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Paracetamol

1. NAME
   1.1 Substance
   1.2 Group
   1.3 Synonyms
   1.4 Identification numbers
      1.4.1 CAS number
      1.4.2 Other numbers
   1.5 Main brand names, main trade names
   1.6 Main manufacturers, main importers
2. SUMMARY
   2.1 Main risks and target organs
   2.2 Summary of clinical effects
   2.3 Diagnosis
   2.4 First aid measures and management principles
3. PHYSICO-CHEMICAL PROPERTIES
   3.1 Origin of the substance
   3.2 Chemical structure
   3.3 Physical properties
      3.3.1 Colour
      3.3.2 State/Form
      3.3.3 Description
   3.4 Other characteristics
      3.4.1 Shelf-life of the substance
      3.4.2 Storage conditions
4. USES
   4.1 Indications
      4.1.1 Indications
      4.1.2 Description
   4.2 Therapeutic dosage
      4.2.1 Adults
      4.2.2 Children
   4.3 Contraindications
5. ROUTES OF EXPOSURE
   5.1 Oral
   5.2 Inhalation
   5.3 Dermal
   5.4 Eye
   5.5 Parenteral
   5.6 Other
6. KINETICS
   6.1 Absorption by route of exposure
   6.2 Distribution by route of exposure
   6.3 Biological half-life by route of exposure
   6.4 Metabolism
   6.5 Elimination and excretion
7. PHARMACOLOGY AND TOXICOLOGY
   7.1 Mode of action
      7.1.1 Toxicodynamics
      7.1.2 Pharmacodynamics
   7.2 Toxicity
      7.2.1 Human data
         7.2.1.1 Adults
         7.2.1.2 Children
      7.2.2 Relevant animal data
      7.2.3 Relevant in vitro data
   7.3 Carcinogenicity
   7.4 Teratogenicity
   7.5 Mutagenicity
   7.6 Interactions
   7.7 Main adverse effects
8. TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS
   8.1 Material sampling plan
      8.1.1 Sampling and specimen collection
         8.1.1.1 Toxicological analyses
         8.1.1.2 Biomedical analyses
         8.1.1.3 Arterial blood gas analysis
         8.1.1.4 Haematological analyses
         8.1.1.5 Other (unspecified) analyses
      8.1.2 Storage of laboratory samples and specimens
         8.1.2.1 Toxicological analyses
         8.1.2.2 Biomedical analyses
         8.1.2.3 Arterial blood gas analysis
         8.1.2.4 Haematological analyses
         8.1.2.5 Other (unspecified) analyses
      8.1.3 Transport of laboratory samples and specimens
         8.1.3.1 Toxicological analyses
         8.1.3.2 Biomedical analyses
         8.1.3.3 Arterial blood gas analysis
         8.1.3.4 Haematological analyses
         8.1.3.5 Other (unspecified) analyses
   8.2 Toxicological Analyses and Their Interpretation
      8.2.1 Tests on toxic ingredient(s) of material
         8.2.1.1 Simple Qualitative Test(s)
         8.2.1.2 Advanced Qualitative Confirmation Test(s)
         8.2.1.3 Simple Quantitative Method(s)
         8.2.1.4 Advanced Quantitative Method(s)
      8.2.2 Tests for biological specimens
         8.2.2.1 Simple Qualitative Test(s)
         8.2.2.2 Advanced Qualitative Confirmation Test(s)
         8.2.2.3 Simple Quantitative Method(s)
         8.2.2.4 Advanced Quantitative Method(s)
         8.2.2.5 Other Dedicated Method(s)
      8.2.3 Interpretation of toxicological analyses
   8.3 Biomedical investigations and their interpretation
      8.3.1 Biochemical analysis
         8.3.1.1 Blood, plasma or serum
         8.3.1.2 Urine
         8.3.1.3 Other fluids
      8.3.2 Arterial blood gas analyses
      8.3.3 Haematological analyses
      8.3.4 Interpretation of biomedical investigations
   8.4 Other biomedical (diagnostic) investigations and their interpretation
   8.5 Overall interpretation of all toxicological analyses and toxicological investigations
   8.6 References
9. CLINICAL EFFECTS
   9.1 Acute poisoning
      9.1.1 Ingestion
      9.1.2 Inhalation
      9.1.3 Skin exposure
      9.1.4 Eye contact
      9.1.5 Parenteral exposure
      9.1.6 Other
   9.2 Chronic poisoning
      9.2.1 Ingestion
      9.2.2 Inhalation
      9.2.3 Skin exposure
      9.2.4 Eye contact
      9.2.5 Parenteral exposure
      9.2.6 Other
   9.3 Course, prognosis, cause of death
   9.4 Systematic description of clinical effects
      9.4.1 Cardiovascular
      9.4.2 Respiratory
      9.4.3 Neurological
         9.4.3.1 Central nervous system (CNS)
         9.4.3.2 Peripheral nervous system
         9.4.3.3 Autonomic nervous system
         9.4.3.4 Skeletal and smooth muscle
      9.4.4 Gastrointestinal
      9.4.5 Hepatic
      9.4.6 Urinary
         9.4.6.1 Renal
         9.4.6.2 Other
      9.4.7 Endocrine and reproductive systems
      9.4.8 Dermatological
      9.4.9 Eye, ear, nose, throat: local effects
      9.4.10 Haematological
      9.4.11 Immunological
      9.4.12 Metabolic
         9.4.12.1 Acid-base disturbances
         9.4.12.2 Fluid and electrolyte disturbances
         9.4.12.3 Others
      9.4.13 Allergic reactions
      9.4.14 Other clinical effects
      9.4.15 Special risks
   9.5 Other
   9.6 Summary
10. MANAGEMENT
   10.1 General principles
   10.2 Life supportive procedures and symptomatic/specific treatment
   10.3 Decontamination
   10.4 Enhanced elimination
   10.5 Antidote treatment
      10.5.1 Adults
      10.5.2 Children
   10.6 Management discussion
   11. ILLUSTRATIVE CASES
      11.1 Case reports from literature
12. Additional information
   12.1 Specific preventive measures
   12.2 Other
13. REFERENCES
14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE ADDRESS(ES)
    Paracetamol

