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    MONOGRAPH FOR UKPID




    AMITRIPTYLINE HYDROCHLORIDE




    HY Allen
    ZM Everitt
    AT Judd

    National Poisons Information Service (Leeds Centre)
    Leeds Poisons Information Centre
    Leeds General Infirmary
    Leeds
    LS1 3EX
    UK


    This monograph has been produced by staff of a National Poisons
    Information Service Centre in the United Kingdom.  The work was
    commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review group: Directors of the UK National Poisons Information
    Service.


    MONOGRAPH FOR UKPID

    Drug name

    Amitriptyline hydrochloride.

    Chemical group

    Tricyclic antidepressant.

    Origin of substance

    Synthetic.

    Name

    UK Brand name(s)

    e.g. Lentizol(R), Tryptizol(R), Domical(R), Elavil(R).
    Also available in compound preparations with perphenazine as
    Triptafen(R) and Triptafen-M(R).

    Synonyms

    Common names/street names

    Pharmacotherapeutic group

    Drug acting upon CNS; antidepressant; tricyclic.

    Reference number

    Product licence

    Lentizol(R) 25 mg capsules: 0018/0173R
    Lentizol(R) 50 mg capsules: 0018/0174R
    Tryptizol(R) 10 mg tablets: 0025/0093
    Tryptizol(R) 25 mg tablets: 0025/0094
    Tryptizol(R) 50 mg tablets: 0025/0095
    Tryptizol(R) injection: 0025/5036
    Tryptizol(R) syrup: 0025/5037

    Other

    CAS 549-18-8

    Manufacturer

    of Lentizol(R)
    Name           Parke-Davis Medical
    Address        Lambert Court, Chestnut Avenue, Eastleigh, Hampshire
                   SO53 3ZQ
    Telephone      01703 620500
    Fax            01703 629812

    of Tryptizol(R)
    Name           Thomas Morson Pharmaceuticals (a subsidiary of Merck
                   Sharp & Dohme Ltd)
    Address        Hertford Road, Hoddesdon, Hertfordshire EN11 9BU
    Telephone      01992 467272
    Fax            01992 451006

    of Domical(R)
    Name           Berk Pharmaceuticals (a subsidiary of Approved
                   Prescription Services Ltd)
    Address        Brampton Road, Hampden Park, Eastbourne, East Sussex
                   BN22 9AG
    Telephone      01323 501111
    Fax            01232 520306

    of Elavil(R)
    Name           DDSA Pharmaceuticals Ltd
    Address        310 Old Brompton Road, London SW5 9JQ
    Telephone      0171 373 7884
    Fax            0171 370 4321

    Supplier/importer

    In addition to the branded products listed above, non-proprietary
    products are available from Antigen, APS and Cox.

    Name           Antigen Pharmaceuticals Ltd
    Address        Antigen House, 82 Waterloo Rd, Hillside, Southport,
                   Merseyside, PR8 4QW
    Telephone      01704 562777
    Fax            01704 562888

    Name           APS (Approved Prescription Services Ltd)
    Address        Brampton Road, Hampden Park, Eastbourne, East Sussex
                   BN22 9AG
    Telephone      01323 501111
    Fax            01323 520306

    Name           AH Cox & Co Ltd
    Address        Whiddon Valley, Barnstaple, Devon EX32 8NS
    Telephone      01271 311257
    Fax            01271 321326

    Presentation

    Form

    Oral tablets, modified release capsules, and mixture. Injection for
    intramuscular or intravenous administration.

    Formulation details

    Tablets of 10 mg, 25 mg, and 50 mg.
    Modified release capsules of 25 mg and 50 mg.
    Mixture (as amitriptyline embonate) equivalent to 10mg/5ml.
    Injection of 10mg/ml.

    Pack size(s)

    Lentizol(R)
         25 mg and 50 mg modified release capsules: blister packs of 56 or
         100.
    Tryptizol(R)
         10 mg tablets: blister packs of 30,
         25 mg tablets: blister packs of 30,
         50 mg tablets: blister packs of 30,
         mixture: bottle of 200 ml,
         injection: vials of 10 ml.

    Packaging

    Lentizol(R) 25 mg: pink capsules of 25 mg amitriptyline hydrochloride
    in a modified release form, marked 'LENTIZOL 25',
    Lentizol(R) 50 mg: pink/red capsules of 50 mg amitriptyline
    hydrochloride in a modified release form, marked 'LENTIZOL 50'.

