IPCS/CEC EVALUATION OF ANTIDOTES SERIES
VOLUME 3
ANTIDOTES FOR POISONING BY PARACETAMOL
First drafts of the chapters, subsequently reviewed and revised
by the Working Group, were prepared by:
Dr. L. F. Prescott, Clinical Pharmacology Unit, Royal Infirmary,
Edinburgh, United Kingdom (Overview)
Dr. D. G. Spoerke and Dr. B. H. Rumack, Micromedex Inc., Denver,
Colorado, USA (N-acetylcysteine)
Dr. T. J. Meredith, UK Department of Health, London, United
Kingdom, and Ms J. Tempowski, National Poisons Information
Service (London Centre), London, United Kingdom (Methionine)
IPCS/CEC Evaluation of Antidotes Series
IPCS International Programme on Chemical Safety
CEC Commission of the European Communities
Volume 1 Naloxone, flumazenil and dantrolene as antidotes
Volume 2 Antidotes for poisoning by cyanide
Volume 3 Antidotes for poisoning by paracetamol
This important new series will provide definitive and authoritative
guidance on the use of antidotes to treat poisoning. The
International Programme on Chemical Safety (IPCS) and the Commission
of the European Communities (CEC) (ILO/UNEP/WHO) have jointly
undertaken a major programme to evaluate antidotes used clinically
in the treatment of poisoning. The aim of this programme has been
to identify and evaluate for the first time in a scientific and
rigorous way the efficacy and use of a wide range of antidotes.
This series will therefore summarise and assess, on an antidote by
antidote basis, their clinical use, mode of action and efficacy. The
aim has been to provide an authoritative consensus statement which
will greatly assist in the selection and administration of an
appropriate antidote. This scientific assessment is complemented by
detailed clinical information on routes of administration,
contraindications, precautions and so on. The series will therefore
collate a wealth of useful information which will be of immense
practical use to clinical toxicologists and all those involved in the
treatment and management of poisoining.
Scientific Editors
T.J. MEREDITH
Department of Health, London, United Kingdom
D. JACOBSEN
Ulleval University Hospital, Oslo, Norway
J.A. HAINES
International Programme on Chemical Safety,
World Health Organization, Geneva, Switzerland
J-C. BERGER
Health and Safety Directorate,
Commission of the European Communities, Luxembourg
EUR 15693 EN
Published by Cambridge University Press on behalf of the World Health
Organization and of the Commission of the European Communities
CAMBRIDGE UNIVERSITY PRESS
The mention of specific companies or of certain manufacturers'
products does not imply that they are endorsed or recommended by the
World Health Organization in preference to others of a similar
nature that are not mentioned.
Neither the Commission of the European Communities nor any person
acting on behalf of the Commission is responsible for the use which
might be made of the information contained in this report.
(c) World Health Organization, Geneva, 1995 and
ECSC-EEC-EAEC, Brussels-Luxembourg, 1995
First published 1995
Publication No. EUR 15693 EN of the Commission of the European
Communities, Dissemination of Scientific and Technical Knowledge
Unit, Directorate-General Information Technologies and Industries,
and Telecommunications, Luxembourg
ISBN 0 521 49576 8 hardback
CONTENTS
PREFACE
ABBREVIATIONS
1. OVERVIEW OF ANTIDOTAL THERAPY FOR
ACUTE PARACETAMOL POISONING
1.1. Introduction and historical review
1.2. Toxicity in man
1.3. Assessment of the severity of intoxication
1.4. Mechanisms of toxicity and antidotal activity
1.5. Factors influencing the toxicity of paracetamol
1.5.1. Factors that may increase paracetamol toxicity
1.5.2. Factors that may reduce paracetamol toxicity
1.6. Diagnosis of paracetamol intoxication
1.7. Management of severe paracetamol poisoning
1.7.1. Supportive care
1.7.1.1 Role of N-acetylcysteine in
paracetamol-induced liver failure
1.7.1.2 Role of liver transplantation
1.7.2. Specific antidotal therapy
1.7.2.1 Intravenous N-acetylcysteine
1.7.2.2 Oral N-acetylcysteine
1.7.2.3 Oral methionine
1.7.2.4 Intravenous methionine
1.7.2.5 Oral versus intravenous therapy
1.7.2.6 Comparative efficacy of
N-acetylcysteine and methionine
1.7.3. Summary of treatment recommendations
1.8. Areas for future research
1.8.1. Choice of antidote
1.8.2. Optimum dose and route of administration
1.8.3. Role of N-acetylcysteine in liver failure
1.8.4. Role of N-acetylcysteine 24-50 h after the
overdose
1.8.5. New approaches to the treatment of
paracetamol poisoning
1.8.6. Treatment failure
1.8.7. The treatment line
1.8.8. The role of ethanol
1.8.9. Paracetamol poisoning in pregnancy
1.9. References
2. METHIONINE
2.1. Introduction
2.2. Name and chemical formula
2.3. Physico-chemical properties
2.3.1. Melting point (decomposition)
2.3.2. Solubility in vehicle of administration
2.3.3. Optical properties
2.3.4. pH
2.3.5. pKa
2.3.6. Stability in light
2.3.7. Thermal stability/flammability
2.3.8. Loss of weight on drying
2.3.9. Excipients and pharmaceutical aids
2.3.10. Pharmaceutical incompatibilities
2.4. Pharmaceutical formulation and synthesis
2.5. Analytical methods
2.5.1. Quality control of antidote
2.5.2. Methods for identification of antidote
2.5.3. Methods for analysis of antidote in biological
samples
2.5.4. Methods for analysis of toxic agent
2.6. Shelf-life
2.7. General properties
2.7.1. Mode of antidotal activity
2.7.2. Other properties
2.8. Animal studies
2.8.1. Pharmacodynamics
2.8.2. Pharmacokinetics
2.8.2.1 Metabolism
2.8.3. Toxicology
2.8.3.1 Acute toxicity
2.8.3.2 Subacute and chronic toxicity
2.8.3.3 Toxicity in experimental liver damage
2.8.4. Effect in pregnancy
2.9. Volunteer studies
2.9.1. Methionine in patients with hepatic dysfunction
2.10. Clinical studies - clinical trials
2.10.1. Study by Prescott et al. (1976)
2.10.1.1 Patients and treatment
2.10.1.2 Investigations
2.10.1.3 Results of treatment
2.10.1.4 Toxicity of methionine
2.10.1.5 Likelihood of benefit due to antidote
2.10.2. Study by Solomon et al. (1977)
2.10.2.1 Results of treatment
2.10.2.2 Toxicity of methionine
2.10.2.3 Likelihood of benefit due to antidote
2.10.3. Study by Hamlyn et al. (1981)
2.10.3.1 Results of treatment
2.10.3.2 Likelihood of benefit due to antidote
2.11. Clinical studies - case reports
2.11.1. Study by Vale et al. (1981)
2.11.1.1 Patients and treatment
2.11.1.2 Investigations
2.11.1.3 Results of treatment
2.11.1.4 Liver damage
2.11.1.5 High-risk patients
2.11.1.6 Renal impairment
2.11.1.7 Deaths
2.11.1.8 Toxicity of methionine
2.11.1.9 Likelihood of benefit due to antidote
2.12. Summary of evaluation
2.12.1. Indications
2.12.2. Advised route and dosage
2.12.3. Other consequential or supportive therapy
2.12.4. Areas of use where there is insufficient
information to make recommendations
2.12.5. Proposals for further studies
2.12.6. Adverse effects
2.12.7. Restrictions of use
2.13. Model information sheet
2.13.1. Uses
2.13.2. Dosage and route
2.13.3. Precautions/contraindications
2.13.4. Adverse effects
2.13.5. Use in pregnancy and lactation
2.13.6. Storage
2.14. References
3. N-ACETYLCYSTEINE
3.1. Introduction
3.2. Name and chemical formula
3.3. Physico-chemical properties
3.3.1. Melting point
3.3.2. Physical state
3.3.3. Solubility
3.3.4. Optical properties
3.3.5. pKa
3.3.6. pH
3.3.7. Stability
3.3.8. Incompatibilities
3.3.9. Proprietary names and manufacturers
3.4. Pharmaceutical formulation and synthesis
3.5. Analytical methods
3.5.1. Quality control of antidote
3.5.2. Methods for identification of the antidote
3.5.3. Methods for analysis of the antidote in
biological samples
3.5.4. Methods for analysis of toxic agent
3.6. Shelf-life
3.6.1. Formulations for oral use
3.6.2. Formulations for intravenous use
3.7. General properties
3.7.1. Mode of antidotal activity
3.7.2. Effect in paracetamol-induced liver failure
3.7.3. Other therapeutic uses
3.8. Animal studies
3.8.1. Pharmacodynamics
3.8.2. Pharmacokinetics
3.8.3. Toxicology
3.8.4. Studies with modified cytochrome P-450 activity
3.9. Volunteer studies
3.9.1. Absorption and bioavailability
3.9.2. Distribution
3.9.3. Elimination
3.9.4. Oral N-acetylcysteine and interaction with
activated charcoal
3.9.5. Pharmacodynamics
3.10. Clinical studies - clinical trials
3.10.1. Efficacy of intravenous N-acetylcysteine
3.10.2. Efficacy of oral N-acetylcysteine
3.10.3. Oral versus intravenous N-acetylcysteine
3.10.4. Therapeutic drug monitoring during
N-acetylcysteine treatment
3.10.5. N-Acetylcysteine in paracetamol-induced
liver failure
3.11. Clinical studies - case reports
3.11.1. Adverse effects
3.11.2. Use in pregnancy
3.12. Summary of evaluation
3.12.1. Indications
3.12.2. Advised route and dosage
3.12.2.1 Intravenous N-acetylcysteine
3.12.2.2 Oral N-acetylcysteine
3.12.3. Other consequential or supportive therapy
3.12.4. Controversial issues and areas where there is
insufficient information to make recommendations
3.12.5. Proposals for further studies
3.12.6. Adverse effects
3.12.7. Restrictions of use
3.13. Model information sheet
3.13.1. Uses
3.13.1.1 Use in liver failure
3.13.2. Dosage and route
3.13.2.1 Intravenous N-acetylcysteine
3.13.2.2 Oral N-acetylcysteine
3.13.3. Precautions/contraindications
3.13.4. Pharmaceutical incompatibilities and drug
interactions
3.13.5. Adverse effects
3.13.6. Use in pregnancy and lactation
3.13.7. Storage
3.14. References
WORKING GROUP ON VOLUME 3, EVALUATION OF ANTIDOTES
Members
Dr D.N. Bateman*, Department of Clinical Pharmacology, University of
Newcastle, Newcastle-upon Tyne, United Kingdom
Professor C. Bismuth, Hôpital Fernand Widal, Paris, France
Professor B. Fahim, The Poison Control Unit, Ains Shams University
Hospital, Cairo, Egypt
Dr R. Fernando, National Poisons Information Centre, Faculty of
Medicine, Colombo, Sri Lanka
Dr R.E. Ferner, West Midlands Poisons Unit, Dudley Road Hospital,
Birmingham, United Kingdom
Dr J.A. Holme, National Institute of Public Health, Oslo, Norway
Professor A. Jaeger, Pavillon Pasteur, Hospice Civil de Strasbourg,
Service de Reanimation Medicale et Centre Anti-poisons, Strasbourg,
France
Dr C.K. Maitai, College of Health Sciences, Department of
Pharmacology, University of Nairobi, Nairobi, Kenya
Dr T.J. Meredith*, Department of Health, London, United Kingdom
Dr H. Persson, Poison Information Centre, Karolinska Sjukhuset,
Stockholm, Sweden (Joint Chairman)
Dr J. Pimentel, Intensive Care Unit, University Hospital, Coimbra,
Portugal
Professor L. Prescott*, Scottish Poison Information Service, The
Royal Infirmary, Edinburgh, Scotland (Joint Chairman)
Dr J. Pronczuk, C.I.A.T., Hopital de Clinicas, Montevideo, Uruguay
Dr M.-L. Ruggerone, Ospedale Niguarda, Centro Antiveleni, Milan, Italy
Dr B.H. Rumack*, Micromedex Inc., Denver, Colorado, USA
Dr H. Smet, Centre Belge Anti-Poisons, Brussels, Belgium
Dr D.G. Spoerke, Micromedex Inc., Denver, Colorado, USA
Dr J. Szajewski, Warsaw Poison Control Centre, Szpital Praski III.
Oddzial Chorob Wewnetrznych, Warsaw, Poland
Dr U. Taitelman, National Poisons Information Centre, Rambam Medical
Centre, Haifa, Israel
Dr W. Temple, National Toxicology Group, Otago University Medical
School, Dunedin, New Zealand (Joint Rapporteur)
Ms J. Tempowski, Guy's Hospital, London, United Kingdom
Dr J.A. Vale*, West Midlands Poison Unit, Dudley Road Hospital,
Birmingham, United Kingdom
Professor A.N.P. van Heijst, Bosch en Duin, The Netherlands
Dr G. Volans, Poisons Unit, New Cross Hospital, London, United Kingdom
Dr E. Wickstrom, National Poison Centre, Oslo, Norway
Dr T. Zilker, Toxikologische Abteilung, II. Med. Klinik rechts der
Isar, Munich, Germany
Secretariat
Dr J.-C. Berger*, Health and Safety Directorate, European
Commission, Luxembourg
Dr J.A. Haines*, International Programme on Chemical Safety, World
Health Organization, Geneva, Switzerland
Dr M. ten Ham, Drug Safety Programme, World Health Organization,
Geneva, Switzerland
* Members of the drafting group that worked specifically on the
texts in this volume at the Working Group meeting.
PREFACE
The need for an international evaluation of the clinical efficacy
of antidotes and other substances used in the treatment of poisoning
was first recognized at a joint meeting of the World Federation of
Associations of Clinical Toxicology Centres and Poisons Control
Centresa, the International Programme on Chemical Safety (IPCS) and
the Commission of the European Communities (CEC), held at WHO
headquarters, Geneva, 6-9 October 1985. At the same time, the need to
encourage the more widespread availability of those antidotes that are
effective was recognised. As a result, a joint IPCS/CEC project was
subsequently initiated to address these problems.
In the preparatory phase of the project, an antidote was defined
for working purposes as a therapeutic substance used to counteract the
toxic action(s) of a specified xenobiotic. A preliminary list of
antidotes for review, as well as of other agents used to prevent the
absorption of poisons, to enhance their elimination and to treat their
effects on body functions, was established. For the purpose of the
review process, antidotes and other substances were classified
according to the urgency with which treatment with the antidote was
thought on current evidence to be required and the (currently judged)
clinical efficacy of the antidote in practice. Those corresponding to
the WHO concept of an essential drug were designated as such. Some
have already been incorporated into the WHO list of essential
drugsb. Antidotes and similar substances for veterinary use were
also listed. A methodology on the principles for evaluation of
antidotes and other agents used in the treatment of poisonings was
developed and this has subsequently been used as a framework for
drafting monographs on specific antidotes (see also the introduction
to this series in volume I for more information on the programme).
Among the priorities established for evaluation in this project
were antidotes for paracetamol poisoning. The reason for this was the
many patients poisoned with this over-the-counter analgesic, many of
whom suffered serious liver damage and subsequently died, and the fact
that there were two antidotes available, namely N-acetylcysteine and
methionine, with apparently similar efficacy but with different
availability and therapy costs. Furthermore, there were significant
disagreements between research centres concerning the route by which
the antidotes should be administered.
a Now World Federation of Associations of Poisons Control Centres
and Clinical Toxicology.
b WHO (1992) Use of Essential Drugs. Model list of essential drugs
(seventh list). Fifth Report of the WHO Expert Committee. WHO
Technical Report Series 825, Geneva, World Health Organization.
Another important factor for avoiding complications in
paracetamol poisoning is early administration of the antidotes; there
is marked loss of efficacy when they are administered more than 10 h
after ingestion of paracetamol. It is of interest that, during the
course of preparation of this volume, there was increasing published
evidence of the beneficial effect of therapy with N-acetylcysteine
even when administered at a very late stage of poisoning. This
observation further underlined the need for a scientific evaluation of
this area by leading experts in the field.
Of the two antidotes in this volume, N-acetylcysteine has been
most widely studied clinically. There are far fewer published
clinical data on methionine and therefore a special attempt has been
made to evaluate both the preclinical and the few clinical data
available for this antidote.
The review and evaluation of these antidotes was initiated at a
joint meeting of the IPCS and the CEC, organized by the Northern
Poisons Unit and held at the Medical School of the University of
Newcastle-upon-Tyne, United Kingdom, 13-17 March 1989. In preparation
for this meeting, monographs were drafted, using the proforma, on
N-acetylcysteine by Dr B.H. Rumack and Dr D.G. Spoerke, and on
methionine by Dr T.J. Meredith and Ms J. Tempowski. After
presentation in plenary, the draft documents on N-acetylcysteine and
methionine were reviewed by a Working Group consisting of Dr D.N.
Bateman (Chairman), Dr T.J. Meredith (Rapporteur), Dr L. Prescott, Dr
B.H. Rumack and Dr J.A. Vale. Following the meeting, preliminary
revisions of the N-acetylcysteine monograph were undertaken by Dr
T.J. Meredith in consultation with Dr D.N. Bateman, Dr L. Prescott and
Dr B.H. Rumack. Both monographs were again reviewed at a Working
Group consisting of Dr D.N. Bateman, Dr J.-C. Berger, Dr J.A. Haines,
Dr T.J. Meredith and Dr L. Prescott, held at the Royal Infirmary,
Edinburgh, United Kingdom, 25-26 September 1989, after which Dr L.
Prescott prepared an overview chapter of antidotal therapy for acute
paracetamol poisoning.
Following this meeting, further drafting work was undertaken by
authors and the overview chapter was reviewed by Dr D.N. Bateman and
Dr J.A. Holme. Draft texts were further revised by the series editors
(Dr T.J. Meredith, Dr D. Jacobsen, Dr J.A. Haines, and Dr J.-C.
Berger). The efforts of all who helped in the preparation and
finalization of this volume are gratefully acknowledged.
ABBREVIATIONS
ALAT alanine aminotransferase
ASAT aspartate aminotransferase
AUC area under the curve
GSH glutathione
HPLC high-performance liquid chromatography
NAD nicotinamide adenine dinucleotide
NAPQI N-acetyl- p-benzoquinone imine
U units (international)
IPCS/EC Evaluation of Antidotes Series
Volume 3
Antidotes for Poisoning by Paracetamol
First drafts of the chapters, subsequently reviewed and revised by the
Working Group, were prepared by:
Dr L.F. Prescott, Clinical Pharmacology Unit, Royal Infirmary,
Edinburgh, United Kingdom (Overview)
Dr D.G. Spoerke and Dr B.H. Rumack, Micromedex Inc., Denver, Colorado,
USA ( N-acetylcysteine)
Dr T.J. Meredith, UK Department of Health, London, United Kingdom, and
Ms J. Tempowski, National Poisons Information Service (London Centre),
London, United Kingdom (Methionine)
1. OVERVIEW OF ANTIDOTAL THERAPY FOR ACUTE PARACETAMOL POISONING
1.1 Introduction and historical review
Paracetamol (acetaminophen, N-acetyl- p-aminophenol, APAP,
NAPA, 4-hydroxy-acetanilide) was first introduced into clinical
medicine towards the end of the last century but it attracted little
attention and was soon forgotten (Smith, 1958). There was a
resurgence of interest in paracetamol when it was found to be the
major metabolite of acetanilide and phenacetin (Brodie & Axelrod,
1948a,b) and it was commonly assumed to be responsible for the
therapeutic effects of both of these drugs. Paracetamol has since
been used increasingly as a substitute for other analgesics such as
aspirin and phenacetin, and in the United Kingdom its sales have
exceeded those of aspirin for more than a decade. As a consequence of
the "back door" introduction of paracetamol, there were no formal
preclinical animal toxicity studies such as would be required today,
and its potential hepatotoxicity was not suspected until the first
clinical reports of severe and fatal liver damage following overdosage
(Davidson & Eastham, 1966; Thomson & Prescott, 1966). Severe hepatic
necrosis was first observed in cats treated with paracetamol (25 mg/kg
and then 50 mg/kg) for 22 weeks (Eder, 1964), and it was also
described in rats given doses in the range of the acute LD50 and the
100-day LD50 (Boyd & Bereczky, 1966; Boyd & Hogan, 1968). The
ability of paracetamol to produce acute centrilobular hepatic necrosis
in experimental animals has since been confirmed repeatedly and there
are major species differences in susceptibility. Mice and hamsters
are very sensitive while rats are resistant, and these differences
have been related to species differences in the extent of the
metabolic activation of paracetamol (Tee et al., 1987).
Apart from single case reports from South Africa (Pimstone & Uys,
1968) and the USA (Boyer & Rouff, 1971), the initial clinical
descriptions of liver damage following paracetamol overdosage came
from the United Kingdom, and substantial numbers of patients were
involved (MacLean et al., 1968; Proudfoot & Wright, 1970; Prescott et
al., 1971; Farid et al., 1972; Clark et al., 1973b). With its
increasing use, poisoning with paracetamol has since emerged as a
significant problem in many other countries. In the United Kingdom,
paracetamol is taken in overdose most frequently by young adults who
are not being prescribed psychotropic drugs by their general
practitioners (Prescott & Highley, 1985). In one study of 737
patients in Newcastle-upon-Tyne it was taken by 11% of patients aged
more than 65 years, 25% of those aged 35-64 years and 41% of patients
less than 35 years of age (Wynne et al., 1987). Overall, paracetamol
is involved in some 15 to 30% of deliberate self-poisonings in the
United Kingdom, and there is considerable regional variation (Platt et
al., 1988).
Much publicity has been given to paracetamol poisoning and there
is no doubt that the problems have often been exaggerated. Only a
small minority of patients is at risk of severe liver damage and the
liver has remarkable powers of regeneration. Recovery from even
severe damage is usually rapid and complete, and the overall mortality
rate is low. In England and Wales in 1984, a total of 176 deaths was
attributed to poisoning with paracetamol alone and a further 305 to
paracetamol taken with other drugs, notably d-propoxyphene. However,
a survey of such deaths showed that half of those officially recorded
as being due to paracetamol and a quarter of those attributed to
paracetamol taken with d-propoxyphene could not be substantiated.
Furthermore, more than 90% of patients dying outside hospital had no
evidence of hepatic necrosis at necropsy (Meredith et al., 1986). In
a series of 394 fatal poisonings in New Zealand from 1975 to 1982,
only 2 deaths were related to paracetamol overdosage (Cairns et al.,
1983), and over a period of 20 years only one death was attributed to
paracetamol among children in the United Kingdom (Fraser, 1980).
1.2 Toxicity in man
The major target organ in paracetamol poisoning is the liver and
the primary lesion is acute centrilobular hepatic necrosis. In adults
the single acute threshold dose for severe liver damage (which has
been arbitrarily defined as elevation of the plasma alanine or
aspartate aminotransferase activity above 1000 U/l) is 150 to 250
mg/kg but there is marked individual variation in susceptibility
(Mitchell, 1977; Prescott, 1983). Children under the age of about 10
years appear to be much more resistant than adults, but in any event
they rarely ingest enough paracetamol to cause liver damage (Rumack,
1984). Only a small proportion of unselected adult patients who take
an overdose of paracetamol are at risk of severe liver damage.
Without specific antidotal therapy, less than 10% would suffer severe
liver damage but 1 to 2% will develop fulminant hepatic failure and
this is often fatal. One to 2% of patients develop acute renal
failure requiring dialysis (Hamlyn et al., 1978; Prescott, 1983).
When the patient is first seen, the severity of intoxication with
paracetamol cannot usually be determined on clinical grounds alone, as
there are no specific symptoms or signs. Consciousness is not
depressed unless other drugs have also been taken or there is a very
high plasma paracetamol concentration of the order of 6.62 mmol/l
(1000 mg/l) with a metabolic acidosis (Gray et al., 1987). Nausea and
vomiting usually develop within a few hours of ingestion of a
hepatotoxic dose of paracetamol and at this stage liver function tests
may be normal or only slightly deranged. From about 18 to 72 h after
ingestion there may be hepatic tenderness and abdominal pain due to
swelling of the liver capsule. Unless hepatic failure develops, there
is usually rapid improvement after the third day with eventual
complete recovery.
The maximum abnormality of liver function tests is usually
delayed until the third day. The characteristic changes include
dramatic elevation of the plasma alanine and aspartate transaminase
activity from normal values of less than 40 to as much as 10 000 or
even 20 000 U/l with mild to moderate increases in the plasma
bilirubin concentration and prothrombin time ratio. The sudden
dramatic increase in the activity of plasma transaminases is
presumably caused by their release from a large mass of necrotic
hepatocytes, and the prolongation of the prothrombin time reflects
acute impairment of synthesis of the vitamin K-dependent clotting
factors. There is little or no increase in the plasma alkaline
phosphatase activity unless liver damage is severe or the patient is
a chronic alcoholic. Liver biopsies show extensive centrilobular
hepatic necrosis with little inflammatory reaction. In patients who
recover, liver function tests become normal within 1 to 3 weeks and
follow-up histological examination reveals regeneration, repair and
eventually a return to normal appearances (Portmann et al., 1975;
Lesna et al., 1976). Other reported complications of paracetamol
poisoning include disturbances of coagulation with disseminated
intravascular coagulation (Clark et al., 1973a), acute pancreatitis
(Gilmore & Tourvas, 1977), impaired carbohydrate tolerance (Record et
al., 1975), myocarditis (Wakeel et al., 1987) and hypophosphataemia
(Jones et al., 1989). In the context of massive hepatic necrosis and
fulminant hepatic failure, it is doubtful whether these abnormalities
can be specifically related to paracetamol toxicity per se. Serial
measurements of the prothrombin time probably give the best guide to
prognosis (Harrison et al., 1990).
Oliguric renal failure may become apparent within 24 to 48 h
after the overdose of paracetamol, and in this setting it is almost
always associated with back pain, microscopic haematuria and
proteinuria. This early impairment of renal function can occur in the
absence of significant hepatic injury (Cobden et al., 1982; Prescott,
1983). Renal failure may be mild and transient or severe and prolonged
requiring dialysis. It may also occur later, after the onset of
hepatic encephalopathy.
Fulminant hepatic failure may develop in severely poisoned
patients from the third to the sixth day. It is characterized by
deepening jaundice, encephalopathy, increased intracranial pressure,
grossly disordered haemostasis with disseminated intravascular
coagulation and haemorrhage, hyperventilation, acidosis, hypoglycaemia
and renal failure. The prognosis is very poor (Clark et al., 1973b;
Canalese et al., 1981).
1.3 Assessment of the severity of intoxication
Because of the absence of early specific symptoms and signs, the
only reliable method of assessment of the severity of poisoning (and
hence the need for antidotal therapy) is emergency measurement of the
plasma paracetamol concentration in relation to the time since
ingestion. Patients with concentrations above a line joining plots on
a semi-logarithmic graph of 1.32 mmol/l (200 mg/l) at 4 h and 0.20
mmol/l (30 mg/l) at 15 h after ingestion (called the "treatment line")
have about a 60% chance of developing severe liver damage as defined
by elevation of the plasma transaminase activity above 1000 U/l. In
patients with concentrations above a parallel line joining 2 mmol/l
(300 mg/l) at 4 h and 0.33 mmol/l (50 mg/l) at 15 h the probability
rises to 90% (Fig. 1).
Plasma paracetamol concentrations determined less than 4 h after
the overdose cannot be interpreted because of the possibility of
continuing absorption. The "treatment line" defined above was derived
from studies in patients admitted to the Regional Poisoning Treatment
Centre in Edinburgh from 1969-1973 before effective treatment became
available (Prescott et al., 1971, 1974, 1977). Its validity for
patients in the United Kingdom was subsequently confirmed in studies
carried out in London (Gazzard et al., 1977) and Newcastle-upon-Tyne
(Hamlyn et al., 1978). The data from the original studies carried out
in Edinburgh were later used by Rumack & Matthew (1975) to develop the
"nomogram" which is used in the USA. Although generally accepted as
a good guide to management and the need for specific treatment, the
"treatment line" is not infallible. Patients with values above the
line often do not develop liver damage while severe liver damage may
rarely occur in patients with paracetamol concentrations as low as
0.83 mmol/l (125 mg/l) at 4 h. In the USA, patients are given
N-acetylcysteine when concentrations are above a lower treatment
line corresponding to 1 mmol/l (150 mg/l) at 4 h (Smilkstein et al.,
1988, 1991) (Fig. 1).