    International Programme on Chemical Safety
    Poisons Information Monograph 396
    Pharmaceutical

    This Monograph has the following sections
    completed: 1, 2, 3, 5, 7.2, 7.4, 9 & 10.


    1.  NAME

        1.1  Substance

             Paracetamol

        1.2  Group

        1.3  Synonyms

             4-Hydroxyanilid kyseliny octove;
             Abensanil; Acamol;
             Acetagesic; Acetalgin;
             Acetaminofen; Acetaminophen;
             Algotropyl; Alvedon; Amadil;
             Anaflon; Anelix; Apamid;
             Apamide; APAP; Ben-u-ron;
             Bickie-mol; Calpol; Cetadol;
             Clixodyne; Datril;
             Dial-a-gesic; Dirox;
             Dymadon; Eneril; Excedrin;
             Febrilix; Febro-gesic;
             Febrolin; Fendon; Finimal;
             Hedex; Homoolan; Lestemp;
             Liquagesic; Lonarid; Lyteca;
             Lyteca syrup; Multin; NAPA;
             Napafen; Napap; Naprinol;
             NCI-C55801; Nobedon; Pacemo;
             Panadol; Panets;
             Paracetamole; Paracetamolo;
             Parmol; Pedric; Phendon;
             Pyrinazine; SK-Apap;
             Tabalgin; Tapar; Temlo;
             Tempanal; Tempra; Tralgon;
             Tussapap; Tylenol; Valadol;
             Valgesic

        1.4  Identification numbers

             1.4.1  CAS number

                    103-90-2

             1.4.2  Other numbers

                    NIOSH/RTECS: AE4200000

        1.5  Main brand names, main trade names

        1.6  Main manufacturers, main importers

    2.  SUMMARY

        2.1  Main risks and target organs

             The clinical course of  paracetamol poisoning is often
             classified into four stages. During stages one and two the
             patient may present minor signs of toxicity, including nausea
             and vomiting, or they may be asymptomatic. During stage
             three, hepatic toxicity and subsequent multi-system failure
             and death may occur. Hepatic recovery should occur in
             patients that survive stage three.

