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.
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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 antidota