A 24-year-old man is brought to the emergency department due to weakness, lethargy, nausea, and dizziness. He took fifty 325-mg acetaminophen tablets approximately 6 hours ago. Vital signs are normal. Pupils are equal, round, and reactive to light; there is mild epigastric tenderness. Laboratory results include an elevated serum acetaminophen level. Intravenous infusion of N-acetylcysteine is started. This treatment is most likely to improve the patient's condition by which of the following mechanisms?
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Metabolism of acetaminophen occurs in the liver and involves several enzymatic pathways. Most of the drug (~90%) undergoes sulfation and glucuronidation into nontoxic metabolites prior to elimination through the urine; a small amount (~2%) of acetaminophen is directly excreted by the kidneys. The remaining acetaminophen is metabolized by hepatic cytochrome P450 into the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI).
With an appropriate dose of acetaminophen, the small amount of NAPQI produced is converted to a nontoxic form via conjugation by hepatic glutathione and is then excreted in the urine. However, with an acetaminophen overdose, the liver sulfation and glucuronidation pathways become overwhelmed, resulting in excessive NAPQI formation. Once intrahepatic glutathione stores are depleted, the unconjugated NAPQI level rises and causes oxidative damage to the liver.
Management of acetaminophen overdose includes N-acetylcysteine (NAC), which provides the liver a precursor to produce more glutathione. By increasing intrahepatic glutathione stores, NAC facilitates NAPQI detoxification and prevents further hepatotoxicity.
(Choice A) Although hepatic glucuronidation is an important step in the metabolism of acetaminophen, NAC works by replenishing glutathione stores, not by activating glucuronidation enzymes.
(Choice B) Opioids exert toxicity by overstimulating their receptors, which can be reversed by competitive inhibition (ie, naloxone). NAPQI does not bind a specific receptor. Instead, it generates reactive oxygen species and forms adducts with hepatic proteins.
(Choice D) Management of some drug overdoses (eg, salicylates such as aspirin) includes urine alkalinization (ie, sodium bicarbonate), which can increase urinary excretion of the toxin. Urine alkalinization is not helpful for acetaminophen overdose because unconjugated NAPQI is not excreted through the urine.
(Choice E) Cimetidine inhibits cytochrome P450, which can decrease acetaminophen metabolism, but it has not been shown to be effective in acetaminophen overdose.
Educational objective:
Acetaminophen overdose overwhelms normal metabolic pathways in the liver and depletes intrahepatic glutathione stores, leading to excessive production of N-acetyl-p-benzoquinone imine (NAPQI), a toxic metabolite. Management includes administration of N-acetylcysteine, which increases intrahepatic glutathione stores and facilitates NAPQI detoxification.