Paracetamol Hepatotoxicity
Paracetamol was introduced a half century ago, considered a safe and effective analgesic. However, since the first report of hepatotoxicity in 1966, has accumulated considerable knowledge about its pathogenesis and treatment. At present, the toxicity is a significant cause of poisoning mortality in many countries. The prognosis depends significantly from its early recognition and initiation of specific therapeutic measures early.
Pharmacokinetics
The therapeutic dose of paracetamol is 10 to 15 mg / kg in children and 250 to 1000 mg in adults, with the maximum recommended dose 80 mg / kg in children and adults 4 g per day. The minimum toxic dose is 150 mg/kg to 10 g for children and adults, but this dose may vary depending on the basal levels of glutathione and other factors. Paracetamol is rapidly absorbed, reaching maximum plasma concentrations within 2 hours of ingestion. The therapeutic plasma concentration is 10 to 20 mg/mL. The half-life of paracetamol is 2 to 4 hours.
Pathogenesis of toxicity
In normal conditions, the paracetamol is glucuronidated and sulfated in the liver by 90% and then eliminated in the urine. 10% remaining half is excreted directly by the kidneys and the other half is metabolized by cytochrome P450. The subfamilies CYP2E1, 1A1 and 3A4 of the cytochrome converted to paracetamol in N-acetyl-p-benzoquinonemina (NAPQI), a highly reactive intermediate metabolite electrophilic. This compound is able to bind covalently to macromolecules of hepatocytes, resulting in oxidative stress and hepatocellular necrosis.
NAPQI is rapidly conjugated with glutathione to form cysteine ??and mercaptan, which are not toxic. When there is an overdose of paracetamol, the other tracks are saturated and a higher proportion of drug to the cytochrome. When stocks deplete glutathione by 70%, NAPQI begins to accumulate causing hepatocellular damage.
From the foregoing we the factors that may influence the toxicity of paracetamol:
- Induction of cytochrome P450 may be other drugs or chronic alcohol consumption. Interestingly, acute alcohol intake may even be protective against damage by paracetamol, as it competes in its metabolism by CYP2E1, decreasing production of NAPQI.
- Glutathione depletion: Periods of fasting and malnutrition, conditions common in alcoholism, can lead to depletion of glutathione and increased risk of paracetamol toxicity (4).
- Genetic factors: The polymorphisms in the different cytochromes may explain differences in susceptibility to poisoning. It has also been reported that decreased glucuronidation in Gilbert’s syndrome increases the toxicity of paracetamol.
Clinical Manifestations
Although the early manifestations of acetaminophen toxicity are mild and nonspecific (and not predict the severity of hepatotoxicity), are important to recognize early.
Stage I (first 24 h): There may be nausea, vomiting, lethargy, although it may be completely asymptomatic.
Stage II (24 to 72 h): Begin the evidence of hepatotoxicity in laboratory tests, while the initial symptoms can be changed by right hipocondro pain with hepatomegaly. Oliguria may occur concomitantly and pancreatitis.
Stage III (72 to 96 hours): Reached the maximum elevation of transaminases, sometimes leading to exceed 10,000 IU/mL. Clinically there may be jaundice, encephalopathy and coagulopathy. 25 to 50% of those affected have concomitant renal failure acute tubular necrosis.
Stage IV (4 days to 2 weeks): Patients who survive the previous stage enter a recovery phase whose duration depends on the severity of the initial commitment. Histological changes occur predominantly in the zone III (centrilobular), which has the highest concentration of CYP2E1. There are no reported cases of chronic liver damage by paracetamol.
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