-benzoquinoneimine (NAPQI),

which can lead to oxidant cell injury, hepatic failure, and death.

Around 90% of acetaminophen undergoes phase II conjugation to glucuronide and sulfate conjugates

that are excreted in the urine. An additional 2% is excreted unchanged in the urine. The remaining

amount (8%–10%) is converted by cytochrome P450 (CYP2E1) to NAPQI. NAPQI is normally converted

by glutathione to cysteine conjugates, which are renally excreted. In an overdose, the sulfation and

glucuronidation pathways become saturated, leading to glutathione depletion and a subsequent buildup

of NAPQI (Clin Liver Dis 2013;17:587-607).

estimated and may vary with individual patients).

Phase I occurs within the first 24 hours after ingestion. Patients may present with minimal or no signs

of distress. Potential signs and symptoms include nausea, vomiting, diaphoresis, and anorexia.

may present with right upper quadrant pain, increases in liver transaminases, elevated total bilirubin

concentrations, and prolonged prothrombin time.

Phase III occurs 72–96 hours after initial exposure and is the peak of the hepatotoxic effects. Patients

may present with lactic acidosis, acute renal failure, acute pancreatitis, and fulminant hepatic failure, as

evidenced by jaundice, extensive coagulopathies, hypoglycemia, and hepatic encephalopathy.

Phase IV occurs about 1 week after exposure and marks the recovery phase if the patient survives phase

III.

The goal of treatment is to prevent the development of hepatic toxicity and reduce mortality.

within the first hour after exposure, is not vomiting, and has no alterations in mental status. However,

with the availability of highly efficacious antidotal therapy, the risks often outweigh the benefits.

Antidote therapy is recommended with acetylcysteine. The mechanism of action for acetylcysteine is to

increase the synthesis and bioavailability of glutathione, substituting for glutathione by binding to the

reduced sulfur group of NAPQI, and supplying a substrate for sulfation, thereby increasing nontoxic

metabolism. Additional mechanisms of action have also been proposed, including its facilitation of

reactive oxygen and nitrogen species scavenging.

Guidelines suggest that acetylcysteine treatment be administered to patients within the first 8 hours of

exposure if they can be stratified as being at possible or probable risk of hepatotoxicity by the Rumack-

Matthew nomogram (Figure 1). If patients cannot be stratified because of unknown time of ingestion,

they should receive acetylcysteine if any of the following conditions apply: significantly elevated

alanine aminotransferase (ALT) concentration, serum acetaminophen concentrations greater than 20

mcg/mL, or history of chronic ingestions exceeding 4 g/day with an elevated serum ALT concentration

2007;50:292-313).

This includes patients presenting more than 24 hours postingestion with evidence of hepatotoxicity.