title: Novel acetylcysteine regimens for treatment of paracetamol overdose.
abstract: Paracetamol (acetaminophen) overdose remains the leading cause of death or transplantation due to acute liver failure in many parts of the world. Acetylcysteine has long been recognized as an effective antidote, via oral or intravenous administration, minimizing the risk and severity of acute liver injury if administered sufficiently early after a paracetamol overdose. Despite this, its mechanisms of action remain obscure, and there is uncertainty regarding the optimal dose and duration of treatment. The intravenous infusion protocol was originally developed as a three-step loading regimen; it causes very high early peak plasma concentrations of acetylcysteine whereas the later maintenance infusion is associated with much lower concentrations. This pharmacokinetic profile is associated with two particular concerns: a high rate of occurrence of adverse effects that occur after the initial loading infusion, and the possibility that the maintenance phase of treatment might deliver too low a dose of acetylcysteine for optimum protection against liver injury. Recently described novel administration regimens offer different rates of intravenous acetylcysteine administration in both the loading and maintenance phases. These alternative regimens appear to be well tolerated in small patient groups, but too few clinical data are available to evaluate their comparative efficacy in preventing paracetamol-induced liver injury.
authors.affiliation: Acute Medical Unit, York Teaching Hospital NHS Foundation Trust, Wigginton Road, York YO31 8HE, UK.
authors.forename: W Stephen
authors.initials: WS
authors.lastname: Waring
keywords: acute liver toxicity; overdose; paracetamol
references.citation: J Toxicol Sci. 2008 Dec;33(5):549-53
references.pmid: 19043276
references.citation: J Biomed Sci. 2010 Aug 24;17 Suppl 1:S35
references.pmid: 20804611
references.citation: Clin Toxicol (Phila). 2008 Jul;46(6):496-500
references.pmid: 18584360
references.citation: J Nutr. 2006 Jun;136(6 Suppl):1652S-1659S
references.pmid: 16702335
references.citation: Clin Sci. 1966 Oct;31(2):207-14
references.pmid: 5955722
references.citation: Crit Care. 2009;13(2):R55
references.pmid: 19358737
references.citation: Can J Gastroenterol. 2002 Oct;16(10):672-6
references.pmid: 12420024
references.citation: Emerg Med Australas. 2011 Feb;23(1):63-7
references.pmid: 21284815
references.citation: Lancet. 1976 Oct 2;2(7988):738-9
references.pmid: 61415
references.citation: Arch Toxicol. 1984 Mar;55(1):11-5
references.pmid: 6732501
references.citation: Pediatrics. 2012 Feb;129(2):349-53
references.pmid: 22271694
references.citation: Int J Emerg Med. 2011 Aug 30;4(1):54
references.pmid: 21878099
references.citation: Ann Emerg Med. 2005 Apr;45(4):402-8
references.pmid: 15795719
references.citation: Ann Emerg Med. 2009 Oct;54(4):606-14
references.pmid: 19556028
references.citation: Clin Ther. 2011 Sep;33(9):1322-30
references.pmid: 21890206
references.citation: Drug Saf. 2012 Feb 1;35(2):149-57
references.pmid: 22149359
references.citation: J Pharmacol Exp Ther. 1973 Oct;187(1):203-10
references.pmid: 4147720
references.citation: Pharmacoepidemiol Drug Saf. 2010 Oct;19(10):1064-70
references.pmid: 20712021
references.citation: Med J Aust. 2008 Mar 3;188(5):296-301
references.pmid: 18312195
references.citation: Br J Clin Pharmacol. 2001 Jan;51(1):87-91
references.pmid: 11167669
references.citation: Lancet. 1974 Apr 6;1(7858):588-92
references.pmid: 4132259
references.citation: Drug Metab Dispos. 2009 Aug;37(8):1779-84
references.pmid: 19439490