1.4 Mechanisms of toxicity and antidotal activity
Until Mitchell and his colleagues elucidated the mechanisms of
paracetamol hepatotoxicity, there was no effective treatment for
paracetamol poisoning (Mitchell et al., 1973a,b; Potter et al., 1973;
Jollow et al., 1973). In a series of classical studies they showed
that a minor route of paracetamol metabolism involved its conversion
by cytochrome P-450-dependent mixed-function oxidase to a reactive
arylating metabolite, now known to be N-acetyl- p-benzoquinone
imine (NAPQI), which may cause acute hepatic necrosis with toxic doses
of paracetamol (Dahlin et al., 1984; Holme et al., 1984). Initially,
the reactive metabolite of paracetamol was believed to result from
oxidation of the drug to N-hydroxy-paracetamol followed by
dehydration to NAPQI (Hinson et al., 1980; Holme et al., 1982). More
recent studies indicate a direct two-electron oxidation of paracetamol
to NAPQI by cytochrome P-450, or alternatively, a one-electron
oxidation to N-acetyl- p-benzosemiquinone imine by peroxidase,
prostaglandin H synthetase or cytochrome P-450 (Dahlin et al., 1984;
Potter & Hinson, 1987). NAPQI causes a depletion of both the
mitochondrial and cytosolic pools of reduced glutathione (GSH)
(Tirmenstein & Nelson, 1989). Once GSH is depleted, cellular proteins
are directly arylated and oxidized by the reactive metabolite (Albano
et al., 1985; Holme & Jacobsen, 1986), resulting in inhibition of
enzyme activities. Two of the enzymes that have been shown to be
inhibited in paracetamol-treated animals are glutathione peroxidase
and thiol transferase (Tirmenstein & Nelson, 1990). Inhibition of
these enzymes renders the cell vulnerable to endogenous activated
oxygen species with further oxidation of protein thiols. Decreased
plasma membrane Ca2+-ATPase activity and impaired mitochondrial
sequestration of Ca2+ lead to influx of extracellular Ca2+
(Tsokos-Kuhn et al., 1988; Tirmenstein & Nelson, 1989), with
large-scale calcium cycling by mitochondria resulting in oxidative
stress and cell death (Thomas & Reed, 1988). Disturbed Ca2+
homeostasis is likely to activate Ca2+-dependent catabolic processes
such as phospholipid degradation, protein degradation, disruption of
the cytoskeleton and DNA fragmentation (Ray et al., 1990; Orrenius et
al., 1991). Although several lines of evidence suggest that Ca2+
influx is an early event in the development of toxicity, results from
a recent paper indicate that this is not always the case (Herman et
al., 1992). Furthermore, secondary microcirculatory changes may
exacerbate the original injury and extend the necrosis through
ischaemic infarction of the periacinar region. Macrophages and
neutrophils are attracted to the damaged areas and lead to additional
protein thiol modification by releasing oxidants (Mitchell, 1988).
The maintenance of hepatic glutathione (GSH) concentrations by
administration of N-acetylcysteine was first suggested as a
treatment for paracetamol poisoning by Prescott & Matthew (1974). GSH
itself, due to its inability to cross the plasma membrane, cannot be
used as an antidote. However, GSH precursors such as
N-acetylcysteine have been found to be effective both in
experimental animals and in humans (Boobis et al., 1989).
N-acetylcysteine may reduce the severity of liver necrosis by
directly conjugating with and/or reducing the reactive metabolite
NAPQI (Tee et al., 1986). In addition, N-acetylcysteine forms other
nucleophiles, such as cysteine and GSH, that are also capable of
detoxifying NAPQI (Corcoran et al., 1985; Boobis et al., 1989).
N-acetylcysteine is effective as an antidote when given some
time after paracetamol exposure (Devalia et al., 1982). It appears
that N-acetylcysteine, either directly or through synthesis to
cysteine and GSH, decreases the toxic effect of activated oxygen and
reduces oxidized thiol groups on enzymes (Boobis et al., 1989). In
addition, N-acetylcysteine has been shown to decrease the amount of
paracetamol bound covalently to proteins, possibly by dissociation of
the covalently bound paracetamol from proteins and/or enhancing
degradation of the arylated proteins (Bruno et al., 1988; Rundgren et
al., 1988).
The ability of N-acetylcysteine to restore the function of
enzymes after paracetamol exposure and its capacity to detoxify,
either directly or indirectly, reactive metabolites through
facilitation of GSH synthesis, are probably both responsible for its
protective effect against paracetamol toxicity in humans.
Theoretically, N-acetylcysteine could be preferred to
methionine for the treatment of paracetamol poisoning. Unlike
N-acetylcysteine and glutathione, methionine is not a thiol and
therefore cannot form an adduct directly with the reactive metabolite
of paracetamol. Furthermore, enzymes such as cystathione synthetase
and cystathionase, which are necessary for the essential conversion of
methionine to cysteine in vivo, themselves have functional SH groups
which might be expected to be vulnerable to inactivation by
paracetamol. In such circumstances, it might also be expected that
methionine would be less effective than N-acetylcysteine in the late
treatment of severe paracetamol poisoning. Despite these theoretical
arguments, clear differences in clinical efficacy have not been
established.
1.5 Factors influencing the toxicity of paracetamol
Paracetamol hepatotoxicity depends on the metabolic balance
between the rate of formation of the toxic arylating metabolite and
the rate of glutathione conjugation. In animals, experimental
stimulation of metabolic activation of paracetamol and glutathione
depletion increases toxicity, while, conversely, toxicity is decreased
by inhibition of paracetamol oxidation and stimulation of glutathione
synthesis. In addition, inhibition of direct detoxification such as
sulfate conjugation and glucuronidation may increase the proportion of
the dose which is activated. One might assume that the same factors
apply in humans but this has never been proved. Both the rate of
formation and the total amount of NAPQI formed depend on the rate of
absorption and environmental and genetic determinants of oxidative
drug-metabolizing enzyme activity, as well as on the capacity of
parallel pathways for elimination of paracetamol (glucuronide and
sulfate conjugation).
1.5.1 Factors that may increase paracetamol toxicity
Of a number of purified rabbit hepatic isoenzymes of cytochrome
P-450, P-4502E1 and P-4501A2 exhibit appreciable activity in the
bioactivation of paracetamol (Morgan et al., 1983). Using monoclonal
antibodies, isoenzymes P-4502E1 and P-4501A2 have been found to be
approximately equally responsible for paracetamol bioactivation in
human hepatic microsomes (Raucy et al., 1989). There are large human
interindividual differences in the oxidative metabolism of paracetamol
(Raucy et al., 1989). In animals cytochrome P-4502E1 is induced by
pretreatment with ethanol (Morgan et al., 1982), and diabetes, acetone
or fasting (Jeffery et al., 1991). Song et al. (1990) have been able
to quantify cytochrome P-4502E1 in the peripheral blood lymphocytes of
some individuals and have shown the level to be considerably enhanced
in diabetic patients who do not respond to insulin. The level of
hepatic cytochrome P-4502E1 has been found to be elevated in
alcoholics (Perrot et al., 1989; Raucy et al., 1989).
Chronic administration of ethanol to mice, rats or hamsters can
enhance the hepatotoxic effects of paracetamol, and there have been a
number of anecdotal case reports of paracetamol-induced hepatic injury
among alcoholics resulting from apparent therapeutic misadventure
(Zimmerman, 1986; Seeff et al., 1986; Floren et al., 1987). There is,
however, some disagreement as to whether therapeutic doses of
paracetamol produce liver injury in patients with chronic alcoholism
(Prescott, 1986; Mitchell, 1988). Of interest is the fact that acute
intake of ethanol at the time of paracetamol overdose is protective in
animals and humans (Zimmerman, 1986). Taking into consideration
animal and human studies, a reduction of the threshold for use of
N-acetylcysteine after paracetamol overdose in patients with chronic
alcoholism has been suggested by McClements et al. (1990). There are,
however, no firm data in support of this recommendation.
Depletion of hepatic glutathione stores by feeding a low protein
diet or by pretreatment with diethylmaleate will markedly augment
paracetamol toxicity (Price & Jollow, 1983). Decreased concentrations
of glutathione may also explain any increased susceptibility to
paracetamol in alcoholics (Lauterburg & Velez, 1988; Smilkstein et
al., 1988).
A possible protective effect of antioxidants and a possible
increased toxicity of paracetamol in vitamin E-deficient mice
(Fiarhurst et al., 1982) have no documented clinical significance.
1.5.2 Factors that may reduce paracetamol toxicity
Many compounds, such as N-acetylcysteine and methionine (see
section 1.4), have been shown to reduce paracetamol toxicity either by
reacting directly with NAPQI or by facilitating glutathione synthesis.
Since the first step in paracetamol metabolism is its bioactivation to
NAPQI, inhibition of this process is, theoretically, of clinical
relevance. Several experimental studies have shown a more or less
protective effect on paracetamol toxicity, as discussed below.
However, the clinical relevance of these experimental results has yet
to be established.
Pretreatment with piperonyl butoxide or cobaltous chloride, which
inhibit hepatic microsomal function, protects against paracetamol-
induced hepatotoxicity in animals. Cimetidine protects against
hepatotoxicity of paracetamol in animals by inhibiting its metabolic
activation (Speeg et al., 1985). However, the effect of cimetidine in
the prevention of liver damage in humans is uncertain (Critchley et
al., 1983). Concomitant exposure to ethanol appears to reduce
activation of paracetamol to reactive metabolites in rats (Wong et
al., 1980). In vitro studies with liver slices, however, indicate
that ethanol also protects after paracetamol exposure has ceased,
which could be due to an increase in the NADH/NAD ratio (Mourelle et
al., 1990). Ethanol given acutely appears to reduce the metabolic
activation of paracetamol in humans (Critchley et al., 1983).
Calcium channel blocking agents such as nifedipine (Landan et
al., 1985) and diltiazem (Deakin et al., 1991) have been shown to
reduce marginally the development of paracetamol-induced liver
necrosis in rats. Similar effects have been reported with inhibitors
of phospholipase A2, cyclooxygenase and thromboxane synthetase
(Horton & Wood, 1989).
The hepatotoxic effect of paracetamol in female mice is reduced
by feeding the animals a diet containing 0.75% butylated hydroxyanisol
(Miranda et al., 1983), possibly by increasing the concentration of
reduced glutathione in the liver (Miranda et al., 1985). Other
antioxidants and inhibitors of lipid peroxidation such as
diethyldithiocarbamate and anisyldithiolthione, may also protect
against paracetamol-induced liver damage (Mansuy et al., 1986; Younes
et al., 1988).
1.6 Diagnosis of paracetamol intoxication
Many methods have been described for the estimation of
paracetamol in plasma. These include procedures based on ultraviolet
(UV) spectrophotometry (Routh et al., 1968), colorimetry, (Brodie &
Axelrod, 1948a; Glynn & Kendal, 1975), gas liquid chromatography
(Prescott, 1971) and high performance liquid chromatography with UV
(Howie et al., 1977) or electrochemical detection (Riggin et al.,
1975). More advanced techniques for the identification and estimation
of paracetamol and its metabolites include fast atom bombardment mass
spectrometry (Lay et al., 1987), thermospray liquid
chromatography/mass spectrometry (Betowski et al., 1987) and proton
nuclear magnetic resonance (Bales et al., 1988). At the same time, a
number of operationally simple methods have been introduced for
clinical use. These depend on electrochemical or colour reactions
after enzymatic hydrolysis of paracetamol to p-aminophenol (Price et
al., 1983) and immunoassay including techniques based on fluorescence
polarisation (Hepler et al., 1984; Coxon et al., 1988).
The ideal method for the emergency estimation of plasma
paracetamol in poisoned patients should be inexpensive, simple, rapid
and accurate at least over the range of 0.1-3.31 mmol/l (15 to 500
mg/l). It should not be subject to interference by metabolites or
other drugs, not require the use of complex apparatus and be capable
of being used by staff without special skills or training. No one
method meets all of these criteria, and the subject has been reviewed
critically (Weiner, 1978; Stewart & Watson, 1987). Whatever method is
used, it is particularly important to check the units used by the
laboratory for reporting plasma paracetamol concentrations. Most
clinical toxicologists still use mass units such as mg/l, while some
laboratories report results in SI units. This can cause confusion
which may be dangerous (1 mmol/l is equivalent to 151 mg/l). Serious
problems have also arisen through the inappropriate use of non-
specific methods which can give gross overestimates of plasma
paracetamol concentrations because they also measure metabolites
(Stewart et al., 1979).
1.7 Management of severe paracetamol poisoning
Management of the patient with severe paracetamol poisoning can
be considered under the headings of supportive care and specific
antidotal therapy. The possible role of liver transplantation is also
briefly discussed.
1.7.1 Supportive care
Supportive care is based on removal of unabsorbed drug,
symptomatic treatment and the management of serious complications such
as hepatic and renal failure. Gastric aspiration with lavage, or
induction of emesis with syrup of ipecac (ipecacuanha), is usually
carried out in patients who are thought to have taken at least 100 mg
paracetamol/kg within the previous 1-2 h. Activated charcoal has also
been recommended. Unfortunately, paracetamol is normally absorbed very
rapidly, and it is uncommon to obtain a good return of tablet
material. Provided that more than 4 h have elapsed since the time of
ingestion, a blood sample should be taken for the emergency estimation
of the plasma paracetamol concentration and for baseline measurements
of liver function tests, prothrombin time ratio, and plasma urea,
creatinine and electrolytes. It will be found that most patients are
not severely poisoned and so do not require specific treatment or
further supportive care. In patients with protracted nausea and
vomiting, maintenance of intravenous fluids and electrolytes may be
required and a careful watch should be kept on the fluid balance;
hypophosphataemia has been reported (Jones et al., 1989). Because of
the possibility of impending liver failure with gross impairment of
drug metabolism, other drugs (including anti-emetics) should only be
given if really necessary. The biochemical tests of hepatic and renal
function should be monitored in patients at risk at least every 12 to
24 h, depending on the severity of intoxication and clinical state.
Acute oliguric renal failure during the first 24 to 48 h may be
accompanied by severe back and loin pain. Fluid and electrolyte
balance must be monitored carefully and dialysis is often necessary.
The plasma urea and creatinine concentrations may rise slowly but
progressively over a period of many days before renal function
recovers.
The onset of acute, possibly fatal, hepatic failure is indicated
by a rapid rise of the prothrombin time to a ratio of more than 5.0,
gross elevation of the plasma alanine aminotransferase (ALAT) and
appearance of mild jaundice within 36 to 48 h. In such circumstances
vitamin K1 is usually given parenterally and, depending on the
results of serial clotting screens, the intravenous administration of
clotting factor concentrate or fresh frozen plasma may be necessary to
keep the prothrombin time ratio within a safe range. Careful
attention must be given to fluid, electrolyte and acid-base balance,
and it is important to avoid fluid overload as this will aggravate
cerebral oedema. Neomycin (1 g every 4 to 6 h) and lactulose
administration by nasogastric tube should be considered, as in the
case of acute liver failure from other causes. Hypoglycaemia may
occur at any time and should be prevented by intravenous
administration of fluids containing glucose. Established acute liver
failure should be treated by conventional methods (Williams, 1988) but
the prognosis is very poor, even in specialist centres using measures
such as orthotopic liver transplantation (O'Grady et al., 1988, 1991;
Harrison et al., 1991).
1.7.1.1 Role of N-acetylcysteine in paracetamol-induced liver
failure
The original studies of N-acetylcysteine treatment for
paracetamol poisoning gave no evidence of benefit when this treatment
was delayed for more than 15 h (Prescott et al., 1977, 1979). Later,
the prospective studies by Smilkstein et al. (1988, 1991) suggested
that treatment with oral N-acetylcysteine may be effective up to 24
h after ingestion of the paracetamol. None of these studies were,
however, designed for studying the effect of N-acetylcysteine on
established paracetamol-induced liver failure. In patients with
fulminant hepatic failure after paracetamol overdose (without previous
N-acetylcysteine treatment), N-acetylcysteine significantly
increased the survival rate (48%, 12/25 patients) as compared to
controls (20%, 5/25) (Keays et al., 1991). The intravenous dose
regimen in this prospective randomised controlled study was the same
as recommended for paracetamol overdose, and N-acetylcysteine was
given 53 h (range 36-80 h) after the overdose.
The mechanism(s) for this protective effect of N-acetylcysteine
on established liver failure is not clear but may be related to
increased tissue oxygen consumption and decreased oxidant stress, thus
reducing the oxidation of important protein thiol groups (Keays et
al., 1991).
Earlier fears that the late administration of intravenous
N-acetylcysteine might be hazardous have proved to be unfounded.
The antidote is therefore indicated both in the acute phase of
paracetamol intoxication (section 1.7.2), provided that serum
paracetamol concentrations fall above the so-called treatment line,
and in established paracetamol liver failure.
The role of N-acetylcysteine in other types of acute liver
failure has not been studied, nor has the effect of methionine on
paracetamol-induced liver failure been studied.
1.7.1.2 Role of liver transplantation
It is very difficult to perform, at the right moment, an adequate
triage, based on clinical and biochemical parameters, of patients at
significant risk of dying from hepatic failure in paracetamol
poisoning. The correct time for doing this is early enough to provide
the potential recipient with a donor organ at a time where he/she is
still in an operable condition. Many studies over the years have
indicated that the prothrombin time is the most reliable parameter in
evaluating the risk of dying from liver failure following paracetamol
overdose (Harrison et al., 1990). Patients with a continuous increase
in prothrombin time on day 4 after overdose and a peak prothrombin
time of > 180 seconds appear to have a less than 8% chance of
survival (Harrison et al., 1990).
Recently O'Grady et al. (1991) performed a prospective study of
66 cases of severe paracetamol poisoning transferred to their Liver
Unit in London. Of these, 37 patients (of whom 30 survived) were
considered to have a reasonable prognosis with intensive care. Of 14
out of 29 patients considered to have a very poor prognosis and
registered for urgent liver transplantation, six received liver
transplants, four of whom survived, while seven died and one survived
without a transplant. Three out of 15 patients who had poor
prognostic indicators but were not selected for transplantation
survived.
These results indicate that liver transplantation may have a
definite, but very limited role in the treatment of paracetamol
poisoning. Among arguments against liver transplantation are the fact
that some patients recover completely while waiting in vain for their
donor liver, and that liver transplantation in this acute stage is not
without complications. Even a successful transplantation implies
life-long immunosuppressive therapy.
1.7.2 Specific antidotal therapy
1.7.2.1 Intravenous N-acetylcysteine
Treatment with intravenous N-acetylcysteine is indicated in
patients who present within 15 h of taking paracetamol in overdose and
who have plasma paracetamol concentrations above the treatment line
defined in section 1.3. The regimen consists of intravenous
administration of 150 mg/kg made up in 200 ml of 5% dextrose over 15
min, followed by 50 mg/kg in 500 ml of 5% dextrose over 4 h and 100
mg/kg in 1 litre of 5% dextrose over 16 h. The total dose is 300
mg/kg given over 20 h. This regimen effectively prevents liver
damage, renal failure and death if started within 8 h of paracetamol
ingestion but efficacy falls off rapidly after this time.
Later studies have suggested that treatment with oral or
intravenous N-acetylcysteine may be effective up to 24 h after
ingestion of the paracetamol (Smilkstein et al., 1988, 1991). It
therefore appears reasonable to propose treatment with
N-acetylcysteine as an antidote up to 24 h after ingestion. In the
most recent study by Smilkstein et al. (1991), the intravenous dose
regimen of N-acetylcysteine was increased to 980 mg/kg over 48 h.
Although this study was not scientifically comparable with that of
Prescott et al. (1979), there are indications that less
hepato-toxicity may occur using the 48-h treatment protocol among
patients at "high risk" (Fig. 1) and admitted more than 10 h
post-ingestion.
Because of the critical ingestion-treatment interval of 8 h,
patients who are thought to be at risk and who present at or after
this time should be treated with intravenous N-acetylcysteine
immediately. A blood sample should be taken for the emergency
estimation of the plasma paracetamol concentration, and if this
subsequently turns out to be below the treatment line,
N-acetylcysteine can easily be discontinued. The plasma paracetamol
concentration should also be determined in patients who present
earlier, but treatment with N-acetylcysteine must always be started
by 8 h if the laboratory result is not available. Although it might
appear simpler to give all patients N-acetylcysteine on admission,
this is not appropriate because a majority of patients would be
treated unnecessarily. Moreover, the use of N-acetylcysteine is
some times accompanied by adverse effects.
"Anaphylactoid" reactions to intravenous N-acetylcysteine have
been reported but the overall incidence is low. In some cases the
doses were excessive (Mant et al., 1984), while in others the drug was
not indicated in the first place and should never have been given (Ho
& Beilin, 1983; Dawson et al., 1989). The reactions have usually
consisted of urticaria, hypotension or bronchospasm and most have been
mild and transient. They usually occur during the first 15 to 60 min
of therapy at a time when plasma concentrations of N-acetylcysteine
are highest, and they probably represent a concentration-dependent
pharmacological effect (Bateman et al., 1984; Prescott et al., 1989;
Smilkstein et al., 1991).
1.7.2.2 Oral N-acetylcysteine
N-acetylcysteine is given orally in the USA and there have been
several reports of the results of a National Multicentre Study (Rumack
& Peterson, 1978; Rumack et al., 1981; Smilkstein et al., 1988). The
dose was 140 mg/kg followed by 17 doses of 70 mg/kg every 5 h, and the
total dose was 1330 mg/kg over 72 h (i.e. about 100 g in a 70 kg
adult). This dose is much larger than that used in any other study.
In the most recent update, the cumulative results were described for
2540 patients, and efficacy was assessed according to the initial
plasma paracetamol concentration and the delay between ingestion and
treatment. Hepatotoxicity developed in 6.1% of patients at "probable"
risk when treatment was started within 10 h and in 26.4% when therapy
was commenced 10 to 24 h after ingestion. Hepatotoxicity also
occurred in 41% of the patients at "high risk" treated between 14 and
16 h after ingestion. There were 11 deaths (0.43% of 2540 patients),
but none could clearly be attributed to paracetamol, when
N-acetylcysteine was started within 16 h. On the basis of the
results obtained, the authors suggest that treatment might still be
effective when delayed for as long as 24 h, and that this oral regimen
might be more effective than intravenous N-acetylcysteine,
particularly when treatment was delayed (Smilkstein et al., 1988).
This suggestion was, however, based on comparisons between patients
given oral N-acetylcysteine and patients treated with intravenous
N-acetylcysteine and control patients seen up to 15 years previously
in the United Kingdom. The patients were not comparable from a
demographic point of view and more importantly, the American patients
were less severely poisoned than the patients with whom they were
compared. Smilkstein et al. (1988) presented results for a total of
2540 patients, but only 2023 had plasma paracetamol concentrations
above a treatment line starting at 1 mmol/l (150 mg/l) at 4 h and only
1462 (58%) had concentrations above the treatment line accepted in the
United Kingdom (which starts at 1.32 mmol/l (200 mg/l) at 4 h). Thus
almost half of the American patients were at very low risk and would
not have been treated in the United Kingdom or included in the study.
It is therefore not surprising that oral N-acetylcysteine appeared
to be more effective when given orally than intravenously. However,
when the patients at "high risk" admitted late (16-24 h) were studied
separately, there was an indication in favour of prolonged
N-acetylcysteine treatment in this group.
Even so, oral N-acetylcysteine may be employed in the majority
of patients with paracetamol poisoning who are thought to be at
significant risk of liver damage. Treatment in this manner has been
recommended up to 24 h after ingestion of the paracetamol. No serious
adverse effects have been reported, although nausea and vomiting are
common (Rumack & Peterson, 1978). Intravenous therapy should be
considered in patients who are vomiting and in those who have been
given emetics or oral activated charcoal.
1.7.2.3 Oral methionine
Treatment with oral methionine is indicated in patients who
present within 15 h of taking paracetamol in overdose and who have
plasma paracetamol concentrations above the treatment line defined in
section 1.3. Oral methionine is very safe, and although the plasma
paracetamol concentration should always be measured if possible,
treatment should never be delayed while awaiting the laboratory
result. The dose of methionine is 2.5 g (10 x 250 mg tablets) orally
repeated 4 hourly to a total dose of 10 g over 12 h. There have been
two reports of the use of oral methionine in the treatment of
paracetamol poisoning, and overall the results are similar to those
obtained with N-acetylcysteine.
One study involved a comparison of patients in London and
Newcastle-upon-Tyne, United Kingdom, treated within 10 h with oral
methionine (13 patients), intravenous cysteamine (14 patients) or
supportive therapy only (13 patients). Both active agents gave
significant protection against liver damage but there were no
important differences between them (Hamlyn et al., 1981). In the
other study, the results of treating 132 patients in London with oral
methionine were compared with those of similarly poisoned control
patients who had previously received supportive therapy in Edinburgh
(Vale et al., 1981). As before, oral methionine was found to be very
effective in preventing liver damage when given within 10 h. It was
much less effective when treatment was delayed to 10-24 h. Oral
methionine may therefore be used to treat patients with paracetamol
poisoning who are at significant risk of liver damage. There are no
recommendations at present for the use of oral methionine more than 15
h after ingestion of an overdose of paracetamol. Side-effects to oral
methionine have not been reported in patient with paracetamol
poisoning. Intravenous N-acetylcysteine should be considered in
those who are vomiting and in patients who have been given emetics or
oral activated charcoal.
1.7.2.4 Intravenous methionine
In the study by Prescott et al. (1976), 3 out of 15 patients at
risk of liver damage from paracetamol and treated within 10 h
developed severe liver damage. All three were given intravenous
methionine 9-10 h following the ingestion of paracetamol (see section
2.10 for further details).
Centres in other countries (such as in Oslo, Norway) also have
experience with the use of intravenous methionine (10 g over 12 h) and
none of about 50 patients at risk of liver damage suffered such damage
or side effects provided that methionine was given within 10 h
following paracetamol ingestion (E. Enger, personal communication).
Methionine is no longer given intravenously, there being no
pharmaceutical preparation available.
1.7.2.5 Oral versus intravenous therapy
There is controversy concerning the optimal route of
administration of N-acetyl-cysteine and methionine. The obvious
advantage of the oral route is that most of the absorbed dose passes
directly to the sites of action in the liver. Oral therapy is also
simpler and cheaper, and can be given by non-medical health care
workers in developing countries. Since systemic adverse effects have
not been reported following oral therapy with either
N-acetylcysteine or methionine, it is not so important to identify
patients requiring treatment by prior measurement of the plasma
paracetamol concentration.
On the other hand, the efficacy of oral treatment may be
compromised if absorption is delayed or incomplete as a result of
nausea and vomiting. A substantial proportion of severely poisoned
patients develop nausea and vomiting within a few hours and it is in
these circumstances that effective reliable treatment is most needed.
Oral therapy must be given by nasogastric tube in unconscious patients
and this route is inappropriate in patients who have been given
emetics or oral activated charcoal. Although one route of
administration does not appear to have any striking advantage over the
other, prospective comparative studies in patients admitted at the
critical time of about 8 h after ingestion of paracetamol have not
been carried out.
1.7.2.6 Comparative efficacy of N-acetylcysteine and methionine
On the limited data available, it is not possible to state
whether N-acetylcysteine is superior to methionine. The comparisons
which have been made so far are only valid up to a point because of
the lack of proper controls. As discussed above, there are
theoretical reasons why N-acetylcysteine may be more effective than
methionine in preventing liver damage under certain circumstances;
there are also few data on the use of methionine in children and no
clinical data on its use in established paracetamol-induced liver
failure. There is also an indication of a beneficial effect of
N-acetylcysteine in patients admitted 10-24 h after the overdose
(Smilkstein et al., 1988). Lack of such an indication in methionine-
treated patients may, however, be related to the fact that this
compound has not been studied in as much detail as N-acetylcysteine.
