first studied the pharmacokinetics of intravenous NAC and it is acknowledged that NAC-related adverse events appear to be driven by plasma concentration and infusion duration.
However, one recent study demonstrated that an RCT could be achieved successfully in the patient group to investigate the safer utility of NAC. Adverse effects from NAC include rash, urticaria, vomiting, and anaphylactoid reactions, which can in rare cases be fatal. Many questions still remain regarding the use of NAC and we still do not know what the optimal dose, route, and duration of treatment should be. We have recently reviewed the effectiveness and safety of these options, but ultimately NAC remains the frontline and cornerstone. Additional therapies such as activated charcoal (single or multiple dose), gastric lavage, hemodialysis, methionine, and liver transplantation add a controversial amount of benefit to the armory to treat paracetamol poisoning. This is partly as a result of a challenging patient population and the heterogeneous nature of hospital presentation. Given the high incidence of paracetamol overdose, it is surprising that very few changes have been made in over 40 years to its clinical management and very few studies looking at optimizing NAC use exist, let alone randomized controlled trials (RCTs).
A comprehensive understanding of the molecular initiating events leading to paracetamol hepatotoxicity from the seminal work of Mitchell and Brodie enabled opportunities to treat patients and has ultimately led to the development of an antidote, acetylcysteine (NAC). These mechanisms ultimately lead to hepatocyte death, sterile inflammation, multiorgan failure, and patient death. Cytochrome P450 (CYP2E1, 1A2, and 2D6) mediated reactive metabolite formation ( N-acetyl- p-benzoquinone imine) hepatic glutathione depletion and covalent adduction of cellular proteins are prerequisites for toxicity.
Paracetamol hepatotoxicity has been widely studied by basic and clinical pharmacologists it is reproducible in animal models and the biochemical basis is well defined. However, reports exist demonstrating that transient, clinically insignificant, increases in alanine aminotransferase can occur in 25–40% of healthy volunteers after ingesting therapeutic doses for 1–2 weeks. Decades of clinical experience suggest that acute liver injury is unlikely at therapeutic doses. It accounts for roughly 38,000 hospital admissions annually in England alone that directly leads to between 150 and 250 deaths per year. Paracetamol overdose remains a major medical problem and one of the major reasons for acute liver failure in the Western world.
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