Acetaminophen toxicity

Background

Effective analgesic and antipyretic with minimal anti-inflammatory properties. Two theories are proposed for its poor anti-inflammatory action – first, it is thought to be predominantly active in the brain, and second, it appears to be unable to inhibit COX in the presence of peroxides, which are abundant at sites of inflammation.

Peak plasma concentration within 30-60 minutes of oral intake. Traditional dosing has been 325-650 mg q4-6 hours, with a total daily dose not to exceed 4000 mg (2000 mg for chronic alcoholics). According to Goodman & Gilman, however, “In 2009, an FDA advisory panel recommended a lower maximum daily dose of acetaminophen of 2600 mg and a decrease in the maximum single dose from 1000 mg to 650 mg.”

Acetaminophen has minimal GI effects (especially compared to NSAIDs) and no effect on the cardiovascular and respiratory systems, platelets, or coagulation.

Toxicity

Normally acetaminophen is metabolized via glucuronidation (40% to 67%), sulfation (20–40%), and N-hydroxylation/rearrangement/GSH conjugation (less than 15%). With excessive dosing of acetaminophen, the glucuronide and sulfate conjugation pathways become saturated, and increasing amounts of acetaminophen then undergoes N-hydroxylation (CYP-mediated) to form NAPQI, which is a toxic metabolite. Ultimately this may lead to hepatic necrosis, renal tubular necrosis, hypoglycemic coma, and death. If GSH levels become depleted, as they do in overdose, NAPQI levels can increase to toxic levels.

N-acetylcysteine (NAC) is the first-line treatment, 140 mg/kg is given orally or 150 mg/kg IV, followed by 70 mg/kg every 4 hours for 17 doses. NAC works by detoxifying NAPQI, by repleting GSH and conjugating NAPQI directly. NAC works even in the setting of activated charcoal administration. Glucose should be managed aggressively.

Acetaminophen Toxicity

• Manifestations: hepatic necrosis, renal tubular necrosis, hypoglycemic coma
• Mechanism: glucouronidation/sulfation pathways become saturated, GSH becomes depleted
• Treatment: NAC (140 mg/kg PO, 150 mg/kg IV), charcoal, glucose management, possible liver transplantation