This question can only be answered by careful prospective comparative
studies in large numbers of properly matched patients with appropriate
controls.
1.7.3 Summary of treatment recommendations
Paracetamol poisoning is not an immediate threat to life, and
little can be achieved in the way of first aid outside the hospital.
The most that can be done is to induce vomiting by pharyngeal
stimulation, and to arrange transport to hospital. Definitive hospital
treatment is based on early administration of sulfhydryl donors such
as N-acetylcysteine and methionine, and supportive care. The latter
includes removal of unabsorbed drug and management of complications
such as hepatic and renal failure. N-acetylcysteine also has a
documented therapeutic effect in established paracetamol-induced liver
failure.
Intravenous and oral N-acetylcysteine and oral methionine are
normally indicated in patients who are thought to have taken more than
100 mg paracetamol/kg in the preceding 24 h, or who have plasma
paracetamol concentrations above a treatment line joining plots on a
semilogarithmic graph of 200 mg/l at 4 h after ingestion and 30 mg/l
at 15 h. Every effort must be made to start therapy within 8 h as
their efficacy declines progressively after this time. Treatment is
required in only a small proportion of unselected patients and
measurement of the plasma paracetamol concentration should be
determined first if time and circumstances allow.
The recommended dosage regimens are given in detail in sections
2.13.2 and 3.13.2.
1.8 Areas for future research
1.8.1 Choice of antidote
Multicentre studies are the only practical way to compare the
relative efficacy and safety of N-acetylcysteine and methionine.
Appropriate controls will be necessary with stratification according
to factors such as age, sex, severity of poisoning, use of ethanol and
other drugs, and the ingestion-to-treatment interval. It is possible
that for optimal results, different drugs and different routes may be
indicated for different clinical circumstances. Since both antidotes
are effective and safe, however, a very large number of patients will
be necessary to document what is likely to be a marginal effect. Such
a study may be difficult to justify when health resources globally are
limited.
1.8.2 Optimum dose and route of administration
Work is also required to define optimal dosage regimens and
routes of administration. The regimens in current use were chosen
arbitrarily and there seems little doubt that some could be changed
with benefit. For example, the total dose and duration of treatment
with oral methionine (10 g over 12 h) is much less that the total dose
and duration of treatment with oral N-acetylcysteine (100 g over
72 h) yet their efficacy is comparable. The dose of oral
N-acetylcysteine may therefore be unnecessarily large.
The initial rapid intravenous infusion of N-acetylcysteine
produces very high plasma concentrations in the range of 300 to 900
mg/l, which may be more than is necessary. Most adverse reactions to
intravenous N-acetylcysteine occur early when concentrations are
highest, and they could probably be avoided without loss of efficacy
by modifying the infusion rates according to predictions based on the
kinetics of N-acetylcysteine in patients with severe paracetamol
poisoning (Prescott et al., 1989). Information is also required
concerning the bioavailability and plasma concentrations of oral
N-acetylcysteine and methionine in patients with paracetamol
poisoning. The proper characterization of the action of these agents
depends on the full definition of the dose- or concentration-response
curves, but this would be a formidable task. However, further useful
information could be obtained about the concentration-time-response
relationships of the antidotes in relation to the severity of
poisoning and the time since ingestion.
1.8.3 Role of N-acetylcysteine in liver failure
The effect of N-acetylcysteine on paracetamol-induced fulminant
liver failure should be studied further, if possible in a double-
blinded manner. The mechanisms behind this effect also warrant further
study. A similar study to investigate a possible therapeutic effect of
methionine could be considered, perhaps in comparison with
N-acetylcysteine, in a double-blind design.
The possible role of N-acetylcysteine in other types of liver
failure might also be justified if the effect on paracetamol-induced
liver failure was reproduced in a double-blind study.
1.8.4 Role of N-acetylcysteine 24-50 h after the overdose
In the studies of Smilkstein et al. (1988, 1991), an antidotal
effect of N-acetyl-cysteine was demonstrated up to 24 h after the
ingestion of paracetamol. As seen from Fig. 1 the treatment line is
only useful up to 24 h post-ingestion. In the study by Keays et al.
(1991), the average time from ingestion to inclusion in the study was
53 (36-80) h in the N-acetylcysteine-treated group. Thus we are
left with a time period from 24 to 50 h after ingestion where there
are no scientific data as to whether N-acetylcysteine is beneficial
or not. Until such data become available, it may be reasonable to
give N-acetylcysteine to patients admitted 24-50 h after ingestion
of paracetamol if they are considered to be at risk of developing
liver failure.
1.8.5 New approaches to the treatment of paracetamol poisoning
There seems little doubt that a large number of sulfhydryl
compounds may be effective in preventing liver damage after
paracetamol overdosage. Given that antidotes such as
N-acetylcysteine and methionine act indirectly via glutathione, it
is difficult to envisage other precursors with the same mechanisms of
protection that would be safer and more effective. At present, the
greatest need is for a new approach to the prevention of severe
hepatotoxicity in patients who present too late for effective
treatment with existing antidotes. Such treatment would have to be
based on mechanisms other than inhibition of the metabolic activation
of paracetamol or stimulation of glutathione synthesis.
Future research may also find a role for cytochrome P-450
inhibitors, such as ethanol, in reducing the severity of paracetamol-
induced liver toxicity. There is experimental evidence of efficacy but
clinical data are scarce. The effects of different agents on the
metabolism and toxicity of paracetamol could be better predicted if
the specific isoenzymes of cytochrome P-450 that are involved in the
metabolic activation of paracetamol in man were characterized.
1.8.6 Treatment failure
Patients occasionally suffer liver damage despite apparently
adequate treatment started well within the critical time of 8 to 10 h.
In such cases it is easy to assume that the patient's history is
inaccurate, or that failure of oral therapy is due to delayed or
incomplete absorption. However, similar problems have been encountered
following intravenous administration of antidote, and further studies
are needed to establish the reasons for treatment failure.
1.8.7 The treatment line
The line on a semilogarithmic graph joining plots of 200 mg/l at
4 h after ingestion of paracetamol and 30 mg/l at 15 h is used to
determine the need for antidotal therapy in most countries (Fig. 1).
The decision to treat only those patients with paracetamol
concentrations above this line represents a compromise between the
unnecessary treatment of the majority of poisoned patients on the one
hand and failure to treat a very small minority who will suffer liver
damage at concentrations below the line on the other. With
N-acetylcysteine it is important to ensure that treatment really is
necessary, although the position of the established treatment line is
probably about right. It is also a useful guide for treatment with
methionine, but, as this is so cheap and safe, unnecessary treatment
is of less consequence and the line could probably be lowered to
correspond to 150 mg/l at 4 h.
1.8.8 The role of ethanol
It is important to know whether acute or chronic heavy
consumption of ethanol has significant effects on susceptibility to
the hepatotoxicity of paracetamol following overdosage. To this end,
the outcome of poisoning should be compared in a sufficiently large
number of chronic alcoholics and appropriate control patients matched
for severity of poisoning and delay in treatment. A similar approach
might be used to determine whether early acute administration of
ethanol influences the outcome of paracetamol poisoning.
1.8.9 Paracetamol poisoning in pregnancy
Limited information is available concerning the effects of an
overdose of paracetamol at different times during the course of
pregnancy but serious problems for mother and child seem to be
uncommon (MacElhatton et al., 1990). National registers of patients
who take an overdose of paracetamol during pregnancy should be kept
with proper follow-up, so that the outcome and effects of different
treatments can be compared.
1.9 References
Albano E, Rundgren M, Harvison PS, Nelson SD, & Moldeus P (1985)
Mechanisms of N-acetyl-p-benzoquinone imine cytotoxicity. Mol
Pharmacol, 28: 306-311.
Bales JR, Bell JD, Nicholson JK, Sadler PJ, Timbrell JA, Hughes RD,
Bennett PN, & Williams R (1988) Metabolic profiling of body fluids by
proton NMR: self-poisoning episodes with paracetamol (acetaminophen).
Magn Reson Med, 6: 300-306.
Bateman DN, Woodhouse KW, & Rawlins MD (1984) Adverse reactions to
N-acetyl-cysteine. Human Toxicology, 3: 393-398.
Betowski LD, Korfmacher WA, Lay JO, Potter DW, & Hinson JA (1987)
Direct analysis of rat bile for acetaminophen and two of its
conjugated metabolites via thermospray liquid chromatography/mass
spectrometry. Biomed Environ Mass Spectrom, 14: 705-709.
Boobis AR, Fawthrop DJ, & Davis DS (1989) Mechanisms of cell deaths.
Trends Pharmacol Sci, 10: 275-280.
Boyd EM & Bereczky GM (1966) Liver necrosis from paracetamol. Br J
Pharmacol, 26: 606-614.
Boyd EM & Hogan SE (1968) The chronic oral toxicity of paracetamol at
the range of the LD50 (100 days) in albino rats. Can J Physiol
Pharmacol, 46: 239-245.
Boyer TD & Rouff SC (1971) Acetaminophen induced hepatic necrosis and
renal failure. J Am Med Assoc, 218: 440-441.
Brodie BB & Axelrod J (1948a) The estimation of acetanilide and its
metabolic products aniline, N-acetyl- p-aminophenol and
p-aminophenol (free and total conjugated) in biological fluids and
tissues. J Pharmacol Exp Ther, 94: 22-28.
Brodie BB & Axelrod J (1948b) The fate of acetanilide in man. J
Pharmacol Exp Ther, 94: 29-38.
Bruno MK, Cohen SD, & Khairallah EA (1988 ) Antidotal effectiveness of
N-acetylcysteine in reversing acetaminophen-induced hepatotoxicity.
Enhancement of the proteolysis of arylating proteins. Biochem
Pharmacol, 37: 4319-4325.
Cairns FJ, Koelmeyer TD, & Smeeton WMI (1983) Deaths from drugs and
poisons. N Z Med J, 96: 1045-1048.
Canalese J, Gimson AES, Davis M, & Williams R (1981) Factors
contributing to mortality in paracetamol-induced hepatic failure. Br
Med J, 282: 199-201.
Clark R, Borirakchanyavat V, Gazzard BG, Rake MO, Shilkin KB, Flute
PT, & Williams R (1973a) Disordered haemostasis in liver damage from
paracetamol overdose. Gastroenterology, 65: 788-795.
Clark R, Thompson RPH, Borirakchanyavat V, Widdop B, Davidson AR,
Goulding R, & Williams R (1973b) Hepatic damage and death from
overdose of paracetamol. Lancet, 1: 66-70.
Cobden I, Record CO, Ward MK, & Kerr DNS (1982) Paracetamol-induced
acute renal failure in the absence of fulminant liver damage. Br Med
J, 284: 21-22.
Corcoran GB, Racz WJ, Smith CV, & Michell JR (1985) Effects of
N-acetylcysteine on acetaminophen covalent binding and hepatic
necrosis in mice. J Pharmacol Exp Ther, 232: 864-872.
Coxon RE, Gallacher G, Landon J, & Rae C (1988) Development of a
specific polarization fluoroimmunoassay for paracetamol in serum. Ann
Cli Biochem, 25: 49-52.
Critchley JAJH, Dyson EH, Scott AW, Jarvie DR, & Prescott LF (1983) Is
there a place for cimetidine or ethanol in the treatment of
paracetamol poisoning? Lancet, 1: 1375-1376.
Dahlin DC, Miwa GT, Lu AYH, & Nelson SD (1984) N-acetyl- p-
benzoquinone imine: a cytochrome P-450 mediated oxidation product of
acetaminophen. Proc Natl Acad Sci (USA), 81: 1327-1331.
Davidson DGD & Eastham WN (1966) Acute liver necrosis following
overdosage of paracetamol. Br Med J, 2: 497-499.
Dawson AH, Henry DA, & McEwen J (1989) Adverse reactions to
N-acetylcysteine during treatment for paracetamol poisoning. Med J
Aust, 150: 329-331.
Deakin CD, Gove CD, Fagan EA, Tredger JM, & Williams R (1991) Delayed
calcium channel blockade with diltiazem reduces paracetamol
hepatotoxicity in mice. Hum Exp Toxicol, 10: 119-123.
Devalia JL, Ogilvie RC, & McClean AE (1982) Dissociation of cell death
from covalent binding by flavones in a hepatocyte system. Biochem
Pharmacol, 31: 3745-3749.
Eder H (1964) Chronic toxicity studies on phenacetin, N-acetyl- p-
aminophenol (NAPA) and acetylsalicylic acid on cats. Acta Pharmacol
Toxicol, 21: 197-204.
Farid NR, Glynn JP, & Kerr DNS (1972) Haemodialysis in paracetamol
self-poisoning. Lancet, 2: 396-398.
Fiarhurst S, Barber DJ, Clark B, & Horton AA (1982) Studies on
paracetamol induced lipid peroxidation. Toxicology, 23: 249-259.
Floren CH, Thesleff P, & Nilsson A (1987) Severe liver damage caused
by therapeutic doses of acetaminophen. Acta Med Scand, 222: 285-288.
Fraser NC (1980) Accidental poisoning deaths in British children
1958-77. Br Med J, 280: 1595-1598.
Gazzard BG, Hughes RD, Widdop B, Goulding R, Davis M, & Williams R
(1977) Early prediction of the outcome of a paracetamol overdose based
on an analysis of 163 patients. Postgrad Med J, 53: 243-247.
Gilmore IT & Tourvas E (1977) Paracetamol-induced acute pancreatitis.
Br Med J, 1(6063): 753-754.
Glynn JP & Kendal SE (1975) Paracetamol measurements. Lancet, 1:
1147-1148.
Gray TA, Buckley BM, & Vale JA (1987) Hyperlactataemia and metabolic
acidosis following paracetamol overdose. Q J Med, 65: 811-821.
Hamlyn AN, Douglas AP, & James O (1978) The spectrum of paracetamol
(acetaminophen) overdose: clinical and epidemiological studies.
Postgrad Med J, 54: 400-404.
Hamlyn AN, Lesna M, Smith PA, & Watson AJ (1981) Methionine and
cysteamine in paracetamol (acetaminophen) overdose, prospective
controlled trial of early therapy. J Int Med Res, 9: 226-231.
Harrison PM, O'Grady JG, Keays RT, Alexander GJM, & Williams R (1990)
Serial prothrombin time as prognostic indicator in paracetamol induced
fulminant hepatic failure. Br Med J, 301: 964-966.
Harrison PM, Wendon JA, Gimson AES, Alexander GJM, & Williams R (1991)
Improvement by acetylcysteine of hemodynamics and oxygen transport in
fulminant hepatic failure. N Engl J Med, 324: 1852-1857.
Hepler B, Weber J, Sutheimer C, & Sunshine I (1984) Homogenous enzyme
immunoassay of acetaminophen in serum. Am J Clin Pathol, 81: 602-610.
Herman AW, Mahar SO, Burcham PC, & Madsen BW (1992) Level of cytosolic
free calcium during acetaminophen toxicity in mouse hepatocytes. Mol
Pharmacol, 41: 665-670.
Hinson JA, Pohl LR, Monks TJ, Gillette JR, & Guengerich FP (1980)
3-Hydroxy-acetaminophen: a microsomal metabolite of acetaminophen.
Evidence against an epoxide as the reactive metabolite of
acetaminophen. Drug Metab Dispos, 8: 289-294.
Ho SWC & Beilin LJ (1983) Asthma associated with N-acetylcysteine
infusion and paracetamol poisoning: report of two cases. Br Med J,
287: 876-877.
Holme JA & Jacobsen D (1986) Mechanism of paracetamol toxicity.
Lancet, 1: 804-805.
Holme JA, Wirth PJ, Dybing E, & Thorgeirsson SS (1982) Cytotoxic
effects of N-hydroxyparacetamol in suspensions of isolated rat
hepatocytes. Acta Pharmacol Toxicol, 51: 87-95.
Holme JA, Dahlin DC, Nelson SD, & Dybing E (1984) Cytotoxic effects of
N-acetyl- p-benzoquinone imine, a common arylating intermediate of
paracetamol and N-hydroxyparacetamol. Biochem Pharmacol, 33:
401-406.
Horton AA & Wood JM (1989) Effects of inhibitors of phospholipase A2,
cyclo-oxygenase and thromboxane synthetase on paracetamol
hepatotoxicity in the rat. Eicosanoids, 2: 123-129.
Howie D, Adriaenssens PI, & Prescott LF (1977) Paracetamol metabolism
following overdosage. Application of high performance liquid
chromatography. J Pharm Pharmacol, 29: 235-237.
Jeffery EH, Arndt K, & Haschek WM (1991) The role of cytochrome
P-4502E1 in bioactivation of acetaminophen in diabetic and acetone-
treated mice. Adv Exp Med Biol, 283: 249-251.
Jollow DJ, Mitchell JR, Potter WZ, Davis DC, Gillette JR, & Brodie BB
(1973) Acetaminophen-induced hepatic necrosis. II. Role of covalent
binding in vivo. J Pharmacol Exp Ther, 187: 195-202.
Jones AF, Harvey JM, & Vale JA (1989) Hypophosphataemia and
phosphaturia in paracetamol poisoning. Lancet, 2: 608-609.
Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJM, &
Williams R (1991) Intravenous acetylcysteine in paracetamol induced
fulminant hepatic failure: a prospective controlled trial. Br Med J,
303: 1026-1029.
Landan EJ, Naukam RJ, Rama F, & Sastry BV (1985) Effects of calcium
channel blocking agents on calcium and centrilobular necrosis in the
liver of rats treated with hepatotoxic agents. Biochem Pharmacol, 35:
697-705.
Lauterburg BH & Velez ME (1988) Glutathione deficiency in alcoholics;
risk factor for paracetamol hepatotoxicity. Gut, 29: 1153-1157.
Lay JO, Potter WD, & Hinson JA (1987) Fast atom bombardment mass
spectro-metry and fast atom bombardment mass spectrometry/mass
spectrometry of three glutathione conjugates of acetaminophen. Biomed
Environ Mass Spectrom, 14: 517-521.
Lesna M, Watson AJ, Douglas AP, Hamlyn AN, & James OFW (1976)
Evaluation of paracetamol-induced damage in liver biopsies. Virchows
Arch Pathol Anat Histol, 370: 333-344.
McClements BM, Hyland M, Callender MF, & Blair TL (1990) Management of
paracetamol poisoning complicated by enzyme induction due to alcohol
or drugs. Lancet, 335: 1526.
MacElhatton PR, Sullivan FM, Volans GN, & Fitzpatrick R (1990)
Paracetamol poisoning in pregnancy: an analysis of the outcomes of
cases referred to the Teratology Information Service of the National
Poisons Information Service. Hum Exp Toxicol, 9: 147-153.
MacLean D, Peters TJ, Brown RAG, McCathie M, Baines GF, & Robertson
PGC (1968) Treatment of acute paracetamol poisoning. Lancet, 2:
849-852.
Mansuy D, Sassi A, Dansette PM, & Plat M (1986) A new potent inhibitor
of lipid peroxidation in vitro and in vivo, the hepatoprotective
drug anisyldithiolthione. Biochem Biophys Res Commun, 135: 1015-1021.
Mant TGK, Tempowski JH, Volans GN, & Talbot JCC (1984) Adverse
reactions of acetylcysteine and effects of overdose. Br Med J, 298:
217-219.
Meredith TJ, Prescott LF, & Vale JA (1986) Why do patients still die
from paracetamol poisoning? Br Med J, 293: 345-346.
Miranda CL, Henderson MC, Smith JA, & Buhler DR (1983) Protective role
of dietary butylated hydroxyanisole against chemical-induced acute
liver damage in mice. Toxicol Appl Pharmacol, 69: 73-80.
Miranda CL, Henderson MC, & Buhler DR (1985) Dietary butylated
hydroxyanisole reduces covalent binding of acetaminophen to mouse
tissue proteins in vivo. Toxicol Lett, 25: 89-93.
Mitchell JR (1977) Host susceptibility and acetaminophen liver injury.
Ann Int Med, 87: 377-388.
Mitchell JR (1988) Acetaminophen toxicity. N Engl J Med, 319:
1601-1602.
Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JR, & Brodie BB
(1973a) Acetaminophen-induced hepatic necrosis. I. Role of drug
metabolism. J Pharmacol Exp Ther, 187: 185-194.
Mitchell JR, Jollow DJ, Potter WZ, Gillette JR, & Brodie BB (1973b)
Acetaminophen-induced hepatic necrosis. IV. Protective role of
glutathione. J Pharmacol Exp Ther, 187: 211-217.
Morgan ET, Koop DR, & Coon MJ (1982) Catalytic activity of cytochrome
P-450 isozyme 3a isolated from liver microsomes of ethanol-treated
rabbits. J Biol Chem, 257: 13951-13957.
Morgan ET, Koop DR, & Coon MJ (1983) Comparison of six rabbit liver
cytochrome P-450 isozymes in formation of a reactive metabolite of
acetaminophen. Biochem Biophys Res Commun, 112: 8-13.
Mourelle M, Beales D, & McLean AE (1990) Electron transport and
protection of liver slices in the late stage of paracetamol injury.
Biochem Pharmacol, 40: 2023-2028.
O'Grady JG, Gimson AES, O'Brien CJ, Pucknell A, Hughes RD, & Williams
R (1988) Controlled trials of charcoal hemoperfusion and prognostic
factors in fulminant hepatic failure. Gastroenterology, 94: 1186-1192.
O'Grady JG, Wendon J, Tan KC, Potter D, Cottam S, Cohen AT, Gimson
AES, & Williams R (1991) Liver transplantation after paracetamol
overdose. Br Med J, 303: 221-223.
Orrenius S, McConkey DJ, & Nicotera P (1991) Role of calcium in toxic
and programmed cell death. Adv Exp Med Biol, 283: 419-425.
Perrot N, Nalpas B, Yang CS, & Beaune PH (1989) Modulation of
cytochrome P-450 isozymes in human liver by ethanol and drug intake.
Eur J Clin Invest, 19: 549-555.
Pimstone BL & Uys CJ (1968) Liver necrosis and cardiomyopathy
following paracetamol overdosage. S Afr Med J, 42: 259-262.
Platt S, Hawton K, Kreitman N, Fagg J, & Foster J (1988) Recent
clinical and epidemiological trends in parasuicide in Edinburgh and
Oxford: a tale of two cities. Psychol Med, 18: 405-418.
Portmann B, Talbot IC, Day DW, Davidson AR, Murray-Lyon IM, & Williams
R (1975) Histopathological changes in the liver following a
paracetamol overdose: correlation with clinical and biochemical
parameters. J Pathol, 117: 169-181.
Potter DW & Hinson JA (1987) Mechanisms of acetaminophen oxidation to
N-acetyl- p-benzoquinone imine by horseradish peroxidase and
cytochrome P-450. J Biol Chem, 262: 966-973.
Potter WZ, Davis DC, Mitchell JR, Jollow DJ, Gillette JR, & Brodie BB
(1973) Acetaminophen-induced hepatic necrosis. III. Cytochrome P-450-
mediated covalent binding in vitro. J Pharmacol Exp Ther, 187:
203-210.
Prescott LF (1971) Gas-liquid chromatographic estimation of
paracetamol. J Pharm Pharmacol, 23: 807-808.
Prescott LF (1983) Paracetamol overdosage: pharmacological
considerations and clinical management. Drugs, 25: 290-314.
Prescott LF (1986) Effects of non-narcotic analgesics on the liver.
Drugs, 32(Suppl 4): 129-147.
Prescott LF & Matthew H (1974) Cysteamine for paracetamol overdosage.
Lancet, 1: 998.
Prescott LF & Highley MS (1985) Drugs prescribed for self-poisoners.
Br Med J, 290: 1633-1636.
Prescott LF, Wright N, Roscoe P, & Brown SS (1971) Plasma-paracetamol
half-life and hepatic necrosis in patients with paracetamol
overdosage. Lancet, 1: 519-522.
Prescott LF, Newton RW, Swainson CP, Wright N, Forrest ARW, & Matthew
H (1974) Successful treatment of severe paracetamol overdosage with
cysteamine. Lancet, 1: 588-592.
Prescott LF, Park J, Sutherland GR, Smith IJ, & Proudfoot AT (1976)
Cysteamine, methionine and penicillamine in the treatment of
paracetamol poisoning. Lancet, 2: 109-114.
Prescott LF, Park J, Ballantyne A, Adriaenssens P, & Proudfoot AT
(1977) Treatment of paracetamol (acetaminophen) poisoning with
N-acetylcysteine. Lancet, 2: 432-434.
Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, &
Proudfoot AT (1979) Intravenous N-acetylcysteine: the treatment of
choice for paracetamol poisoning. Br Med J, 2(6198): 1097-1100.
Prescott LF, Donovan JW, Jarvie DR, & Proudfoot AT (1989) The
disposition and kinetics of intravenous N-acetylcysteine in patients
with paracetamol overdosage. Eur J Clin Pharmacol, 37: 501-506.
Price VF & Jollow DJ (1983) Mechanism of ketone-induced protection
from acetaminophen hepatotoxicity in the rat. Drug Metab Dispos, 11:
451-457.
Price CP, Hammond PM, & Scawen MD (1983) Evaluation of an enzymic
procedure for the measurement of acetaminophen. Clin Chem, 29:
358-361.
Proudfoot AT & Wright N (1970) Acute paracetamol poisoning. Br Med J,
3: 557-558.
Raucy JL, Lasker JM, Lieber CS, & Black M (1989) Acetaminophen
activation by human liver cytochrome P-4502E1 and P-4501A2. Arch
Biochem Biophys, 271: 270-283.
Ray SD, Sorge CL, Raucy JL, & Corcoran GB (1990) Early loss of large
genomic DNA in vivo with accumulation of calcium in the nucleus
during acetaminophen-induced liver injury. Toxicol Appl Pharmacol,
106: 346-351.
Record CO, Chase RA, Alberti KGMM, & Williams R (1975) Disturbances in
glucose metabolism in patients with liver damage due to paracetamol
overdose. Clin Sci Mol Med, 49: 473-479.
Riggin RM, Schmidt AL, & Kissinger PT (1975) Determination of
acetaminophen in pharmaceutical preparations and body fluids by high-
performance liquid chromatography with electrochemical detection. J
Pharm Sci, 64: 680-683.
Routh JI, Shane NA, Arredondo FG, & Paul WD (1968) Determination of
N-acetyl- p-aminophenol in plasma. Clin Chem, 14: 882-885.
Rumack BH (1984) Acetaminophen overdose in young children. Am J Dis
Child, 138: 428-433.
Rumack BH & Matthew H (1975) Acetaminophen poisoning and toxicity.
Paediatrics, 55: 871-876.
Rumack BH & Peterson RG (1978) Acetaminophen overdose: incidence,
diagnosis and management in 416 patients. Paediatrics, 62(Suppl 2):
898-903.
Rumack BH, Peterson RC, Koch GC, & Amara IA (1981) Acetaminophen
overdose. 662 cases with evaluation of oral acetylcysteine treatment.
Arch Int Med, 141: 380-385.
Rundgren M, Porubek DJ, Harvison PJ, Cotgreave IA, Moldeus P, & Nelson
SD (1988) Comparative cytotoxic effects of N-acetyl- p-benzoquinone
imine and two dimethylated analogues. Mol Pharmacol, 34: 566-572.
Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, & Benjamin SB (1986)
Acetaminophen hepatotoxicity in alcoholics. A therapeutic
misadventure. Ann Intern Med, 104: 399-404.
Smilkstein MJ, Knapp GL, Kulig KW, & Rumack BH (1988) Efficacy of oral
N-acetylcysteine in the treatment of acetaminophen over dose;
analysis of the National Multicenter study (1976 to 1985). N Engl J
Med, 319: 1557-1562.
Smilkstein MJ, Bronskin AC, Linden C, Augenstein WL, Kulig KW, &
Rumack BH (1991) Acetaminophen overdose: A 48-h intravenous
N-acetylcysteine treatment protocol. Ann Emerg Med, 20: 1058-1063.
Smith PK (1958) Acetophenetidin: A critical bibliographic review. New
York, Interscience Publishers, p 3.
Song BJ, Veech RL, & Saenger P (1990) Cytochrome P-4502E1 is elevated
in lymphocytes from poorly controlled insulin-dependent diabetics. J
Clin Endocrinol Methods, 71: 1036-1040.
