Paracetamol (acetaminophen) is the deethylated active metabolite of phenacetin that was also introduced in the last century, but has come into common use only since 1950.
Paracetamol has negligible anti inflammatory action. It is a poor inhibitor of PG synthesis in peripheral tissues, but more active on COX in the brain. One explanation offered for the discrepancy between its analgesic-antipyretic and anti inflammatory actions is its inability to inhibit COX in the presence of peroxides which a regenerated at sites of inflammation, but are not present in the brain. The ability of paracetamol to inhibit COX-3 (an isoenzyme so far located in dog brain) could also account for its analgesic-antipyrctic action.
Paracetamol poisoning occurs especially in small children who have low hepatic glucuronide conjugating abil ity. If a large dose (> 150 mg/kg or > 10 g in an adult) is taken, serious toxicity can occur. Fatality is common with > 250 mg/kg. Early manifestations are just nausea, vomiting, abdominal pain and liver tenderness with no impairme nt of consciousness. After 12-18 hours centrilobular hepatic necrosis occurs which may be accompanied by renal tubular necrosis and hypoglycaemia that may progress to coma. Jaundice starts after 2 days. Further course depends on the dose taken. Fulminating hepatic failure and death are likely if the plasma levels are high. If the levels a re lower recovery with supportive treatment is the rule.
Mechanism of toxicity acetyl-p-benzoquinoneimine (NABQI) is a highly reactive arylating minor metabolite of pa racetamol which is detoxified by conjugation with glutathione. When a very large dose of paracetamol is taken, glucuronidation capacity is saturated, more of the minor metabol ite is formed hepatic glutathione is deplete and this metabolite binds covalently to proteins in liver cells (and renal tubules) causing necrosis. Toxicity thus shows a threshold effect manifesting only when glutathione is depleted to a critical point. In chronic alcoholics even 5 g taken in one day can result in hepatotoxicity because alcoholism induces CYP2E1 that metabolises paracetamol to NABQI. Paracetamol is not recommended in premature infants (< 2 kg) for fear of hepatotoxicity.
Note: Exercising abundant caution, because paracetamol is an over-the-counter drug, the US-FDA (2009) has recommended to reduce the amount of th is drug m any single dosage form (tab./ceap.) to 650 mg (in place of 1000 mg earlier limit), and the lotal daily dose for an adult to 2600 mg (in place of 4000 mg earlier).
Treatment Paracetamol poisoning
If the patient is brought early, vomiting should be induced or gastric lavage done. Activated charcoal is given orally or through the tube to prevent further absorption. Other supportive measures, as needed, should be taken. Specific antidote: N-acetylcysteine 150 mg/kg should be infused i. v. in 200 ml 5% glucose solution over 15 min, followed by the same dose given i. v. over the next 20 hours. Alternatively, 75 mg/kg may be given orally every 4- 6 hours for 2- 3 days. It replenishes the glutathione stores of Iiver and prevents binding of the toxic metabolite to other cellular constituents.
Ingestion-treatment interval is critical; earlier the better. It is practically ineffective if started 16 hours or more after paracetamol ingestion.
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