Introduction
This topic covers acute poisoning with two common antipyretic-analgesics, paracetamol (acetaminophen) and acetylsalicylic acid (aspirin). Both drugs are sold without prescription, so overdose, whether deliberate or accidental, is common. A good exam answer gives the toxic dose, the mechanism of injury, the course of the poisoning in phases, the diagnostic tests, and the specific antidote and supportive treatment for each drug.
Paracetamol: toxic dose and mechanism
Paracetamol is safe at therapeutic doses. Toxicity follows an acute ingestion above about 150 mg/kg body weight, or more than about 12 g in an adult. Risk is higher with chronic alcohol use, malnutrition, fasting, and enzyme-inducing drugs such as anticonvulsants.
- Most of a therapeutic dose is conjugated in the liver by glucuronidation and sulfation and excreted safely.
- A small fraction is oxidised by cytochrome P450 enzymes (mainly CYP2E1, also CYP1A2 and CYP3A4) to the reactive metabolite NAPQI (N-acetyl-p-benzoquinone imine).
- NAPQI is normally detoxified by conjugation with glutathione.
- In overdose, glutathione stores are used up. NAPQI then binds covalently to hepatocyte proteins and mitochondria, causing centrilobular hepatic necrosis.