Acetaminophen Toxicity: What Pharmacists Need to Know

Erica Dimitropoulos, PharmD; Emily M. Ambizas, PharmD, CGP

Disclosures

US Pharmacist. 2014;39(3):HS2-HS8. 

In This Article

Pharmacokinetics

Upon ingestion, acetaminophen is rapidly absorbed from the gastrointestinal (GI) tract and quickly distributed throughout the body. Peak plasma concentrations are achieved within 30 to 60 minutes;[4] food may delay time to peak concentration, but the extent of absorption is not affected.[12] With overdoses, peak plasma concentrations are usually achieved within 4 hours.[13] The half-life of acetaminophen is approximately 2 to 3 hours after therapeutic doses, yet can be increased to more than 4 hours in patients with hepatic injury.[4,12,14]

Acetaminophen is extensively metabolized by the liver via three main hepatic pathways: glucuronidation, sulfation, and CYP450 2E1 oxidation.[12] Approximately 90% of acetaminophen is conjugated to sulfated and glucuronidated metabolites that are renally eliminated.[14] Of the remaining acetaminophen, approximately 2% is excreted unchanged in the urine and the rest undergoes CYP450-mediated oxidation to form a reactive metabolite, N-acetyl-pbenzoquinone imine (NAPQI).[15–18] Under normal circumstances, this toxic metabolite reacts with sulfhydryl groups in glutathione, converting it to harmless metabolites before being excreted in the urine.[4]

Toxicity

Drugs may have toxic effects due to various reasons. Toxicity of some drugs is related to the formation of an undesirable metabolite; consequently, toxicity of acetaminophen is related to the production of NAPQI. With large acute doses or with chronic use, the major metabolic pathways—the glucuronide and sulfate conjugation systems—become saturated, and more acetaminophen is metabolized by the CYP450 system. This results in increased production of NAPQI. When glutathione is approximately 70% depleted, NAPQI begins to accumulate in the hepatocytes, resulting in hepatic damage.[15,16,18] Therefore, the replacement of glutathione with glutathione-mimicking compounds such as N-acetylcysteine serves as a useful antidote to acetaminophen toxicity.

Acetaminophen toxicity can result from either an acute overdose or from chronic overuse. Acute overdose is defined as consumption of a toxic amount of a drug within an 8-hour period, whereas chronic overdose occurs as a result of repeated doses at or above the recommended limit.[12] Unintentional overdoses may also occur as a result of ingestion of multiple products containing acetaminophen. The recommended dose of acetaminophen in adults is 650 to 1,000 mg every 4 to 6 hours, not to exceed 4,000 mg in a 24-hour period; in children, the recommended dose is 10 to 15 mg/kg every 4 to 6 hours, not to exceed 50 to 70 mg/kg in 24 hours.[12] Single doses of more than 150 mg/kg or 7.5 g in adults have been considered potentially toxic, although the minimal dose associated with liver injury can range anywhere from 4 to 10 g.[6,12,14,19] In children, single doses of 120 mg/kg to 150 mg/kg have been associated with hepatotoxicity; however, doses <200 mg/kg are unlikely to result in toxicity.[14,20]

While the exact maximum dose has not been well defined, the American Association of Poison Control Centers (AAPCC) has recommended that regardless of the amount of drug ingested, a patient should be brought for medical evaluation if he or she displays signs or symptoms consistent with toxicity.[21] The AAPCC has provided guidelines for hospital referral both for acute, single, unintentional ingestion of acetaminophen and for repeated supratherapeutic ingestion of acetaminophen ( Table 1 ).[21]

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