Paracetamol Pathophysiology

Paracetamol has been used as a pain killer since the 1950's.

After taken orally, paracetamol is well absorbed from the stomach and small intestine and reaches a peak plasma concentration in one hour. It is inactivated by the liver by conjugation leading to two metabolites; glucoronide or sulfate. It is then renally excreted through urine.

When taken in overdose the liver conjugation becomes inundated, causing paracetamol to be metabolised by an alternative pathway.

This alternative pathway results in a toxic metabolite, N-acetyl-p-benzoquinone imine (NABQI), which is itself inactivated by glutathione, rapidly preventing any harm. However, glutathione reserves can be run down quickly and, when this occurs, NABQI reacts with nucleophilic aspects of the cells, leading to necrosis. Necrosis occurs in the liver and in the kidney tubules.

The P-450 enzyme system is responsible for the detoxification of compounds taken orally. Toxicity is increased in patients with a strain on the P-450 enzyme system caused by drugs such as rifampicin, phenobarbital, phenytoin, carbamazepine and alcohol.

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