o grady_paracetamol induced acute liver failure prevention and management

Jourmd of Hepatology 1997; 26 (Suppl. I): 41-46 Prhlted ht Demnark • All rights reserved Mtmksgaard. Copenhagen Copyright © European Association for the Study of the Liter 1997 Journal of Hepatology ISS N 0 1 6 9 -5 1 8 5 ISBN 87-16-15656-0 Paracetamol-induced acute liver failure: prevention and management John G. O'Grady hsstitute of Liver Studies. King ~" College Hospital. London. UK p ARACETAMOLis one of the most widely used anal- gesics. Approximately 30 million packs containing paracetamol are sold annually in the UK (l). The popu- larity of paracetamol has been based on its reputation for low toxicity particularly when compared with its main alternative, aspirin. The latter has been associated with the development of Reye's syndrome in children and gastric irritation in adults. The toxicity profile of paracetamol has largely been identified in association with overdosages, although recently attention has been focused on enhanced toxicity in patients subject to enzyme induction, e.g. epileptics and chronic alcohol con- sumers (2-5). The hepatotoxicity is not directly due to paracetam ol, but is caused by an unstable metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which is in- activated by glutathione (6). NAPQ I accumulates when glutathione is depleted, leading to lipid peroxidation and cell damage and N-acetylcysteine and methionine act as substrates for the repletion of glutathione stores (6). Additional mechanisms that have been proposed for the hepatotoxicity implicate neutrophiis or macro- phages and these may be abrogated by the anti-oxidant effect of N-acetylcysteine (3,7). Estimates of the number of paracetamol overdoses in the UK range up to 70000 per year (1). The esti- mated number of deaths following paracetamol overdose range between 150 and 500 per year in the UK, with no evidence that this number is decreasing (8,9). A similar number of patients survive after prolonged and expensive hospitalisation or even after salvage by liver transplantation. Prevention strategies The dose-dependent nature of the hepatotoxicity of paracetamol, and the parasuicidal rather than suicidal intent in the majority of cases, suggest that a consider- Correspondence: Dr John G. O'Grady, MD, Institute of Liver Studies, King's College Hospital, Denmark Hill, London SE5 9PJ, U K. Tel: 0171-346 3255. Fax: 0171-346 3 ! 67. e-mail: [email protected]. able proportion could be prevented. The marketing of paracetamol in the UK as an inexpensive preparation of up to 50 g in a bottle m eans that it is widely avail- able when parasuicidal gestures are contemplated. The UK government is currently consulting on a proposal to restrict the sale of paracetamol to quantities of 6 g in general outlets and 15 g in pharmacies (1). An analysis of 560 patients with severe paracetamol hepatotoxicity showed that only 8% had taken less than 12 g and of these only 27% died or required liver transplantation (8). The addition of methionine, an alternative antidote to N-acetylcysteine, to paracetamol tab- lets is an alternative mechanism to reduce the toxicity of paracetamol in an overdose situation. Hepatotoxicity of paracetamol taken with therapeutic intent may result from excessive dosing through lack of realization of the maximal recommended dose (despite explicit labelling) or lack of awareness of the presence of paracetamol in a considerable number of multiple drug combinations. Chronic alcohol con- sumers and patients with enzyme induction secondary to antiepileptic therapy are also at risk of hepatotoxicity from paracetamol taken with therapeutic intent (2- 5). In one series of 67 patients with liver damage attri- buted to therapeutic usage, 64% were considered to be alcohol abusers (4). Educational initiatives to promote awareness of these issues are necessary if the explicit advice on drug packaging and infor~nation sheets is to be effective. Management of overdose N-Acetylcysteine is an effective antidote to paracetamol toxicity when given up to 24 h after the overdose (10). The decision to give N-acetylcysteine is deter- mined by the blood concentration of paracetamol cor- rected for the interval after the overdose. N-Acetylcys- teine is recommended when the level is above a line that joins 1.32 mmol/1 (200 mg/l) at 4 h and 0.19 mmol/ l (30 rag/l) at 15 h (8). This treatment chart has recently been modified to reflect the lower threshold for treating patients prone to enzyme induction (chronic alcohol 41

o grady_paracetamol induced acute liver failure prevention and management

Documents