Speeg KV, Mitchell MC, & Maldonado L (1985) Additive protection of
cimetidine and N-acetylcysteine treatment against acetaminophen-
induced hepatonecrosis in the rat. J Pharmacol Exp Ther, 234: 550-554.
Stewart MJ & Watson ID (1987) Analytical reviews in clinical
chemistry: methods for the estimation of salicylate and paracetamol in
serum, plasma and urine. Ann Clin Biochem, 24: 552-565.
Stewart MJ, Adriaenssens PI, Jarvie DR, & Prescott LF (1979)
Inappropriate methods for the emergency determination of plasma
paracetamol. Ann Clin Biochem, 16: 89-95.
Tee LBG, Boobis AR, Huggett AC, & Davies DS (1986) Reversal of
acetaminophen toxicity in isolated hamster hepatocytes by
dithiothreitol. Toxicol Appl Pharmacol, 83: 294-314.
Tee LBG, Davies DS, Seddon CE, & Boobis AR (1987) Species differences
in the hepatotoxicity of paracetamol are due to differences in the
rate of conversion to its cytotoxic metabolite. Biochem Pharmacol, 36:
1041-1052.
Thomas CE & Reed DJ (1988) Effect of extracellular Ca++ omission on
isolated hepatocytes. II. Loss of mitochondrial membrane potential and
protection by inhibitors of uniport Ca++ transduction. J Pharmacol
Exp Ther, 245: 501-507.
Thomson JS & Prescott LF (1966) Liver damage and impaired glucose
tolerance after paracetamol overdosage. Br Med J, 2(5512): 506-507.
Tirmenstein MA & Nelson SD (1990) Acetaminophen-induced oxidation of
protein thiols: Contributions of impaired thiol-metabolising enzymes
and the breakdown of adenosine nucleotides. J Biol Chem, 265:
3059-3065.
Tirmenstein MA & Nelson SD (1989) Subcellular binding and effects on
calcium homeostasis produced by acetaminophen and a non-hepatotoxic
regioisomer, 3-hydroxyacetoanilide in mouse liver. J Biol Chem, 264:
9814-9819.
Tsokos-Kuhn JO, Hughes H, Smith CV, & Mitchell JR (1988) Alkylation of
the liver plasma membrane and inhibition of the Ca2+ ATPase by
acetaminophen. Biochem Pharmacol, 37: 2125-2131.
Vale JA, Meredith TJ, & Goulding R (1981) Treatment of acetaminophen
poisoning. Arch Intern Med, 141: 394-396.
Wakeel RA, Davies HT, & Williams JD (1987) Toxic myocarditis in
paracetamol poisoning. Br Med J, 295: 1097.
Weiner K (1978) A review of methods for plasma paracetamol estimation.
Ann Clin Chem, 15: 187-196.
Williams R (1988) Management of acute liver failure Postgrad Med J,
64: 769-771.
Wong LT, Whitehouse LW, Solomonraj G, & Paul CJ (1980) Effect of
concomitant single dose of ethanol on the hepatotoxicity and
metabolism of acetaminophen in mice. Toxicology, 17: 297-309.
Wynne H, Bateman DN, Hassanyeh F, Rawlins MD, & Woodhouse KW (1987)
Age and self-poisoning: the epidemiology in Newcastle-upon-Tyne. Hum
Toxicol, 6: 511-515.
Younes M, Sause C, Seigers C-P, & Lemoine R (1988) Effect of
deferrioxamine and diethyldithiocarbamate on paracetamol-induced
hepato- and nephrotoxicity. The role of lipid peroxidation. J Appl
Toxicol, 84: 261-265.
Zimmerman HJ (1986) Effects of alcohol on other hepatotoxins.
Alcoholism: Clin Exp Res, 10: 3-15.
2. METHIONINE
2.1 Introduction
The amino acid methionine is indicated for the treatment of acute
paracetamol (acetaminophen) poisoning provided that patients present
sufficiently early to benefit from therapy (see below, and Meredith et
al., 1978; Vale et al., 1981; Meredith, 1987).
Methionine acts as a glutathione precursor (McLean & Day, 1975;
Vina et al., 1978; Vina et al., 1980) and protects against
paracetamol-induced hepatic and renal toxicity provided that it is
administered within 8-10 h of ingestion of the overdose (Meredith et
al., 1978; Vale et al., 1981; Meredith, 1987). Some protection is
afforded even when methionine is administered later than this, and the
point at which methionine treatment becomes "ineffective" has not been
determined with certainty (Vale et al., 1981; Meredith, 1987).
However, no significant benefits have been documented in cases where
more than 10 h has elapsed after a paracetamol overdose (Prescott et
al., 1979; Meredith et al., 1986). The need for specific protective
therapy with methionine in cases of paracetamol overdose may be judged
by measurement of plasma paracetamol concentrations in relation to the
time elapsed since ingestion (Vale et al., 1981). However, methionine
is usually administered orally and it is therefore unsuitable for use
in patients who are vomiting and for those in coma.
2.2 Name and chemical formula
It should be noted that L-methionine is the physiologically
active enantiomorph but the pharmaceutical preparation is usually the
racemic mixture.
International
non-proprietary name: methionine
Synonyms: DL-methionine, Racemethionine, DL-2-
amino-4-(methylthio)butyric acid, alpha-
amino-gamma-methylmercaptobutyric acid,
2-amino-4-methylthiobutanoic acid,
gamma-methylthio-alpha-aminobutyric acid
IUPAC-name: 2-amino-4-(methylthio)butyric acid
CAS Number: L-methionine 63-68-3
DL-methionine 59-51-8
EINECS Number: L-methionine 2005629
DL-methionine 2004321
NIOSH Number: L-methionine PD0457000
DL-methionine PD0456000
Empirical formula: C5H11NO2S
Chemical structure: CH3-S-CH2-CH2-CH-COOH
|
NH2
Relative molecular mass: 149.2
Conversion table: 1 mmol = 149.2 mg 1 g = 6.7 mmol
1 µmol = 149.2 µg 1 mg = 6.7 µmol
Manufacturers:
The major manufacturers of DL-methionine worldwide are
Rhone-Poulenc and Degussa (Goldfarb et al., 1981). Pharmaceutical
grade methionine is produced by the following companies:
Degussa Ltd, Earl Road, Stanley Green, Handforth, Wilmslow,
Cheshire SK9 3RL, United Kingdom (tel: +44 (0)61-486-6211; fax:
+44 (0)61-485-6445)
Degussa AG, Anwendungstechnik Av, Rodenbacher Chausee 4, Postfach
1345, D-6450 Hanaul, Germany (tel: (01049) 59-35-54; telex:
415200-0 dw d)
Rhone Poulenc, 217 High St, Uxbridge, Middlesex UB8 1LQ, United
Kingdom (tel: +44 (0)895-74080; fax: +44 (0)895-39323)
Walton Pharmaceuticals Ltd, Bowes House, 17 Bowes Road,
Walton-on-Thames, Surrey KT12 3HS, United Kingdom (tel: +44
(0)932-241032; fax: +44 (0)932-255461)
2.3 Physico-chemical properties
2.3.1 Melting point (decomposition)
266-267 °C (Degussa AG, 1985)
2.3.2 Solubility in vehicle of administration
Methionine is usually given orally in a solid dose formulation,
although in animal studies and in trials in humans, it has been
administered parenterally (Prescott et al., 1976; Solomon et al.,
1977).
The solubility in water at 20 °C is 29.1 g/l; it is also soluble
in dilute acids and dilute solutions of alkaline hydroxides.
Methionine is very slightly soluble in ethanol and practically
insoluble in ether (Degussa AG, 1985; Budavari, 1989; Martindale,
1989).
2.3.3 Optical properties
DL-methionine has no significant optical properties.
2.3.4 pH
The pH of a 1% aqueous solution is 5.6-6.1 (Martindale, 1989).
2.3.5 pKa
DL-methionine has two ionizable groups and it therefore possesses
two pKa values. The pKa of the carboxyl group is 2.28, and that
of the amino group, 9.21 (Weast & Astle, 1978).
2.3.6 Stability in light
Methionine should be stored in the dark.
2.3.7 Thermal stability/flammability
DL-methionine decomposes at about 267 °C (Degussa AG, 1985),
emitting fumes of sulfur and nitrogen oxides (Sax, 1989).
2.3.8 Loss of weight on drying
The loss of weight is < 0.3% on drying at 105 °C for 3 h
(Degussa AG, 1985).
2.3.9 Excipients and pharmaceutical aids
An intravenous preparation may be made by dissolving methionine
in 5% dextrose immediately before use and sterilizing by passage
through a biological filter (Prescott et al., 1976).
2.3.10 Pharmaceutical incompatibilities
Methionine has been shown to be adsorbed by activated charcoal.
Klein-Schwartz & Oderda (1981) added 10-ml aliquots (n=4) of a
methionine solution (25 mg/ml) to 3, 6 and 10 g samples of activated
charcoal in 50 ml of 0.1N hydrochloric acid. The 3 g charcoal-
methionine mixtures were agitated for 30 seconds, 10 min, 30 min and
60 min, and then suction filtered. Based on the results of this
time-course study, the 6- and 10-g samples were studied after 30
seconds of agitation. The binding of methionine by activated charcoal
was found to occur rapidly (46.9% within 30 seconds). A tendency
towards desorption was noted over the 60-min observation period (37.2%
at 60 min), but did not achieve statistical significance. As the
amount of charcoal was increased, and therefore as the ratio of
charcoal to methionine increased, the percentage of methionine
adsorbed increased. The percentages adsorbed by 3, 6, and 10 g of
charcoal were 46.9 ± 4.0% (mean ± 1.96 SE), 76.8 ± 1.4%, and 89.5 ±
1.5%, respectively. A statistically significant difference was found
between all three groups (P < 0.01).
2.4 Pharmaceutical formulation and synthesis
The raw materials for synthesis of DL-methionine are acrolein,
methanethiol (methyl mercaptan), hydrogen cyanide, and ammonia or
ammonium carbonate. These compounds are utilised in a number of
different processes to yield the amino acid.
The Strecker process involves the addition of methanethiol to
acrolein to form ß-methylthiopropionaldehyde, which is reacted with
cyanide to give alpha-hydroxy-gamma-methylthiobutyronitrile. This
compound is treated with ammonia to produce alpha-amino-gamma-
methylthiobutyronitrile, which is hydrolysed to DL-methionine
(Goldfarb et al., 1981; Ullman, 1985).
A variation on this method involves the treatment of alpha-
hydroxy-gamma-methyl-thiobutyronitrile with ammonia and carbon dioxide
or ammonium carbonate to yield 5-(ß-methylthioethyl)hydantoin. This
product is subjected to alkaline hydrolysis at elevated temperature
and pressure to yield sodium methionate. DL-methionine is isolated by
acidification of the sodium methionate solution to the isoelectric
point of the amino acid (pH = 5.7) (Goldfarb et al., 1981; Ullman,
1985).
L-methionine may be produced by the acylase-catalysed hydrolysis
of N-acetyl-DL-methionine (Hoppe & Martens, 1984; Ullman, 1985).
Details of contaminants, excipients and pharmaceutical aids
remain confidential to manufacturers.
Methionine is available as tablets of 250 mg (racemate).
The incorporation of methionine into tablets of paracetamol has
been suggested as a means of protecting against hepatic and renal
toxicity following paracetamol overdosage (McLean, 1974; McLean & Day,
1975). A preparation is now available commercially which contains
paracetamol 500 mg and DL-methionine 250 mg (Pameton, Sterling
Winthrop). Its use has been recommended in psychiatric wards in
patients with depression who need a simple analgesic, and in families
who are at risk (McLean, 1986). However, the formulation costs more
than any other brand of paracetamol and its efficacy in preventing
liver damage in humans following intentional paracetamol poisoning has
not yet been established.
2.5 Analytical methods
2.5.1 Quality control of antidote
The preparation must contain not less than 99% and not more than
the equivalent of 101% of DL-2-amino-4-(methylthio)butyric acid,
calculated with reference to the dried substance (European
Pharmacopoeia, 1989).
The European Pharmacopoiea (1989) describes the following assay
method:
Dissolve 0.14 g of the substance in 3 ml of anhydrous formic
acid. Add 30 ml of glacial acetic acid. Immediately after dissolution
titrate with 0.1N perchloric acid, determining the end-point
potentiometrically.
1 ml of 0.1N perchloric acid is equivalent to 14.92 mg
DL-methionine.
2.5.2 Methods for identification of antidote
The European Pharmacopoiea (1989) stipulates that the preparation
must be tested with either infrared absorption spectrophotometry or
thin layer chromatography and the spectrum or chromatogram obtained
compared with that for a reference sample of DL-methionine. In
addition, one or both of the tests described below should be carried
out. If the sample was tested spectrophotometrically then only test a)
need be carried out; if chromatographically, then tests a) and b)
should be carried out.
Additional tests:
a) Dissolve 2.5 g in 1N hydrochloric acid and dilute to 50 ml
with the same acid. The angle of optical rotation is
-0.05 ° to +0.05 °.
b) Dissolve 0.1 g of substance and 0.1 g of glycine in 4.5 ml
of 2M sodium hydroxide. Add 1 ml of a 2.5% (w/v) solution of
sodium nitroprusside. Heat to 40 °C for 10 min. Allow to
cool and add 2 ml of a mixture of 1 volume of phosphoric
acid and 9 volumes of hydrochloric acid. A deep red
colour develops.
2.5.3 Methods for analysis of antidote in biological samples
Plasma methionine concentrations may be measured using ion
exchange chromatography. There are several automated amino acids
analysers available which utilize this technique. Before analysis it
is necessary to deproteinise the plasma sample by mixing with
sulfosalicylic acid. An equal volume of an external standard is added
and the mixture centrifuged. The supernatant is injected into the
analyser (Smolin et al., 1981).
Finkelstein et al. (1982) describe a method for measuring
methionine and its metabolites using ion-exchange chromatography and
subsequent radio-enzymatic assay.
2.5.4 Methods for analysis of toxic agent
Section 1.6 gives details of analytical techniques available for
measuring plasma or serum paracetamol concentrations.
2.6 Shelf-life
DL-methionine should be stored in closed containers in cool, dry,
dark conditions. Degussa AG (1985) recommended that the time limit
for storage is two years.
2.7 General properties
2.7.1 Mode of antidotal activity
Methionine acts as a glutathione precursor and replenishes
glutathione stores depleted as a consequence of paracetamol overdose
(McLean & Day, 1975). Glutathione is a naturally occurring
tripeptide, composed of glycine, glutamic acid and cysteine, which
inactivates the reactive intermediate metabolite of paracetamol,
N-acetyl- p-benzoquinoneimine (NAPQI), by conjugation, resulting in
the formation of mercapturate and cysteine conjugates (Jagenburg &
Toczko, 1964), which are then excreted in the urine (see section 1.4
for details). Although, methionine acts as a glutathione precursor
(McLean & Day, 1975; Vina et al., 1978; Stramentinoli et al., 1979;
Vina et al., 1980), it must first undergo demethylation and then
transulfuration to produce cysteine (see section 2.8.2.1 for further
details of methionine metabolism).
2.7.2 Other properties
L-methionine has been administered to patients with Parkinson's
disease with differing results. Pearce & Waterbury (1974) found that
patients on levodopa or other antiparkinsonian therapy deteriorated
when given supplementary methionine. The patients were placed on a
low methionine diet (0.5 g/day; 3.35 mmol/day) and were given either
1.5 g (10.05 mmol) of L-methionine or placebo daily on a randomized,
double-blind basis. Clinical deterioration was noted from the fifth
day of the trial and was reversed after discontinuation of the
methionine. In a longer term, open study Smythies & Halsey (1984)
gave patients, whose parkinsonism was maximally controlled by drug
therapy, doses of L-methionine starting at 1 g/day (6.7 mmol/day) and
rising to 5 g/day (33.5 mmol/day). After a total of eleven weeks,
there was subjective improvement in 10 of 15 patients.
Oral administration of a large amount of methionine to
schizophrenic patients treated with a monoamine oxidase inhibitor has
been reported to produce either an intensification of schizophrenic
symptoms or superimposed toxic symptoms (Pollin et al., 1961; Brune &
Himwich, 1962; Park et al., 1965; Berlet et al., 1965). The reason
for this observation has not been established, but Kakimoto et al.
(1967) found evidence of amino acid imbalance (increased urinary
excretion of serine, threonine, glutamine and histidine) in eight
schizophrenic patients given isocarboxazid (1 mg/kg per day) and oral
L-methionine (0.3 g/kg per day; 2 mmol/kg per day) together, but not
when given isocarboxazid alone.
DL-methionine has been given in doses of 200 mg three or four
times daily to lower the pH of the urine and thus reduce odour and
irritation due to ammoniacal urine (Martindale, 1989). DL-methionine
is also used as a dietary supplement, as is L-methionine which is also
used in amino acid solutions given parenterally (Martindale, 1989).
2.8 Animal studies
2.8.1 Pharmacodynamics
There is considerable species difference in susceptibility to
paracetamol-induced liver damage, which correlates with differences in
the activity of the oxidative pathway in these species. Thus, while
doses of 750 mg/kg (4.96 mmol/kg) are sufficient to cause severe
hepatic necrosis in mice, doses of 1250-1500 mg/kg (8.3-9.9 mmol/kg)
cause very little hepatic necrosis in rats, despite being lethal
(Mitchell et al., 1973). In animal experiments to test the efficacy
of methionine, therefore, rats are usually sensitized to paracetamol
by pretreatment with phenobarbitone or other microsomal enzyme-
inducing compounds.
The time-scale for the development of liver damage in laboratory
animals is shorter than in humans. The results of animal studies
investigating the efficacy of methionine in relation to the time of
administration of paracetamol overdose cannot, therefore, readily be
extrapolated to humans. Nonetheless, in view of the rapidity of
glutathione depletion and the onset of covalent binding and consequent
liver damage, preventative treatment would seem to be needed soon
after paracetamol overdose in order to be maximally effective. Animal
studies investigating the efficacy of methionine in the prevention of
liver damage have largely involved its prior or simultaneous
administration with paracetamol.
When methionine was given to mice 5 min before, and 20 min after,
a toxic intraperitoneal dose (710 mg/kg; 4.7 mmol/kg) of paracetamol,
mortality was reduced from 43 to 16.7%. Methionine was administered
intramuscularly at a concentration of 7.5 mg/kg (0.05 mmol/kg)
(Stramentinoli et al., 1979). It is not clear from the report of this
study whether this represented the total dose of methionine given or
if the total dose was, in fact, 15 mg/kg (0.1 mmol/kg) (Stramentinoli
et al., 1979). The effective dose of methionine represented either 1
or 2% (w/w) of the dose of paracetamol.
The development of liver damage in mice, as indicated by
elevation of alanine aminotransferase (ALAT) activity, was prevented
completely by the intraperitoneal administration of L-methionine (1000
mg/kg; 6.7 mmol/kg) at the same time as oral administration of
paracetamol (300 mg/kg; 1.98 mmol/kg) (Miners et al., 1984). In the
control group, given no antidotal therapy, ALAT activity rose above
16 000 U/l, whereas in the group given methionine the ALAT activity
remained within the normal range. The LD50 of paracetamol was
increased more than three-fold, from 295 mg/kg (1.95 mmol/kg) to 910
mg/kg (6 mmol/kg). However, the co-administration of methionine did
not completely prevent depletion of hepatic glutathione content, which
dropped by about one third.
That the protective effect of methionine was due to facilitation
of glutathione synthesis was suggested by two findings in this study.
Firstly, the co-administration of methionine resulted in an increased
proportion of the dose of paracetamol being excreted as glutathione-
derived and sulfate conjugates. There was no significant change in
the amount excreted as glucuronide conjugates or as unchanged
paracetamol. Secondly, the protective effect of methionine was
removed by pretreating the animals with buthionine sulfoximine. This
compound specifically inhibits glutathione synthesis without affecting
any of the other enzyme systems pertinent to the mechanism of
paracetamol toxicity (Miners et al., 1984).
In another study where the toxin and protective agent were given
simultaneously, McLean & Day (1975) compared the efficacy of different
doses of methionine. They used rats sensitized by pretreatment with
phenobarbitone and gave the drugs orally. When the test animals were
given paracetamol (1 g/kg; 6.6 mmol/kg), 90% showed histological
evidence of liver damage and 16.7% died. When methionine was given at
a concentration of 300 mg/kg (2 mmol/kg), i.e. 30% (w/w), liver damage
was prevented completely. A 25% dose of methionine increased the
LD50 of paracetamol more than three-fold, from 2 g/kg (13.2 mmol/kg)
to more than 7.5 g/kg (49.6 mmol/kg). Neuvonen et al. (1985) also
found that the simultaneous oral administration of L-methionine was
effective in reducing the toxicity of paracetamol. In their studies on
mice, a 20% dose of L-methionine increased the LD50 of paracetamol
from a mean of 610 mg/kg (4 mmol/kg) to a mean of 1096 mg/kg (7.2
mmol/kg). Methionine has also been shown to be effective in reducing
mortality in dogs (Maxwell et al., 1975). When paracetamol (750
mg/kg; 4.95 mmol/kg) and methionine (150 mg/kg; 1 mmol/kg) were given
orally, mortality was reduced from 67% in controls to zero.
These studies confirm the usefulness of methionine in preventing
or reducing paracetamol-induced liver damage when it is given at the
same time as the toxin. Other animal work has shown that methionine
is effective when given after paracetamol.
Legros (1976) treated mice given an oral lethal dose of
paracetamol (875 mg/kg; 5.78 mmol/kg) with intraperitoneal methionine
administered 2 and 6 h later. The lowest dose tested was 25 mg/kg
(0.17 mmol/kg) given twice, the total representing 5.7% of the dose of
paracetamol. This dose significantly reduced the mortality of the
animals from 75% in the untreated group to 20%. Mortality decreased
with increasing dose of methionine. The optimal dose was found to be
200 mg/kg (1.34 mmol/kg), the total representing 45.7% of the dose of
paracetamol, which reduced mortality to 3%.
In the same study an attempt was made to define the time-limit
for the efficacy of methionine. Using the dosage of 200 mg/kg (1.34
mmol/kg), the optimal time was found to be within 2 h of paracetamol
administration. At this time interval, mortality was reduced to 10%
compared with 65% in control animals. As the delay before
administering methionine increased so its efficacy decreased, so that
by 6 h after administration of paracetamol the antidote was
ineffective. Even after 8 h, however, when the animals would have
sustained some liver damage, the administration of methionine did not
increase mortality above control levels (Legros, 1976).
2.8.2 Pharmacokinetics
Animal studies describing the rate of absorption or elimination
of orally or parenterally administered methionine have not been found
in the literature (except as below).
When rats were given intraperitoneal L-methionine in a dose of
149.2 mg/kg (1 mmol/kg), peak concentrations in the liver were reached
1 h after the injection and concentrations fell to less than twice
normal by 3 h. In rats fed a low protein diet, the rate of decline of
hepatic methionine was slower, so that the 3 h level was 700% of
control (Finkelstein et al., 1982).
2.8.2.1 Metabolism
The liver is the main site of methionine metabolism; as much as
48% of methionine metabolism occurs here (Zeisel & Poole, 1979). The
mechanism is well understood and has been reviewed extensively by
Stipanuk (1986), Mato et al. (1990) and Pisi & Marchesini (1990). It
is illustrated diagrammatically in Fig. 2.
The main pathway of methionine metabolism involves
transmethylation and transulfuration, but there is increasing evidence
for the importance of a transamination pathway (Benevenga, 1984).
The first step in the metabolism of methionine involves its
activation to the high energy sulfonium compound, S-adenosyl-L-
methionine. This is achieved by the transfer of the adenosyl moiety
of ATP to the sulfur atom of methionine. Thus one mole of ATP is
required for each mole of methionine metabolized in this system.
S-adenosyl-L-methionine synthetase (also called methionine adenosyl
transferase) catalyses this reaction.
S-adenosyl-L-methionine is then demethylated to produce
S-adenosyl-L-homo-cysteine, which is hydrolysed in a reversible
reaction to yield homocysteine and adenosine.
The formation of homocysteine marks a branch point in this
pathway of methionine metabolism. Homocysteine may either be
remethylated to methionine, used for the resynthesis of S-adenosyl-
L-homocysteine by reversal of hydrolysis, or irreversibly converted to
cystathionine.
The final stage in the transulfuration pathway is the cleavage of
cystathionine to produce cysteine and alpha-ketobutyrate. This is
catalysed by the enzyme cystathionine-ß-synthase, which is deficient
in individuals with homocystinuria. Homozygotes would be unable to
utilize DL-methionine as a glutathione precursor; obligate
heterozygotes also demonstrate an impaired ability to form
cystathionine (Boers et al., 1985).
Another metabolic pathway for methionine involves decarboxylation
of S-adenosyl-L-methionine and synthesis of polyamines and also,
possibly, the synthesis of methylthio compounds.
An alternative pathway for methionine metabolism that is
independent of the formation of S-adenosyl-L-methionine has been
suggested (Benevenga, 1984). It is thought that methionine is
transaminated to alpha-keto-gamma-methiolbutyrate which is then
decarboxylated to 3-methylthiopropionate. In vitro experiments
suggest that this compound may be further metabolized to yield
methanethiol and hydrogen sulfide. It is possible that the toxicity
(see below) of methionine may be due, at least in part, to the
formation of these compounds via the transamination pathway
(Benevenga, 1984; Finkelstein & Benevenga, 1986).
Methionine transamination takes place in several tissues
including heart, brain and spleen. Mitchell & Benevenga (1978) have
calculated, however, that 48% of transamination may occur in the
muscle and 40% in the liver.
The Cystathionine Pathway;V03AN02.BMP
2.8.3 Toxicology
2.8.3.1 Acute toxicity
Although L-methionine is an essential amino acid, it has been
shown to be toxic in excess. D-methionine is thought to be less
toxic, presumably because it is not metabolically active itself but
only after it has been converted by deamination and reamination to the
L-form. The rate of conversion may limit the cellular concentration
of L-methionine (Benevenga, 1974; Bowman & Rand, 1980).
In the rat the oral LD50 of L-methionine is 36 g/kg (241
mmol/kg) and the intraperitoneal LD50 is 4.3 g/kg (29 mmol/kg)
(NIOSH, 1992). For DL-methionine in the rat the lowest published
intraperitoneal lethal dose is 2 g/kg (13.4 mmol/kg) (NIOSH, 1992).
In mice the lowest published lethal doses of DL-methionine are: oral -
4 g/kg (26.8 mmol/kg); intraperitoneal - 1.5 g/kg (10 mmol/kg); and
intravenous - 300 mg/kg (2 mmol/kg) (NIOSH, 1992).
The effects of excess methionine have been investigated in a
number of animal species and differential toxicity has been noted
(Hardwick et al., 1970).
Loss of appetite and death was found in guinea-pigs given large
doses of L-methionine (Hardwick et al., 1970). These animals were
fasted for 18 h and then given methionine doses of 492 mg/kg (3.3
mmol/kg) by gavage at 8-h intervals. The animals stopped eating and
died at an average of 42 h (maximum 65 h) after initiation of the
experiment, i.e. after a total dose of 2.5 g/kg (16.5 mmol/kg). There
were no deaths among the control group of fasted animals.
Terminally, the experimental animals were found to be
hypothermic, immobile and opisthotonic. They had severe hypoglycaemia
(blood sugar averaged 207 mg/l compared with 1295 mg/l in controls)
with significantly depressed hepatic glycogen stores and generalised
aminoacidaemia. On postmortem examination, the liver was found to be
fatty; lipid was concentrated in the periportal hepatocytes with a
little present around the central veins. Hepatic lipid appeared as
early as 16 h into the experiment, after a total dose of 584 mg/kg
(6.6 mmol/kg). No hepatic lipid was found in control animals.
Hepatic ATP concentrations were only one-third that of the control
guinea-pigs. Even after a single dose of L-methionine (492 mg/kg; 3.3
mmol/kg), both blood sugar and hepatic glycogen were significantly
lower than in the controls. The administration of adenine at the same
time as L-methionine prevented a decrease in blood sugar and hepatic
ATP concentration (Hardwick et al., 1970).
