l-5-oxo-pyrrolidine-2-paracetamol carboxylate reduces toxicity after administration of an overdose of paracetamol to mice. the liver glutathione values in mice induced by intraperitoneal injection of the ester are superimposable with the gsh levels recorded in untreated mice control group. the mice group treated with an equivalent dose of paracetamol showed a significative decrease of glutathione of 35% (p<0.01 vs untreated control group). the oral ld50 was found to be greater than 2000 mg kg-1, whereas the intraperitoneal ld50 was 1900 mg kg-1. these results taken together with the good hydrolysis and bioavailability data show that this ester is a potential candidate as a prodrug of paracetamol. treatment gastrointestinal decontamination in adults, the initial treatment for paracetamol overdose is gastrointestinal decontamination. paracetamol absorption from the gastrointestinal tract is complete within two hours under normal circumstances, so decontamination is most helpful if performed within this timeframe. gastric lavage, better known as stomach pumping, may be considered if the amount ingested is potentially life-threatening and the procedure can be performed within 60 minutes of ingestion. administration of activated charcoal is the most common gastrointestinal decontamination procedure as it efficiently adsorbs paracetamol, thereby reducing its gastrointestinal absorption. administering activated charcoal also poses less risk of aspiration than gastric lavage. it appears that the most benefit from activated charcoal is gained if it is given within 30 minutes to two hours of ingestion. administering activated charcoal later than 2 hours can be considered in patients that may have delayed gastric emptying due to co-ingested drugs or following ingestion of sustained- or delayed-release paracetamol preparations. activated charcoal should also be administered if co-ingested drugs warrant decontamination. there was reluctance to give activated charcoal in paracetamol overdose, because of the concern that it may also absorb the oral antidote acetylcysteine. studies have shown that 39% less acetylcysteine is absorbed into the body when they are administered together. there are conflicting recommendations regarding whether to change the dosing of oral acetylcysteine after the administration of activated charcoal, and even whether the dosing of acetylcysteine needs to be altered at all. intravenous acetylcysteine has no interaction with activated charcoal. inducing vomiting with syrup of ipecac has no role in paracetamol overdose because the vomiting it induces delays the effective administration of activated charcoal and oral acetylcysteine. liver injury is extremely rare after acute accidental ingestion in children under 6 years of age. children with accidental exposures do not require gastrointestinal decontamination with either gastric lavage, activated charcoal, or syrup of ipecac. acetylcysteine acetylcysteine is the antidote for paracetamol toxicity acetylcysteine, also called n-acetylcysteine or nac, works to reduce paracetamol toxicity by replenishing body stores of the antioxidant glutathione. glutathione reacts with the toxic napqi metabolite so that it does not damage cells and can be safely excreted. nac was usually given following a treatment nomogram (one for patients with risk factors, and one for those without) but the use of the nomogram is no longer recommended as the evidence base to support the use of risk factors was poor and inconsistent and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice. cysteamine and methionine have also been used to prevent hepatotoxicity, although studies show that both are associated with more adverse effects than acetylcysteine. additionally, acetylcysteine has been shown to be a more effective antidote, particularly in patients presenting greater than 8 hours post-ingestion and for those who present with liver failure symptoms. if the person presents less than eight hours after paracetamol overdose, then acetylcysteine significantly reduces the risk of serious hepatotoxicity and guarantees survival. if acetylcysteine is started more than 8 hours after ingestion, there is a sharp decline in its effectiveness because the cascade of toxic events in the liver has already begun, and the risk of acute liver necrosis and death increases dramatically. although acetylcysteine is most effective if given early, it still has beneficial effects if given as late as 48 hours after ingestion. if the person presents more than eight hours after the paracetamol overdose, then activated charcoal is not useful, and acetylcysteine is started immediately. in earlier presentations, charcoal can be