        2.2  Summary of clinical effects

             Paracetamol poisoning may occur if a child has ingested
             more than 150mg/kg or an adult has ingested more than 150
             mg/kg or 7.5g and over.
    
             Stage I (0-24 hours)
             During this stage patients may experience nausea and vomiting
             or may be asymptomatic.
    
             Stage II (24-72 hours)
             During this stage patients may be asymptomatic although
             increase in transaminases, bilirubin and prothrombin time may
             begin to occur.
    
             Stage III (72-96 hours)
             Fuminant hepatic and multi-system fail may occur.
    
             Stage IV (96 hours - two weeks)
             Hepatic recovery should occur in patients that survive stage
             three.

        2.3  Diagnosis

             If the time of ingestion is known, a paracetamol serum
             concentration should be obtained at least 4 hours or longer
             after ingestion. If the time of the ingestion is unknown and
             thought to be greater than 4 hours, the paracetamol
             concentration should be measured immediately upon
             presentation. Paracetamol serum concentrations should be
             based on the treatment nomogram (see Figure 1, Section 1.4,
             of the Antidotes for poisoning by Paracetamol).

        2.4  First aid measures and management principles

             Support airway, breathing and circulation. Management of
             paracetamol poisoning may  include gastrointestinal
             decontamination with one of the following: syrup of ipecac
             induced emesis, gastric lavage or administration of activated
             charcoal. N-acetylcysteine is the proven antidote for 
             paracetamol poisoning and is most effective when administered

             within 8 hours after the initial ingestion of the poison.
             Although N-acetylcysteine has been administered up to and
             beyond 72 hours after ingestion. Some centres have used
             methionine as an alternative to NAC during the first 8 hours
             after ingestion (see Antidotes for poisoning by Paracetamol).
             Haemodialysis and haemoperfusion have not been proven to be
             effective in paracetamol poisoning.

    3.  PHYSICO-CHEMICAL PROPERTIES

        3.1  Origin of the substance

             Synthetic

        3.2  Chemical structure

             Chemical Name: N-Acetyl-p-aminophenol

             Other chemical names:
    
             4'-Hydroxyacetanilide
             4'-Hydroxyacetanilide Parmol
             4-Acetamidophenol
             4-Hydroxyacetanilide
             Acetamide, N-(4-hydroxyphenyl)-
             Acetamide, N-(p-hydroxyphenyl)-
             N-(4-Hydroxyphenyl)acetamide
             N-(Hydroxy-4 phenyl)acetamide
             N-(p-Fluorophenyl)-beta-methyl-1-pyrrolidinepropionamide
             N-Acetyl-4-aminophenol
             4-Acetaminophenol
             p-Acetamidophenol
             p-Acetaminophenol
             p-Acetylaminophenol
             p-Hydroxyacetanilide
             p-Acetamido-phenol
    
             Molecular formula: C8H9NO2
             Molecular weight: 151.2

        3.3  Physical properties

             3.3.1  Colour

                    White

             3.3.2  State/Form

                    Solid-crystals

             3.3.3  Description

                    Melting point 169 to 170.5 
                    Solubility in water: very slightly soluble in cold
                    water but greater solubility in hot water.
                    Solubility in organic solvents: soluble in methanol,
                    ethanol, dimethylformamide, ethylene dichloride,
                    acetone, ethyl acetate.  Slightly soluble in ether.
                    Insoluble in petroleum ether, pentane, benzene.
                    (Budavari, 1996).

        3.4  Other characteristics

             3.4.1  Shelf-life of the substance

             3.4.2  Storage conditions

    4.  USES

        4.1  Indications

             4.1.1  Indications

             4.1.2  Description

        4.2  Therapeutic dosage

             4.2.1  Adults

             4.2.2  Children

        4.3  Contraindications

    5.  ROUTES OF EXPOSURE

        5.1  Oral

             The main route of exposure to paretamol.

