Cyclooxygenase inhibitors, NSAID - Acetaminophen, paracetamol: COX-3 inhibitor
Acetaminophen or paracetamol is a para-aminophenol derivative. It is currently the most frequently used analgesic and antipyretic drug.
Acetaminophen does not have anti-inflammatory properties and does not cause gastric lesions. This characteristic is explained by the fact that acetaminophen preferentially inhibits COX-3 present in the central nervous system, where it penetrates readily.
In an adult, the usual dosage is 0.5 to 1g per intake, repeated if necessary three times per day. Its bioavailability by oral route is almost complete, its plasma half-life is approximately two hours. The usual plasma acetaminophen concentration during treatment ranges from 10 to 20 mg/L, when blood is sampled one hour after administration. It is metabolized primarily into glucuronide and sulphate conjugates. But in the event of poisoning, in absence of a sufficient store of endogenous glutathione which neutralizes it, acetaminophen is partly transformed into a very toxic metabolite, N-acetyl-p-benzoquinoneimine.
Acetaminophen is used for the treatment of pain and fever. A lot of preparations contain paracetamol as single ingredient or as multi-ingredient combination, with codeine for example.
The adverse effects of acetaminophen are rare and usually mild but in overdoses of voluntary or accidental origin, it elicits extremely severe poisonings, sometimes fatal in the absence of treatment. After an asymptomatic period, an irreversible hepatic necrosis appears about the third or fourth day after the beginning of the poisoning without being preceded by evocative clinical signs. Then, aggravation leads to an acute hepatic failure towards the fifth or sixth day. This necrosis is explained by the formation by hepatic microsomes of a toxic metabolite which is to a certain extent inactivated by endogenous glutathione and cystein. When they are exhausted, toxicity appears.
Drugs with HS group like N-acetylcysteine and to a lesser extent methionine, provided that they are given within the first eight hours after paracetamol ingestion, are effective antidotes. In the event of suspicion of poisoning by acetaminophen, the following steps must be taken:
- if the determination of acetaminophen is not immediately possible N-acetylcysteine should be administered;
- if the acetaminophen determination is possible, to take account of the plasma concentrations according to the supposed time of the poisoning. The following plasma concentrations are regarded as overdosage:
- 200 mg/L, 4 hours following acetaminophen intake
- 100 mg/L, 8 hours afterwards
- 50 mg/L, 12 hours afterwards.
As the hour of the poisoning is generally not known with precision, it is preferable to start treatment when the acetaminophen concentrations are definitely higher than those usually observed in therapeutics.
N-acetylcysteine is administered as an antidote either by oral route or by intravenous perfusion in large doses, 150 mg/kg at first, then 75 mg/kg every four hours during two to three days.
Apart from N-acetylcysteine, other compounds can reduce the toxicity of acetaminophen, it is the case of methionine which in certain formulations is combined on a purely preventive basis with acetaminophen.
Acetaminophen intake during pregnancy does not seem, according to current data, to increase the risk of malformations in the child.
Remarks
- Phenacetin is converted in the body into acetaminophen and other possibly more toxic metabolites. It is used less and less.
- The sustained use, in high doses, of acetaminophen or nonsteroidal antiinflammatory drugs,with the probable exception of aspirin, could increase the risk of renal impairment.
- Nefopam, a product known for more than thirty years, is a non-opioid central analgesic, non-anti-inflammatory and non-antipyretic, whose mechanism of action remains to be clarified. It has some antidepressant properties by inhibition of noradrenaline and serotonin reuptake. It has antimuscarinic effects.
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