Paracetamol overdose

Paracetamol (acetaminophen) is a widely used analgesic and antipyretic drug that is relatively safe when taken at prescribed therapeutic doses. However, it has become increasingly common for overdoses of paracetamol to be taken for suicidal intent. In the United Kingdom, for example, around 200 deaths a year result from overdoses of paracetamol. This has prompted some to call for changes in its availability, with newspaper headlines such as "Doctors demand curbs on killer paracetamol" (Sunday Times, London, 14th November, 1993). When taken in overdoses, paracetamol causes primarily centrilobular hepatic necrosis, but this may also be accompanied by renal damage and failure. 

One study in 10 healthy subjects reported that diphenhydramine 250 mg taken with paracetamol 5 g (simulated paracetamol overdose) had little effect on the absorption of paracetamol. However, a case has been described where the diphenhydramine component of a paracetamol product Tylenol PM) taken in overdose (paracetamol 7.5 g and diphenhydramine 375 mg) delayed the absorption of paracetamol, so that the peak serum-paracetamol level did not occur until 8 hours after ingestion... 

Prescott, L.F. (1983). Paracetamol overdose. Pharmacologic considerations and clinical management Drugs 25, 290-314. 

Treatment of paracetamol overdose is based on replenishment of antioxidant thiols to supplement the role of glutathione the most commonly used antidote is N-acetyl cysteine, but is only effective if given within a particular time window after ingestion. 

Paracetamol overdose is most likely to cause hepatic necrosis and to a lesser extent renal necrosis. Hepatic necrosis is maximal within 3-4 hours of ingestion and may lead to encephalopathy, haemorrhage, hypoglycaemia, cerebral oedema and death. Acetylcysteine tends to protect the liver if given within 10-12 hours of paracetamol poisoning. The maximum adult dose of paracetamol is 4 g in 24 hours. 

Paracetamol Alcobol (cbronic) In overdose, bepatotoxicity may occur at lower doses... 

Activated charcoal may be given as first aid if the patient presents within an hour of ingestion. Antidotal treatment is almost universally effective if administered within 6 hours of overdose. The serum paracetamol concentration measured between 4 and 16 hours determines whether antidotal treatment with acetylcysteine is required, but if a significant overdose has been taken and no result is available by 6 hours after overdose, antidote should be... 

This may be induced in the main by viral infection and by drugs, typically paracetamol (acetaminophen) overdose but occasionally dose independently by antidepressants and antituberculous drugs amongst others (Table 5). 

Direct organ toxicity. Some substances may directly damage cells of a particular organ or system, either because they or their metabolites are specifically toxic to these cells, or because they are concentrated in one area, e.g. the renal fluoride ion toxicity of methoxyflurane, or the liver damage that occurs in paracetamol overdose because of a toxic intermediate product binding to hepatocytes. Secondary effects. Some effects are only indirectly related to the action of the drug, e.g. vitamin deficiency in patients whose gut flora have been modified by broad-spectrum antibiotics. 

In contrast to local irritants and corrosive acids and alkalis, other chemicals, such as the drug paracetamol (see chap. 7), cause systemic toxicity, damaging the liver, possibly irreversibly and with some delay after an oral overdose. Penicillin can also cause systemic toxicity as a result of an immune reaction, which may be immediate and serious, if it is anaphylaxis (see chap. 7). However, this effect, if not fatal, is reversible. 

The half-life will be independent of the dose, provided that the elimination is first order and therefore should remain constant. Changes in the half-life, therefore, may indicate alteration of elimination processes due to toxic effects because the half-life of a compound reflects the ability of the animal to metabolize and excrete that compound. When this ability is impaired, for example, by saturation of enzymic or active transport processes, or if the liver or kidneys are damaged, the half-life may be prolonged. For example, after overdoses of paracetamol, the plasma half-life increases severalfold as the liver damage reduces the metabolic capacity, and in some cases, kidney damage may reduce excretion (see chap. 7). 

Alcohol is an inducer of CYP2E1, which can lead to situations of enhanced drug toxicity in alcoholics or heavy drinkers (e.g., from paracetamol overdose). 