        5.2  Inhalation

             Not relevant.

        5.3  Dermal

             Not relevant.

        5.4  Eye

             Not relevant.

        5.5  Parenteral

             Not relevant.

        5.6  Other

             Paracetamol can be administered rectally.

    6.  KINETICS

        6.1  Absorption by route of exposure

        6.2  Distribution by route of exposure

        6.3  Biological half-life by route of exposure

        6.4  Metabolism

        6.5  Elimination and excretion

    7.  PHARMACOLOGY AND TOXICOLOGY

        7.1  Mode of action

             7.1.1  Toxicodynamics

             7.1.2  Pharmacodynamics

        7.2  Toxicity

             7.2.1  Human data

                    7.2.1.1  Adults

                             Susceptibility to paracetamol
                             overdose varies. In healthy adults a dose of
                             150mg/kg or 7.5 g or more in total may be
                             hepatotoxic. Doses of >350mg/kg would
                             usually be expected to cause severe liver
                             damage in almost all cases (Prescott, 1983).
                             The acute toxic dose for high risk patients
                             (for example, liver disease) is unknown.

                    7.2.1.2  Children

                             Young children seem to be less
                             susceptible to hepatotoxicity following
                             paracetamol overdose than adults. The exact
                             reasons are unclear. It is thought that
                             children may have a more efficient
                             detoxification pathway with a faster turnover
                             rate of glutathione (Rumack 1985; Penna and
                             Buchanan 1991) or increased sulphate
                             conjugation of acetaminophen (Miller et al.,
                             1976).

             7.2.2  Relevant animal data

             7.2.3  Relevant in vitro data

        7.3  Carcinogenicity

        7.4  Teratogenicity

             Although paracetamol does cross the placenta the
             occasional use of therapeutic doses in healthy women does not
             seem to be associated with an increased risk of malformation
             and has not been proved to be teratogenic.
    
             There seems to be the same degree of renal and hepatotoxicity
             in the baby as in the mother, so large doses of paracetamol
             that cause severe maternal toxicity have been associated with
             foetal kidney and liver damage. There is structural damage
             (i.e. affecting organ formation) in a 1st trimester exposure
             and functional damage (i.e. affecting organ maturation and/or
             function) in 2nd and 3rd trimester exposures. There is also
             an association with foetal anaemia and neonatal jaundice if
             the overdose is taken near term.

        7.5  Mutagenicity

        7.6  Interactions

        7.7  Main adverse effects

    8.  TOXICOLOGICAL ANALYSES AND BIOMEDICAL INVESTIGATIONS

        8.1  Material sampling plan

             8.1.1  Sampling and specimen collection

                    8.1.1.1  Toxicological analyses

                    8.1.1.2  Biomedical analyses

                    8.1.1.3  Arterial blood gas analysis

                    8.1.1.4  Haematological analyses

                    8.1.1.5  Other (unspecified) analyses

             8.1.2  Storage of laboratory samples and specimens

                    8.1.2.1  Toxicological analyses

                    8.1.2.2  Biomedical analyses

                    8.1.2.3  Arterial blood gas analysis

                    8.1.2.4  Haematological analyses

                    8.1.2.5  Other (unspecified) analyses

             8.1.3  Transport of laboratory samples and specimens

                    8.1.3.1  Toxicological analyses

                    8.1.3.2  Biomedical analyses

                    8.1.3.3  Arterial blood gas analysis

                    8.1.3.4  Haematological analyses

                    8.1.3.5  Other (unspecified) analyses

        8.2  Toxicological Analyses and Their Interpretation

             8.2.1  Tests on toxic ingredient(s) of material

                    8.2.1.1  Simple Qualitative Test(s)

                    8.2.1.2  Advanced Qualitative Confirmation Test(s)

                    8.2.1.3  Simple Quantitative Method(s)

                    8.2.1.4  Advanced Quantitative Method(s)

             8.2.2  Tests for biological specimens

                    8.2.2.1  Simple Qualitative Test(s)

                    8.2.2.2  Advanced Qualitative Confirmation Test(s)

                    8.2.2.3  Simple Quantitative Method(s)

                    8.2.2.4  Advanced Quantitative Method(s)

                    8.2.2.5  Other Dedicated Method(s)

             8.2.3  Interpretation of toxicological analyses

        8.3  Biomedical investigations and their interpretation

             8.3.1  Biochemical analysis

                    8.3.1.1  Blood, plasma or serum

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.2  Urine

                             "Basic analyses"
                             "Dedicated analyses"
                             "Optional analyses"

