Analgesics and Anti-inflammatories - Paracetamol (1)

Question 1

Paracetamol overdose - give an overview of the pharmacology.

Answer 1

At toxic doses, the three different Phase II reactions in the metabolism of paracetamol are saturated. This results in accumulation of a toxic Phase I metabolite, which leads to hepatotoxicity and death. (See Chapter 4 of Katzung)

Question 2

Name the two dominant phase II reactions in the metabolism of paracetamol. These two make up 95% of the total excreted metabolites - producing non-toxic metabolites.

Answer 2

Glucuronidation and Sulfation.

Question 3

Name the third phase II reaction in the metabolism of paracetamol - the one that detoxifies the toxic phase I metabolite.

Answer 3

Conjugation with glutathione.

Question 4

As hepatic _______ decreases, in paracetamol overdose, the toxic phase I metabolite may bind to hepatocyte proteins, leading to liver cell damage and necrosis.

Answer 4

Glutathione.

Question 5

Paracetamol can be toxic after doses as low as _____ are ingested.

Answer 5

10g

Question 6

Paracetamol can be fatal after doses as low as _____ are ingested.

Answer 6

25g

Question 7

What is the basic guideline for management of paracetamol overdose?

Answer 7

If it has been less than 4hrs since ingestion of unknown dose: wait until 4hrs, take a serum level.
If it has been 4-8hrs since ingestion of unknown dose: take a serum level, and treat as per nomogram.
If the dose is known to be >15g, give NAC.

Question 8

Describe what you know about the mechanism of action of the antidote to paracetamol overdose.

Answer 8

N-acetylcysteine is a sulfhydryl group donor. It may restore depleted hepatic glutathione levels.

Question 9

NAC is most effective when administered ____ hours after paracetamol ingestion.

Answer 9

Within 8 hours.

Question 10

What is the dose of NAC to give?

Answer 10

Initial dose of 150mg/kg over 15 minutes. Then 50mg/kg infusion over 4 hours. Then 100mg/kg infusion over 16 hours.