PARACETAMOL

  • Need to understand mechanism of toxicity and antidote.
Structure/Class  
Pharmacodynamics
  1. Functions as a COX-1 and COX-2 inhibitor. No anti-inflammatory properties.
Absorption/administration
  1. Well absorbed from the GIT.
    • Peak plasma levels 30-60 minutes.
    • It is slightly protein bound.
Distribution
  1. T ½ of 2-3 hours. This is increased in liver disease to >6 hours
Metabolism
  1. Hepatic
    • >95% undergoes glucuronidation and sulfation.
    • 5% will undergo metabolism via CYP 450 mechanisms (Phase 1 reaction – hydroxylation) to form NAPQI. NAPQI is toxic, but usually detoxified by glutathione.
Excretion
  1. Renal
Indications  
Contraindications  
Special precautions  
Interactions  
Adverse events  
Dosing/administration  
Toxicology
  1. A dose of >200mg/kg or >7g in adults is considered to be potentially toxic. The mechanism is as follows:
    • Paracetamol normally undergoes glucuronidation and sulfation.
    • In ODs à these pathways are saturated and then paracetamol is broken down by a Phase 1 reaction.
    • More NAPQI is formed à this consumes glutathione (GSH). Once GSH is depleted, NAPQI then becomes hepatotoxic.
  2. Signs and symptoms
    • Initially, nausea/vomiting and abdominal pain.
    • Then signs of hepatic failure – raised transaminases and raised INR.
    • Hepatic encephalopathy and death.
  3. Risk of toxicity is based on paracetamol nomogram.
  4. Treatment – NAC. It functions either as a sulfhydryl donor in order to inactivate NAPQI, or as a glutathione substitute.
    • Liver transplant in severe cases.
Withdrawal syndrome  
Special notes