                    8.3.1.3  Other fluids

             8.3.2  Arterial blood gas analyses

             8.3.3  Haematological analyses

                    "Basic analyses"
                    "Dedicated analyses"
                    "Optional analyses"

             8.3.4  Interpretation of biomedical investigations

        8.4  Other biomedical (diagnostic) investigations and their
             interpretation

        8.5  Overall interpretation of all toxicological analyses and
             toxicological investigations

        8.6  References

    9.  CLINICAL EFFECTS

        9.1  Acute poisoning

             9.1.1  Ingestion

                    Paracetamol poisoning usually occurs in four stages:
    
                    Stage I (0-24 hours)
    
                    During this stage, the patient may be asymptomatic or
                    experience gastrointestinal effects including
                    anorexia, nausea and vomiting. Pallor, diaphoresis and
                    malaise may also be present.
    
                    Stage II (24-72 hours)
    
                    Patients may be asymptomatic. They may experience
                    right upper quadrant pain during this phase.
                    Laboratory evidence of paracetamol poisoning may begin
                    to occur. This includes increases in hepatic
                    transaminases including AST and ALT, prolongation of
                    the PT and increases in bilirubin.
    
                    Stage III (72-96 hours)
    

                    Fulminant hepatic toxicity  may occur. This includes
                    significant increases in transaminases and bilirubin
                    as well as significant prolongation of PT. Liver
                    biopsy will reveal a centrilobular necrosis.
                    Elevations in serum creatinine and BUN may also occur
                    during this phase. Decreases in cholesterol, glucose
                    and albumin are also observed. There may be laboratory
                    evidence of a metabolic acidosis. Clinical
                    presentation often includes nausea and vomiting, right
                    upper quadrant abdominal pain, jaundice and
                    coagulation defects followed by hepatic encephalopathy
                    and coma. Renal failure and cardiac involvement may
                    occur during this stage. Death is due to hepatic
                    failure and is usually preceded by an acidosis and
                    oliguria.
    
                    Stage IV (96 hours - 2 weeks)
    
                    Resolution of hepatic dysfunction occurs in those
                    patients who do not die or require liver transplant
                    during Phase III.

             9.1.2  Inhalation

             9.1.3  Skin exposure

             9.1.4  Eye contact

             9.1.5  Parenteral exposure

             9.1.6  Other

        9.2  Chronic poisoning

             9.2.1  Ingestion

             9.2.2  Inhalation

             9.2.3  Skin exposure

             9.2.4  Eye contact

             9.2.5  Parenteral exposure

             9.2.6  Other

        9.3  Course, prognosis, cause of death

        9.4  Systematic description of clinical effects

             9.4.1  Cardiovascular

             9.4.2  Respiratory

             9.4.3  Neurological

                    9.4.3.1  Central nervous system (CNS)

                    9.4.3.2  Peripheral nervous system

                    9.4.3.3  Autonomic nervous system

                    9.4.3.4  Skeletal and smooth muscle

             9.4.4  Gastrointestinal

             9.4.5  Hepatic

             9.4.6  Urinary

                    9.4.6.1  Renal

                    9.4.6.2  Other

             9.4.7  Endocrine and reproductive systems

             9.4.8  Dermatological

             9.4.9  Eye, ear, nose, throat: local effects

             9.4.10 Haematological

             9.4.11 Immunological

             9.4.12 Metabolic

                    9.4.12.1 Acid-base disturbances

                    9.4.12.2 Fluid and electrolyte disturbances

                    9.4.12.3 Others

             9.4.13 Allergic reactions

             9.4.14 Other clinical effects

             9.4.15 Special risks

             There may be an increased risk of spontaneous
             abortion with first trimester exposures.