The fall in hepatic ATP concentration was accompanied by a
comparable increase in the concentration of adenosyl thionium
compounds. This suggested that the reduction in ATP was, at least
partly, due to its utilization in the activation of methionine to
S-adenosyl-L-methionine (Hardwick et al., 1970).
The same dose fed to rats had no adverse effect; none of the
animals were ill at 21 days when the study terminated (Hardwick et
al., 1970).
2.8.3.2 Subacute and chronic toxicity
Although less relevant to acute treatment with methionine in
humans, the following observations have been made in long-term animal
studies.
Excessive dietary L-methionine has been shown to depress hepatic
cytochrome oxidase activity in rats fed 3% methionine for seven days,
compared with animals fed 0.3% (Finkelstein & Benevenga, 1986).
Suppression of growth was shown in another, longer term feeding
study (Stekol & Szaran, 1962). This study examined the D- and
L-enantiomorphs separately. D-and L-methionine supplements were fed to
30-day-old rats in four different proportions: 0.5%, 1.0%, 2.0% and
4.0% for periods of 1, 2, 3, 4 and 9 months. Both the 2% and 4%
supplements of both enantiomorphs suppressed weight gain, D-methionine
more so than L-methionine. After one month the rats given these
supplements were found to have enlarged livers and spleens, while the
pancreas was smaller and softer than normal. Some rats exhibited
hydronephrosis. On microscopic examination these organs showed
moderate to severe degenerative changes, although there were also
signs of regeneration in the liver. At this time there was no
increase in hepatic fat. The gonads, heart and other organs showed no
changes. L-methionine caused greater damage than D-methionine. Rats
fed 1% methionine for 1 month showed milder changes and those given
0.5% methionine showed no changes. After 3 months of feeding the 1-4%
supplements, the tissues were normal except for an increase in droplet
fat in the liver with each subsequent month (Stekol & Szaran, 1962).
In a study of the ability of rats of different ages to utilize
L-methionine, it was found that 30-day-old animals utilized far less
methionine in the production of phospholipids, choline and creatine
than those older than 90 days. This reduction in methionine
utilization may partly account for the organ damage seen in these
animals, as adult rats fed 4% methionine suffered no organ damage
(Stekol & Szaran, 1962).
Another study, in which different age groups of mice were fed
supplementary L-methionine for 42 days, did not show such a clear
age-related difference (Massie & Aiello, 1984). When 42-day-old mice
were fed methionine in their drinking-water at a concentration of 0.05
mol/litre, they did not show any reduction in weight gain but did have
a significantly shorter life-span than control mice. Older mice (581
days) given the same regimen had a similar life-span to that of the
young mice. Their life-span was not significantly different from that
of their control group, although the control group was considered to
have an unusually short life-span. The cause of death was not
investigated. The estimated total daily intake of L-methionine by the
mice in this study was 1.67 g/kg (11.2 mmol/kg), i.e. 1.03% of the
animals' total solid intake. This concentration was found to cause
only minor organ changes (Massie & Aiello, 1984).
2.8.3.3 Toxicity in experimental liver damage
Although the study by Legros (1976) (section 2.8.1) showed no
increase in mortality in mice with paracetamol-induced liver damage
who were given methionine, a study in rats with liver damage has shown
that oral methionine may cause hepatic encephalopathy when
administered in combination with ammonia. Higashi (1982b) induced
liver damage in rats by administering carbon tetrachloride.
Intragastric methionine 3.4 g/kg (23 mmol/kg) was then given, followed
an hour later by an intraperitoneal dose of ammonium acetate
(5 mmol/kg). While rats given methionine or ammonium acetate alone did
not develop hepatic encephalopathy, those given the two agents in
combination did so. Encephalopathy did not develop when glycine or
leucine was substituted for methionine.
When the interval between administration of methionine and
ammonium acetate was varied, the severity of encephalopathy was also
found to vary. Only mild and brief encephalopathy developed if the
ammonium compound was given either immediately or 30 min after
methionine. The most severe encephalopathy developed in rats given
ammonium acetate 120 min after methionine. This suggests that
methionine metabolites may be responsible for enhancement of the
encephalopathic effect of ammonia in rats with liver damage (Higashi,
1982b).
2.8.4 Effect in pregnancy
As described above, excessive dietary methionine reduces weight
gain, and in pregnant rats this may adversely affect fetal
development. When rats were given a diet containing 4% methionine
from day one of pregnancy, their food intake, and thus their weight
gain compared to control animals, was reduced. Fewer rats were able
to maintain their pregnancy and both average fetal weight and
placental weight were abnormally low. It is possible that some of
this adverse effect was due to impaired secretion of ovarian hormones
(Viau & Leathem, 1973).
2.9 Volunteer studies
Volunteer studies to investigate the pharmacokinetics of
methionine following therapeutic doses (or overdoses) of paracetamol
have not been undertaken. However, Stegink et al. (1986) studied the
ability of adult volunteers to utilize L-methionine and D-methionine
for nutritional purposes. The data indicate that adult humans do not
utilize D-methionine efficiently as a methionine source.
In a study to investigate methionine metabolism in patients with
liver disease, Higashi (1982a) measured serum methionine
concentrations in 20 healthy control subjects; values of 19 ± 12
µmol/l (2.8 ± 1.8 mg/l) were obtained. An intravenous methionine
loading test was performed in five of the control subjects to obtain
elimination constants. Serum methionine concentrations were 19 ± 4
µmol/l (2.8 ± 0.6 mg/l) prior to the administration of 10 mg
methionine per kg body weight; the mean elimination constant was
24.0 ± 6.3 x 10-3 min-1.
Plasma concentrations achieved after an oral loading dose of
methionine have been measured in two studies. In both cases
L-methionine in a dose of 0.1 g (0.7 mmol) per kg body weight was
given to male volunteers. In the study by Murphy-Chutorian et al.
(1985), the subjects were a group of 138 men, aged 31 to 65 years
(mean 53 years), referred for cardiac catheterization. Plasma
methionine concen-trations were measured before, and 6 h after, dosing
with L-methionine; the concentrations in 39 subjects found to have
normal coronary arteries were 20.25 ± 4.68 µmol/l (3.02 ± 0.7 mg/l)
before, and 483.3 ± 141.9 µmol/l (72.1 ± 21.2 mg/l) after loading; the
corresponding concentrations in the remaining 99 subjects were 20.53
± 7.53 µmol/l (3.06 ± 1.12 mg/l) and 537.5 ± 165.0 µmol/l (80.2 ± 24.6
mg/l), respectively. The differences in plasma methionine
concentrations were not statistically significant.
By comparison, Boers et al. (1985) examined a group of 20 men
aged 22-61 years (mean 42 years) and found a considerably higher mean
peak methionine concentration of 1063 ± 65 µmol/l (158.6 ± 9.7 mg/l)
between 1 and 8 h after dosing. The fasting methionine concentration
was slightly higher than in the study of Murphy-Chutorian et al.
(1985), i.e. 28 ± 2 µmol/l (4.2 ± 0.3 mg/l). Boers et al. (1983) also
measured methionine concentrations in pre- and post-menopausal women
given the same dose of methionine. In 10 pre-menopausal women (aged
14-42, mean 25 years) the fasting concentration of methionine was 26
± 2 µmol/l (3.9 ± 0.3 mg/l) and the peak concentration after the oral
loading dose was 1033 ± 60 µmol/l (154 ± 9 mg/l). In 10 post-
menopausal women (aged 45-59, mean 54 years) the corresponding figures
were 21 ± 1 µmol/l (3 ± 0.15 mg/l) and 1107 ± 53 µmol/l (165 ± 8
mg/l).
Elimination values for methionine after the loading dose were 0.1
± 0.03 l/h per kg for men and 0.08 ± 0.02 l/h per kg for both groups
of women (Boers et al., 1983).
2.9.1 Methionine in patients with hepatic dysfunction
Phear et al. (1956) studied the effects of DL-methionine
administered orally to 17 patients with liver disease. Nine patients
suffered from cirrhosis of the liver and had previously experienced
episodes of impending hepatic coma (chronic portal systemic
encephalopathy). Electroencephalograms were compatible with this
diagnosis. In eight of the patients, the extent of the portal venous
collateral circulation was assessed by transplenic portal venography
and a very extensive collateral circulation was demonstrated. In the
ninth patient, disturbance of blood clotting prohibited this
investigation. Enteric-coated tablets containing 250 mg DL-methionine
were given in divided doses between 6 am and 9 pm; the total daily
dose, usually 10 g, varied between 8 and 20 g. During the
administration of methionine, neurological deterioration occurred in
seven patients, and in two this effect was reproduced when the drug
was administered a second time. This occurred from 1 to 4 days after
commencing methionine administration and after total doses of 11 to
46 g methionine.
Two of the nine patients tolerated 80 and 99 g methionine without
neurological change. A further seven patients with portal cirrhosis
who had never exhibited neurological complications, tolerated 50-102
g methionine without neurological change. Liver function was
considered to be less severely impaired than in the patients who were
sensitive to the drug and an extensive collateral circulation was
demonstrated in only three. A patient with extra-hepatic portal vein
obstruction also showed no change.
In four patients who deteriorated after methionine
administration, the control blood methionine concentrations were
normal in two (9 and 18 mg/l; normal < 20 mg/l) and elevated in two
(26 and 39 mg/l). The concentration was increased in two (24 and 27
mg/l) and normal (13, 12, 20, 15 and 15 mg/l) in five of the patients
who were unaffected by methionine feeding. In both groups, the rise
in blood methionine concentrations after methionine administration was
comparable. Moreover, neurological deterioration occurred without
significant change in blood ammonium, blood pH or serum bilirubin
levels.
In summary, this study showed that oral methionine caused
neurological deterioration in patients with large collateral channels
between the portal and systemic venous systems with chronic portal
systemic encephalopathy. Clearly, this situation is very different
from that which obtains in the early stages following acute
paracetamol overdosage.
2.10 Clinical studies - clinical trials
Only one controlled trial of oral DL-methionine therapy in
paracetamol poisoning has been undertaken (Hamlyn et al., 1980, 1981;
Meredith, 1987). However, there have been two studies of the
intravenous use of methionine in paracetamol poisoning (Prescott et
al., 1976; Solomon et al., 1977).
2.10.1 Study by Prescott et al. (1976)
Prescott et al. (1976) reported 60 patients with paracetamol
poisoning that were treated with intravenous cysteamine, L-methionine,
or D-penicillamine and in whom the incidence and severity of hepatic
necrosis were compared with those in 70 patients who received
supportive therapy only.
2.10.1.1 Patients and treatment
The admission plasma paracetamol concentration, related to the
time after ingestion, was used as a guide to the severity of
intoxication and the need for treatment. Gastric aspiration and
lavage were carried out on all patients admitted within 4 h of
overdosage. Patients with nausea and vomiting were given maintenance
intravenous fluids and cyclizine intramuscularly if necessary.
Vitamin K and fresh-frozen plasma or clotting factor concentrates were
given if the prothrombin time ratio exceeded 3.0. Once specific
treatment became available, it was given to all patients with plasma
paracetamol concentrations above the line in Fig. 3.
Twenty patients (mean age 27 years) received methionine, and
three were thought to be at particular risk. Methionine was given
intravenously in an initial loading dose of 5 g injected over 10 min
followed by an infusion of a further 15 g over 20 h. The methionine
was stored in vials, dissolved in 5% dextrose immediately before use
and sterilized by passage through a bacterial filter.
2.10.1.2 Investigations
The following investigations were carried out daily for 5 days in
most patients: haemoglobin, total and differential white blood cell
count, platelet count, plasma urea, electrolytes, creatinine,
bilirubin, alkaline phosphatase, aspartate and alanine
aminotransferases (ASAT, ALAT), blood glucose level, prothrombin time
ratio and electrocardiogram. The plasma paracetamol concentration on
admission was estimated by a rapid spectrophotometric method (Routh et
al., 1968). Additional blood samples were taken 4-8 hourly for up to
72 h and the plasma concentrations of unchanged paracetamol in these
and the admission sample were subsequently determined by gas-liquid
chromatography (Prescott, 1971a). Urine was collected for 3-5 days
for estimation of paracetamol and its sulfate and glucuronide
conjugates to determine the minimum amount of paracetamol absorbed
(Prescott, 1971a,b). Many collections were incomplete.
2.10.1.3 Results of treatment
The actual or extrapolated plasma paracetamol concentration 4 h
after ingestion was used as a guide to the risk of liver damage. To
assess the effects of treatment within 10 h, patients were placed into
four groups of increasing risk according to the 4-h plasma paracetamol
concentration (<150, 150-250, 250-300, and > 300 mg/l). In these
four groups the mean plasma paracetamol concentrations on admission
and at 4 h after ingestion did not differ significantly among
different treatment regimens (Table 1). The severity of intoxication
and the risk of liver damage could therefore be regarded as similar,
allowing direct comparisons of the results of early treatment. The
incidence and severity of hepatic necrosis were assessed using
standard liver function tests, together with a "liver damage score"
which was calculated for each patient as the sum of the minimum values
of prothrombin time ratio, plasma bilirubin, and ASAT + ALAT/1000.
Thus with upper normal limits of 1.3, 1.0 mg/dl, 40 and 40 U/l,
respectively, the liver damage score would be 2.38. Liver damage was
defined as "severe" if the ASAT or ALAT activity exceeded 1000 U/l.
Tests of statistical significance were carried out with Student's
test, chi2, and Fisher's exact test as appropriate.
a) Supportive therapy only: The results of laboratory
investigations in patients receiving supportive therapy only are
set out in Table 1. The incidence and severity of hepatic
necrosis rose progressively with increasing 4-h plasma
paracetamol concentrations. With one exception, liver damage was
insignificant in the patients with 4-h values less than 150 mg/l,
whereas every patient with a paracetamol concentration greater
than 300 mg/l developed severe liver damage. In the latter group
the mean maximum values for ASAT, ALAT, bilirubin, and
prothrombin time ratio were 5293 and 3751 U/l, 7.3 mg/dl and 2.4,
respectively. The same pattern of increasing liver damage was
reflected in the liver damage scores. Three patients died in
hepatic failure and four developed acute renal failure.
b) Methionine: None of the 15 patients treated with methionine
within 10 h of ingestion died or developed acute renal failure,
and in 12 liver damage was absent or trivial. However, three
patients sustained severe damage with mean values of ASAT, ALAT,
bilirubin, prothrombin time ratio and liver damage score of 8133
and 6867 U/l, 3.3 mg/dl, 2.8 and 21.2, respectively. The
ingestion-treatment intervals were 8.8, 9.5 and 9.7 h, and the
4-h paracetamol concentrations were 357, 252 and 353 mg/l. Only
one patient was thought to be at particular risk. The inclusion
of these three patients is largely responsible for the high mean
values in Table 1. The incidence of severe liver damage in the
methionine group with a 4-h paracetamol concentration greater
than 300 mg/l was significantly less than in the corresponding
group receiving supportive therapy only (p < 0.01), but in all
other comparisons of treatment with methionine and supportive
therapy the differences were not statistically significant.
Liver-function tests were only mildly disturbed in five patients
receiving methionine 10-12 h after overdosage (see Table 1).
2.10.1.4 Toxicity of methionine
There were no adverse effects on haemoglobin, white blood cell
count, platelet count, or plasma urea, creatinine, electrolyte, and
calcium and blood glucose concentrations that could be attributed to
treatment with methionine.
2.10.1.5 Likelihood of benefit due to antidote
Intravenous methionine appeared to be effective in most patients.
However, three patients treated within 10 h suffered severe liver
damage, including one, who was apparently not at great risk with a 4-h
plasma paracetamol concentration of 252 mg/l. The results of
treatment with cysteamine and D-penicillamine in this study have not
been presented in detail, but none of 23 patients given cysteamine
within 10 h of ingestion suffered severe liver damage or renal
failure, and none died.
Cysteamine was partially effective at 10-12 h, but ineffective
12 h or more after ingestion. Of five patients treated with
D-penicillamine, one developed severe liver damage with acute renal
failure.
2.10.2 Study by Solomon et al. (1977)
Solomon et al. (1977) reported 12 patients with paracetamol
poisoning, half of whom were treated with cysteamine and half with
intravenous amino acid preparations (Aminosol 10%, Aminoplex 14)
containing methionine and cysteine.
2.10.2.1 Results of treatment
In only one patient in the cysteamine-treated group was the ALAT
activity raised, and the bilirubin concentration was not raised above
normal in any patient. In the amino acid-treated group, two patients
showed a mild rise in ALAT activity, and serum bilirubin
concentrations remained normal in all patients.
2.10.2.2 Toxicity of methionine
No side effects attributable to therapy occurred in the amino
acid-treated group, but nausea, vomiting and muscle twitching variably
occurred in all the patients treated with cysteamine.
Table 1. Results (mean ± SEM) of investigations in patients receiving either supportive therapy or methioninea
No. of 4-h Plasma Mean 4-h Mean minimum Mean No. of Mean maximum
patients paracetamol plasma urinary ingestion- patients (%)
(n=95) concentration paracetamol recovery of treatment with severe ASAT ALAT bilirubin prothrombin
(mg/l) (mg/l) paracetamol interval liver damageb (U/l) (U/l) concentration time ratio
(g) (h) (mg/dl)
Supportive therapy only (n=70)
16 < 150 92 ± 11 7.4 ± 0.7 - 1 (6) 90 ± 44 107 ± 60 0.8 ± 0.1 1.3 ± 0.02
23 150-250 199 ± 5 9.5 ± 1.3 - 6 (26) 515 ± 190 591 ± 232 1.1 ± 0.1 1.6 ± 0.1
15 250-300 275 ± 15 12.1 ± 1.2 - 6 (40) 1412 ± 704 1702 ± 754 2.1 ± 0.6 1.6 ± 0.1
16 > 300 404 ± 26 15.6 ± 3.2 - 16 (100)c 5293 ± 798 3751 ± 779 7.3 ± 1.5 2.4 ± 0.2
Methionine < 10 h (n=20)
5 150-250 219 ± 4 13.5 ± 0.7 5.7 ± 0.8 0 (0) 26 ± 5 31 ± 9 1.0 ± 0.1 1.4 ± 0.02
3 250-300 277 ± 13 12.6 ± 0.7 8.7 ± 0.6 1 (33) 1087 ± 1057 1096 ± 1052 1.1 ± 0.2 1.4 ± 0.2
7 > 300 379 ± 27 15.7 ± 1.7 7.7 ± 0.5 2 (29) 3070 ± 1968 2539 ± 1606 2.1 ± 0.7 2.0 ± 0.4
Methionine > 10 h (n=5)
5 314 ± 30 - 11.1 ± 0.2 0 251 ± 178 268 ± 182 1.1 ± 0.2 1.4 ± 0.1
a From: Prescott et al. (1976)
b ASAT or ALAT > 1000 U/l
c 3 deaths
2.10.2.3 Likelihood of benefit due to antidote
Unfortunately, it is impossible to determine whether methionine
had any beneficial effect in these patients, for the reasons set out
below.
Firstly, the amino acid solutions contained cysteine as well as
methionine. Cysteine alone has been shown to protect against
paracetamol toxicity in mice (Strubelt et al., 1974) and it is thought
to act as a glutathione precursor (Reed & Beatty, 1980). Indeed,
N-acetylcysteine is first converted to cysteine by deacetylation
before it acts as a glutathione precursor (Lauterberg et al., 1983).
Cysteine may also act as a source of sulfate for conjugation with
unchanged paracetamol (Glazenberg et al., 1984). Secondly, in six
patients plasma paracetamol concentrations were measured within 4 h of
ingestion of the overdose and are therefore uninterpretable. Only
five of the six remaining patients were at risk when judged by the
criterion now applied before considering specific therapy [a plasma
paracetamol concentration falling above a line joining 200 mg/l (1.32
mmol/l) at 4 h and 50 mg/l (0.33 mmol/l) at 12 h after ingestion of
the overdose when plotted on a semi-logarithmic paracetamol
concentration time scale (Meredith et al., 1986)]. Only one of these
five patients was treated with an amino acid solution and she
developed minor disturbance of hepatic function with a peak ALAT
activity of 67 U/l.
2.10.3 Study by Hamlyn et al. (1981)
Hamlyn et al. (1981) were stimulated by case reports (Crome et
al., 1976) of the successful use of oral methionine in the treatment
of paracetamol poisoning to undertake a collaborative, controlled
trial.
2.10.3.1 Results of treatment
In total, 40 patients at risk from hepatic and renal toxicity due
to serious paracetamol overdose were studied. Hepatic necrosis, as
judged by "blind" histological assessment, occurred significantly less
often in actively treated patients (methionine p < 0.02, cysteamine
p < 0.01). Significant differences in peak serum ASAT activity were
seen, the geometric means being 1046 U/l in the supportive group,
96 U/l in the cysteamine group, and 139 U/l following methionine
treatment (Wilcoxon sum of ranks p < 0.01 in favour of methionine,
p < 0.002 in favour of cysteamine). These differences in favour of
cysteamine and methionine were also reflected in peak serum bilirubin
concentrations and prothrombin time ratios.
2.10.3.2 Likelihood of benefit due to antidote
This trial is the only controlled study of the use of oral
methionine in the treatment of paracetamol poisoning, although it was
not truly prospective because four patients had been included in an
earlier trial and had been reported previously (Douglas et al., 1976).
A convincing hepatoprotective effect of early intravenous cysteamine
and oral methionine was demonstrated. However, no clear difference in
efficacy of the two protective agents was shown, although early
methionine administration was associated with few, if any, undesirable
side-effects.
2.11 Clinical studies - case reports
The London Centre of the National Poisons Information Service in
the United Kingdom recommended the use of oral methionine from 1974
(Crome et al., 1976) in patients thought to be at risk of paracetamol-
induced liver damage. Initially, this was as an alternative to
intravenous cysteamine and then later to intravenous
N-acetylcysteine (Meredith, 1987).
2.11.1 Study by Vale et al. (1981)
Vale et al. (1981) reported on the efficacy of oral methionine
therapy in 132 patients at risk of paracetamol-induced hepatic and
renal toxicity. Some of these patients had been reported previously
(Crome et al., 1976; Meredith et al., 1978; Vale et al., 1979);
because of the retrospective nature of the study, it does not
constitute a formal clinical trial.
2.11.1.1 Patients and treatment
This study included 132 adult patients who were initially seen
within 24 h of their overdose, which occurred between 1974 and 1979.
These patients had plasma paracetamol concentrations falling above a
line joining plots of 200 mg/l (1.32 mmol/l) at 4 h and 70 mg/l (0.46
mmol/l) at 12 h. More severely poisoned patients, with plasma
paracetamol concentrations above a line joining 300 mg/l (1.98 mmol/l)
at 4 h and 75 mg/l (0.50 mmol/l) at 12 h, were classified as a high-
risk group. Where necessary, the plasma paracetamol plots were
extended to 24 h.
Of the 132 patients, 88 patients claimed to have taken only
paracetamol, 16 took ethanol in addition, eight took benzodiazepines,
three took dextropropoxyphene hydrochloride in combination with
paracetamol (Distalgesic), and 17 ingested other drugs (including
aspirin, tricyclic antidepressants, and orphenadrine hydrochloride).
The mean age of the 132 patients was 26 years (range, 14 to 73 years);
48 were male and 84 were female.
All patients underwent gastric lavage within 6 h of ingestion of
the overdose. Patients with persistent nausea and vomiting were also
given intravenous fluid replacement and anti-emetics. Each patient
received methionine orally in a dose of 2.5 g, which was then repeated
on three subsequent occasions at 4-hourly intervals (i.e. 10 g during
12 h).
2.11.1.2 Investigations
All patients had plasma paracetamol levels measured on admission
and at least once subsequently. Haematological and biochemical tests
were performed on admission and daily thereafter for at least 7 days.
Severe liver damage was defined as an increase in serum ASAT activity
to a level above 1000 U/l, and renal impairment as a serum creatinine
concentration greater than 300 µmol/l.
2.11.1.3 Results of treatment
The efficacy of methionine was assessed by comparing it with the
results of supportive therapy alone [when given to 57 similarly
poisoned patients treated at the Royal Infirmary, Edinburgh (Prescott
et al., 1979)]. Chi-square statistics were used for this purpose,
with Yates' correction for continuity. Comparisons were also made
with patients treated with oral (Rumack & Peterson, 1978) and
intravenous (Prescott et al., 1979) N-acetylcysteine. It should be
noted, however, that in these two other studies (Rumack & Peterson,
1978; Prescott et al., 1979), the "treatment" lines adopted joined
plots of 200 mg/l (1.32 mmol/l) at 4 h and 50 mg/l (0.33 mmol/l) at
12 h, and that they cannot therefore be compared directly.
The patients were divided into two main groups depending on
whether oral methionine was given either within, or later than, 10 h
after paracetamol ingestion. These two groups of patients were
further subdivided into those who were at moderate risk and those who
were at high risk of severe liver damage on the basis of their plasma
paracetamol concentrations (Table 2).
2.11.1.4 Liver damage
a) Oral methionine given within 10 h: Only seven of the 96
patients given methionine within ten hours had severe liver
damage, as compared with 33 (58%) of the 57 patients given
supportive treatment (Table 3).
Patients given methionine showed an increase in mean maximum
serum ASAT activity to 294 U/l, compared to a mean maximum level of
more than 2000 U/l in those treated supportively. (Between 1969 and
1973, the liver enzyme test results at the Royal Infirmary, Edinburgh,
were reported as more than 850 or 1000 U/l; therefore, a precise
figure cannot be given.)
Table 2. Severity of poisoning and time of methionine administration
in 132 patients at risk of paracetamol-induced hepatorenal
toxicity
Commencement of treatment
(hours after overdose)
< 10 10-24
All patientsa (n = 132) 96 36
High-risk patientsb (n = 74) 43 31
a Plasma paracetamol concentration > 200 mg/l (1.32 mmol/l) at
4 h and > 70 mg/l (0.46 mmol/l) at 12 h
b Plasma paracetamol concentration > 300 mg/l (1.98 mmol/l) at
4 h and > 75 mg/l (0.50 mmol/l) at 12 h
Of the seven patients in whom severe liver damage developed, six
were severely poisoned (high-risk cases), but only one had transient
hepatic failure; none of these patients died. All seven patients
underwent gastric lavage within 5´ h of ingestion of the overdose, and
all received methionine within 8 h, although two vomited the first
dose.
The incidence of severe liver damage in patients given methionine
was significantly less than that found in those treated supportively
(chi2 corrected for continuity, 44.8; p < 0.0001).
b) Oral methionine given within 10-24 h
In 36 cases, methionine was given 10-24 h after ingestion
(Table 3). Severe liver damage occurred in 17 (47%), and the mean
maximum ASAT activity was 1464 U/l. These results were not
statistically different from those found in patients given supportive
treatment only.
2.11.1.5 High-risk patients
Severe hepatic damage occurred in 89% of high-risk patients
treated supportively (Table 4), whereas only 14% of those treated with
oral methionine within 10 h of ingestion had severe liver damage
(chi2 corrected for continuity, 36.1; p < 0.0001). In patients
treated between 10 and 24 h after ingestion, those in whom severe
liver damage developed numbered half those of the group receiving
supportive treatment alone (chi2 corrected for continuity, 10.9;
p < 0.0001).
2.11.1.6 Renal impairment
One patient given oral methionine within 10 h had transient renal
failure (even though his maximum ASAT activity was only 160 U/l).
Renal impairment occurred in two other patients (6%) treated between
10 and 24 h after ingestion, whereas six (11%) of 57 patients in the
group treated supportively suffered the same complication.
2.11.1.7 Deaths
None of the patients given oral methionine within 10 h died of
hepatic failure, but two high-risk patients, both treated later than
10 h after ingestion, died.
2.11.1.8 Toxicity of methionine
Methionine did not produce any serious side effects. Twenty-two
(17%) of the 132 patients vomited before treatment with methionine,
but only seven (5%) vomited afterwards.
2.11.1.9 Likelihood of benefit due to antidote
Comparative data for oral and intravenous acetylcysteine are
shown in Tables 3-4. When given within 10 h, both methionine and
N-acetylcysteine protected against death caused by hepatic failure.
