Analgesic Pharmacology — Paracetamol Toxicity

Pharmacological effects of Paracetamol

• Arachidonic acid ——(COX)—–>
  • Prostaglandins   → inflammation, sensitise spinal nerves to pain
  • Prostacycline  → vasodilation
  • Thromboxane   → platelet aggregation and activation
• Paracetamol: Weak COX-1 and COX-2 inhibitor in peripheral tissues
• Relatively selective for COX-2 → less inhibition of thromboxane production
• Possible cause for antipyretic effect:
  • Inhibition of COX-3 (variant of COX-1), leading to central effects

Toxic Effects and Management

Toxicity

• Occurs in doses >4g/day
  • Overdose dose lower in chronic alcoholics, elderly and children
• Paracetamol
  • → glucuronidation
  • → sulphation
  • → N-hydroxylation to NAPQI
• In overdose, glucuronidation and sulphation pathways saturated → increased production of toxic NAPQI
• NAPQI usually conjugated with hepatic glutathione
  • In overdose, glutathione exhausted → accumulation of NAPQI
• NAPQI bonds with hepatocyte sulfhydryl groups → cell death and necrosis

Therapy

• Decision to treat based on paracetamol overdose nomogram
  • Serum paracetamol level, time since dose
• If within 4 hours → activated charcoal
• Hepatic failure, GI upset, renal failure (less common)
• N-acetyl-cysteine should be given
  • Replenishes glutathione stores
  • Directly conjugates NAPQI
• Monitoring and supportive care:
  • Bilirubin
  • Transaminases
  • Creatinine (dialysis)
  • Liver synthetic function (albumin, INR) (vitamin K, maybe FFP, but discuss with liver unit first)
  • Blood sugar (glucose infusion) 
  • Conscious level (hepatic encephalopathy) (lactulose, intubation)

Mooney 2016

Answer by Mooney