    Tryptizol(R) 10 mg: blue tablets of 10 mg amitriptyline hydrochloride
    marked 'MSD23',
    Tryptizol(R) 25 mg: yellow tablets of 25 mg amitriptyline
    hydrochloride marked' MSD 45',
    Tryptizol(R) 50 mg: brown tablets of 50 mg amitriptyline hydrochloride
    marked 'MSD 102',
    Tryptizol(R) syrup: pink suspension of amitriptyline embonate
    equivalent to 10 mg/5 ml amitriptyline,
    Tryptizol(R) injection: colourless solution for injection containing
    10mg/ml amitriptyline hydrochloride.

    Compound preparations

    Triptafen(R): pink tablets of 25 mg amitriptyline hydrochloride and 2
    mg perphenazine.
    Triptafen-M(R): pink tablets of 10 mg amitriptyline hydrochloride and
    2 mg perphenazine.

    Amitriptyline is also available in generic and branded-generic
    formulations, the appearance of which will differ from the branded
    products listed.

    Physico-chemical properties

    Solubility in water

         Freely soluble (Martindale 1996).

    Solubility in ether

         Practically insoluble (Martindale 1996).

    Solubility in other solvents

         Freely soluble in alcohol, chloroform, methyl alcohol and
         methylene chloride (Martindale 1996).

    Chemical structure

         3-(10,11-Dihydro- 5H-dibenz-[ a,d]cyclohepten-5-
         ylidene)propyldimethylamine hydrochoride

         C20H23N,HCl = 313.9

    Uses

    Indication

    Symptomatic treatment of depressive illness especially where sedation
    is required. Nocturnal enuresis in children.

    Therapeutic dosage

    in adults
    In depression
    by mouth: 75-150 mg daily in single or divided doses (lower doses in
    elderly and adolescents).
    by IM or IV injection: 10-20 mg four times daily.

    in children
    For nocturnal enuresis:
         6-10 years: 10-20 mg daily by mouth.
         11-16 years: 25-50 mg daily by mouth.
    Modified release preparations are not licensed for use in children.

    Contra-indications

    Recent myocardial infarction or coronary artery insufficiency. Heart
    block or other cardiac arrhythmia. Mania. Severe liver disease.
    Co-administration with monoamine oxidase inhibitors. Hypersensitivity
    to amitriptyline. Lactation. Children under 6 years of age.

    Abuses

    Pharmacokinetics

    Absorption

    Amitriptyline is well absorbed orally with maximum plasma
    concentrations being reached after approximately 3 hours (Schulz et
    al. 1985). It undergoes extensive first-pass metabolism, the systemic

    bioavailability being in the region of 45%(Schulz et al. 1985).
    Little information is available on the disposition of amitriptyline
    following parenteral administration.

    Distribution

    Amitriptyline is widely distributed throughout the body with an
    apparent volume of distribution of about 19 L/kg (Schulz et al. 1985).
    Approximately 95% of amitriptyline in the plasma is bound to proteins
    (Schulz et al. 1985). The plasma protein binding of tricyclic
    antidepressants is pH sensitive, with a small reduction in plasma pH
    being associated with large increases in unbound (pharmacologically
    active) drug (Nyberg & Martensson 1984).

    Metabolism

    There is wide individual variation in the pharmacokinetic profile of
    amitriptyline. Amitriptyline is metabolised in the liver, the primary
    routes of metabolism being demethylation, hydroxylation and
    conjugation. It is considered that the metabolic pathways are mediated
    by the enzymes CYP2D6 and CYP2C19, although other enzymes are probably
    also involved (Schmider et al. 1995). The major active metabolites
    formed are nortriptyline, 10-hydroxyamitriptyline, and
    10-hydroxynortriptyline. Both nortriptyline and
    10-hydroxynortriptyline contribute significantly to the antidepressant
    effect (Bertilsson et al. 1979).

    Elimination

    Amitriptyline is excreted mainly in the urine as conjugated and
    unconjugated metabolites. Less than 5% is excreted as unchanged drug
    (Dollery 1991).
    Significant gastric and biliary secretion of amitriptyline and its
    metabolites occurs, resulting in enteroenteric and enterohepatic
    circulations (Gard et al. 1973).
    Dialysis as a means of promoting drug and metabolite elimination is
    ineffective (Dawling et al. 1982).

    Half-life

    substance

    Amitriptyline: 21 hours (range 13-36 hours)(Schulz et al. 1985).

    metabolite(s)

    Nortriptyline: 25 hours (Dawling et al. 1982).
    10-hydroxynortriptyline: 26 hours (Dawling et al. 1982).

