Pharmacology for Anaesthesia and Intensive Care

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9 Analgesics

120 mg in 5 ml. A preparation containing 100 mg methionine and 500 mg parac-

etamol is available but at increased cost. A solution of 1 g in 100 mls is available for

intravenous use. The adult dose is 4 g.day−^1 in divided doses. The initial paediatric

dose is 15–30 mg.kg−^1 which is then reduced to 10–15 mg.kg−^1 every 4 hours with a

maximum dose of 90 mg.kg−^1 .day−^1.

Kinetics

Paracetamol is well absorbed from the small bowel and has an oral bioavailability of

80%. Unlike the other NSAIDs it does not cause gastric irritation, is less protein bound

(10%) and has a larger volume of distribution. Paracetamol is metabolized by the liver

mainly to glucuronide conjugates but also to sulphate and cysteine conjugates. These

are actively excreted in the urine, only a small fraction being excreted unchanged. N-

acetyl-p-amino-benzoquinoneimine is a highly toxic metabolite of paracetamol that

is produced in small amounts following therapeutic doses. It is rapidly conjugated

with hepatic glutathione to render it harmless.

Toxicity

Following a toxic dose, the normal hepatic conjugation pathways become satu-

rated so that more N-acetyl-p-amino-benzoquinoneimine is produced which rapidly

exhausts hepatic glutathione. It is then free to form covalent bonds with sulphydryl

groups on hepatocytes resulting in cell death and centrilobular hepatic necrosis.

Treatment with oral methionine and oral or intravenous acetylcysteine is directed

at replenishing hepatic glutathione. Methionine enhances glutathione synthesis

while acetylcysteine is hydrolyzed to cysteine, which is a glutathione precursor.

Intravenous acetylcysteine is preferred as vomiting is common in paracetamol

overdose.

Features of paracetamol overdose


Normally remain conscious


Nausea and vomiting


Epigastric pain


Sweating


Erythema, urticaria, mucosal lesions


Acute haemolytic anaemia


Peripheral vasodilatation and shock following massive overdose


Delayed hyperglycaemia


Hepatic failure after 48 hours


LFT and clotting (INR) worst at 3–5 days


Cholestasis


Fulminant hepatic failure at 3–7 days