## Paracetamol Metabolism and Hepatotoxicity ### Normal Metabolism Paracetamol is primarily metabolized via three pathways: 1. **Glucuronidation** (40–67%) → paracetamol glucuronide (inactive, excreted) 2. **Sulfation** (20–40%) → paracetamol sulfate (inactive, excreted) 3. **Oxidation via CYP2E1** (5–15%) → N-acetyl-p-benzoquinone imine (NAPQI) ### NAPQI and Toxicity **Key Point:** NAPQI is a highly reactive electrophile that is normally detoxified by glutathione (GSH) conjugation to form non-toxic mercapturic acid derivatives. **High-Yield:** In overdose, glutathione stores become depleted, allowing NAPQI to accumulate and bind covalently to hepatocyte proteins, causing: - Hepatocyte necrosis (centrilobular, Zone 3) - Mitochondrial dysfunction - Oxidative stress - Acute liver failure (in severe cases) ### Clinical Correlation **Clinical Pearl:** The risk of hepatotoxicity increases with: - Doses >150 mg/kg in children or >200 mg/kg in adults - Pre-existing liver disease - Chronic alcohol use (induces CYP2E1) - Malnutrition (depletes GSH) - Concurrent use of other hepatotoxic drugs ### Antidote Mechanism N-acetylcysteine (NAC) works by: 1. Replenishing hepatic glutathione stores 2. Directly conjugating NAPQI 3. Scavenging free radicals [cite:Harrison 21e Ch 438]
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