    Special populations

     Elderly: metabolic changes in the elderly result in higher plasma
    amitriptyline concentrations than in younger populations (Schmider et
    al. 1995).

     Renal impairment: reduced metabolite clearance in renal impairment
    results in accumulation, particularly of the hydroxymetabolites
    (Dawling et al. 1982).
     Hepatic impairment: reduced metabolic capacity in liver impairment
    results in accumulation of amitriptyline (Hrdina et al. 1985).
     Gender: there is some evidence to suggest that higher plasma
    concentrations of amitriptyline occur in females over the age of 50
    than in males of a similar age, but factors other than gender
    complicate the picture (Preskorn & Mac 1985, Schmider et al. 1995).

    Breast milk

    Amitriptyline and its metabolites are secreted into breast milk. In
    one patient the amounts of amitriptyline and nortriptyline in the
    breast milk and serum were approximately equal (Bader & Newman 1980).
    In a second patient the concentrations of amitriptyline, nortriptyline
    and 10-hydroxynortriptyline in breast milk were about 50%, 75%, and
    70% of the maternal serum concentrations respectively (Breyer-Pfaff et
    al. 1995). The doses to the infants in these two cases are
    approximately 3% and 1% of the maternal doses respectively.

    Toxicokinetics

    Absorption

    In a study of 27 tricyclic overdose patients, peak plasma
    concentrations occurred within 3 hours of the overdose (Bramble et al.
    1985).
    There was no evidence of prolonged absorption from the gut following
    amitriptyline overdose in 9 patients (Hulten et al. 1992).

    Distribution

    Amitriptyline is rapidly distributed into body tissues with plasma
    drug concentrations beginning to fall within 3 hours of overdose
    (Bramble et al. 1985).
    The value for protein binding remains within the range observed with
    therapeutic doses and is likewise pH sensitive (Hulten et al. 1992).

    Metabolism

    A comparison of half-life values for amitriptyline following overdose
    with values after therapeutic dosing suggests that saturation of
    metabolic process may occur. Insufficient data are available to draw
    firm conclusions.

    Elimination

    There is evidence to show that enterohepatic or enteroenteral
    circulation of the metabolite nortriptyline occurs (Hulten et al.
    1992).
    Less than 5% of a dose is excreted in urine during the first 24 hours
    after overdose (Gard et al. 1973).

    Half-life

    substance

    Following overdose, half-life values between 15 hours and 81 hours
    have been reported (Hulten et al. 1992, Spiker & Biggs 1976).

    metabolite(s)

    Special populations

    Breast milk

    Adverse effects

    Antimuscarinic effects, sedation, ECG changes, arrhythmias, postural
    hypotension, tachycardia, syncope, sweating, tremor, rashes,
    hypersensitivity reactions, behavioral disturbances, hypomania or
    mania, confusion, interference with sexual function, blood sugar
    changes, weight gain, convulsions, movement disorders and dyskinesias,
    fever, hepatic and haematological reactions.

    Interactions

    Pharmacodynamic

    a) A potentially hazardous interaction may occur between a tricyclic
    antidepressant and a monoamine oxidase inhibitor (including
    moclobemide and selegiline) resulting in increased amounts of
    noradrenaline and serotonin at the synapse. Coma, hyperthermia,
    convulsions, delirium, or death may result (White & Simpson 1984).

    b) There is an increased risk of cardiotoxicity when administered with
    other drugs which prolong the QT interval e.g. anti-arrhythmics,
    astemizole, halofantrine, terfenadine.

    c) The pharmacology of amitriptyline suggests that concomitant
    ingestions of selective serotonin reuptake inhibitors, phenothiazines,
    sympathomimetics, or other tricyclic antidepressants will enhance its
    toxicity.

    Pharmacokinetic

    a)  The metabolism of tricyclic antidepressants is inhibited by most
    selective serotonin reuptake inhibitors resulting in elevated
    tricyclic plasma concentrations. Fluoxetine, fluvoxamine, and
    paroxetine appear to exert a greater effect than sertraline. Limited
    data suggest that citalopram does not inhibit tricyclic metabolism
    (Baettig et al. 1993, Taylor 1995).

    b) As the metabolism of amitriptyline is mediated by cytochrome P450
    microsomal enzymes, particularly CYP2D6 and CYP2C19, the potential
    exists for interactions with drugs which are substrates of these
    pathways.

    c) Cimetidine reduces the metabolic clearance of amitriptyline by
    inhibition of liver enzymes, resulting in higher plasma amitriptyline
    concentrations (Stockley 1996).