By measurement of the blood level of paracetamol in overdose cases, it is possible to estimate the likely outcome of the poisoning, and hence determine the type of treatment. Measurement of the blood level of paracetamol and its various metabolites at various times after the overdose showed that the half-life was increased several folds (Table 7.3), and the patients who sustained liver damage had an impaired ability to metabolize paracetamol to conjugates (Fig. 7.16). 

More recent immunohistochemical studies using antiparacetamol antibodies have shown that covalent binding of a paracetamol metabolite occurs in the damaged centrilobular regions of human liver after overdoses. 

It should also be mentioned that prostaglandin synthetase can activate paracetamol (Fig. 7.20) to reactive metabolites. Although probably not the primary route of activation in the liver, it has been suggested that this could be important in the kidney (which can also be damaged in paracetamol overdose). 

It now seems that an overdose of paracetamol causes a massive chemical stress, which causes an immediate adaptive defense response in the liver cell, which senses danger via redox-sensitive transcription factors. A number of mechanisms are involved, including the release, as a result of the stress, of a transcription factor Nrf-2 from its binding with Keap 1, a cytoplasmic inhibitor. Nrf-2 translocates to the nucleus and with other activators binds to an antioxidant-response element. This leads to transcription of a number of genes, so producing a... 

Although the investigation of the mechanism underlying paracetamol hepatotoxicity has been of intrinsic toxicological interest, there has also been a particularly significant benefit that has arisen from this work. This is the development of an antidote that is now successfully used for the treatment of paracetamol overdose. The antidote now most commonly used is N-acetylcysteine, although methionine is also used in some cases, as it can be given orally. There are various mechanisms by which N-a cetyl cysteine may act ... 

It may relieve the saturation of sulfate conjugation, which occurs during paracetamol overdose. 

Paracetamol is a widely used analgesic, which causes liver necrosis and sometimes renal failure after overdoses in many species. The half-life is increased after overdoses because of impaired conjugation of the drug. Toxicity is due to metabolic activation and is increased in patients or animals exposed to microsomal enzyme inducers. The reactive metabolite (NAPQI) reacts with GSH, but depletes it after an excessive dose and then binds to liver protein. Cellular target proteins for the reactive metabolite of paracetamol have been detected, some of which are enzymes that are inhibited. Therefore, a number of events occur during which ATP is depleted, Ca levels are deranged, and massive chemical stress switches on the stress response. 

Paracetamol causes skin rashes, blood dyscrasia, and liver damage and nephrotoxicity in overdose. Large doses of paracetamol cause nephritis and... 

Overdoses of paracetamol can be very dangerous, as the drug has a narrow therapeutic index and may cause hepatic and renal necrosis. Nausea, vomiting, lethargy, and sweating are the early overdose symptoms. Paracetamol must be given with caution in alcoholics and patients with liver and kidney damage. 

L.F. Prescott, Paracetamol overdose, in paracetamol (acetaminophen) A critical bibliographic review. London Taylor Francis, 401-473, 1996. 

Dextropropoxyphene Dextropropoxyphene, a drug of abuse, and any misuse or overdose of which causes intoxication if taken along with paracetamol or alcohol. The individual develops serious CNS depression leading to death.40-42 Adverse effects can be treated by gastric lavage and administration of activated charcoal and naloxone 43... 

Diflunisal Overdose (15 g) of diflunisal leads to poisoning, which could be fatal.51 Treatment can be given by gastric lavage and supportive care. Interactions of diflunisal with indomethacin, paracetamol, antacids, benzodiazepines, and probenecid have been reported.5 Concomitant use with indomethacin should be avoided, as this could cause fatal GI complications. 

Paracetamol is a popular and safe analgesic if used properly but an overdose is insidiously dangerous. The patient often seems to recover only to die later from liver failure. The problem is that paracetamol is metabolized into an oxidized compound that destroys glutathione. 

Acetylcysteine is given as a glutathione precursor in paracetamol overdose and in many other liver failures, including septic shock. 

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