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Paracetamol Toxicity
Metabolism woes
Paracetamol Toxicity
Hepatotoxicity caused by toxic doses of Paracetamol is clinically important. Understanding the sequence of reactions that brings about the toxicity itself will help in the better management of the the toxicity.
At therapeutic dose paracetamol is detoxified by glucuronide and sulfate conjugation, to form inactive metabolite, which are excreted in urine. Incidentally there also exists a minor alternate metabolic pathway of oxygenation by cytochrome P450 (Mixed function Oxidases) resulting in the formation of toxic metabolite N-acetyl-P-benzoquinoneimine. This pathway does not come in to play when paracetamol is administered at therapeutic doses or if so, the toxic reactive metabolite formed is conjugated with –SH group of glutathione to form non-toxic, harmless end products.
When excess of paracetamol are consumed the glucuronide and sulfate metabolic pathways are saturated. Obviously the alternate pathway of metabolism, oxygenation by cytochrome P450 comes into play. The excess paracetamol consumes all the –SH group of glutathione resulting in its depletion and consequent accumulation of toxic metabolite N-acetyl-P-benzoquinoneimine.
GSH is an important factor in the anti oxidant defense so, depletion of GSH, cells are highly susceptible to oxidant injury. Depletion of GSH also allows the reactive intermediate to bind covalently to cell macromolecules. As metabolism occurs in liver the hepatocytes are affected – cell necrosis – hepatotoxicity. Renal damage and hypo glycemia can also develop.Alcoholics are more susceptible to paracetamol-induced hepatotoxicity why?
Treatment:Early diagnosis is vital for treatment of overdose. Gastric lavage within the first four hours but no activated charcoal as it can bind to antidotes like methionine and acetylcysteine. Antidotes are effective only when given within ten hours of intake of drug. The antidotes advised are methionine and acetylcysteine. Both are precursors of glutathione in he body. Acetylcysteine by IV is the drug of choice, alternatively can also be given orally at 140mg/kg followed by 70mg/kg every 4 hours for 17 days.
Now answer for the above question. Acetaminophen is more toxic under conditions in which cytochrome P450 enzyme are induced, such as following ethanol or Phenobarbital exposure. Infants usually have less of glucuronide and are also susceptible to toxicity.
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