    Ethanol

    Plasma concentrations of amitriptyline are higher when ingested with
    ethanol, probably as a result of reduced first-pass metabolism (Shoaf
    & Linnoila 1991).

    Summary

    Type of product

    A tricyclic antidepressant.

    Ingredients

    Amitriptyline tablets: 10 mg, 25 mg, 50 mg.
    Amitriptyline in a modified release capsule: 25 mg, 50 mg.
    Amitriptyline mixture: equivalent to 10mg/5ml.
    Amitriptyline injection: 10mg/ml.

    Summary of toxicity

    Patients with only mild signs of toxicity may rapidly develop life-
    threatening complications. Where major toxic events occur these
    usually develop within 6 hours of overdose, the risk of toxicity being
    greatest 2-4 hours after ingestion.

    Amitriptyline overdose must be managed on a clinical basis rather than
    on the amount ingested, but as a guide, doses of 750 mg in adults have
    been associated with severe toxicity. Ingestions of tricyclic
    antidepressants in children indicate that doses of 15 mg/kg may prove
    fatal to a child, although recovery has followed reported ingestions
    of over 100 mg/kg.

    Sinus tachycardia, hypotension, and anticholinergic symptoms are
    common features. Cardiotoxicity, impaired consciousness, seizures,
    acidosis, and respiratory insufficiency are associated with severe
    toxicity. The occurrence of seizures may precipitate the onset of
    cardiac arrhythmias and hypotension. Delirium may be a complication on
    recovery.

    Common features

    Dry mouth, blurred vision, dilated pupils, urinary retention, sinus
    tachycardia, drowsiness, hypothermia, and confusion. Hypoxia,
    acidosis, hypotension, convulsions, cardiac arrhythmias, and coma.

    Uncommon features

    Skin blisters, rhabdomyolysis, disseminated intravascular coagulation,
    adult respiratory distress syndrome, and absent brain stem reflexes.

    Summary of management

    SUPPORTIVE

    1.   Maintain a clear airway and adequate ventilation if consciousness
         is impaired.

    2.   If within 1 hour of the ingestion and more than 300 mg has been
         taken by an adult or more than 1mg/kg by a child, give activated
         charcoal.

    3.   Carry out arterial blood gas analysis, and correct any acidosis
         and hypoxia.

    4.   Monitor the cardiac rhythm and blood pressure.

    5.   Single, brief convulsions do not require treatment but if they
         are prolonged or recurrent, they should be controlled with
         intravenous diazepam.

    6.   Other measures as indicated by the patient's clinical condition.

    Epidemiology

    Over an 11 year period between 1975 and 1985, more than 1,200 deaths
    were attributable to amitriptyline poisoning in the UK, or 47 deaths
    per million prescriptions dispensed (Montgomery et al. 1989).
    Fatalities tend to occur in older rather than younger patients. In
    both fatal and non-fatal overdose, there are a greater number of
    ingestions in females than in males (Crome 1986).
    The overall incidence of serious cardiac complications in patients who
    are admitted to hospital following tricyclic overdose is reported to
    be less than 10%. Some degree of coma occurs in about 50% of cases,
    but is only unresponsive to painful stimuli in about 10-15% of cases
    (Crome 1986). Convulsions occur in approximately 6% of patients
    (Taboulet 1995). The death rate in patients admitted to hospital is
    estimated to be 2%-3% (Dziukas & Vohra 1991).

    Mechanism of action/toxicity

    Mechanism of action

    The precise mechanism of antidepressant action is unclear, but results
    from the potent inhibition of noradrenaline and serotonin reuptake
    into presynaptic neurones, and adaptive changes in receptor
    sensitivity (Richelson 1994).

    Amitriptyline inhibits the reuptake of noradrenaline and serotonin
    with similar potency, whilst the metabolite nortriptyline inhibits the
    reuptake of noradrenaline to a greater degree than serotonin. The
    hydroxy metabolites of amitriptyline and nortriptyline inhibit
    noradrenaline reuptake, but to a lesser degree than the parent drugs.
    They do not have any significant effect on serotonin reuptake
    (Bertilsson et al. 1979).

    Amitriptyline is a potent antagonist of both peripheral and central
    muscarinic cholinergic receptors. It has also relatively potent
    antagonist activity at H1 histamine and a1 adrenergic receptors.
    These antagonist actions account for its anticholinergic, sedative,
    and hypotensive properties (Richelson 1994).

