Module 2: Foundational Knowledge

This module covers the key terminology, metabolism and toxicity mechanisms, and core principles of risk assessment and antidotal therapy related to acetaminophen poisoning. High yield learning points:

• Acetaminophen is metabolized primarily by glucuronidation and sulfation into nontoxic metabolites, and to a lesser extent by CYP450 enzymes into the toxic metabolite NAPQI.
• Toxicity results when NAPQI formation outpaces detoxification by glutathione, causing covalent binding to cellular proteins and subsequent hepatic necrosis.
• Risk assessment involves determining the likelihood of toxicity based on ingested dose, time from ingestion, and individual risk factors.
• Antidotal therapy with N-acetylcysteine replenishes glutathione stores to bind NAPQI and prevent further hepatic damage.
• Initiation of N-acetylcysteine within 8 hours of acute overdose provides maximum hepatoprotection, but it can mitigate toxicity at later time points as well.

2.1 Key Terminology

• Acetaminophen (APAP): Also known as paracetamol, an over-the-counter analgesic medication. Therapeutic doses are safe, but intentional or unintentional overdose can lead to hepatotoxicity and liver failure.
• N-acetyl-p-benzoquinone imine (NAPQI): A highly reactive toxic metabolite produced when acetaminophen is metabolized by CYP450 enzymes. NAPQI production is increased after acetaminophen overdose.
• Aminotransferases: Liver enzymes like ALT and AST that are elevated in the blood during acetaminophen-induced hepatocellular injury.
• Rumack-Matthew Nomogram: A graphical plot relating serum acetaminophen concentration to time post-ingestion, used to predict risk of hepatotoxicity.
• N-acetylcysteine (NAC): The antidote for acetaminophen poisoning, administered intravenously or orally to replenish glutathione and prevent liver injury.

2.2 Acetaminophen Metabolism and Toxicity

• Therapeutic doses of acetaminophen are predominantly metabolized by conjugation with glucuronic acid and sulfate.
• A small fraction is metabolized by CYP450 enzymes (mainly CYP2E1) into the reactive and toxic compound NAPQI.
• NAPQI is normally rapidly detoxified by conjugation with glutathione and excreted as nontoxic metabolites.
• In overdose, excessive NAPQI outpaces glutathione stores, leading to covalent binding to proteins in hepatocytes and hepatic necrosis.
• Centrilobular hepatic necrosis is typical, as CYP2E1 is concentrated in this region.

2.3 Core principles of risk assessment and antidotal therapy

1. Risk assessment should determine if the patient is at risk of developing hepatotoxicity based on the dose ingested and time since ingestion. The Rumack-Matthew nomogram is the primary tool used to assess this risk after acute overdose.
2. Antidotal therapy with N-acetylcysteine (NAC) should be administered within 8 hours of ingestion to all patients considered at risk of hepatotoxicity based on the nomogram or history.
3. NAC has three mechanisms of action: increasing glutathione stores, providing alternative sulfhydryl groups to bind the toxic metabolite NAPQI, and serving as an antioxidant.
4. Oral and intravenous NAC have similar efficacy when initiated within 8 hours post-ingestion. The intravenous route is preferred for patients with vomiting or fulminant liver failure.
5. The duration of NAC therapy depends on evidence of toxicity and exposure risk. For acute ingestions, it should be continued until acetaminophen is undetectable and hepatic injury is resolved. In massive or repeated ingestions, longer treatment may be warranted.