Hepatic injury and subsequent hepatic failure due to both intentional and non-intentional overdose of acetaminophen (APAP) has affected patients for decades, and involves the cornerstone metabolic pathways which take place in the microsomes within hepatocytes. APAP hepatotoxicity remains a global issue; in the United States, in particular, it accounts for more than 50% of overdose-related acute liver failure and approximately 20% of the liver transplant cases. The pathophysiology, disease course and management of acute liver failure secondary to APAP toxicity remain to be precisely elucidated, and adverse patient outcomes with increased morbidity and mortality continue to occur. Although APAP hepatotoxicity follows a predictable timeline of hepatic failure, its clinical presentation might vary. N-acetylcysteine (NAC) therapy is considered as the mainstay therapy, but liver transplantation might represent a life-saving procedure for selected patients. Future research focus in this field may benefit from shifting towards obtaining antidotal knowledge at the molecular level, with focus on the underlying molecular signaling pathways.

/pdf/acetaminophen-induced-hepatotoxicity-a-comprehensive-update-s9umgtdshu.pdf

Acetaminophen-Induced Hepatotoxicity: a Comprehensive Update.

Glutathione metabolism and its role in hepatotoxicity.

In therapeutic doses paracetamol is a safe analgesic, but in overdosage it can cause severe hepatic necrosis. Following oral administration it is rapidly absorbed from the gastrointestinal tract, its systemic bioavailability being dose-dependent and ranging from 70 to 90%. Its rate of oral absorption is predominantly dependent on the rate of gastric emptying, being delayed by food, propantheline, pethidine and diamorphine and enhanced by metoclopramide. Paracetamol is also well absorbed from the rectum. It distributes rapidly and evenly throughout most tissues and fluids and has a volume of distribution of approximately 0.9L/kg. 10 to 20% of the drug is bound to red blood cells. Paracetamol is extensively metabolised (predominantly in the liver), the major metabolites being the sulphate and glucuronide conjugates. A minor fraction of drug is converted to a highly reactive alkylating metabolite which is inactivated with reduced glutathione and excreted in the urine as cysteine and mercapturic acid conjugates. Large doses of paracetamol (overdoses) cause acute hepatic necrosis as a result of depletion of glutathione and of binding of the excess reactive metabolite to vital cell constituents. This damage can be prevented by the early administration of sulfhydryl compounds such as methionine and N-acetylcysteine. In healthy subjects 85 to 95% of a therapeutic dose is excreted in the urine within 24 hours with about 4, 55, 30, 4 and 4% appearing as unchanged paracetamol and its glucuronide, sulphate, mercapturic acid and cysteine conjugates, respectively. The plasma half-life in such subjects ranges from 1.9 to 2.5 hours and the total body clearance from 4.5 to 5.5ml/kg/min. Age has little effect on the plasma half-life, which is shortened in patients taking anticonvulsants. The plasma half-life is usually normal in patients with mild chronic liver disease, but is prolonged in those with decompensated liver disease.

Clinical Pharmacokinetics of Paracetamol

Treatment of paracetamol (acetaminophen) poisoning with N-acetylcysteine.

SummaryParacetamol (acetaminophen), normally a very safe drug, may produce acute centrilobular hepatic necrosis when taken in overdosage. There are no specific early symptoms or signs of paracetamol poisoning and consciousness is not impaired. Plasma aminotransferase (AST or ALT) activity may increase dramatically to 10,000 iu/L or more with prolongation of the prothrombin time ratio and mild jaundice. Acute renal failure is an uncommon complication. Maximum abnormalities of liver function are delayed for at least 3 days, and initially the prognosis can only be determined by estimation of the plasma paracetamol concentration in relation to the time after ingestion. Severe liver damage (plasma aminotransferase activity > 1000 iu/L) occurs in about 60% of patients with paracetamol concentrations above a ‘treatment line’ joining semilogarithmic plots of 200 µg/ml at 4 hours and 30 µg/ml at 15 hours after ingestion. Although recovery of liver function is usually rapid and complete, fulminant hepatic failure develops 3 to 6 days after ingestion in a small minority of severely poisoned patients and is often fatal. Contrary to popular belief, only about 15% of unselected patients taking paracetamol in overdosage are severely poisoned with plasma concentrations above the ‘treatment line’. Without specific therapy, severe liver damage only occurs in about 8%, fatal hepatic failure in 1 to 2%, and renal failure in about 1%.Paracetamol damages the liver through the formation of a highly reactive metabolite which is normally trapped and inactivated by preferential conjugation with hepatic glutathione. Following an hepatotoxic dose, glutathione is depleted and the toxic metabolite binds covalently to vital proteins and enzymes causing cell damage and necrosis. Toxicity depends on the balance between the rate of formation of the reactive metabolite of paracetamol and the rate of glutathione synthesis. Glutathione precursors and other sulfhydryl compounds prevent glutathione depletion, covalent binding and liver damage, probably by facilitation of glutathione conjugation.Cysteamine, methionine and N-acetylcysteine prevent liver damage, renal failure and death following paracetamol overdosage if given within 8 to 10 hours; treatment after 15 hours is of no benefit. Cysteamine has long been abandoned because of its toxicity. N-Acetylcysteine or methionine therapy is indicated in patients with plasma paracetamol concentrat ions above the ‘treatment line’. Intravenous N-acetylcysteine appears more effective than methionine and is currently the treatment of choice. Oral therapy is unreliable and cannot be recommended.

Paracetamol overdosage. Pharmacological considerations and clinical management

Oral methionine in the treatment of severe paracetamol (acetaminophen) overdose

Effect of activated charcoal on absorption of nortriptyline

plexes suggests their responsibility in the recurrence of pulmonary haemorrhage. The origin and nature of these immune complexes remain unknown. They may be composed of basal membrane antigens and the corresponding antibodies or they may result from an intercurrent immunological attack of some sort. Our findings emphasise the importance of assaying for immune complexes in patients with Goodpasture's syndrome who suffer recurrences of pulmonary haemorrhages.

https://www.bmj.com/content/bmj/280/6224/1167.1.full.pdf

Haemoperfusion for theophylline overdose.

Activated charcoal is known to reduce the absorption of therapeutic doses of nortriptyline in vivo when administered 30 min after drug ingestion. In a group of volunteers, one sachet (10 g) of a new activated charcoal preparation, ‘Medicoal’ was found to produce a highly significant reduction in nortriptyline absorption when given as long as four hours after nortriptyline dosing. Activated charchoal may therefore be useful in the treatment of tricyclic antide-pressant poisoning even if a delay of several hours ensues before medical help is sought.

Effect of delayed administration of activated charcoal on nortriptyline absorption

The treatment of paraquat poisoning using oral sorbents and charcoal haemoperfusion.

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