    Mechanism of toxicity

    Toxicity is due to depression of myocardial function (a quinidine-like
    effect), central and peripheral muscarininic receptor blockade, a1
    adrenergic receptor blockade, and respiratory insufficiency.
    The risk of toxicity is greatest 2-4 hours after ingestion when plasma
    levels are maximal.

    Features of poisoning

    Acute

    Ingestion

     Mild to moderate toxicity: dilated pupils, sinus tachycardia,
    drowsiness, dry mouth, blurred vision, urinary retention, absent bowel
    sounds, confusion, agitation, body temperature disturbances,
    twitching, delirium, hallucinations, nystagmus, and ataxia.
    Increased tone and hyperreflexia may be present with extensor plantar
    responses (Callaham 1979, Crome 1986, Dziukias & Vohra 1991).

     Severe toxicity: coma, hypotension, convulsions, supraventricular
    and ventricular arrhythmias, hypoxia, metabolic/respiratory acidosis,
    and cardiac arrest (Crome 1986, Dziukias & Vohra 1991).

    ECG changes (in the usual order of appearance) include non-specific ST
    or T wave changes, prolongation of the QT, PR, and QRS intervals,
    right bundle branch block, and atrioventricular block. The terminal
    0.04 second frontal plane QRS axis often shows a right axis deviation
    (Dziukas & Vohra 1991).

     Delayed features: adult respiratory distress syndrome (Varnell et
    al. 1989).

     Uncommon features: skin blisters, rhabdomyolysis, disseminated
    intravascular coagulation, gaze paralysis, and absent brain reflexes
    (Dziukias & Vohra 1991, White 1988, Yang & Dantzker 1991). See case
    report 1.

    Inhalation

    Dermal

    Ocular

    Other routes

    Chronic

    Ingestion

    Inhalation

    Dermal

    Ocular

    Other routes

    At risk groups

    Elderly

    There is an increased risk of toxicity resulting from impaired drug
    metabolism (Schmider et al. 1995).

    Pregnancy

    There is relatively wide experience with the therapeutic use of
    amitriptyline during pregnancy. Although a few birth defects have been
    reported, the number is insufficient to support an association with
    amitriptyline administration (Briggs 1994).

    Children

    Ingestions in children result in features similar to those following
    adult ingestion (Crome & Braithwaite 1978, Goel & Shanks 1974, James &
    Kearns 1995). See case report 2.

    Enzyme deficiencies

    The metabolism of amitriptyline is in part mediated by the microsomal
    enzymes CYP2D6 and CYP2C19 which are subject to genetic polymorphism
    (Schmider et al. 1995). Metabolic processes will differ in individuals
    deficient in these enzymes and there is a risk of amitriptyline
    accumulation.

    Enzyme induced

    The metabolism of amitriptyline is increased in the presence of enzyme
    inducing drugs, but is of doubtful clinical relevance as the
    metabolites formed also have pharmacological activity.

    Others

     Renal impairment: increased risk of toxicity due to accumulation of
    metabolites.
     Hepatic impairment: increased risk of toxicity due to impaired
    amitriptyline metabolism.
     Cardiac disease: increased risk of cardiotoxicity due to underlying
    disease.
     Epilepsy: increased risk of seizures.

    Management

    Decontamination

    In cases where more than 300 mg has been taken by an adult or more
    than 1mg/kg by a child, activated charcoal should be given to reduce
    the absorption if administered within one hour of the drug ingestion.
    Adult dose; 50 g, child dose; 1 g/kg. If the patient is drowsy this
    should be administered via a nasogastric tube, and if there is no gag
    reflex present, using a cuffed endotracheal tube to protect the
    airway.

    Supportive care

    General

    Clear and maintain the airway, and give cardiopulmonary resuscitation
    where necessary. Evaluate the patient's condition and provide support
    for vital functions.

    Management of the symptomatic patient

    1.   Administer intravenous sodium bicarbonate to correct any
    acidosis.

    Adult dose: 50 ml of 8.4%sodium bicarbonate by slow intravenous
    injection; child dose: 1 ml/kg of 8.4% sodium bicarbonate by slow
    intravenous injection.

    Subsequent bicarbonate therapy should be guided by arterial blood pH
    which should be monitored frequently.

    2.   Maintain adequate ventilation to prevent hypoxia with
    supplemental oxygen or artificial ventilation as appropriate.