             Paracetamol is not contraindicated during breast feeding.

        9.5  Other

        9.6  Summary

    10. MANAGEMENT

        10.1 General principles

             Following provision of necessary supportive care,
             management of paracetamol toxicity involves gastric
             decontamination for recent exposures, laboratory analysis to
             determine the degree of toxicity, administration of specific
             antidotes such as N-acetylcysteine and more involved
             supportive care in those patients who experience hepatic and
             multi-system toxicities.

        10.2 Life supportive procedures and symptomatic/specific treatment

             Symptomatic and supportive care should be provided.
    
             Laboratory Analysis:  If a child has ingested more than
             150mg/kg or an adult has ingested more than 150 mg/kg or 7.5g
             and over, a blood paracetamol concentration should be
             measured 4 hours after the ingestion. If a potentially toxic
             paracetamol ingestion has occurred and the time of the
             ingestion is unknown, a blood paracetamol concentration 
             should be measured immediately upon presentation.  Once the
             paracetamol concentration is available, assess the risk of
             the patient developing toxicity by comparing the plasma
             paracetamol concentration to the time after ingestion using
             the treatment nomogram (see Figure 1, Section 1.4, of the
             Antidotes for poisoning by Paracetamol). 
             Some centres treat at half the level if the patient is in a
             high risk group. If a paracetamol concentration is not available
             within 8 hours of the ingestion, then initiate treatment
             without awaiting the level. Stop treatment if their paracetamol
             level is non-toxic.
    
             Other essential laboratory studies that should be obtained in
             the patient who has a toxic paracetamol serum concentration:
             hepatic transaminases including AST and ALT, PT and INR,
             bilirubin, blood glucose, serum creatinine and BUN.  In
             patients with signs of serious toxicity the following should
             also be obtained:  arterial blood gas, albumin, cholesterol,
             complete blood count and a complete coagulation profile.

        10.3 Decontamination

             Syrup of ipecac can be used to induce emesis in
             children if a potentially toxic exposure has occurred within
             30 minutes.  In adults gastric lavage may be used if the
             ingestion is massive and has occurred within 1 hour. 
             Activated charcoal adsorbs acetaminophen.  The paediatric
             dose is 1 gram/kg and the adult dose of is 25 to 50g.

        10.4 Enhanced elimination

             Haemodialysis and haemoperfusion have not been shown to
             be effective in removing paracetamol.

        10.5 Antidote treatment

             10.5.1 Adults

                     N-Acetylcysteine (please also see Antidotes for
                     poisoning by Paracetamol):
                    N-acetylcysteine (NAC) is the antidote of choice for
                    paracetamol toxicity.  NAC acts as a glutathione
                    substitute, increases glutathione synthesis and
                    increases sulphate conjugation of acetaminophen.
    
                    Available Products: Intravenous and oral NAC are
                    available as both a 10% and 20% solution. A 10mL
                    ampoule of NAC 10% contains 100 mg/mL i.e. 1g of NAC
                    total. A 10mL ampoule of NAC 20% contains 200 mg/mL
                    i.e. 2g of NAC in total.
    
                     Adult Dose - Intravenous Infusion:  Administer a
                    loading dose of 150 mg/kg body weight in 200 mLs of 5%
                    dextrose by slow intravenous (IV) infusion over 15
                    minutes. Then administer 50 mg/kg by IV infusion in
                    500mLs of 5% dextrose over 4 hours followed by 100
                    mg/kg in 1 litre of 5% dextrose over the next 16
                    hours. If necessary, NAC can be administered in saline
                    although its stability in saline is thought to be less
                    than 24 hours.
    
                    At the end of antidote treatment a blood sample should
                    be taken for determination of INR, plasma creatinine
                    concentration and blood gases. If they are normal and
                    the patient is asymptomatic the patient may be
                    discharged. If INR and/or plasma creatinine are raised
                    then the patient requires further monitoring and more
                    acetylcysteine should be given at a rate of 150 mg/kg
                    over 24 hours.
    
