Sun14November1246PM 47

A 34-year-old male is admitted to the medical admissions unit following the ingestion of 12 g of paracetamol. He has the clinical and biochemical features of hepatocellular necrosis.

Which of the following is the most important reason why paracetamol causes toxicity?

(Please select 1 option)

Paracetamol has high bioavailability

The conjugation of paracetamol is a rapidly saturable process Incorrect answer selected

Paracetamol is readily absorbed from the gut

Glutathione is rapidly exhausted This is the correct answer

Has a low volume of distribution

Explanation

Paracetamol is metabolised by the liver by phase I and phase II metabolism.

Phase I:

Cytochrome P450 (CYP1A2, CYP2E2, CYP3A4 and CYP2D6) and prostaglandin synthetase to N-acetyl-p-benzoquinoneimine (NAPQI) and N-acetylbenzo-semiquinoneimine. NAPQI is a toxic metabolite and can bind to sulphydryl groups of cellular proteins in hepatocytes. This in turn can lead to centrilobular necrosis.

At low paracetamol doses, glutathione and glutathione transferases prevent NAPQI from binding to hepatocytes by preferentially binding to these toxic metabolites. It is then excreted in the urine as cysteine and mercapturic acid conjugates. At higher doses of paracetamol, depletion of glutathione results in high levels of NAPQI with the potential for hepatocellular damage. If the body had enough glutathione stores, hepatotoxicity would not be an issue.

N-acetylcysteine is the drug of choice for the management of paracetamol overdose and is a precursor for glutathione synthesis.

Phase II:

The main method of metabolism and excretion is conjugation with glucuronic acid to paracetamol glucuronide, accounting for 60% of renally excreted metabolites. Other renally excreted metabolites include paracetamol sulphate (35%), unchanged paracetamol (<5%) and mercapturic acid (3%). Conjugation pathways are capacity limited. The sulphate conjugation pathway is more capacity-limited than the glucuronidation pathway.

Paracetamol absorption is negligible in the stomach because of low pH (pKa value is 9.5). In the alkaline environment of the small intestine the absorption of paracetamol is very rapid and complete. Oral bioavailability is high and approaches 100%. For this reason, the measurement of paracetamol levels in plasma following an oral dose of paracetamol has been used as a surrogate marker of gastric emptying. Peak plasma concentrations are attained at 30-60 minutes having a relatively high volume of distribution at 0.95 L/kg. Its plasma protein binding is 10%-25%.

Answer Statistics

1

1%

2

21%

3

1%

4

79%

5

1%

Times answered: 265