    3.   Carefully maintain plasma potassium levels to prevent
    hypokalaemia.

     In mixed overdoses where a benzodiazepine has also been ingested, 
     the use of the competitive benzodiazepine antagonist flumazenil is 
     contraindicated (Mordel et al. 1992).

    Where symptoms develop following mild to moderate overdose, they may
    persist for 24 hours. Prolonged or delayed complications following
    severe toxicity may require the patient to be hospitalised for several
    days.

    Specific

    Management of cardiotoxicity.

    GENERAL NOTE: in practice it is seldom necessary or advisable to use
    specific drug treatment for arrhythmias. If hypoxia and acidosis are
    reversed and adequate serum potassium levels maintained, then the
    majority of patients show improvement with supportive measures.

    SINUS and SUPRAVENTRICULAR TACHYCARDIAS: no specific treatment
    required (Pimentel & Trommer 1994).

    VENTRICULAR ARRHYTHMIAS: give sodium bicarbonate (even in the absence
    of acidosis) before considering antiarrhythmic drug therapy. Where an
    antiarrhythmic is considered necessary, lignocaine is the preferred
    drug (Pimentel & Trommer 1994).

         ADULT DOSE: 50-100 mg given by IV bolus over a few minutes,
    followed by an intravenous infusion of 4 mg/minute for 30 minutes, 2
    mg/minute for 2 hours, then 1 mg/minute (BNF 1998).
    The use of quinidine, disopyramide, procainamide, and flecainide are
    all contra-indicated as they depress cardiac conduction and
    contractility. The use of beta-blockers should also be avoided as they
    decrease cardiac output and exacerbate hypotension. The efficacy of
    other antiarrhythmic agents (e.g bretylium, amiodarone, calcium
    channel blockers) has not been studied in tricyclic antidepressant
    poisoning (Pimentel & Trommer 1994).

    BRADYARRHYTHMIAS and HEART BLOCK: cardiac pacing may have only limited
    success as the cardiotoxicity of amitriptyline results from depression
    of contractility rather than failure of cardiac pacemakers.

    CARDIAC ARREST: manage in the standard manner but with continuing
    resuscitative measures as some patients have recovered after receiving
    several hours of external cardiac massage (Orr & Bramble 1981).

    Management of coma

    Good supportive care is essential.

    Management of hypotension

    Hypotension should be managed by the administration of intravenous
    fluids and by physical means. The majority of patients ingesting
    amitriptyline have otherwise healthy cardiovascular systems and
    providing cardiac output is good it is unnecessary to use specific
    drug therapy.

    If there is evidence of poor cardiac output (after correction of
    acidosis, hypovolaemia, and hypoxia) then the use of a vasoactive
    agent may need to be considered. Noradrenaline has been shown to be
    helpful in a number of studies (including cases where dopamine therapy
    has failed) (Pimentel & Trommer 1994, Teba et al. 1988, Yang &
    Dantzker 1991).

         ADULT DOSE: IV infusion of noradrenaline acid tartrate 80
    micrograms/ml (equivalent to noradrenaline base 40 micrograms/ml) via
    a central venous catheter at an initial rate of 0.16 to 0.33 ml/minute
    adjusted according to response (BNF 1998).

         CHILD DOSE (unlicensed indication): IV infusion of noradrenaline
    acid tartrate 0.04-0.2 microgram/kg/minute (equivalent to 0.02-0.1
    microgram/kg/minute of noradrenaline base) in glucose 5% or
    glucose/saline via a central venous catheter (Guy's, Lewisham & St
    Thomas Paediatric Formulary, 1997).

    Management of seizures

    Administer intravenous diazepam to control frequent or prolonged
    convulsions.

         ADULT DOSE: 10 mg,
         CHILD DOSE: 0.25-0.4 mg/kg,
         Both by slow IV injection preferably in emulsion form.

    Where seizure activity proves difficult to manage, paralyse and
    ventilate the patient. Continue to monitor the cerebral function to
    ensure the cessation of seizure activity.

    Other management

    Catheterisation may be required to relieve distressing urinary
    retention and to allow continuous monitoring of urine output as a
    means of assessing cardiac output (Crome 1986).
    Respiratory complications should be managed conventionally with early
    respiratory support.
    Control delirium with oral diazepam. Large doses may be required (20-
    30 mg two-hourly in adults).

    Monitoring

    Monitor the cardiac rhythm, arterial blood gases, serum electrolytes,
    blood pressure, respiratory rate and depth, and urinary output.