                     Adult Dose - Oral and Nasogastric Administration:
                    Administer a loading dose of 140 mg/kg body weight. 
                    Four hours after administration of the loading dose,
                    initiate a maintenance dose of 70 mg/kg administered
                    every four hours for 17 doses.  The NAC solution
                    should be diluted to a 5% solution in soda pop, juice
                    or water prior to oral and nasogastric administration. 
                    Oral NAC should be administered as a cold solution
                    through a covered container and straw in order to
                    increase palatability. It is important not to delay in
                    treating a patient with a paracetamol overdose.

                    Although NAC is useful up to 72 hours post ingestion,
                    its efficacy decreases greatly if started more than 8
                    hours post ingestion (Makin et al., 1994, Prescott
                    1983).
    
                     Adverse effects of IV NAC:   IV NAC may cause
                    discomfort along the vein of administration,
                    erythematous or urticarial rashes, nausea, vomiting,
                    diarrhoea, headache, and tinnitus. For mild allergic
                    reactions administer antihistamines and continue
                    treatment.
    
                    Anaphylactoid reactions, including bronchospasm
                    (particularly in asthmatics) and hypotension have been
                    reported in sensitive patients or if the initial
                    infusion is given more rapidly than recommended. In
                    such cases, stop the infusion immediately and give an
                    antihistamine such as diphenhydramine or
                    chlorpheniramine, adrenaline, corticosteroids, and
                    bronchodilators as necessary. In some centres, if it
                    is less than 8 hours after exposure, oral methionine
                    (see below) is administered if activated charcoal has
                    not been given. If more than 8 hours has passed since
                    the overdose, these centres recommend resumption of
                    the NAC infusion at the  lowest rate (100mg/kg over 16
                    hours) with concurrent antihistamine and  steroid
                    treatment.
    
                     Adverse Effects of Oral and Nasogastric NAC:  The
                    most common adverse effect following administration of
                    oral NAC is vomiting.  This is due to the noxious
                    odour and taste of the product.  Efforts to enhance
                    palatability, as described above, should be taken.  If
                    a patient vomits the NAC dose within one hour of
                    administration, the dose should be administered again. 
                    Efforts to prevent further episodes of vomiting should
                    be taken.  Antiemetics such as metoclopramide or
                    ondansetron can be used.  The anti-emetic dose of
                    metoclopramide is 1 mg/kg.  This can be mixed in 50 mL
                    of 0.9% sodium chloride solution or 5% dextrose
                    solution.  It should then be administered
                    intravenously over 30 minutes.  Ondansetron, 150
                    g/kg, should be mixed in 50 mL of 0.9% sodium
                    chloride solution or 50 mL of 5% dextrose solution. 
                    If emesis has occurred following oral NAC
                    administration, a nasogastric or duodenal tube can be
                    placed.  If these interventions are not effective in
                    preventing vomiting, intravenous administration of NAC
                    should be initiated.
    

                    Urticaria has also been observed after oral and
                    nasogastric administration.
    
                     NAC interference with paracetamol measurement:
                    Laboratories using enzymatic kits for paracetamol
                    measurements may find a reduction in the true
                    paracetamol level when NAC has been administered. This
                    applies ONLY when the analytic method has been
                    modified for use on certain types of clinical
                    analysers. When the kits are used manually, according
                    to the manufacturer's instructions there is no
                    interference.
    
                     Methionine (please also see
                     Antidotes for poisoning by Paracetamol):
    
                    Some centres use methionine rather than NAC if the
                    patient presents within 8 hours of ingestion, is
                    conscious, not vomiting and if activated charcoal has
                    not been given.
    
                    Adult Dose: The adult dose is  2.5g orally every 4
                    hours for 4 doses (10g total). Children over 6 years
                    of age should be treated with the adult dose.