The incidence of severe liver damage was not significantly different
in the three treatment groups; similar results were seen for those
patients treated between 10 and 24 h. In this retrospective study,
oral methionine was clearly effective in protecting against severe
liver damage, renal failure and death after paracetamol overdose when
given within 10 h of ingestion.
2.12 Summary of evaluation
2.12.1 Indications
Oral methionine is indicated for the treatment of acute
paracetamol (acetaminophen) poisoning. When 4 h or more have elapsed
after ingestion of an overdose the plasma concentration of paracetamol
should be measured. Specific treatment with methionine is required if
the plasma paracetamol concentration falls above a line which on a
semilog graph joins plots of 200 mg/l (1.32 mmol/l) at 4 h and 30 mg/l
(0.33 mmol/l) at 15 h after the overdose (see Fig. 1 in section 1.3).
In cases where plasma concentrations of methionine are not available,
methionine should be given if more than 100 mg paracetamol/kg is taken
in a single dose.
Table 3. Hepatic and renal damage in patients poisoned with paracetamol given oral methionine, or oral or
intravenous N-acetylcysteine
Treatment No. of No. (%) with Mean No. (%) Mortality
patients severe liver maximum with acute (%)
damage (ASAT ASAT renal
> 1000 U/l) (U/l) failure
Oral methionine 96 7 (7) 294 1 (1) 0
given within 10 ha
Oral N-acetylcysteine
given within 10 h (Rumack 49 8 (16) 210 0 0
& Peterson, 1978)b
Intravenous N-acetylcysteine
given within 10 h (Prescott 62 1 (2) 113 0 0
et al., 1979)b
Oral methionine given
within 10-24 ha 36 17 (47) 1464 2 (6) 2 (6)
Oral N-acetylcysteine
given within 10-24 h (Rumack
& Peterson, 1978)b 51 23 (45) 2207 0 0
Intravenous acetylcysteine
given within 10-24 h
(Prescott et al., 1979)b 38 20 (53) 3814 5 (13) 2 (5)
Supportive treatment only
(Prescott et al., 1979)b 57 33 (58) > 2022 6 (11) 3 (5)
a Plasma paracetamol concentration > 200 mg/l (1.32 mmol/l) at 4 h and > 70 mg/l (0.46 mmol/l) at 12 h
b Plasma paracetamol concentration > 200 mg/l (1.32 mmol/l) at 4 h and > 50 mg/l (0.33 mmol/l) at 12 h
Table 4. Hepatic and renal damage in high-riska patients poisoned with paracetamol given oral methionine
or intravenous N-acetylcysteine
Treatment No. of No. (%) with Mean No. (%) Mortality
patients severe liver maximum with acute (%)
damage (ASAT ASAT renal
> 1000 U/l) (U/l) failure
Oral methionine given
within 10 h 43 6 (14) 464 1 (2) 0
Intravenous N-acetylcysteine
given within 10 h
(Prescott et al., 1979)b 33 1 (3) 185 0 0
Oral methionine given
within 10-24 h 31 14 (45) 1532 2 (6) 2 (6)
Intravenous acetylcysteine
given within 10-24 h
(Prescott et al., 1979) 27 18 (67) 4919 5 (19) 2 (7)
Supportive treatment only
(Prescott et al., 1979) 28 25 (89) > 3186 6 (21) 3 (11)
a Plasma paracetamol concentration > 300 mg/l at 4 h and > 75 mg/l at 12 h
b Plasma creatinine concentration > 300 µmol/l
If the patient is either vomiting or unconscious (usually the
result of taking another drug in addition to paracetamol), then it is
more appropriate to give N-acetylcysteine by the intravenous route.
Children aged less than 6 years tend to swallow only small amounts of
paracetamol and specific treatment is rarely indicated (Meredith et
al., 1978). Nevertheless, plasma paracetamol concentrations should be
measured and interpreted as in adult patients (Meredith, 1987).
Adolescents, who are more likely than younger children to take a
hepatotoxic dose of paracetamol, should be dealt with similarly.
Certain special situations arise in adult patients. Firstly,
some patients take repeated doses of paracetamol over a period of
hours or days that either individually or in total are potentially
hepatotoxic. The interpretation of single measurements of the plasma
paracetamol concentration is therefore difficult or impossible in
these circumstances, and immediate specific therapy is advised
provided that liver dysfunction has not already developed, as shown,
for example, by an elevated prothrombin time ratio. Secondly, a
paracetamol overdose is sometimes taken in combination with drugs that
delay gastric emptying (for example, dextropropoxy-phene or tricyclic
antidepressants) and, therefore, gastrointestinal absorption. The
so-called "treatment line" (which on a semilog graph joins plots of
200 mg/l at 4 h and 30 mg/l at 15 h after ingestion) will be shifted
to the right as a consequence. The extent to which this will occur
cannot easily be predicted and care must be taken to avoid
under-treatment of this group of patients. If there is any doubt,
specific treatment should be given.
2.12.2 Advised route and dosage
Methionine should be given orally in a dose of 2.5 g, followed
by three further doses of 2.5 g at 4-hourly intervals. Adolescents at
risk may be given the same doses, but children aged less than 6 years
should be given 1 g orally followed by three further doses of 1 g at
4-hourly intervals. If a patient is vomiting and is unable to
tolerate oral methionine, intravenous N-acetylcysteine should be
given. The intravenous administration of methionine cannot be
recommended (see section 2.12.4).
2.12.3 Other consequential or supportive therapy
Patients who present to hospital within 1-2 h and who are thought
to have ingested 100 mg paracetamol/kg body weight or more should
undergo gastric lavage. As already mentioned, children aged less than
six years tend to swallow only small amounts of paracetamol and
gastric lavage is probably unnecessary. In neither adults nor
children has the value of syrup of ipecacuanha or activated charcoal
been established. In addition, the former may preclude the
administration of methionine because of resultant persistent nausea
and vomiting, and the latter is likely to adsorb (and therefore annul
the effect of) methionine administered either beforehand or
afterwards. For these reasons syrup of ipecacuanha should not be
employed in the treatment of paracetamol overdosage, and the use of
activated charcoal should be avoided unless intravenous therapy (with
N-acetylcysteine) is to be employed.
2.12.4 Areas of use where there is insufficient information to make
recommendations
The time after ingestion of a paracetamol overdose at which the
oral administration of methionine ceases to provide protection against
hepatic and renal damage has not been established with certainty. The
evidence shows that the degree of protection afforded declines rapidly
once more than 10 h has elapsed after the overdose. On present
evidence, specific treatment should be given up to 15 h after the
overdose provided that the International Normalized Ratio (prothrombin
time) remains normal. There are insufficient data to make
recommendations about methionine therapy for the period 10-24 h after
a paracetamol overdose or thereafter.
There are insufficient published data on the clinical efficacy
and safety in use of methionine administered intravenously (and
neither is a pharmaceutical preparation available). For this reason,
a recommendation concerning the use of methionine in this manner
cannot be made.
2.12.5 Proposals for further studies
The dosage regimen for methionine was empirically based on its
action as a glutathione precursor. Further information is needed
about the optimal dosage, kinetics of absorption and treatment period.
Different formulations of methionine should be studied in paracetamol
overdose patients to define and obtain optimal absorption
characteristics. Childhood dosage regimens should also be
investigated because the dose employed currently may be more than is
necessary, and the use of intravenous preparations of
N-acetylcysteine may sometimes cause problems with fluid overload.
Prospective studies comparing oral methionine and intravenous
N-acetylcysteine therapy should be performed because: (a) those
undertaken so far have used historical controls; and (b) the use of
methionine in developing countries may have wider applicability than
N-acetylcysteine (because of the greater cost of the latter and
difficulties with the cold chain in relation to transportation and
storage). The efficacy of treatment should be assessed during
successive periods of time between 10 and 24 h, or even later, after
paracetamol overdosage to determine the latest point at which it may
be employed effectively. (Unfortunately, the safety in use and
established clinical efficacy of N-acetylcysteine reduces the
likelihood of such studies being undertaken.)
There is no evidence as yet, from the use of methionine in
humans, as to whether protection against paracetamol-induced toxicity
results in retardation of fetal growth or even teratogenicity.
Epidemiological studies are therefore indicated. Finally, it would be
desirable to determine the efficacy of methionine as a protective
agent for paracetamol poisoning in heterozygotes for homocystinuria
(see section 2.8.2.1), but there is the obvious practical difficulty
of being able to study a sufficient number of individuals with this
condition who have taken a paracetamol overdose.
2.12.6 Adverse effects
Oral methionine therapy in the dosage used for paracetamol
poisoning has not been associated in practice with any adverse effects
in patients with or without paracetamol-induced liver failure. There
is, however, evidence of neurological deterioration associated with
methionine administration to patients with chronic hepatic dysfunction
from causes other than paracetamol.
There is also evidence of increased hepatotoxicity when
methionine is given to mice with liver failure induced experimentally
by carbon tetrachloride, but not if induced by paracetamol.
2.12.7 Restrictions of use
On theoretical grounds, methionine is likely to be ineffective in
patients with homocystinuria and N-acetylcysteine should be given
instead following paracetamol overdose.
If patients are vomiting or unconscious, intravenous
N-acetylcysteine should be given in preference to methionine.
N-acetylcysteine is also the preferred agent in patients with
chronic hepatic failure who have taken paracetamol in overdose.
2.13 Model information sheet
2.13.1 Uses
Methionine is indicated for the treatment of acute paracetamol
(acetaminophen) poisoning if a patient is at risk of developing
hepatic or renal toxicity. The risk may be judged by measuring the
plasma paracetamol concentration when more than 4 h have elapsed after
the overdose. Oral methionine should be given if the plasma
paracetamol concentration lies above a line which on a semilog graph
joins plots of 200 mg/l (1.32 mmol/l) at 4 h and 30 mg/l (0.20 mmol/l)
at 15 h after overdose (see Fig. 1 in section 1.3).
Methionine is also indicated if more than 100 mg paracetamol/kg
has been ingested in a single dose and plasma paracetamol
concentrations are not available.
2.13.2 Dosage and route
The dose for adults and adolescents is 2.5 g orally, followed by
a further three doses of 2.5 g at 4-hourly intervals (10 g in total).
Children aged less than 6 years tend to swallow only small amounts of
paracetamol and specific treatment is rarely indicated but, if
necessary, the dose is 1 g orally, followed by a further three doses
of 1 g at 4-hourly intervals.
2.13.3 Precautions/contraindications
If a patient is vomiting or unconscious (usually the result of
taking another drug), then alternative specific treatment should be
administered. Special attention should be given to the need for
treatment in patients who present 10-24 h after the overdose and in
patients who have taken repeated doses of paracetamol. In patients
who have taken other drugs that might delay gastric emptying (for
example, opiates or tricyclic antidepressants) and who present more
than 10 h after the overdose, an intravenous protective agent
( N-acetylcysteine) may be preferred because the kinetics of
absorption of methionine are likely to be disturbed.
N-acetylcysteine, rather than methionine, should be used as
protective therapy in patients with homocystinuria and chronic liver
failure.
2.13.4 Adverse effects
Oral methionine therapy in the dosage used for paracetamol
poisoning has not been associated in practice with any adverse
effects. Early concerns that methionine might contribute to hepatic
encephalopathy in paracetamol-induced liver failure have not been
substantiated, and review of the data suggests that it is unlikely to
occur.
2.13.5 Use in pregnancy and lactation
Animal studies, in which large amounts of methionine (up to 4% of
the total diet) were given orally, have shown suppression of growth,
but there is no evidence in humans that methionine is a hazard in
pregnancy or during lactation. If the mother is at risk of
paracetamol-induced hepatic and renal toxicity, then treatment should
not be withheld. Moreover, it should be remembered that the unborn
fetus is itself at risk of paracetamol-induced hepatotoxicity.
2.13.6 Storage
Methionine should be stored in closed containers in cool, dry,
dark conditions. The recommended time-limit for storage is 2 years.
2.14 References
Benevenga NJ (1974) Toxicities of methionine and other amino acids.
J Agric Food Chem, 22: 2-9.
Benevenga NJ (1984) Evidence for alternative pathways of methionine
catabolism. Adv Nutr Res, 6: 1-18.
Berlet HH, Matsumoto K, Pscheidt GR, Spaide J, Bull C, & Himwich HE
(1965) Biochemical correlates of behavior in schizophrenic patients.
Schizophrenic patients receiving tryptophan and methionine or
methionine together with a monoamine oxidase inhibitor. Arch Gen
Psychiatr, 13: 521-531.
Boers GH, Smals AG, Trijbels FJ, Leermakers AI, & Kloppenborg PW
(1983) Unique efficiency of methionine metabolism in premenopausal
women may protect against vascular disease in the reproductive years.
J Clin Invest, 72: 1971-1976.
Boers GHJ, Fawler B, Smals AGH, Trijbels FJA, Leermakers AI, Kleijer
WJ, & Kloppenborg PWC (1985) Improved identification of heterozygotes
for homocystinuria due to cystathionine synthase deficiency by the
combination of methionine loading and enzyme determination in cultured
fibroblasts. Hum Genet, 69: 164-169.
Bowman WC & Rand MJ (1980) Textbook of pharmacology. Oxford,
Blackwell Scientific Publications, p 1-20.
Brune GG & Himwich HEJ (1962) Effects of methionine loading on the
behaviour of schizophrenic patients. J Nerv Ment Dis, 134: 447-450.
Budavari S ed. (1989) The Merck Index, 11th ed. Rohway, New Jersey,
Merck & Co., Inc., p 5901.
Crome P, Vale JA, Volans GN, Widdop B, & Goulding R (1976) Oral
methionine in the treatment of severe paracetamol (acetaminophen)
overdose. Lancet, 2: 829-830.
Degussa AG (1985) Amino acids: specifications and analytical methods.
Hanau, Germany, Degussa AG.
Douglas AP, Hamlyn AN, & James O (1976) Controlled trial of
cysteamine in treatment of acute paracetamol (acetaminophen)
poisoning. Lancet, 1: 111-115.
European pharmacopoiea (1989) 2nd. Part II, 13th fascicule. Sainte
Ruffine, France, Maisonneuve SA.
Finkelstein A & Benevenga NJ (1986) The effect of methanethiol and
methionine toxicity on the activities of cytochrome oxidase and
enzymes involved in protection from peroxidative damage. J Nutr, 116:
204-215.
Finkelstein JD, Kyle WE, Harris BJ, & Martin JJ (1982) Methionine
metabolism in mammals: concentration of metabolites in rat tissues.
J Nutr, 112: 1011-1018.
Glazenberg EJ, Jekel-Halsema IMC, Baranczyk-Kuzma A, Krijgsheld KR, &
Mulder GJ (1984) D-Cysteine as a selective precursor for inorganic
sulphate in the rat in vivo. Biochem Pharmacol, 33: 625-628.
Goldfarb AS, Goldgraben GR, Herrick EC, Ouellette RP, & Cheremissinoff
PN (1981) Organic chemicals manufacturing hazards. Chapter 4:
Condensation process for DL-methionine production. Ann Arbor,
Michigan, Ann Arbor Science Publishers, Inc., pp 115-194.
Hamlyn AN, Lesna M, Record CO, Smith PA, Watson AJ, Meredith TJ,
Widdop B, Volans GN, & Crome P (1980) Prevention of hepatic necrosis
in severe paracetamol (acetaminophen) poisoning: Prospective
controlled kind of early treatment with cysteamine or methionine. Gut,
21: A448.
Hamlyn AN, Lesna M, Record CO, Smith PA, Watson AJ, Meredith T, Volans
GN, & Crome P (1981) Methionine and cysteamine in paracetamol
(acetaminophen) overdose. Prospective controlled trial of early
therapy. J Int Med Res, 9: 226-231.
Hardwick DF, Applegarth DA, Cockcroft DM, Ross PM, & Calder RJ (1970)
Pathogenesis of methionine-induced toxicity. Metabolism, 19: 381-391.
Higashi T (1982a) Impaired metabolism of methionine in severe liver
diseases I. Clinical and pathophysiological significance of elevated
serum methionine levels. Gastroenterol Jpn, 17: 117-124.
Higashi T (1982b) Impaired metabolism of methionine in severe liver
diseases II. Clinical and experimental studies on the role of impaired
methionine metabolism in the pathogenesis of hepatic encephalopathy.
Gastroenterol Jpn, 17: 125-134.
Hoppe B & Martens J (1984) [Manufacture and extraction of amino
acids.] Chem Zeit, 3: 73-86 (in German).
Jagenburg OR & Toczko K (1964) The metabolism of acetophenetidine.
Isolation and characterization of S-(1-acetamido-4-hydroxyphenyl)-
cysteine, a metabolite of acetophenetidine. Biochem J, 92: 639-643.
Kakimoto Y, Sanmo I, Kanazawa A, Tsujio T, & Kaneko Z (1967)
Metabolic effects of methionine in schizophrenic patients pretreated
with a monoamine oxidase inhibitor. Nature (Lond), 216: 1110-1111.
Klein-Schwartz W & Oderda GM (1981) Adsorption of oral antidotes for
acetaminophen poisoning (methionine and N-acetylcysteine) by
activated charcoal. Clin Toxicol, 18: 283-290.
Lauterberg BH, Corcoran GB, & Mitchell JR (1983) Mechanism of action
of N-acetylcysteine in the protection against the hepatotoxicity of
acetaminophen in rats in vivo. J Clin Invest, 71: 980-991.
Legros J (1976) Animal studies - a theoretical basis for treatment.
J Int Med Res, 4 (Suppl. 4): 46-54.
McLean AEM (1974) Prevention of paracetamol poisoning. Lancet, 1:
729. McLean AEM (1986) Why do patients still die from paracetamol
poisoning? Br Med J, 294: 1172.
McLean AEM & Day PA (1975) The effect of diet on the toxicity of
paracetamol and the safety of paracetamol-methionine mixtures. Biochem
Pharmacol, 24: 37-42.
Martindale (1989) In: Reynolds JEF ed. The extra pharmacopoiea, 29th
ed. London, Pharmaceutical Press, p 843.
Massie HR & Aiello VR (1984) The effect of dietary methionine on the
copper content of tissues and survival of young and old mice. Exp
Gerontol, 19: 393-399.
Mato JM, Corrales F, Martin-Duce M, Ortiz P, Pajares MA, & Cabrero C
(1990) Metabolism and consequences of the impaired trans-sulphuration
pathway in liver disease: Part I Biochemical implications. Drugs,
40(Suppl. 3): 58-64.
Maxwell LF, Cotty VF, Marcus AD, & Barnett L (1975) Prevention of
acetaminophen (paracetamol) poisoning. Lancet, 11: 610-611.
Meredith TJ (1987) Paracetamol poisoning in England and Wales.
University of Cambridge, pp 93-112 (M.D. Thesis).
Meredith TJ, Crome P, Volans GN, & Goulding R (1978) Treatment of
paracetamol poisoning. Br Med J, 1: 1215-1216.
Meredith TJ, Prescott LF, & Vale JA (1986) Why do patients still die
from paracetamol poisoning? Br Med J, 293: 345-346.
Miners JO, Drew R, & Birkett DJ (1984) Mechanism of action of
paracetamol protective agents in mice in vivo. Biochem Pharmacol,
33: 2995-3000.
Mitchell AD & Benevenga NJ (1978) The role of transamination in
methionine oxidation in the rat. J Nutr, 108: 67-78.
Mitchell JR, Jollow DJ, Potter WZ, Davis DC, Gillette JM, & Brodie BB
(1973) Acetaminophen-induced hepatic necrosis. I. Role of drug
metabolism. J Pharmacol Exp Ther, 187: 185-194.
Murphy-Chutorian DR, Wexman MP, Grieco AJ, Heininger JA, Glassman E,
Gaull GE, Ng SKC, Feit F, Wexman K, & Fox AC (1985) Methionine
intolerance: a possible risk factor for coronary artery disease. J Am
Coll Cardiol, 6: 725-730.
Neuvonen PJ, Tokola O, Toivonen ML, & Simell O (1985) Methionine in
paracetamol tablets, a tool to reduce paracetamol toxicity. Int J Clin
Pharmacol Ther Toxicol, 23: 497-500.
NIOSH (1992) Registry of toxic effects of chemical substances (RTECS).
Cincinnati, Ohio, National Institute for Occupational Safety and
Health.
Park LC, Baldessarini MJ, & Kety SS (1965) Methionine effects on
chronic schizophrenics. Patients treated with monoamine oxidase
inhibitors. Arch Gen Psychiatr, 12: 346-351.
Pearce LA & Waterbury LD (1974) L-methionine: a possible levodopa
antagonist. Neurology, 24: 640-641.
Phear EA, Ruebner B, Sherlock S, & Summerskill WHJ (1956) Methionine
toxicity in liver disease and its prevention by chlortetracycline.
Clin Sci, 15: 93-117.
Pisi E & Marchesini G (1990) Mechanisms and consequences of the
impaired trans-sulphuration pathway in liver disease: Part II.
Clinical consequences and potential for pharmacological intervention
in cirrhosis. Drugs, 40(Suppl. 3): 65-72.
Pollin W, Cardon PV, & Kety SS (1961) Effects of amino acids feedings
in schizophrenic patients treated with iproniazid. Science, 133:
104-105.
Prescott LF (1971a) Gas-liquid chromatographic estimation of
paracetamol. J Pharm Pharmacol, 23: 807-808.
Prescott LF (1971b) The gas-liquid chromatographic estimation of
phenacetin and paracetamol in plasma and urine. J Pharm Pharmacol, 23:
111-115.
Prescott LF, Park J, Sutherland GR, Smith IJ, & Proudfoot AT (1976)
Cysteamine, methionine and penicillamine in the treatment of
paracetamol poisoning. Lancet, 2: 109-113.
Prescott LF, Illingworth RN, Critchley JAJH, Stewart MJ, Adam RD, &
Proudfoot AT (1979) Intravenous N-acetylcysteine: the treatment of
choice for paracetamol poisoning. Br Med J, 2: 1097-1100.
Reed DJ & Beatty PW (1980) Biosynthesis and regulation of
glutathione: toxicological implications. In: Hodgson S, Band JR, &
Philpot RM Ed. Reviews in biochemical toxicology. New York, Amsterdam,
Oxford, Elsevier/North Holland, Vol. II, pp 213-241.
Routh JM, Shane NA, Arrendondo EG, & Paul WD (1968) Determination of
N-acetyl- p-aminophenol in plasma. Clin Chem, 14: 882-889.
Rumack BH & Peterson RG (1978) Acetaminophen overdose: incidence,
diagnosis and management in 416 patients. Pediatrics, 62(Suppl.):
898-903.
Sax NI (1989) Dangerous properties of industrial materials, 7th ed.
New York, Van Nostrand Reinhold Company, p 2219.
Smilkstein MJ, Knapp GL, Kulig KW, & Rumack BH (1988) Efficacy of
oral N-acetylcysteine in the treatment of acetaminophen overdose.
Analysis of the National Multicenter Study (1976-1985). N Engl J Med,
319: 1557-1562.
Smolin LA, Benevenga NJ, & Berlow S (1981) The use of betaine for the
treatment of homocystinuria. J Pediatr, 99: 467-472.
Smythies JR, & Halsey JH (1984) Treatment of Parkinson's disease with
L-methionine. South Med J, 77: 1577.
Solomon AE, Briggs JD, Knepil J, Henry DA, Winchester JF, & Birrell R
(1977) Therapeutic comparison of thiol compounds in severe
paracetamol poisoning. Ann Clin Biochem, 14: 200-202.
Stegink LD, Bell EF, Filer LJ, Ziegler EE, Andersen DW, & Seligson FH
(1986) Effects of equimolar doses of L-methionine, D-methionine and
L-methionine-dl-sulphoxide on plasma and urinary amino acid levels in
normal adult humans. J Nutr, 116: 1185-1192.
Stekol JA & Szaran J (1962) Pathological effects of excessive
methionine in the diet of growing rats. J Nutr, 77: 81-90.
Stipanuk M (1986) Metabolism of sulfur-containing amino acids. Ann
Rev Nutr, 6: 179-209.
Stramentinoli G, Pezzoli C, & Galli-Kienle M (1979) Protective role
of S-adenosyl-L-methionine against acetaminophen induced mortality and
hepatotoxicity in mice. Biochem Pharmacol, 28: 3587-3571.
Strubelt O, Siegers CP, & Schutt A (1974) The curative effects of
cysteamine, cysteine and dithiocarb in experimental paracetamol
poisoning. Arch Toxicol, 33: 55-64.
Ullman F (1985) Encyclopedia of industrial chemicals, 5th ed.
Deerfield Beach, New York, Cambridge, Weinheim, Basel, VCH
Verlagsgesellschaft, Vol 2A, pp 71-72.
Vale JA, Meredith TJ, Crome P, Helliwell M, Volans GN, Widdop B, &
Goulding R (1979) Intravenous N-acetylcysteine: the treatment of
choice in paracetamol poisoning? Br Med J, 2: 1435-1436.
Vale JA, Meredith TJ, & Goulding R (1981) Treatment of acetaminophen
poisoning. The use of oral methionine. Arch Intern Med, 141: 394-396.
Viau AT & Leatham JH (1973) Excess dietary methionine and pregnancy
in the rat. J Reprod Fertil, 33: 109-111.
Vina J, Hems R, & Krebs HA (1978) Maintenance of glutathione content
in isolated hepatocytes. Biochem J, 170: 627-630.
Vina J, Romero FJ, Estrela JM, & Vina JR (1980) Effect of
acetaminophen (paracetamol) and its antagonists on glutathione (GSH)
content in rat liver. Biochem Pharmacol, 29: 1968-1970.
Weast RC & Astle MJ ed. (1978) CRC handbook of chemistry and physics,
59th ed. Boca Raton, Florida. CRC Press Inc., p C758.
Zeisel SH & Poole JR (1979) Dietary intake of methionine: influence in
mammals on brain S-adenosylmethionine. In: Transmethylation.
Amsterdam, Oxford, New York, Elsevier Science Publishers, pp 59-68.
3. N-ACETYLCYSTEINE
3.1 Introduction
N-acetylcysteine is the N-acetyl derivative of L-cysteine, a
naturally occurring amino acid. It was originally introduced into
clinical medicine as a mucolytic agent in the 1960s but is now widely
used in the management of paracetamol poisoning, initially having been
used as an alternative to the more toxic agent cysteamine (Prescott et
al., 1977).
N-acetylcysteine has been shown to protect against paracetamol-
induced liver damage and has been used both intravenously and orally
for this purpose. It is given intravenously in a number of countries,
including the United Kingdom and Australia, whereas in the USA its use
has principally been by the oral route. It protects against
paracetamol-induced liver damage when given by both routes (Prescott
et al., 1979; Smilkstein et al., 1988) if given within 8 h of
intoxication. Use of N-acetylcysteine should be guided by plasma
concentrations of paracetamol taken in conjunction with the time of
the overdose (Prescott et al., 1979; Rumack et al., 1981). It is
clear that the efficacy of N-acetylcysteine is reduced with
increasing time after administration of paracetamol and there is no
evidence of antidotal efficacy if given more than 24 h after
poisoning. The intravenous and oral regimens are essentially
empirical and no controlled studies have been performed of the optimal
dose or duration of therapy.
N-acetylcysteine has also been investigated in a number of
other clinical situations in which reactive metabolites are believed
to be important in the toxicity of the poison. In animals,
N-acetylcysteine may protect against hepatotoxicity of halothane
(Keaney & Cocking, 1981). N-acetylcysteine has also been shown in
animals to be protective against heavy metals, alkylating agents and
radiation, and in man to haemorrhagic cystitis secondary to
cyclophosphamide (Flanagan, 1987). The only formal clinical trials in
this situation have been conducted on cyclophosphamide- and
isophosphamide-induced haemorrhagic cystitis. N-acetyl-cysteine is
effective in the management of cystine stones in cystinuria
(Martindale, 1988a).
Recently it has also been shown that N-acetylcysteine reduces
mortality in patients with acute paracetamol-induced liver failure
(Keays et al., 1991). Thus N-acetylcysteine may have two effects in
paracetamol poisoning: firstly, it prevents liver damage from
occurring and secondly, if that does occur, N-acetylcysteine may
significantly reduce mortality in such patients.