    Observe for a minimum of 6 hours post-ingestion where:
    i) more than 1 mg/kg has been ingested by a child,
    ii) more than 300 mg has been ingested by an adult,
    iii) the patient is symptomatic.

    Antidotes

    None available.

    Elimination techniques

    Due to the large volume of distribution and high lipid solubility of
    amitriptyline, haemodialysis and haemoperfusion do not significantly
    increase drug elimination (Lieberman et al. 1985).

    Investigations

    Following severe toxicity:

    i) a chest X-ray will be needed to exclude pulmonary complications,
    ii) measure serum creatine kinase and other skeletal muscle enzyme
    activity (e.g. AST, ALT, and lactic dehydrogenase),
    iii) assess renal function,
    iv) assess haematological status.

    Management controversies

    Gastric lavage is not recommended as the procedure may be associated
    with significant morbidity, and there is no evidence that it is of any
    greater benefit than activated charcoal used alone (Bosse et al.
    1995).
    If the procedure is used (i.e. in cases where activated charcoal
    cannot be administered), a cuffed endotracheal tube should be used to
    protect the airway if the patient is drowsy, and activated charcoal
    left in the stomach following the lavage.

    Repeat doses of oral activated charcoal may prevent the reabsorption
    of tricyclic antidepressants and their metabolites secreted in gastric
    juices and bile (Swartz & Sherman 1984). However, it would not be
    expected from the large volume of distribution of amitriptyline that
    clinically significant increases in body clearance would result.

    Physostigmine salicylate is a short acting reversible cholinesterase
    inhibitor which has been used historically in the management of
    tricyclic overdoses to reverse coma and antimuscarinic effects.
    Reports of serious complications from its use include severe
    cholinergic activity, convulsions, bradycardia, and asystole (Newton
    1975, Pentel & Peterson 1980). The use of physostigmine is no longer
    recommended.

    The use of dopamine in the management of hypotension has been
    advocated, but the pressor effect of this indirect acting inotrope may
    be diminished in tricyclic overdosed patients due to depleted levels
    of noradrenaline (Buchman et al. 1990, Pimentel & Trommer 1994, Teba
    et al. 1988).

    The use of intravenous glucagon has been proposed in cases where
    hypotension is unresponsive to volume expansion and sodium bicarbonate
    administration, because of its positive inotropic effect and possible
    antiarrhythmic property. Its place in therapy has not been established
    (Senner et al. 1995). 

         Adult dose: 10 mg by IV bolus followed by an infusion of 10 mg
    over 6 hours (unlicensed indication and dose).

    There are a number of reports of severe arrhythmias or sudden death
    occurring up to 1 week after tricyclic overdose, but a review of the
    cases show that the patients had continuing toxicity, underlying
    disease, or abnormalities (Stern et al. 1985). See case report 3.

    Several predictors of clinical severity in tricyclic overdoses have
    been suggested, including:

    1.   a maximal limb-lead QRS duration of 0.1 second or longer as a
    predictor of the risk of seizure (Boehnert & Lovejoy 1985),
    2.   a maximal limb-lead QRS duration of 0.16 second or longer as a
    predictor of the risk of ventricular arrhythmias (Boehnert & Lovejoy
    1985),
    3.   plasma tricyclic levels greater than 0.8 mg/L (Caravati & Bossart
    1991),
    4.   the ECG terminal 40-ms frontal plane QRS axis of more than 120
    (Wolfe et al. 1989).
    5.   plasma drug concentrations in excess of 2 mg/L as a predictor of
    the development of lung injury (Roy et al. 1989).

    Whilst none of these features in isolation are predictive of
    life-threatening toxicity, they may be helpful in assessing patient
    risk.

    Case data

    Case report 1

    Massive ingestion of amitriptyline in an adult.

    A 46 year old woman took an estimated 9 g of amitriptyline. One hour
    later she suffered a grand mal seizure. Diazepam, phenobarbitone and
    physostigmine were administered. Her blood pressure was 98/66 mm Hg,
    and the pulse was 94 beats per minute. Arterial blood gas values
    showed a pH of 7.16, PaCO2 of 31 mm Hg, and PaO2 of 373 mm Hg on 100
    percent oxygen. The ECG revealed a widened QRS complex of 160 ms. She
    had metabolic acidosis and an anion gap of 24. Dopamine and adrenaline
    were given to maintain blood pressure. At this time the woman was
    transferred to intensive care facilities as she failed to respond to
    pressor therapy. She was comatose with no response to painful stimuli,
    without spontaneous respiration, and corneal and oculocephalic
    reflexes were absent. The serum amitriptyline level was 2.35 mg/L. Her
    blood pressure remained low (75/50) despite an infusion of 30 

    micrograms/kg/min of dopamine, but rose to 130/70 when noradrenaline
    was substituted for dopamine. Spontaneous respiration returned after
    24 hours, and during the next 3 days corneal, pupillary, and
    oculocephalic reflexes also returned. The patient regained full
    consciousness five days after the ingestion (Yang & Dantzker 1991).

