The disposition and kinetics of intravenous N-acetylcysteine in patients with paracetamol overdosage

Abstract

Seventeen patients received standard treatment with intravenous N-acetylcysteine for 18 episodes of severe poisoning with paracetamol (acetaminophen). The dose of N-acetylcysteine was 150 mg/kg given in 15 min followed by 50 mg/kg in 4 h and 100 mg/kg over the next 16 h. Liver damage was absent or mild on 13 occasions (ALT greater than 500 mu/l) and severe on 5 (ALT less than 1000 mu/l). Total plasma N-acetylcysteine was estimated by HPLC. The mean maximum plasma concentration after the initial loading dose was 554 mg/l. Concentrations then fell rapidly and after 12 h a mean steady-state level of about 35 mg/l was maintained. When the infusion was discontinued N-acetylcysteine disappeared with a half-life of 5.7 h. The mean steady-state volume of distribution, AUC, mean residence time and total clearance were 536 ml/kg, 1748 mg.h.l-1, 2.91 h and 3.18 ml.min-1.kg-1. These values are generally consistent with those previously reported with much smaller doses and the disposition of N-acetylcysteine does not appear to be dose-dependent. The elimination of N-acetylcysteine was not impaired in the patients with severe liver damage, and the pharmacokinetic variables and plasma concentrations were similar in patients with and without hepatotoxicity. The dosage schedule for intravenous N-acetylcysteine should probably be modified since adverse reactions invariably occur early when plasma concentrations are at their highest, and liver damage was prevented just as effectively at the lowest as at the highest Cmax. High initial concentrations of N-acetylcysteine can be avoided with simple alternative regimens based on the kinetic data of this study.

Pharmacokinetics of N‐acetylcysteine are altered in patients with chronic liver disease

“…There is concern that if clearance of NAC were to be impaired in certain disease states that adverse effects (such as anaphylactoid reactions including systemic vasodilation and bronchospasm) might ensue as they tend to occur when plasma concentrations of the drug are at their highest. 9 Although NAC is widely used for the management of paracetamol-induced fulminant hepatic failure, the SUMMARY Background: The threshold plasma paracetamol concentration at which N-acetylcysteine (NAC) treatment is recommended to treat paracetamol poisoning in a patient with induced liver enzymes (for example, with chronic liver disease or taking anticonvulsant drugs) is 50% lower than in a patient without induced liver enzymes. More patients with chronic liver disease might therefore be expected to be exposed to NAC treatment than previously.…”

“…Subjects and methods: NAC was given intravenously in a dose of 600 mg over 3 min to nine patients with biopsyproven cirrhosis (Child's grade; 1 A, 4 B, 4 C; aetiology: effect of liver impairment on its clearance has only been evaluated in one study in which there was no evidence of altered pharmacokinetics in patients with early paracetamol poisoning. 9 In the present study, the pharmacokinetics of intravenous NAC was compared in patients with chronic liver disease and healthy control subjects; this has not previously been undertaken.…”

Benzylpenicillin, acetylcysteine and silibinin as antidotes in human hepatocytes intoxicated with α-amanitin

“…ACC concentrations corresponded to its plasma levels obtained after the recommended dosage during the treatment in paracetamol toxicity (Prescott et al, 1989). BPCN concentrations corresponded to its plasma levels obtained after the dosage recommended in the therapy of the toadstool death cap poisoning, i.e.…”

N-Acetylcysteine derivative inhibits procoagulant activity of human islet cells

“…The tubing loop model mimics more closely the in vivo situation, in which inhibitors of coagulation are expressed by the vessel walls, than procoagulant activity assessed in isolated plasma. In relation to the prospect of therapeutic application, 5 mmol/l of Nacystelyn is in the range of N-acetyl-L-cysteine concentrations measured after in vivo administration in patients with paracetamol intoxication [12]. Intravenous injection of N-acetyl-L-cysteine was usually well tolerated in both patients and healthy volunteers, although allergic reactions were observed occasionally [4].…”