             10.5.2 Children

                     N-acetylcysteine (NAC) (please also see
                     Antidotes for poisoning by Paracetamol):
    
                     Paediatric Dose - Intravenous Infusion: In children
                    who weigh greater than 20kg, administer an NAC loading
                    dose of 150 mg/kg in 100 mLs of 5% dextrose over 15
                    minutes.  Then administer 50 mg/kg in 250mLs of 5%
                    dextrose over 4 hours followed by 100 mg/kg in 500mLs
                    of 5% dextrose over the next 16 hours.  For children
                    who weigh less than 20 kg, administer the NAC doses
                    listed for children greater than 6 years old and
                    adjust the infusion volumes based on the daily fluid
                    requirements of the child by weight.
    
                     Paediatric Dose - Oral and Nasogastric
                     Administration:  Administer a loading dose of 140
                    mg/kg body weight.  Four hours after administration of
                    the loading dose, initiate a maintenance dose of 70
                    mg/kg administered every four hours for 17 doses.  The
                    NAC solution should be diluted to a 5% solution in
                    soda pop, juice or water prior to oral and nasogastric
                    administration.  Oral NAC should be administered as a
                    cold solution through a covered container and straw in
                    order to increase palatability.
    

                     Methionine
    
                     Paediatric Dose: Children over 6 years of age should
                    be treated with the adult dose.  In children less than
                    6 years of age, the dose is 1 g administered orally
                    every 4 hours for 4 doses (4g total).

        10.6  Management discussion

             Activated charcoal does not significantly interfere
             with the absorption of NAC from the gastrointestinal tract.
             One complication associated with the concurrent
             administration of NAC and charcoal is an increased risk for
             vomiting.
    
             Criteria for Liver Transplant: If the patient has any of the
             following:  evidence of acidosis, coagulopathy that does not
             respond to therapy or that persists as transaminases
             decrease, hypoglycaemia, renal failure, hypotension (mean
             arterial pressure less than 60mmHg) or encephalopathy, as
             they are all possible indications of irreversible hepatic
             toxicity and potential multi-system failure.
    
             Some centres will administer both oral or intravenous NAC in
             patients who present after 72 hours,  including those
             patients who present with signs of hepatic toxicity.

    11. ILLUSTRATIVE CASES

        11.1 Case reports from literature

    12. Additional information

        12.1 Specific preventive measures

        12.2 Other

             For further information please also see 
                   Antidotes for poisoning by Paracetamol

    13. REFERENCES

        Budavari S ed. (1996) The Merck Index: an encyclopedia of
        chemicals, drugs and biologicals, 12th ed. Rahway, New Jersey,
        Merck and Co., Inc.
    
        Makin A.J, Wendon J, Williams R. (1994)  Management of severe
        cases of paracetamol overdosage.  Br J of Hosp Med, 52(5):
        210-3
    
        Miller R.P., Roberts R.J., Fischer L.J. (1976) Acetaminophen
        kinetics in neonates, children and adults. Clin Pharm & Ther,
        19:284-94.
    

        Penna A., Buchanan N. (1991) Paracetamol poisoning in children and
        hepatotoxicity. Br J Clin Pharmac, 32: 143-149
    
        Prescott L.F. (1983)  Paracetamol Overdosage, Pharmacological
        Considerations and Clinical Management.  Drugs 25: 290-314
    
        Rumack B.H. (1985)  Acetaminophen: Acute overdose Toxicity in
        children.  Drug Intell Clin Pharm. 19: 911-2

    14. AUTHOR(S), REVIEWER(S), DATE(S) (INCLUDING UPDATES), COMPLETE
        ADDRESS(ES)

        Author:     Medical Toxicology Unit, 
                    Guy's and St Thomas' Trust
                    Avonley Road, London SE14 5ER, UK

        Date:       November, 1996

        Review:     As for author. 1996

        Peer review:         INTOX meeting, March 1998, London, UK 
                             (Members of group: Drs G. Allridge, L.
                             Lubomovir, R. Turk, C. Alonso, S. de Ben, K.
                             Hartigan-Go, N. Bates)

        Editor:              Dr M.Ruse (September, 1998)
    


    See Also:
       Toxicological Abbreviations
       Paracetamol (ICSC)
       Paracetamol  (IARC Summary & Evaluation, Volume 73, 1999)