    Case report 2

    Ingestion of 1.15 g amitriptyline in a young child.

    A 20-month-old girl reportedly ingested 23 tablets of amitriptyline 50
    mg. She was cyanotic, comatose, and had continuous clonic-tonic
    seizures. Her rectal temperature was 34.7C, the heart rate was 115
    beats/min, and her blood pressure was 59/27 mm Hg. The ECG tracing was
    consistent with ventricular tachycardia. After extensive resuscitative
    measures, including mechanical ventilation, the girl recovered and was
    discharged home one week later (Beal & May 1989).

    Case Report 3

    Unexpected death 7 days after overdose in adult.

    A 34 year old woman was admitted to hospital following an intentional
    overdose of amitriptyline and diazepam. She was comatose, had a sinus
    tachycardia, nonspecific ST and T wave changes, and was normotensive.
    Her electrolyte levels were normal except for a potassium value of 3.3
    mmmol/L. During 44 hours of monitoring no arrhythmias occurred and her
    mental status returned to normal. On the second day her usual
    hydrochlorothiazide diuretic therapy was restarted, the potassium
    level being 4 mmmol/L at this time. Five days after admission her
    potassium level was 3.2 mmmol/L. Seven days after recovery from
    overdose the patient was found unresponsive and in refractory
    ventricular fibrillation. Venous blood samples during unsuccessful
    resuscitative efforts showed a potassium level of 2.6 mmmol/L.
    Post-mortem plasma amitriptyline and nortriptyline levels were both
    0.2 mg/L. An autopsy did not reveal an anatomic cause of death (Babb &
    Dunlop 1985).

    Analysis

    Agent/toxin/metabolite

    There is no clear relationship between plasma amitriptyline
    concentration and clinical response or toxicity. Consequently the
    measurement of plasma drug concentration following overdose is not
    routinely advised, although it may have diagnostic value.

    Sample container

    Storage conditions

    Transport

    Interpretation of data

    There is considerable variation in plasma concentrations of
    amitriptyline and its metabolites between individuals.
    As a guide, a therapeutic range for amitriptyline of 0.15-0.25 mg/L
    has been proposed, whilst moderate to severe toxicity is associated
    with combined amitriptyline and nortriptyline concentrations of 1 mg/L
    or greater (Bramble et al. 1985, Preskorn & Mac 1985).

    Conversion factors

    1 mg/L = 3.186 micromoles/L
    1 micromole/L = 0.314 mg/L

    Other

    The molecular weight of amitriptyline hydrochloride is 313.9

    Other toxicological data

    Carcinogenicity

    Tumour-inducing effects have not been reported (Dollery 1991).

    Reprotoxicity

    Teratogenicity

    There are occasional reports suggesting an association between
    amitriptyline and congenital abnormalities (particularly limb
    reductions), but analysis of over 500,000 births failed to confirm
    such an association.
    A surveillance study between 1985 and 1992 involving over 200,000
    completed pregnancies exposed to amitriptyline (of which 467 were
    during the first trimester) observed 25 major birth defects (20
    expected in a control population). These data do not support an
    association between amitriptyline and congenital defects (Briggs
    1994).

    Relevant animal data

    There is evidence of amitriptyline-induced teratogenicity in some
    animals. Encephaloceles and bent tails in hamsters, and skeletal
    malformations in rats have been reported (Briggs 1994).

    Relevant  in vitro data

    Authors

    HY Allen
    ZM Everitt
    AT Judd

    National Poisons Information Service (Leeds Centre)
    Leeds Poisons Information Centre
    Leeds General Infirmary
    Leeds
    LS1 3EX
    UK

    This monograph was produced by the staff of the Leeds Centre of the
    National Poisons Information Service in the United Kingdom. The work
    was commissioned and funded by the UK Departments of Health, and was
    designed as a source of detailed information for use by poisons
    information centres.

    Peer review was undertaken by the Directors of the UK National Poisons
    Information Service.

    Prepared September 1996
    Updated May 1998

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    See Also:
       Toxicological Abbreviations