Paracetamol causes:

Ref: Goodman & Gillman 13th ed. P 696* Paracetamol/Acetaminophen is a non-selective COX inhibitor* Use: Analgesic and antipyretic agent. Preferred in patients where aspirin is contraindicated* Usual dose: 325-650mg every 4-6 hours. Maximum FDA recommended dose is 4gm/day* Peak plasma concentration: 30-60 minutes* Half-life: 2 hours* Metabolism of acetaminophen in liver by:# Hepatic conjugation with glucuronic acid (~60%),# Sulfuric acid (~35%),# Cysteine (~3%);# CYP mediated N-hydroxylation to form NAPQI (N-acetyl-p-benzoquinone imine)* Note: NAPQI is one of the highly reactive intermediate metabolite of acetaminophen metabolism. This usually reacts with sulfhydryl groups is GSH - rendered harmless.* In hepatotoxicity condition GSH level depleted.SIDE EFFECTS* The most serious acute adverse effect of over dosage of acetaminophen is a potentially fatal hepatic necrosis.* Due to hepatotoxicity there is saturation of glucuronide and sulfate conjugation and increasing amounts undergo CYP-mediated N-hydroxylation to form excess of NAPQI (it accumulates due to depletion of GSH).* The highly reactive NAPQI causes enzymatic dysfunction, produces oxidative stress and apoptosis.* In adults hepatotoxicity may occur after ingestion of single dose of 10-15g. Doses of 20-25g is potentially fatal.TREATMENT OF ACETAMINOPHEN TOXICITY:* Activated charcoal within 4 hours of ingestion decreases absorption by 50-90%* N-acetylcysteine: antidote of choice for acetaminophen toxicity. It acts by detoxifying NAPQI by:# Repleting GSH stores# Conjugate directly with NAPQI by serving as a GSH substituteIn Paracetamol Toxicity:* Liver enzyme abnormalities typically peak 72-96 hours after ingestion* Biopsy: Centrilobular necrosis with sparing of the periportal area* Other side effects: Renal tubular necrosis and Hypoglycemic coma