Acetaminophen overdose, biomarkers, and management

Abstract

Acetaminophen is manufactured in huge quantities worldwide. Approximately 3.2 thousand million tablets of acetaminophen are consumed by the public every year in the UK (mean of 55 tablets/person). Acetaminophen poisoning accounts for up to 48% of all poisons admissions to hospital. It is a weak inhibitor of COX-1 and COX-2 in peripheral tissues and possesses no significant anti-inflamatory effects. The oral dose of acetaminophen is 0.5-1g per 4-6 h to a maximum of 4 g in a day. Approximately 95% of acetaminophen is metabolised to glucuronide and sulphate conjugates which are excreted in the urine. About 5% of acetaminophen is metabolised through the cytochrome P-450 2E1 to produce a highly reactive toxic metabolite, N-acetyl-p-benzoquinonimine (NAPQI). At therapeutic doses, the small amounts of NAPQI produced by acetaminophen metabolism are detoxified by liver stores of hepatic glutathione and is excreted in bile or urine as mercapturic acid conjugate. In overdose, stores of glutathione become depleted. Without the glutathione substrate, NAPQI becomes available to bind to proteins and DNA of hepatocytes causing direct cellular injury. Generation of reactive oxygen species and nitric oxide, lipid peroxidation, mitochondrial dysfunction, disruption of calcium homeostasis and induction of apoptosis are all mechanisms have suggested that may be involved in acetaminophen-induced hepatotoxicity. Severe liver damage has been defined as an increase in plasma activities of aspartate aminotransferase (AST), alanine aminotransferase (ALT), sorbitol dehydrogenase (SDH), ornithine carbamyltransferase (OCT), lactic dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), glutathione S-transferases, and F-protein. Increase in prothrombin time, plasma concentrations of creatinine, biliverdin, bilirubin, and phosphate, and reduction in blood pH, bicarbonate, and glucose have also been demonstrated as biomarkers of acetaminophen overdose. We recently showed an increase in plasma concentration of taurine as a probable biomarker of acetaminophen poisoning. Different antidotes such as: cimetidine, cysteamine, methionine, and glycyrrhizin have already used for the treatment of acetaminophen overdose. However, N-acetylcysteine (NAC) is a clinically approved drug which is used with three treatment regimens: a 20-hour continuous infusion of NAC, a 48-hour regimen of intermittent intravenous infusions and a 72-hour regimen of intermittent oral doses. NAC should be given if the plasma acetaminophen concentration is above a line joining 200mg/L (1.32mmol/L) at four hours after ingestion and 30mg/L (0.20mmol/L) at 15 hours on a semilogarithmic plot. Few adverse reactions have been reported in 5% of patients who receive NAC particularly in intravenous forms. The most of these reactions are anaphylactoid such as flushing, pruritus, urticaria, angioedema, cough, headache, shortness of breath, wheezing, hypotension, status epilepticus, and cortical blindness. é 2012 Nova Science Publishers, Inc. All rights reserved.