references.citation: Br Med J. 1979 Nov 3;2(6198):1097-100
references.pmid: 519312
references.citation: J Hepatol. 2009 Feb;50(2):306-13
references.pmid: 19070386
references.citation: Clin Toxicol (Phila). 2010 Feb;48(2):111-4
references.pmid: 20136478
references.citation: J Gastroenterol Hepatol. 1999 Aug;14(8):817-21
references.pmid: 10482436
references.citation: Eur J Clin Pharmacol. 1989;37(5):501-6
references.pmid: 2598989
references.citation: Lancet. 1990 Jun 30;335(8705):1572-3
references.pmid: 1972496
references.citation: Hepatology. 2005 Dec;42(6):1364-72
references.pmid: 16317692
references.citation: Clin Evid. 2005 Dec;(14):1738-44
references.pmid: 16620471
references.citation: Br Med J. 1966 Aug 27;2(5512):497-9
references.pmid: 5913083
references.citation: Clin Toxicol (Phila). 2011 Jun;49(5):423-5
references.pmid: 21740141
references.citation: Acad Emerg Med. 2008 Jan;15(1):54-8
references.pmid: 18211314
references.citation: BMJ. 1991 Oct 26;303(6809):1026-9
references.pmid: 1954453
references.citation: Ann Pharmacother. 2011 Jun;45(6):713-20
references.pmid: 21586653
references.citation: Med J Aust. 2005 Nov 21;183(10):535-6
references.pmid: 16296969
references.citation: Lancet. 1977 Aug 27;2(8035):432-4
references.pmid: 70646
references.citation: Lancet. 1976 Jul 17;2(7977):109-13
references.pmid: 59181
references.citation: J Toxicol Clin Toxicol. 1998;36(4):277-85
references.pmid: 9711192
references.citation: Liver Transpl. 2002 Nov;8(11):1055-62
references.pmid: 12424720
references.citation: Health Bull (Edinb). 1978 Jul;36(4):204-12
references.pmid: 669953
references.citation: Clin Toxicol (Phila). 2011 Oct;49(8):755-9
references.pmid: 21970774
references.citation: Clin Toxicol (Phila). 2010 Jun;48(5):424-30
references.pmid: 20524832
references.citation: Clin Pharmacokinet. 1991 Feb;20(2):123-34
references.pmid: 2029805
references.citation: Arch Intern Med. 1981 Feb 23;141(3 Spec No):380-5
references.pmid: 7469629
references.citation: Biochem Pharmacol. 1980 Jul 1;29(13):1968-70
references.pmid: 7397003
references.citation: Ann Emerg Med. 2007 Sep;50(3):272-9
references.pmid: 17210206
references.citation: Adv Exp Med Biol. 1986;197:993-1003
references.pmid: 3766306
references.citation: J Pharmacol Exp Ther. 1973 Oct;187(1):211-7
references.pmid: 4746329
references.citation: Clin Toxicol (Phila). 2011 Aug;49(7):643-7
references.pmid: 21854081
references.citation: Lancet. 1974 May 18;1(7864):998
references.pmid: 4133694
references.citation: Expert Rev Clin Pharmacol. 2012 May;5(3):311-8
references.pmid: 22697593
references.citation: Pediatrics. 1978 Nov;62(5 Pt 2 Suppl):880-9
references.pmid: 724340
references.citation: Emerg Med J. 2008 Mar;25(3):140-3
references.pmid: 18299359
references.citation: Toxicol Appl Pharmacol. 1981 Sep 15;60(2):220-8
references.pmid: 7281185
references.citation: Expert Opin Drug Metab Toxicol. 2012 Feb;8(2):219-37
references.pmid: 22248238
references.citation: J Pharmacol Exp Ther. 1973 Oct;187(1):195-202
references.pmid: 4746327
references.citation: Clin Pharmacol Ther. 1974 Oct;16(4):676-84
references.pmid: 4417718
references.citation: Biochem Pharmacol. 1981 Oct 1;30(19):2723-5
references.pmid: 7295356
references.citation: Clin Toxicol (Phila). 2008 Sep;46(8):697-702
references.pmid: 18803085
references.citation: Crit Care Med. 1998 Jan;26(1):40-3
references.pmid: 9428541
references.citation: Lancet. 2002 Oct 12;360(9340):1151-2
references.pmid: 12387966
references.citation: Pharmacology. 1974;12(3):129-43
references.pmid: 4445191
references.citation: N Engl J Med. 2008 Jul 17;359(3):285-92
references.pmid: 18635433