3.2 Name and chemical formula
International non-
proprietary name: N-acetylcysteine
Synonyms: Acetylcysteine; N-acetyl-L-cysteine; NSC-11180;
L-alpha-acetamido-ß-mercaptopropionic acid
IUPAC name: N-acetyl-3-mercaptoalanine
CAS number: 616-91-1
Empirical formula: C5H9NO3S
Chemical structure:
HSCH2CHCOOH
|
NHCOCH3
N-acetylcysteine
Relative molecular
mass: 163.2
Conversion table: 1 g = 6.1 mmol
1 mg = 6.1 µmol
1 mmol = 163.2 mg
1 µmol = 163.2 µg
3.3 Physico-chemical properties
3.3.1 Melting point
109-110 °C
3.3.2 Physical state
N-acetylcysteine consists of a white crystalline powder with a
slightly acetic odour. In its liquid formulation for drug use, it has
an odour common to sulfhydryl-containing compounds, i.e. an odour
similar to that of hydrogen sulfide ("rotten eggs").
3.3.3 Solubility
Solubility values in water of 1 part in 8 (British Pharmacopoeia,
1993) and 1 part in 5 (United States Pharmacopeia, 1990) and in
ethanol of 1 part in 2 (British Pharmacopoeia, 1993) and 1 part in 4
(United States Pharmacopeia, 1990) have been reported.
N-acetylcysteine is practically insoluble in chloroform and ether
(Martindale, 1988b).
3.3.4 Optical properties
N-acetylcysteine has no significant optical properties.
3.3.5 pKa
The pKa value is 9.5 (Clarke, 1986).
3.3.6 pH
A 1% solution has a pH of 2.0 to 2.8. Sterile solution is
buffered with sodium hydroxide to a pH of 7.
3.3.7 Stability
N-acetylcysteine should be stored in airtight containers at a
temperature below 15 °C and protected from light (Martindale, 1988b).
3.3.8 Incompatibilities
N-acetylcysteine is incompatible with many metals, with rubber,
and with oxygen and oxidizing substances. Some antibiotics including
amphotericin, ampicillin sodium, erythromycin lactobionate and some
tetracyclines are either physically incompatible with, or may be
inactivated on mixture with, N-acetylcysteine. A change in colour
of solutions of N-acetylcysteine to light purple does not indicate
significant impairment of safety or efficacy.
3.3.9 Proprietary names and manufacturers
Many preparations of N-acetylcysteine are marketed, most as
mucolytics. The proprietary names, manufacturers and countries
include:
Airbron (Allen & Hanburys, Canada; Duncan Flockhart, United
Kingdom); Brunac (Bruschettini, Italy); Eurespiran (Nicholas,
Germany); Exomuc (Bouchara, France); Fabrol (Ciba, Denmark;
Inpharzam, Sweden; Zyma, United Kingdom); Fluimucil (Arsac,
France; Inpharzam, Germany; Azmbom, Italy, Netherlands; Zambon,
Spain; Inpharzam, Switzerland); Fluprowit (Thiemann, Germany);
Granon (DAK, Denmark); Ilube (Duncan Flockhart, United Kingdom);
Inspir (Sweden); L Cimexyl (Cimex, Switzerland); Lysomucil
(Belgium); Muco Sanigen (Beecham-Wulfing, Germany); Mucocedyl
(Kettelhack Riker, Germany); Mucofilin Sol (Japan); Mucolysin
(Durascan, Denmark); Mucolyticum (Bristol, Germany); Mucomist
(Bristol Italiana Sud, Italy); Mucomyst (Astra, Argentina,
Australia, Belgium; Bristol, Canada; Astra, Denmark; Allard,
France, Netherlands; Draco, Norway; Tika, Sweden, Switzerland;
Mead Johnson Pharmaceutical, USA); Mucosal (Dey, USA); Mucothiol
(Ozothine, France); Mucret (Astra, Germany); Nac (Canada);
Parvolex (Glaxo, Australia; Allen & Hanburys, Canada; Duncan,
Flockhart, United Kingdom); Solmucol (Ibsa, Switzerland); Tixair
(Valpan, France).
Preparations available for use in paracetamol poisoning include
Parvolex (for intravenous use) and Mucomyst (for oral and intravenous
administration).
It should be noted that in some parts of the world a similar
compound S-carboxymethylcysteine is available rather than
N-acetylcysteine. Although its efficacy is not proven, animal data
appear to be comparable to those for N-acetylcysteine (Ioannides et
al., 1983).
3.4 Pharmaceutical formulation and synthesis
A synthetic route has been described by Smith & Gorin (1961).
Cysteine methyl ester hydrochloride and ethyl acetimidate
hydrochloride are condensed to synthesize methyl 2-methyl-2-
thiazoline-4-carboxylate hydrochloride. In the presence of hydro-
chloric acid, this compound is converted to N-acetylcysteine and
S-acetylcysteine.
Commercial products usually contain ethylenediaminetetraacetic
acid (EDTA) to remove trace amounts of metals, such as copper, that
will catalyse oxidation of N-acetylcysteine.
The available commercial preparations for oral use contain a
10-20% solution of N-acetylcysteine. This formulation needs to be
diluted before administration to avoid gastrointestinal irritation.
Dilution is best performed with water or a commercial carbonated or
still flavoured drink.
3.5 Analytical methods
N-acetylcysteine exists in biological systems in the oxidized
or reduced form, and also in combination with thiol groups of, for
example, proteins. Methods to measure these other forms have been
described (Burgunder et al., 1989). As the levels necessary to
protect the liver and kidney against paracetamol damage are unknown,
it is inappropriate at present to measure levels of N-acetylcysteine
in blood or serum during treatment. The concentrations of
N-acetylcysteine that are toxic to man have not been established but
there are indications of a relationship between adverse effects of
N-acetylcysteine and high plasma N-acetylcysteine levels (> 300
mg/l) (Prescott et al., 1989).
3.5.1 Quality control of antidote
N-acetylcysteine can be assayed in formulations by liquid
chromatography (United States Pharmacopeia, 1990) or
spectrophotometrically after reaction according to Ellman (1959) and
Fontana & Toniolo (1974).
3.5.2 Methods for identification of the antidote
N-acetylcysteine is identified by its infrared spectrum
directly when dispersed in potassium bromide or, if in solution, after
isolation by precipitation subsequent to saturation with sodium
chloride at pH 2-3 (United States Pharmacopeia, 1990; personal
communication from Astra Draco, Sweden).
3.5.3 Methods for analysis of the antidote in biological samples
Techniques for quantifying N-acetylcysteine in plasma and urine
by high performance liquid chromatography have been developed and
appear to be highly accurate (Kagedal et al., 1984; Lewis et al.,
1984). Other similar methods have been described (Frank et al., 1984;
Drummer et al., 1986; Johansson & Westerlund, 1986).
3.5.4 Methods for analysis of toxic agent
Methods for paracetamol analysis are discussed in section 1.6.
3.6 Shelf-life
3.6.1 Formulations for oral use
The shelf-life in the unopened commercial container appears to
vary depending on the volume and concentration of the product. The
average quoted shelf-life is 24 months (10-60 months) when the product
is protected from light.
In the original opened container the shelf-life is 96 h but this
shelf-life is reduced to one hour after dilution or preparation of
N-acetylcysteine for administration.
3.6.2 Formulations for intravenous use
Duncan Flockhart state that N-acetylcysteine for intravenous
use has a shelf-life of 3 years when stored at 25 °C and protected
from light.
3.7 General properties
3.7.1 Mode of antidotal activity
The toxicity of paracetamol in overdose is thought to be mediated
by its conversion to N-acetyl- p-benzoquinone imine (NAPQI) and the
subsequent arylation and oxidation of critical thiol groups in the
cell membrane (see section 1.4 for further details).
N-acetylcysteine could theoretically protect against paracetamol
toxicity in a number of ways (see chapter 1). Commonly cited mechanism
is that N-acetylcysteine can provide necessary sulfhydryl groups
through synthesis of glutathione (GSH). In addition to acting as a
conjugating agent, glutathione may have other effects including
reduction of oxidized thiol groups such as those of the calcium
translocases in cell membranes (Tee et al., 1986). The mode of
antidotal action of N-acetylcysteine in the possible management of
other forms of intoxication is likely to be similar to that in
paracetamol poisoning (Flanagan, 1987).
3.7.2 Effect in paracetamol-induced liver failure
The mechanism of action of the protective effect of
N-acetylcysteine on paracetamol-induced liver failure in humans has
not been established. Most probably it is related to the ability of
N-acetylcysteine to reverse tissue hypoxia through improved tissue
microperfusion (Harrison et al., 1990; Keays et al., 1991).
3.7.3 Other therapeutic uses
The most common medical use of N-acetylcysteine is inhalation
therapy to reduce the viscosity of pulmonary secretions by reducing
disulfide linkages of mucoproteins (Sheffner, 1983). It is also used
to dissolve cystine stones in cystinuria (Martindale, 1988a). These
properties are not relevant to its antidotal use.
The hypothesis that N-acetylcysteine might prevent nitrate
tolerance has also been investigated on the basis that this tolerance
was due to lack of reduced sulfhydryl groups in vascular smooth
muscle. This has not been found to be the case (Parker et al., 1987;
Hogan et al., 1990).
The suggestion that acetylcysteine may produce a reduction in
lipoprotein a in patients with hyperlipidaemia and an associated risk
of atherosclerosis (Gavish & Breslow, 1991) has been questioned by
others (Stalenhoef et al., 1991).
3.8 Animal studies
3.8.1 Pharmacodynamics
Following a suggestion for the use of N-acetylcysteine by
Prescott & Matthew (1974), studies in a number of animal species have
shown that paracetamol-induced hepatic damage can be prevented.
Piperno et al. (1978) reported that in the mouse N-acetylcysteine
protected against paracetamol-induced liver damage and that this
protective effect could be demonstrated even when administration was
instituted 4´ h after dosing with paracetamol. More recent studies
have concentrated on the mechanism of this effect.
Lauterburg et al. (1983) studied the effects of
N-acetylcysteine on rats in vivo. N-acetylcysteine was found
not to form significant amounts of conjugate with the reactive
intermediate, though it did result in increased glutathione synthesis.
It was concluded that this mechanism is likely to be the most
important one that operates in vivo. Studies by Corcoran et al.
(1985) using mice did not support the hypothesis that
N-acetylcysteine increases the proportion of paracetamol sulfated to
a degree that would reduce the amount of toxic intermediate produced.
The pharmacodynamics of N-acetylcysteine as derived from
studies on animals are discussed further in section 1.4.
3.8.2 Pharmacokinetics
Studies using radiolabelled N-acetylcysteine in rats showed
moderately good absorption of the drug given by the oral route. The
percentage of radioactivity recovered in the urine and faeces was 42,
33 and 20% by the intravenous, intramuscular and oral routes,
respectively. A similar study in dogs dosed orally resulted in 36%
recovery in the urine and faeces (Bonanomi & Gazzaniga, 1980).
Distribution and elimination studies have only been performed with
radio-labelled N-acetylcysteine and radioactivity measurements
(Bonanomi & Gazzaniga, 1980). The results are difficult to interpret,
but there is an indication of rapid distribution and elimination.
3.8.3 Toxicology
The LD50 of N-acetylcysteine has been examined in a number of
species and values range from 700 mg/kg intraperitoneally in the mouse
to between 5100 and 6000 mg/kg orally in the rat (NIOSH, 1983;
Johnston et al., 1983).
The oral LD50 in the mouse was found to be 7900 mg/kg compared
to an intravenous LD50 of 3800 mg/kg (NIOSH, 1983). The oral LD50
in dogs was > 1000 mg/kg (Gosselin et al., 1984).
Respiratory failure is the usual terminal event in laboratory
animals acutely poisoned with N-acetylcysteine (Johnston et al.,
1983).
N-acetylcysteine has not been shown to be teratogenic in rats
or rabbits (Bonanomi & Gazzaniga, 1980; USPCI, 1985). When
administered to rabbits during the critical phase of embryogenesis, no
malformation resulted (Johnston et al., 1983).
N-acetylcysteine is negative in the Ames mutagenicity test, and
also reduces the mutagenic affect of chemical carcinogens in the same
assay (Wilpart et al., 1985).
3.8.4 Studies with modified cytochrome P-450 activity
The important step in paracetamol metabolism is the formation of
the reactive intermediate NAPQI by the cytochrome P-450 system.
Inhibition or stimulation of activity of this enzyme group will
therefore reduce or increase paracetamol toxicity, as discussed in
section 1.5.
3.9 Volunteer studies
No studies on the efficacy of N-acetylcysteine in paracetamol
poisoning have been carried out in volunteers. Studies on the
pharmacokinetics of N-acetylcysteine, and effects of paracetamol on
these, have however been performed.
From a pharmacokinetic point of view, one can look at
N-acetylcysteine in two ways (Olsson et al., 1988). The reduced
form can be considered as the parent drug and all other forms as
metabolites. Alternatively, all N-acetylcysteine, irrespective of
the fraction oxidized, may be regarded as the parent drug. The latter
approach has been considered most logical from a clinical point of
view (Olsson et al., 1988), although it is the reduced form that is
the active form in paracetamol poisoning.
3.9.1 Absorption and bioavailability
Human studies that attempt to quantify N-acetylcysteine
absorption have shown great variations in plasma area under the curve
(AUC). Difficulties in clarifying this issue relate to the complicated
pharmacokinetics and difficulties with the assay (reduced versus total
N-acetylcysteine), and the possible contribution of a significant
first-pass effect.
N-acetylcysteine appears to be absorbed rapidly when given as
standard release preparations, the Tmax being around 40-45 min in
the study of Borgstrom et al. (1986), and exists as the free reduced
species in plasma for only a short time. It also causes an increase
in protein and non-protein sulfhydryl concentrations (Maddock, 1980).
When given orally, as tablets or a solution, total
N-acetylcysteine was found to have a bioavailability as low as 6-10%
(Borgstrom et al., 1986; Olsson et al., 1988). The bioavailability
was lowest when a slow-release preparation was used.
The good absorption and low bioavailability is most probably due
to an extensive first-pass elimination by the liver. However, the
rather low hepatic extraction ratio (0.26) in one study argues against
this theory (Borgstrom et al., 1986). Rapid uptake and deacetylation
by tissues in the gut wall and liver, to form cysteine, glutathione,
and inorganic sulfite, have been proposed to be the most probable
explanation for the extensive first-pass effect (Borgstrom et al.,
1986; Olsson et al., 1988). It is not clear whether this first-pass
effect favours the administration of N-acetylcysteine by the oral
route, as suggested by some authors (Borgstrom et al., 1986).
3.9.2 Distribution
The volume of distribution of total N-acetylcysteine in healthy
volunteers receiving low doses (200-600 mg) was 0.33-0.47 litres/kg
(Borgstrom et al., 1986; Olsson et al., 1988) compared to 0.54
litres/kg in patients receiving standard N-acetylcysteine treatment
intravenously (Prescott et al., 1989). The volume of distribution of
N-acetylcysteine therefore appears to be independent of dose. The
volume of distribution of reduced N-acetylcysteine was 0.59
litres/kg in healthy volunteers (Olsson et al., 1988).
The mechanism of plasma protein binding of N-acetylcysteine is
unlike that of other drugs. N-acetylcysteine is oxidized by
reacting with thiol groups in plasma proteins to form mixed
disulfides. In the study by Olsson et al. (1988), plasma proteins
were precipitated with perchloric acid and dithiothreitol and the
supernatant stored at -70 °C to prevent oxidation of reduced
N-acetylcysteine. Reduced N-acetylcysteine was measured by
chromatography of deproteinized plasma. The total plasma concentration
of N-acetylcysteine, including protein-bound N-acetylcysteine, was
assayed after initial reduction of disulfide bonds in plasma. With
this technique, covalent protein binding of N-acetylcysteine in
plasma increased with time after dosing to a maximum of about 50% 4 h
after intravenous administration. This percentage fell to
approximately 20% after 12 h.
3.9.3 Elimination
Borgstrom et al. (1986) studied the pharmacokinetics of
N-acetylcysteine given intravenously and orally as three separate
oral formulations to ten normal volunteers. Renal clearance accounted
for about 30% of the total body clearance. Total body clearance was
of the order of 0.2 litres/h per kg and the terminal elimination half-
life of N-acetylcysteine, measured in this study by HPLC, was
2.27 h.
Other workers have measured both free N-acetylcysteine and
total plasma sulfhydryls. Thus Burgunder et al. (1989) noted that
only a small proportion of the administered N-acetylcysteine was in
its free form, the majority being present as disulfides.
Administration of N-acetylcysteine increased free cysteine, but
total cysteine and free and total glutathione in plasma were
unchanged. Olsson et al. (1988) reported the terminal elimination
half-life of total N-acetylcysteine, measured as free and disulfide,
to be 6.25 h after oral administration and 5.15 h (range, 3.4-13)
after intravenous administration.
In patients receiving the standard intravenous N-acetylcysteine
treatment, the half-life of total N-acetylcysteine was 5.7 h
(Prescott et al., 1989).
3.9.4 Oral N-acetylcysteine and interaction with activated charcoal
Three in vitro studies have indicated effective adsorption of
N-acetylcysteine by activated charcoal (Chinouth et al., 1980;
Klein-Schwarz & Oerda, 1981; Rybolt et al., 1986). In studies on
volunteers, the in vivo effects of charcoal have been contradictory.
Two studies showed no statistical difference in plasma AUC between
N-acetylcysteine alone and N-acetylcysteine plus charcoal
(Krenzelok et al., 1980; Renzi et al., 1985). In contrast, Ekins et
al. (1987) reported a decrease in the mean peak plasma
N-acetylcysteine level of 29% and a decrease in mean plasma AUC of
39% in the activated charcoal group.
Although the clinical implication of an interaction between
N-acetylcysteine and activated charcoal appears unclear, it is
generally recommended that the use of activated charcoal should be
avoided if N-acetylcysteine is being administered orally.
3.9.5 Pharmacodynamics
Burgunder et al. (1989) measured the effects of giving
paracetamol in a dose of 2 g with 2 g N-acetylcysteine orally. In a
control experiment, this dose of paracetamol alone resulted in a
decrease in both plasma cysteine and glutathione levels. In contrast,
administration of paracetamol with 2 g N-acetylcysteine resulted in
an increase in cysteine and glutathione levels. The authors concluded
that, in humans, N-acetylcysteine supports glutathione synthesis
when demand for this is increased, as is the case after paracetamol
administration.
3.10 Clinical studies - clinical trials
3.10.1 Efficacy of intravenous N-acetylcysteine
Prescott et al. (1977) first reported the effects of
N-acetylcysteine given in a dose of 300 mg/kg body weight over 20 h
to 15 patients whose plasma paracetamol concentrations (range 262-369
mg/l at 4 h) suggested the likelihood of subsequent hepatic
dysfunction. In this study, 11 out of 12 patients treated within 10
h either suffered no liver dysfunction or developed only mild
disturbance, as judged by liver function tests. The other patient,
and three further patients treated more than 10 h after ingestion of
paracetamol, developed liver damage.
In a subsequent report dealing with a hundred cases of severe
paracetamol poisoning (Prescott et al., 1979), only 1 of 62 patients
treated within 10 h developed severe liver damage. This was in
comparison with a 58% incidence of severe liver damage in a
retrospective series of patients who had received supportive treatment
alone (33 of 57 patients). This study also showed that efficacy after
10 h diminishes and that treatment after 15 h with intravenous
N-acetylcysteine is likely to be ineffective. Furthermore
paracetamol-induced renal damage did not occur in patients treated
less than 10 h after overdose. The incidence of renal impairment in
patients treated after this time (13%, 5/38) was similar to that in a
group treated supportively (11%, 6/57). Only four patients with renal
impairment required haemodialysis.
The dosage regimen used in both the studies of Prescott consisted
of an initial loading dose of 150 mg/kg in 200 ml of 5% dextrose over
15 min followed by 50 mg/kg in 500 ml of 5% dextrose over 4 h and a
final 100 mg/kg in one litre of 5% dextrose given over 16 h. The
total dose was thus 300 mg/kg over 20 h. The basis for this dosage
regimen was empirical and not based on experimental data. The
treatment line was defined as a line joining the following plots on a
semi-logarithmic graph of plasma paracetamol concentration: 200 mg/l
at 4 h after ingestion and 30 mg/l at 15 h (Fig. 1). As a result of
this study intravenous N-acetylcysteine was adopted as a treatment
for paracetamol poisoning in the United Kingdom and in most countries
worldwide.
Smilkstein et al. (1991) reported a non-randomized open
multicentre trial of 179 patients with acute paracetamol overdose and
plasma concentrations above the treatment line. All patients received
a 48-h intravenous N-acetylcysteine dosage regimen consisting of a
loading dose of 140 mg/kg, followed by 12 doses of 70 mg/kg every 4 h,
giving a total dose of 980 mg/kg over 48 h. For patients classified
as having a "probable risk", as defined in the Smilkstein et al.
(1988) study, hepato-toxicity occurred in 5 out of 50 (10%) patients
treated within 10 h of ingestion and in 23 of 85 (27%) patients
treated 10 to 24 h after ingestion. Of the high-risk patients treated
16 to 24 h after ingestion, 11 of 19 (58%) developed hepatotoxicity.
When compared with historical controls in the 20-h intravenous
protocol (Prescott et al., 1979), these results were equivalent for
patients treated within 10 h post-ingestion and superior for patients
treated after 10 h (27 versus 53%). Smilkstein et al. (1991),
however, used a treatment line that was 25% lower than that of
Prescott et al. (1979), thus precluding valid comparison of data.
However, when comparing the high-risk patients treated 16-24 h post-
ingestion in the Smilkstein et al. (1991) study, i.e. patients with
paracetamol concentrations above a treatment line between 300 mg/l at
4 h and 75 mg/l at 12 h (Fig. 1), there is some evidence for less
hepatotoxicity resulting from use of the 48-h intravenous protocol (58
versus 82%).
3.10.2 Efficacy of oral N-acetylcysteine
Oral N-acetylcysteine is the most widely used antidote for
paracetamol poisoning in the USA. Rumack and his colleagues have
published a series of reports on their experience with
N-acetylcysteine in cases of paracetamol poisoning. Rumack &
Peterson (1978) reported on 100 patients who had ingested toxic doses
and were treated with N-acetylcysteine. In this series, 17% of 49
patients beginning therapy within 10 h of paracetamol poisoning
developed hepatotoxicity. Treatment between 10 and 24 h was less
successful; 45% of patients treated at this time developed severe
hepatotoxicity.
In a second report (Rumack et al., 1981) only 7% of 57 patients
treated within 10 h after ingestion developed hepatotoxicity, 29% of
52 patients treated between 10 and 16 h developed hepatotoxicity and
63% of 39 patients beginning treatment at 16 to 24 h after ingestion
developed hepatic dysfunction.
Smilkstein et al. (1988) reported on their experience over a 10-
year period (1976-1985) in a large prospective study involving 2540
patients treated orally with a loading dose of N-acetylcysteine of
140 mg/kg, followed by 17 oral maintenance doses of 70 mg/kg (i.e. a
total of 18 doses). In this large series no deaths were directly
related to paracetamol toxicity in patients in whom N-acetylcysteine
therapy began within 16 h after ingestion. There was, however, a
relationship between delay in treatment and the risk of
hepatotoxicity, as judged by liver function tests in patients in whom
plasma paracetamol concentrations indicated a likelihood of
hepatotoxicity. In patients considered at high risk of hepatotoxicity,
as judged by paracetamol concentrations, 8.3% (17 out of 206) of
patients treated within 10 h developed hepatotoxicity, 34.4% (199 of
578) patients treated 10 to 16 h after presentation developed
hepatotoxicity, and 41% (116 of 283) of patients treated 16 to 24 h
after presentation developed hepatotoxicity. The 95% confidence
intervals for the three groups were 5-13%, 31-37%, and 35-46%,
respectively. High risk was defined as initial plasma paracetamol
concentrations above the line intersecting 300 mg/l at 4 h and 75 mg/l
at 12 h (n=1067) (see Fig. 1).
3.10.3 Oral versus intravenous N-acetylcysteine
In summary, the frequency of severe liver damage in patients
treated within 10 h was 2% in patients (n=62) treated with intravenous
N-acetylcysteine, compared to 17% (n=49), 7% (n=57) and 8% (n=206)
in patients treated with oral N-acetyl-cysteine (sections 3.10.1 and
3.10.2). However, there have been no studies published which allow a
direct comparison of oral versus intravenous N-acetylcysteine
treatment, nor has the optimal duration of either the oral or
intravenous regimen been clearly established on the basis of
comparative clinical trials.
3.10.4 Therapeutic drug monitoring during N-acetylcysteine treatment
The doses of N-acetylcysteine given in both the oral and
intravenous dose regimen are empirical and are not based on studies of
the plasma concentrations of N-acetylcysteine required for antidotal
activity. Although there are pharmacokinetic data available for the
standard intravenous dose regimen, there is no indication for
measuring N-acetylcysteine in plasma during this treatment (Prescott
et al., 1989).
3.10.5 N-acetylcysteine in paracetamol-induced liver failure
When N-acetylcysteine was introduced as an antidote in
paracetamol poisoning, there was some concern that late administration
(> 24 h post-ingestion) of N-acetyl-cysteine, and thereby amino and
sulfhydryl-groups, could be potentially dangerous in the presence of
failing liver function. Keays et al. (1991) performed an open
randomized study of 50 consecutive patients with paracetamol-induced
fulminant hepatic failure without previous N-acetylcysteine
treatment. The study could not be performed blind because the
N-acetylcysteine solution has an easily identifiable pungent aroma.
The N-acetylcysteine dose given was the standard 20-h intravenous
regimen. The rate of survival was significantly higher among the
patients given N-acetylcysteine (48%, 12/25) as compared to controls
(20%, 5/25). The N-acetyl-cysteine-treated patients also had a
significantly lower incidence of cerebral oedema and hypotension
requiring inotropic support. The average time from paracetamol
ingestion to inclusion in the study was 53 h (range 36-80) in the
N-acetylcysteine-treated group as compared to 56 h (33-96) among
controls.
The mechanism for the therapeutic effect of N-acetylcysteine in
paracetamol-induced liver failure is not clear but may be related to
increased tissue oxygen consumption and decreased oxidant stress,
thereby reducing the oxidation of important protein thiol groups
(Keays et al., 1991). Although this study was not placebo-controlled,
it seems justified at present to give N-acetylcysteine to all
patients with paracetamol-induced fulminant liver failure.
3.11 Clinical studies - case reports
Clinical studies of the use of oral and intravenous
N-acetylcysteine have clearly documented its effect and have thus
limited the need for efficacy information from case reports. However,
case reports have provided valuable information about the adverse
effects and toxicity of N-acetylcysteine in humans.
3.11.1 Adverse effects
The principal toxic effects of N-acetylcysteine when given
intravenously consist of anaphylactoid reactions following therapeutic
doses (Bateman et al., 1984a,b; Gervais et al., 1984; Mant et al.,
1984; Tenenbein, 1984). This effect could be a pseudo-allergic
reaction, since it appears to be due to histamine release (Bateman et
al., 1984b). The most appropriate therapy for this adverse effect
appears to be intravenous antihistamines. Flushing of the chest or
face is common and usually begins 15 to 75 min after the initiation of
the infusion, being associated with peak N-acetylcysteine
concentrations of between 300 and 900 mg/l. These concentrations are
considerably higher than peak levels obtained following the oral
regimen (Prescott et al., 1989). Occasionally more severe
anaphylactic reactions to intravenous N-acetylcysteine have been
reported (Walton et al., 1979; Vale & Wheeler, 1982). Urticarial
reactions may also follow the use of oral N-acetylcysteine (Charley
et al., 1987).
Extravasation of a 20% N-acetylcysteine solution caused pain
and inflammation (Casola & van Sonnenburg, 1984).
Nausea and vomiting are very common during oral
N-acetylcysteine therapy in paracetamol overdose. Dilution to at
least a 9% solution prior to oral administration is therefore
recommended (Shaw, 1969). Granules of N-acetylcysteine (200 mg)
given in sachets did not result in histopathological changes in the
gastrointestinal mucosa (Marini et al., 1980). Diarrhoea may also
occur following N-acetylcysteine administration (Ferrari, 1980).
