What are the hepatic risks of acetaminophen and the antidote for overdose?

• A. Nephrotoxicity; N-acetylcysteine.
• B. Hepatotoxicity; N-acetylcysteine.
• C. Pulmonary fibrosis; N-acetylcysteine.
• D. Cardiac arrhythmias; N-acetylcysteine.

Answer: (B)

Acetaminophen overdose primarily threatens the liver, causing hepatotoxicity. This happens because a subset of the drug is metabolized by CYP enzymes to a reactive metabolite called NAPQI. Normally, NAPQI is detoxified by conjugation with glutathione, but in overdose glutathione stores become depleted. When glutathione runs low, NAPQI binds to cellular proteins in hepatocytes, driving oxidative stress and liver cell injury that can progress to acute liver failure if not treated.

The antidote, N-acetylcysteine, works by replenishing glutathione stores, acting as a precursor to glutathione synthesis, and also providing antioxidant support. By restoring glutathione, NAC enhances detoxification of NAPQI and protects liver cells from further damage. Early administration is crucial and significantly improves outcomes, including reducing the risk of severe liver injury and death.

While kidney injury can occur with acetaminophen toxicity, the hallmark and most clinically relevant risk is hepatic injury, and the established antidote is N-acetylcysteine.