Paracetamol Poisoning ✅ Flashcards
What is the most common medication taken in overdose by children in developed countries?
Paracetamol
Why is paracetamol the most common drug taken in overdose?
Due to its wide over-the-counter availability
Why is it hard to determine the toxic dose of paracetamol?
It can be very variable
What are higher doses of paracetamol associated with?
Greater risk of adverse effects
What single dose of paracetamol is considered to have a reasonable likelihood of causing toxicity?
200mg/kg
Can doses lower than 200mg/kg of paracetamol cause problems?
Yes, lower single doses can result in significant problems, as can multiple smaller doses which cumulatively exceed this threshold taken within a 24 hour period
What phases is paracetamol toxicity divided into?
- 0-24 hours
- 24-72 hours
- 72-120 hours
What features may be present 0-24 hours after a paracetamol overdose?
- Nausea
- Vomiting
- Excessive sweating
What features may be present 24-72 hours after paracetamol overdose?
- Right upper quadrant pain
- Liver dysfunction
- Possible renal impairment
What features may be present 72-120 hours after paracetamol overdose?
- Hepatic necrosis leading to liver failure
- Renal failure
- Cerebral oedema
- Death
What is the biochemical evidence of paracetamol-induced liver damage?
- Elevated blood concentrations of AST and ALT
- Prolonged prothrombin time
What evidence of a paracetamol overdose might be found on blood gas?
Metabolic acidosis in severe cases
What causes AKI in paracetamol overdose?
- May be primary manifestation of paracetamol toxicity
- Can occur as result of hepatorenal syndrome or multi-organ failure
By what processes is paracetamol metabolised?
- Sulfation
- Glucuronidation
- Hydroxylation by CYP450
What is formed from sulfation of paracetamol?
Sulfate moiety
Is the sulfate moiety formed from paracetamol sulfation toxic?
No
What is formed from the glucuronidation of paracetamol?
Glucuronide moiety
Is the glucuronide moiety formed from paracetamol glucuronidation toxic?
No
What is formed from the hydroxylation by paracetamol by CYP450?
NAPQI (N-acetyl-p-benzo-quinone imine)
Is the NAPQI formed by the hydroxylation of paracetamol toxic?
Yes
What happens to the NAPQI formed in paracetamol metabolism?
It is conjugated to glutathione
What is produced from the conjugation of NAPQI to glutathione?
Cysteine and mercapturic acid conjugates
Are cysteine and mercapturic acid conjugates toxic?
No
What % of metabolism of therapeutic doses of paracetamol is done by sulfation and glucuronidation?
Over 90%
Where does glucuronidation and sulfation of paracetamol take place?
In the liver
What % of paracetamol undergoes metabolism to NAPQI at therapeutic doses?
Approx 5%
Why does NAPQI not have toxic effects at therapeutic doses?
Because the small amount produces is easily detoxified by conjugation with glutathione
What happens to the metabolism pathways of paracetamol in overdose?
The glucuronidation and sulfation pathways become saturated and a much higher proportion of paracetamol is converted to NAPQI
What happens with the excessive amounts of NAPQI in paracetamol overdose?
Hepatic stores of glutathione are depleted rapidly, and NAPQI remains in its active toxic form causing acute hepatic necrosis
What is the treatment for paracetamol overdose?
Administration of N-acetylcysteine (NAC)
In what timeframe should NAC be given in paracetamol overdose?
Within 8 hours of ingestion
What is the purpose of NAC in paracetamol overdose?
Helps limit hepatotoxicity and prevents death
What happens to the effectiveness of NAC the longer that administration is delayed after this time?
It is progressively less effecrtive
How does NAC work in paracetamol overdose?
Primarily by augmenting glutathione reserves, which enhances the ability to detoxify NAPQI
How is the need for administration of NAC guided in paracetamol overdose?
Measurement of plasma paracetamol levels at least 4 hours after overdose, and the use of a monogram to assess risk of toxicity
What factors put individuals at greater risk of paracetamol toxicity?
- Starvation/malnutrition
- CYP450-inducing drugs
- Neonates
Why does starvation/malnutrition put individuals at a greater risk of paracetamol toxicity?
Probably as a result of depleted hepatic glutathione stores
Give 2 examples of CYP450-inducing drugs?
- Carbamazepine
- Phenytoin
How is paracetamol metabolism different in a neonate?
- The sulfation pathway is the primary metabolic pathway for paracetamol in the neonate because of low glucuronidation activity
- The CYP450 pathway displays significantly lower activity than in later life
What is the result of the CYP450 pathway of paracetamol metabolism showing significantly lower activity in the neonatal period than in later life?
May be protective
What is used to identify patients in which liver transplantation should be considered?
King’s College criteria
What are the King’s College criteria indicating a referral for consideration of transplant should be considered?
- Arterial pH <7.3
- All 3 of;
- INR >6.5
- Serum creatinine >300
- Grade III/IV hepatic encephalopathy
