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Pharmacology of Paracetamol Toxicity

In this section:

• Hepatotoxicity
• Mitochondrial stunning/paralysis

Heptatotoxicity
Paracetamol poisoning remains the most common cause of acute liver failure.  The majority of patients who sustain an acute liver injury from paracetamol toxicity and are treated in hospital will recover, however some can require extended ICU level care, and a small proportion will require a liver transplant to survive. Some patients will die despite optimal treatment. 

Phase 1 metabolism has 3 pathways – 2 of which results in non-toxic metabolites that are excreted, and the third, via P450 enzymes, produces the toxic metabolite NAPQI (N-acetyl-P benzoquinonamine).
At therapeutic doses the first two pathways comprise about 95% of paracetamol metabolism, the remaining 5% follows the third pathway resulting in NAPQI.

NAPQI is further metabolised in phase 2 into non-toxic conjugates via the substrate glutathione.
In paracetamol overdose, an increased amount of NAPQI is produced, and the phase 2 metabolism is saturated with a depletion of glutathione stores.  Thus excess NAPQI results from increased production and reduced metabolism. 

Excess NAPQI causes hepatotoxicity by directly binding to a range of proteins in the liver  and causing cellular damage and acute liver injury.

NAC works by replenishing glutathione stores and restoring the metabolism pathway of NAPQI to non-toxic metabolites.

The highest risk groups for liver toxicity after paracetamol poisoning, are:

• Very large overdoses (greater than 2-3 times the minimum toxic dose of 10 grams or 200mg/kg in patients less than 50kg)
• Modified release paracetamol overdoses
• Late presenters
• Those with underlying risk factors
  • Conditions leading to malnutrition and/or induced CYP enzymes

Mitochondrial stunning/paralysis

• Seen in massive paracetamol overdose
• Characterised by rapid onset:
  • Altered mental status: lethargy, confusion, coma
  • Lactic acidosis
  • +/- hypotension
• In acute overdose these signs occur in the absence of/much earlier than signs of liver injury, and can develop within hours of massive paracetamol overdose
• This is in contrast to coma/acidaemia in fulminant hepatic failure which:
  • Develops over days
  • Portends a poor prognosis
  • May be refractory to treatment with IV bicarbonate and vasopressors
  • Mechanism unclear
    • High concentrations of paracetamol may directly impair mitochondrial respiration by:
      • Affecting mitochondrial gene expression
      • Interfering with the electron transport chain, oxidative phosphorylation and pyruvate dehydrogenase
• Separate/different to the NAPQI/glutathione depletion mechanism of hepatic toxicity
  • This evolves over days
  • Lactic acidosis in this context is due to the damaged livers inability to metabolise lactate
• Mitochondrial stunning is reversible:
  • By lowering the concentration of paracetamol in the bloodstream
  • This can be achieved by haemodialysis which removes drug from the circulation
    • NB Dialysis will also remove N-acetylcysteine – so may need to increase to dose to compensate for removal by dialysis
  • NAC has no direct effect on/does not treat mitochondrial stunning as it does not affect serum paracetamol levels
  • NAC only helps restore glutathione stores/prevents hepatotoxicity

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References

Antidote removal during haemodialysis for massive acetaminophen overdose

Understanding lactic acidosis in paracetamol (acetaminophen) poisoning