One report suggested that liver enzyme changes may have occurred in a
3-year-old male child with cystic fibrosis treated with both oral and
rectal N-acetylcysteine for meconium ileus. Liver enzyme levels
were elevated on two separate occasions, but the doses of
N-acetylcysteine delivered were considerably larger than those
recommended for antidotal use for paracetamol poisoning in a child of
this age. Intrinsic hepatobiliary disease in the infant could not be
ruled out (Bailey & Andres, 1987).
Bronchospasm, which may be part of the anaphylactoid reaction to
intravenous N-acetylcysteine (Ho & Beilin, 1983; Mant et al., 1984),
may occur after N-acetyl-cysteine inhalation in the management of
pulmonary disease (Dano, 1971). Intracranial hypertension has also
been reported following inhalational therapy (Venturelli & Tein,
1984).
Cardiovascular collapse and death was reported in a 4-year-old
child who received 2.17 g N-acetylcysteine intravenously as a
loading dose and intravenous infusion of 0.36 g/h (Anon, 1984). This
dose is in excess of that recommended.
In another case reported by Mant et al. (1984), hepatorenal
failure secondary to paracetamol overdose was associated with
disseminated intravascular coagulation. This patient also received
between 2 and 6´ times the recommended loading dose of intravenous
N-acetylcysteine, but a cause-and-effect relationship between
N-acetyl-cysteine and disseminated intravascular coagulation cannot
be established. Similarly, haemolysis developed in a patient with
glucose-6-phosphate dehydrogenase deficiency who had received a 6-fold
overdose of N-acetylcysteine, but this cannot be explained on the
basis of oxidative haemolysis, and other mechanisms must, presumably,
have been responsible.
In the study by Smilkstein et al. (1991), 980 mg
N-acetylcysteine/kg was given intravenously over 48 h to 223
patients initially entering the study. Adverse reactions to
N-acetylcysteine occurred in 32 out of 223 cases (14%), consisting
in 29 out of 32 patients (91% of reactions) of transient, patchy skin
erythema or mild urticaria during the loading dose (140 mg/kg) that
did not require discontinuation of therapy. One patient suffered a
potentially life-threatening reaction as 12 g (instead of 3.6 g) was
given as the fifth dose. The patient developed oedema, diffuse rash,
wheezing, throat tightness, and itching. All symptoms and signs
responded to antihistamine administration.
3.11.2 Use in pregnancy
Experience in 59 pregnant patients suggested that use of
N-acetylcysteine in pregnancy did not result in toxic effects on the
fetus (Bronstein & Rumack, 1984). In practice, the risk to the mother
and baby of paracetamol-induced liver damage probably far outweighs
any potential risk of N-acetylcysteine, and pregnancy should not be
considered a contraindication to the use of this agent.
3.12 Summary of evaluation
3.12.1 Indications
N-acetylcysteine is indicated in the management of moderate to
severe paracetamol poisoning. If at all possible, plasma paracetamol
concentrations should be used to predict the likelihood of paracetamol
toxicity (see Fig. 1), and therefore the need for treatment. The
treatment line (Fig. 1) differs, in that American studies have
generally used a line 25% below the one proposed originally (joining
200 mg/l at 4 h and 50 mg/l at 12 h). The treatment line used should
therefore be identified before comparing results between studies.
In patients presenting up to 8 h after overdose, it is reasonable
to measure paracetamol levels to assess the need for treatment
according to the treatment line most commonly employed (Fig. 1) before
starting treatment. After this time, if the history suggests an
intake greater than 7 g (or 100 mg/kg) paracetamol in adults, therapy
should be started immediately, even before the plasma paracetamol
concentration has been measured. If the concentration suggests that
paracetamol toxicity is unlikely (i.e. it falls below a line joining
200 mg/l at 4 h and 30 mg/l at 15 h, Fig. 1), N-acetylcysteine can
be discontinued. In the case of a potentially toxic paracetamol
concentration, N-acetylcysteine should be continued and the full
treatment regimen completed even if paracetamol concentrations
subsequently fall below the treatment line.
Treatment with N-acetylcysteine may be instituted up to 24 h
after a paracetamol overdose. The efficacy of the oral and
intravenous regimens falls when treatment is started more than 8 h
after the ingestion of paracetamol. The antidotal efficacy, when
treatment is started later than 24 h, has not been established.
Intravenous N-acetylcysteine has been shown to increase
significantly the survival rate in patients with paracetamol-induced
fulminant liver failure through unknown mechanisms, and should
therefore be given in such cases. There are currently no data on the
use of N-acetylcysteine in patients admitted 24-50 h post-ingestion
and who are at particular risk of developing liver failure. However,
it appears to be safe to use intravenous N-acetylcysteine in these
patients, and since they may benefit from this treatment, the use of
N-acetylcysteine in this manner should be considered.
3.12.2 Advised route and dosage
3.12.2.1 Intravenous N-acetylcysteine
Intravenous N-acetylcysteine should be given as an initial
loading dose of 150 mg/kg body weight in 200 ml of 5% dextrose over 15
min, followed by 50 mg/kg in 500 ml of 5% dextrose over 4 h and then
100 mg/kg in 1 litre of 5% dextrose over the next 16 h. The total
dose by this route will be 300 mg/kg over 20 h.
There are indications that a dosage regimen of 980 mg/kg over 48
h may be more effective for patients admitted 10-24 h post-ingestion,
especially those at "high risk". The fact that N-acetylcysteine also
increases survival in patients with established acute paracetamol-
induced liver failure ( N-acetylcysteine being given in this instance
at about 50 h post-ingestion) may support the use of a 48-h dosing
regimen to "high risk" patients admitted late after ingestion of a
paracetamol overdose.
3.12.2.2 Oral N-acetylcysteine
A 5% solution of N-acetylcysteine should be given as an oral
loading dose of 140 mg/kg. The available commercial preparations of
N-acetylcysteine are 10 and 20% solutions, and these need to be
diluted. Seventeen further doses of 70 mg N-acetylcysteine/kg
should be given as a 5% solution in diluent every 4 h. The total dose
by this route will be 1330 mg/kg over 72 h.
The intravenous regimen is preferable to the oral one because of
the predictable occurrence of vomiting in seriously poisoned patients
when using the oral regimen. The relative efficacy of the two
regimens in the prevention of paracetamol-induced hepatotoxicity
cannot be judged on present evidence.
3.12.3 Other consequential or supportive therapy
Symptomatic treatment of ensuing complications should be
according to conventional principles of intensive care. Special
emphasis should be given to the treatment of liver failure and acute
renal failure, as discussed in section 1.7. At present, liver
transplantation has no clearly defined role in the treatment of acute
liver failure due to paracetamol poisoning, although it may be useful
in selected cases being treated at specialist centres (see section
1.7.1.2).
3.12.4 Controversial issues and areas where there is insufficient
information to make recommendations
Studies to determine the relative efficacy of the oral and
intravenous regimens have not been performed. Data exist suggesting
that the 48-h intravenous infusion regimen and the 72-h oral regimen
may be more effective than the 20-h intravenous regimen when the
latter is used as the historical control. Direct comparison of the
results from the 48 and 72-h studies with those from the 20-h study is
not possible.
From a practical point of view, the shortest dosing regimen is
desirable, provided that it is effective. One problem when comparing
the different N-acetylcysteine studies is the efficacy parameter or
end-point "severe liver damage", defined as an ALAT/ASAT activity of
> 1000 U/l. Firstly, this is a measurement of hepatic necrosis and
not of liver function/protein synthesis. Secondly, clinical
experience shows that more than 99% of patients suffering from
paracetamol-induced hepato-toxicity where ALAT/ASAT activity is >
1000 U/l will recover completely without long-term sequelae provided
that appropriate therapy is given. This parameter was arbitrarily
chosen in early studies of paracetamol poisoning. However, in view of
the marginal differences in outcome when different dosage regimens are
employed, the need for a new efficacy parameter should be considered
by clinical toxicologists and hepatologists.
When comparing the results obtained from use of the 20-h
intravenous dosing regimens with those from the 48-h intravenous and
72-h oral dosing regimens, no differences are observed when end-points
such as mortality or permanent sequelae are considered.
Possible benefit from the use of N-acetylcysteine in patients
admitted late and at risk of developing fulminant liver failure has
not been proven and remains controversial (see section 3.12.1).
3.12.5 Proposals for further studies
Future studies on intravenous N-acetylcysteine should be
performed with the 20-and 48-h regimens in such a way as to make the
data obtained comparable. Such studies should concentrate on patients
in the high-risk group admitted late (10-24 h post-ingestion). The
use of firmer end-points than an ALAT/ASAT activity > 1000 U/l should
be considered.
It would be useful to investigate whether side-effects of
N-acetylcysteine might be avoided and antidotal efficacy maintained
if the initial intravenous bolus dose is given more slowly.
The possible benefit of N-acetylcysteine treatment in patients
admitted late (24-50 h after poisoning), and at particular risk of
developing liver failure, needs further study. Since the treatment
nomogram does not extend beyond 24 h, it would be useful to study
correlations between ingested dose and the risk of liver failure and
whether there is a dose threshold for this risk.
3.12.6 Adverse effects
N-acetylcysteine appears to have a good therapeutic index and
side-effects are few, consisting mainly of mild flushing. These
side-effects are more common following intravenous administration and
are considered to be dose-dependent. The incidence and severity of
side-effects may therefore be reduced by giving the initial bolus dose
more slowly. There have been some reports of serious side-effects
associated with the intravenous administration of N-acetylcysteine.
These appear to be anaphylactoid and have generally been reported when
more than the recommended dose has been given in error; at least one
death has resulted. Antihistamines appear to be effective.
Oral N-acetylcysteine may cause gastrointestinal irritation;
dilution to a solution of 9% or less is recommended to reduce the
incidence and severity of this side-effect.
3.12.7 Restrictions of use
If a patient has previously experienced a severe anaphylactoid
reaction to N-acetylcysteine, oral methionine should be given in
preference. Otherwise there are no contraindications to the use of
N-acetylcysteine following the ingestion of paracetamol. If the
time of ingestion is difficult to assess, current evidence indicates
that no harm will come if N-acetylcysteine is given later than 24 h
after ingestion of paracetamol.
3.13 Model information sheet
3.13.1 Uses
N-acetylcysteine is indicated in the treatment of paracetamol
poisoning if:
a) plasma paracetamol levels taken between 4 and 8 h post-ingestion
fall above "the treatment line" indicated in Fig. 1;
b) more than 100 mg paracetamol/kg has been ingested in a single
dose and plasma paracetamol concentrations are not available;
c) acute paracetamol-induced liver failure has developed or is
likely to develop (see 3.13.1.1).
N-acetylcysteine treatment should be started as soon as
possible if the criteria above are fulfilled, as its antidotal
efficacy rapidly declines once more than 8 h have elapsed from the
time of ingestion of paracetamol. No antidotal effect has been
documented when N-acetylcysteine has been given later than 24 h
post-ingestion. However, harm is unlikely if N-acetylcysteine is
given later than this, e.g., in the event of an incomplete or
uncertain case history.
In the event of an unreliable case history, where the time of
ingestion and/or amount of paracetamol ingested is not known, it is
reasonable to adopt a low threshold for the use of N-acetylcysteine,
i.e. if in doubt, N-acetylcysteine should be administered.
If a plasma sample taken later than 8 h post-ingestion shows that
the plasma paracetamol concentration is definitely below the treatment
line, N-acetylcysteine treatment should be stopped.
3.13.1.1 Use in liver failure
N-acetylcysteine significantly increases survival in patients
with acute paracetamol-induced fulminant liver failure when given
according to the 20-h intravenous dosing regimen indicated in section
3.13.2.1. There appear to be no contraindications to this therapy,
which should be instituted as soon as possible in patients admitted in
this late stage of poisoning or who for some other reason have not
received N-acetylcysteine previously.
In patients admitted more than 24 h post-ingestion who are not
suffering from liver failure but who are at particular risk of
developing it (> 150-200 mg paracetamol/kg ingested), it would seem
reasonable to give N-acetylcysteine intravenously according to the
dosage regimen given in section 3.13.2.1.
3.13.2 Dosage and route
3.13.2.1 Intravenous N-acetylcysteine
Intravenous N-acetylcysteine should be given as an initial
loading dose of 150 mg/kg body weight in 200 ml of 5% dextrose over 15
min, followed by 50 mg/kg in 500 ml of 5% dextrose over 4 h and then
100 mg/kg in 1 litre of 5% dextrose over the next 16 h. The total
dose given by this route will be 300 mg/kg over 20 h.
In patients admitted 10-24 h after ingestion of paracetamol, and
especially if large amounts are ingested, one may consider using the
48-h intravenous dosage regimen instead: an initial loading dose of
140 mg N-acetylcysteine/kg, followed by 12 doses of 70 mg/kg every
4 h, i.e. a total of 980 mg/kg over 48 h (in 5% dextrose).
3.13.2.2 Oral N-acetylcysteine
A 5% solution of N-acetylcysteine should be given as an oral
loading dose of 140 mg/kg. The available commercial preparations of
N-acetylcysteine are 10 and 20% solutions and need to be diluted.
This can be done using water or a commercial carbonated or still
flavoured drink. Seventeen further doses of 70 mg
N-acetylcysteine/kg should be given as a 5% solution in diluent
every 4 h. The total dose given by this route will be 1330 mg/kg over
72 h.
The intravenous treatment regimen is preferred to the oral one
(see sections 3.12.2 and 3.12.4) unless the intravenous
N-acetylcysteine formulation is unavailable or there is lack of
expertise/equipment for such treatment.
3.13.3 Precautions/contraindications
Previous severe anaphylactoid reactions to N-acetylcysteine
should be considered an absolute contraindication if methionine is
available as an alternative antidote. But in the case of a
potentially severe paracetamol intoxication where methionine is
unavailable, a history of such a reaction is a relative
contraindication.
3.13.4 Pharmaceutical incompatibilities and drug interactions
N-acetylcysteine is incompatible with solutions containing
certain antibiotics, including ampicillin sodium, amphotericin,
erythromycin lactobionate and some tetracyclines. Activated charcoal
should not be given if oral N-acetylcysteine is administered.
3.13.5 Adverse effects
In about 15% of patients given N-acetylcysteine intravenously,
mild urticaria is seen during infusion of the bolus dose. This does
not usually require discontinuation of infusion, although a slower
infusion rate of the bolus dose (1-2 h) may be advisable. If more
pronounced skin erythema or urticaria develops, an antihistamine
should be given.
Patients should be monitored for possible anaphylactoid reactions
including bronchospasm, hypotension and urticaria; such reactions are
more common with intravenous N-acetylcysteine. Management of these
reactions involves the following measures:
a) stop the N-acetylcysteine infusion, at least temporarily;
b) administer an antihistamine intravenously;
c) in the rare event of severe bronchospasm consider using nebulized
salbutamol or, in severe cases, parenteral adrenaline. If the
reaction is mild, N-acetylcysteine may be restarted cautiously.
As an alternative, especially in the case of a severe reaction,
the use of oral methionine is advisable.
Other adverse reactions to oral N-acetylcysteine include
vomiting and diarrhoea.
3.13.6 Use in pregnancy and lactation
There is no evidence of toxic effects on the fetus arising from
the use of standard oral doses of N-acetylcysteine in pregnant women
poisoned by paracetamol. The risk to the mother and baby of
paracetamol-induced liver damage is likely to far outweigh any
potential risk of N-acetylcysteine administration.
3.13.7 Storage
The shelf-life of the intravenous preparation (Parvolex) is
stated by the manufacturer, Duncan Flockart, to be 3 years at room
temperature.
The shelf-life of oral N-acetylcysteine is usually 2 years.
A change in colour of solutions of N-acetylcysteine to light
purple does not indicate significant impairment of safety or efficacy.
3.14 References
Anon (1984) Death after N-acetylcysteine. Lancet, 1: 1421.
Bailey DJ & Andres JM (1987) Liver injury after oral and rectal
administration of N-acetylcysteine for meconium ileus equivalent in
a patient with cystic fibrosis. Pediatrics, 79: 281-282.
Bateman DN, Woodhouse KW, & Rawlins MD (1984a) Adverse reactions to
N-acetylcysteine. Lancet 2: 228.
Bateman DN, Woodhouse KW, & Rawlins MD (1984b) Adverse reactions to
N-acetylcysteine. Hum Toxicol, 3: 393-398.
Bonanomi L & Gazzaniga A (1980) Toxicological, pharmacokinetic and
metabolic studies on acetylcysteine. Eur J Respir Dis, 61(Suppl 111):
45-51.
Borgstrom L, Kagedal B, & Paulsen O (1986) Pharmacokinetics of
N-acetylcysteine in man. Eur J Clin Pharmacol, 31: 217-222.
British Pharmacopoeia (1993) London, Her Majesty's Stationery Office.
Bronstein AC & Rumack BH (1984) Acute acetaminophen overdose during
pregnancy: review of fifty-nine cases. Vet Hum Toxicol, 26: 401.
Burgunder JM, Varriale A, & Lauterburg BH (1989) Effect of
N-acetylcysteine on plasma cysteine and glutathione following
paracetamol administration. Eur J Clin Pharmacol, 36: 127-131.
Casola G & van Sonnenberg E (1984) Skin damage from acetylcysteine
leak during percutaneous abscess drainage. Radiology, 152: 233.
Charley G, Dean BS, & Krenzelok EP (1987) Oral N-acetylcysteine-
induced urticaria: a case report. Vet Hum Toxicol, 29: 477.
Chinouth RW, Czajka PA, & Peterson RG (1980) N-acetylcysteine
absorption by activated charcoal. Vet Hum Toxicol, 22: 392-394.
Clarke ECG (1986) Clarke`s identification and isolation of drugs, 2nd
ed. London, Pharmaceutical Press.
Corcoran GB, Todd EL, Racz WJ, Hughes H, Smith CW, & Mitchell JR
(1985) Effects of N-acetylcysteine on the disposition and metabolism
of acetaminophen in mice. J Pharmacol Exp Ther, 232: 857-863.
Dano G (1971) Bronchospasm caused by acetylcysteine in children with
bronchial asthma. Acta Allergol, 26: 181-190.
Drummer OH, Christophidis N, Horowitz JD, & Louis WJ (1986)
Measurement of penicillamine and N-acetylcysteine in human blood by
high-performance liquid chromatography and electrochemical detection.
J Chromatogr, 374: 251-257.
Ekins BR, Ford DC, Thompson MI, Bridges RR, Rollins DE, & Jenkins RD
(1987) The effect of activated charcoal on N-acetylcysteine
absorption in normal subjects. Am J Emerg Med, 5: 483-487.
Ellman GL (1959) Tissue sulfhydryl groups. Arch Biochem Biophys, 82:
70-77.
Ferrari V (1980) Safety and drug interactions of oral acetylcysteine
related to utilization data. Eur J Respir Dis, 61(Suppl 111):
151-157.
Flanagan RJ (1987) The role of acetylcysteine in clinical toxicology.
Med Toxicol, 2: 93-104.
Fontana A & Toniolo C (1974) In: Patai S ed. The chemistry of the
thiol group -Part I. New York, Chichester, Brisbane, Toronto, John
Wiley & Sons, p 288.
Frank H, Thiel D, & Langer K (1984) Determination of N-acetyl-
L-cysteine in biological fluids. J Chromatogr, 309: 261-267.
Gavish D & Breslow JL (1991) Lipoprotein(a) reduction by
N-acetylcysteine. Lancet, 337: 203-204.
Gervais R, Lussier-Labelle F, & Beaudet P (1984) Anaphylactoid
reaction to acetylcysteine. Clin Pharm, 3: 586-587.
Gosselin RE, Smith RP, & Hodge HC ed. (1984) Clinical toxicology of
commercial products, 5th ed. Baltimore, Maryland, Williams & Wilkins.
Harrison PM, O'Grady JG, Keays RT, Alexander GJM, & Williams R (1990)
Serial prothrombin time as a prognostic indicator in paracetamol
induced fulminant hepatic failure. Br Med J, 301: 964-966.
Ho SW & Beilin LJ (1983) Asthma associated with N-acetylcysteine
infusion and paracetamol poisoning: report of two cases. Br Med J,
287: 876-877.
Hogan JC, Lewis MJ, & Henderson AH (1990) Chronic administration of
N-acetylcysteine fails to prevent nitrate tolerance in patients with
stable angina pectoris. Br J Clin Pharmacol, 30: 573-577.
Ioannides C, Hall DE, Mulder DE, Steele CM, Spickett J, Delaforge M,
& Parke DV (1983) A comparison of the protective effects of
N-acetylcysteine and S-carboxymethylcysteine against paracetamol-
induced hepatotoxicity. Toxicology, 28: 313-321.
Johansson M & Westerlund D (1986) Determination of N-acetylcysteine,
intact and oxidized in plasma by column liquid chromatography and
post-column derivatization. J Chromatogr, 385: 343-356.
Johnston RE, Hawkins HC, & Weikel JH Jr (1983) The toxicity of
N-acetylcysteine in laboratory animals. Sem Oncol, 10(Suppl 1):
17-24.
Kagedal B, Kallberg M, & Martensson J (1984) Determination of non-
protein-bound N-acetylcysteine in plasma by high-performance liquid
chromatography. J Chromatogr, 311: 170-175.
Keaney NP & Cocking G (1981) N-acetylcysteine protection against
halothane hepatotoxicity: experiments in rats. Lancet, 2: 95.
Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJM, &
Williams R (1991) Intravenous acetylcysteine in paracetamol induced
fulminant hepatic failure: a prospective controlled trial. Br Med J,
303: 1026-1029.
Klein-Schwarz W & Oerda GM (1981) Absorption of oral antidotes for
acetaminophen (methionine and N-acetylcysteine) by activated
charcoal. Clin Toxicol, 18: 283-290.
Krenzelok EP, North DS, & Peterson RG (1980) The effect of activated
charcoal administration on N-acetylcysteine serum levels in human
subjects. Vet Hum Toxicol, 22: 56-58.
Lauterburg BH, Corcoran GB, & Mitchell JR (1983) Mechanism of action
of N-acetylcysteine in the protection against the hepatotoxicity of
acetaminophen in rats in vivo. J Clin Invest, 71: 980-991.
Lewis PA, Woodward AJ, & Maddock J (1984) High-performance liquid
chromatographic assay for N-acetylcysteine in plasma and urine. J
Pharm Sci, 73: 996-998.
Maddock J (1980) Biological properties of acetylcysteine: assay
development and pharmacokinetic studies. Eur J Respir Dis,
61(Suppl 111): 52-58.
Mant TGK, Tempowski JH, Volans GN, & Talbot JC (1984) Adverse
reactions of acetylcysteine and effects of overdose. Br Med J, 289:
217-219.
Marini U, Visconti G, & Spotti D (1980) Controlled endoscopic study on
gastroduodenal safety of acetylcysteine after oral administration. Eur
J Respir Dis, 61(Suppl 111): 147-150.
Martindale (1988a) In: Reynolds JEF ed. The extra pharmacopoeia, 29th
ed. London, Pharmaceutical Press.
Martindale (1988b) In: Reynolds JEF ed. The extra pharmacopoeia, 29th
ed. Denver, Colorado, Micromedex, Inc. (CDROM version).
NIOSH (1983) Registry of toxic effects of chemical substances
1981-1982 (RTECS). Cincinnati, Ohio, National Institute for
Occupational Safety and Health.
Olsson B, Johansson M, Gabrielsson J, & Bolme P (1988)
Pharmacokinetics and bioavailability of reduced and oxidized
N-acetylcysteine. Eur J Clin Pharmacol, 34: 77-82.
Parker JO, Farell B, Lahey KA, & Rose BF (1987) Nitrate tolerance: the
lack of effect of N-acetylcysteine. Circulation, 76: 572-576.
Piperno E, Mosher AH, Berssenbruegge DA, Winkler JD, & Smith RB (1978)
Pathophysiology of acetaminophen overdosage toxicity; implications for
management. Pediatrics, 62(Part 2 Suppl): 880-889.
Prescott LF & Mattew H (1974) Cysteamine for paracetamol overdosage.
Lancet, 1: 998.
Prescott LF, Park J, Vallantyre A, Adrianssen P, & Proudfoot AT (1977)
Treatment of paracetamol (acetaminophen) poisoning with
N-acetylcysteine. Lancet, 2: 432-434.
Prescott LF, Illingworth RN, Critchley JA, Stewart MJ, Adam RD, &
Proudfoot AT (1979) Intravenous N-acetylcysteine: the treatment of
choice for paracetamol poisoning. Br Med J, 2: 1097-1100.
Prescott LF, Donovan JW, Jarvie DR, & Proudfoot AT (1989) The
disposition and kinetics of intravenous N-acetylcysteine in patients
with paracetamol overdosage. Eur J Clin Pharmacol, 37: 501-506.
Renzi FD, Donovan JW, & Martin TG (1985) Concomitant use of activated
charcoal and N-acetylcysteine. Ann Emerg Med, 14: 568-572.
Rumack BH & Peterson RG (1978) Acetaminophen overdose: Incidence,
diagnosis and management in 416 patients. Pediatrics, 62: 898-903.
Rumack BH, Peterson RC, Koch GG, & Amara IA (1981) Acetaminophen
overdose: 662 cases with evaluation of oral acetylcysteine treatment.
Arch Intern Med, 141: 380-385.
Rybolt TR, Burell DE, & Schultz JM (1986) In vitro coabsorption of
acetaminophen and N-acetylcysteine onto activated carbon powder. J
Pharm Sci, 75: 904-906.
Shaw A (1969) Safety of N-acetylcysteine in treatment of meconium
obstruction of the newborn. J Pediatr Surg, 4: 119-125.
Sheffner AL (1983) The reduction in vitro in viscosity of
mucoprotein solutions by a new mucolytic agent N-acetyl-L-cysteine.
Ann NY Acad Sci, 106: 298-310.
Smilkstein MJ, Knapp GL, Kulig KW, & Rumack BH (1988) Efficacy of oral
N-acetylcysteine in the treatment of acetaminophen overdose:
Analysis of the National Multicenter study (1976 to 1985). N Engl J
Med, 319: 1557-1562. Smilkstein MJ, Bronstein AC, Linden C, Augenstein
WL, Kulig KW, & Rumack BH (1991) Acetaminophen overdose: A 48-hour
intravenous N-acetylcysteine treatment protocol. Ann Emerg Med, 20:
1058-1063.
Smith HA & Gorin G (1961) S-methyl-S-thiazdine-4-carboxylic acid:
Formation from N-acetylcysteine and hydrolysis. J Org Chem, 26:
820-823.
Stalenhoef AFH, Kroon AA, & Demacker PNM (1991) N-acetylcysteine and
lipoprotein. Lancet, 337: 491.
Tee LBG, Boobis AR, Huggett AC, & Davies DS (1986) Reversal of
acetaminophen toxicity in isolated hamster hepatocytes by
dithiothreitol. Toxicol Appl Pharmacol, 83: 294-314.
Tenenbein M (1984) Hypersensitivity-like reactions to
N-acetylcysteine. Vet Hum Toxicol, 26 (Suppl 2): 3-5.
United States Pharmacopeia (1990) 22nd ed. Rockville, Maryland, United
States Pharmacopeial Convention, Inc.
USPCI (1985) Acetylcysteine (Inhalation). Rockville, Maryland, United
States Pharmacopeial Convention, Inc., pp 10-11.
Vale JA & Wheeler DC (1982) Anaphylactoid reactions to acetylcysteine
(letter). Lancet, 2: 988.
Venturelli J & Tein I (1984) Increased intracranial pressure
associated with N-acetylcysteine inhalation therapy (letter). Crit
Care Med, 12: 926-927.
Walton NG, Mann TAN, & Shaw KM (1979) Anaphylactoid reaction to
N-acetyl-cysteine (letter). Lancet, 2: 1298.
Wilpart M, Mainguet P, Geeroms D, & Roberfroid M (1985) Desmutagenic
effects of N-acetylcysteine on direct and indirect mutagens. Mutat
Res, 142: 169-177.