given when the patient arrives and acetylcysteine is initiated while waiting for the paracetamol level results to return from the laboratory. in united states practice, intravenous (iv) and oral administration are considered to be equally effective and safe if given within 8 hours of ingestion. however, iv is the only recommended route in australasian and british practice. oral acetylcysteine is given as a 140 mg/kg loading dose followed by 70 mg/kg every four hours for 17 more doses, and if the patient vomits within 1 hour of dose, the dose must be repeated. oral acetylcysteine may be poorly tolerated due to its unpleasant taste, odor, and its tendency to cause nausea and vomiting. if repeated doses of charcoal are indicated because of another ingested drug, then subsequent doses of charcoal and acetylcysteine should be staggered. intravenous acetylcysteine is given as a continuous infusion over 20 hours for a total dose 300 mg/kg. recommended administration involves infusion of a 150 mg/kg loading dose over 15 to 60 minutes, followed by a 50 mg/kg infusion over four hours; the last 100 mg/kg are infused over the remaining 16 hours of the protocol. intravenous acetylcysteine has the advantage of shortening hospital stay, increasing both doctor and patient convenience, and allowing administration of activated charcoal to reduce absorption of both the paracetamol and any co-ingested drugs without concerns about interference with oral acetylcysteine. intravenous dosing varies with weight, specifically in children. for patients less than 20 kg, the loading dose is 150 mg/kg in 3 ml/kg diluent, administered over 60 minutes; the second dose is 50 mg/kg in 7 ml/kg diluent over 4 hours; and the third and final dose is 100 mg/kg in 14 ml/kg diluent over 16 hours. the most common adverse effect to acetylcysteine treatment is an anaphylactoid reaction, usually manifested by rash, wheeze, or mild hypotension. adverse reactions are more common in people treated with iv acetylcysteine, occurring in up to 20% of patients. anaphylactoid reactions are more likely to occur with the first infusion (the loading dose). rarely, severe life-threatening reactions may occur in predisposed individuals, such as patients with asthma or atopic dermatitis, and may be characterized by respiratory distress, facial swelling, and even death. if an anaphylactoid reaction occurs the acetylcysteine is temporarily halted or slowed and antihistamines and other supportive care is administered. for example, a nebulised beta-agonist like salbutamol may be indicated in the event of significant bronchospasm (or prophylactically in patients with a history of bronchospasm secondary to acetylcysteine). it is also important to closely monitor fluids and electrolytes. liver transplant in people who develop acute liver failure or who are otherwise expected to die from liver failure, the mainstay of management is liver transplantation. liver transplants are performed in specialist centers. the most commonly used criteria for liver transplant were developed by physicians at king's college hospital in london. patients are recommended for transplant if they have an arterial blood ph less than 7.3 after fluid resuscitation or if a patient has grade iii or iv encephalopathy, a prothrombin time greater than 100 seconds, and a serum creatinine greater than 300 mmol/l in a 24-hour period. other forms of liver support have been used including partial liver transplants. these techniques have the advantage of supporting the patient while their own liver regenerates. once liver function returns immunosuppressive drugs are commenced and they have to take immunosuppressive medication for the rest of their lives. prognosis the mortality rate from paracetamol overdose increases two days after the ingestion, reaches a maximum on day four, and then gradually decreases. acidosis is the most important single indicator of probable mortality and the need for transplantation. a mortality rate of 95% without transplant was reported in patients who had a documented ph less than 7.30. other indicators of poor prognosis include chronic kidney disease (stage 3 or worse), hepatic encephalopathy, a markedly elevated prothrombin time, or an elevated blood lactic acid level (lactic acidosis). one study has shown that a factor v level less than 10% of normal indicated a poor prognosis (91% mortality), whereas a ratio of factor viii to factor v of less than 30 indicated a good prognosis (100% survival). patients with a poor prognosis are usually identified for likely liver transplantation. patients that do not die are expected to fully recover and have a normal life expectancy and quality of life. epidemiology