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    MONOGRAPH FOR UKPID




    DOTHIEPIN 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

    Dothiepin hydrochloride

    Chemical group

    Tricyclic antidepressant

    Origin

    Synthetic

    Name

    UKBrand name(s)

    Prothiaden(R), Dothapax(R), Prepadine(R).

    Synonyms

    Dosulepin hydrochloride (INN).

    Common names

    Product licence number(s)

    Prothiaden(R) 25 mg: 00169/0086
    Prothiaden(R) 75 mg: 00169/0087

    CAS number

    7081-53-0

    Manufacturer

    Prothiaden(R), Knoll Ltd, 9 Castle Quay, Castle Boulevard, Nottingham,
    Nottinghamshire NG7 1FW
    Tel no. 0115 912 5000

    APS, Ashbourne (Dothapax(R)), Berk (Prepadine(R)), Cox, Generics,
    Hillcross, Kent, Pharm and Norton.

    Presentation

    Form

    Capsules, tablets.

    Formulation details

    Capsules of 25mg.
    Tablets of 75mg.

    Pack size(s)

    25mg capsules - packs of 100 and 600.
    75mg tablets - packs of 28 and 500.
    Generics or branded generics may have different pack sizes.

    Packaging

    Prothiaden(R) 25mg - red/brown capsules marked P25
    Prothiaden(R) 75 mg - red sugar-coated tablets marked P75
    Generic formulations or branded generics will differ in presentation.

    Properties

    Chemical structure C19H21NS.HCl = 331.9
    Chemical name 11-(3-Dimethylaminopropylidene)-6,-11-
    dihydrodibenz [b,e]thiepin hydrochloride

    Indications

    Depressive illness especially where an anti-anxiety effect is
    required.

    Therapeutic Dosage

    ADULTS: 50 mg - 150 mg daily in either divided doses or as a single
    dose at night.
    In severely depressed patients, doses of up to 225 mg daily have been
    used.
    CHILD: Not recommended.

    Contra-indications

    Recent myocardial infarction, heart block or other cardiac arrhythmia,
    mania, severe liver disease.

    Abuses

    Epidemiology

    Over a four year period between 1989 and 1992 there were over 600
    deaths from dothiepin overdose (ONS 1996). Tricyclic fatalities tend
    to occur in older rather than in younger patients. In both fatal and
    non-fatal overdose, there are a greater number of tricyclic 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).

    Adverse effects

    Antimuscarinic effects, sedation, arrhythmias, postural hypotension,
    tachycardia, sweating, tremor, rashes, hypomania or mania, confusion,
    interference with sexual function, weight gain, convulsions, 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,
    hypertension, convulsions, delirium, or death may result (Lipman 1981,
    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, or terfenadine.

    c)   The pharmacology of dothiepin 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 dothiepin is mediated by cytochrome P450
    microsomal enzymes, the potential exists for interactions with other
    drugs which are substrates of this system.

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

    Ethanol

    Information about any interaction between dothiepin and ethanol is
    lacking. Two other tricyclic antidepressants (amitriptyline, doxepin)
    are known to interact with ethanol resulting in an increased
    impairment of psychomotor skills, whilst a number of other tricyclics
    appear to interact with ethanol only minimally (Stockley 1996).

    Mechanism of action

    The precise mechanism of antidepressant action is unclear, but results
    from the inhibition of noradrenaline and serotonin reuptake into
    presynaptic neurones, and adaptive changes in receptor sensitivity.
    In addition to inhibiting the reuptake of noradrenaline and serotonin,
    dothiepin is also an antagonist of muscarinic cholinergic receptors,
    histamine receptors, and to a lesser extent alpha1 adrenergic
    receptors (Rudorfer et al. 1994). These antagonist actions account for
    its anticholinergic, sedative, and hypotensive properties.
    The contributions of the metabolites nordothiepin and the combined
    sulphoxides to the total antidepressant activity are similar to that
    of dothiepin itself (Rees 1981).

    Mechanism of toxicity

    The toxicity of dothiepin in overdose results from depression of the
    myocardial function (a quinidine-like effect), anticholinergic
    activity, alpha adrenergic receptor blockade, and respiratory
    insufficiency. The risk of toxicity is greatest 2-4 hours after
    ingestion when plasma levels are at the highest.

    Pharmacokinetics

    ABSORPTION

    Dothiepin is rapidly absorbed after oral administration with maximum
    plasma concentrations being reached after approximately 3 hours
    (Maguire et al. 1983).
    Extensive first-pass metabolism occurs (Rees 1981), the estimated oral
    bioavailability of dothiepin being approximately 30% (Yu et al. 1986).

    DISTRIBUTION

    Dothiepin is widely distributed throughout the body with an apparent
    volume of distribution of over 10 L/kg (Rees 1981).
    Dothiepin is 80-90% bound to plasma proteins at therapeutic
    concentrations (Dollery 1991). The plasma protein binding of tricyclic
    antidepressants is pH sensitive with a small reduction in plasma pH
    being associated with large increases in unbound (pharmacolgically
    active) drug (Nyberg & Martensson 1984).

    METABOLISM

    The metabolic profile of dothiepin varies widely between individuals.
    Dothiepin is metabolised by demethylation and S-oxidation in the
    liver, resulting in the active metabolites, nordothiepin (also known
    as northiaden or desmethyldothiepin), dothiepin sulphoxide and
    nordothiepin sulphoxide, all of which contribute to the antidepressant
    effect (Rees 1981).
    Inactive conjugated glucuronide metabolites have also been isolated
    (Rees 1981).

    ELIMINATION

    The major route of excretion is in urine, although significant faecal
    elimination also occurs. Less than 0.5% of a dose is excreted as
    unchanged dothiepin in urine (Rees 1981).
    Enteroenteric and enterohepatic recycling of dothiepin and its
    metabolites is considered to occur (Pimentel & Trommer 1994, Rees
    1981).

    HALF LIFE

    Dothiepin: 20 hours (Yu et al. 1996).
    Active metabolites: 24-40 hours (Yu et al. 1996).

    SPECIAL POPULATIONS

    ELDERLY:

    Metabolic changes in the elderly result in higher plasma
    concentrations, longer half-lives, and reduced clearance than in
    younger populations (Ogura et al. 1983).

    LIVER IMPAIRMENT:

    Reduced metabolic capacity in liver disease suggests that accumulation
    of dothiepin will occur, but the clinical implications are unclear due
    to a corresponding reduction in active metabolite production.

    RENAL IMPAIRMENT:

    Reduced clearance in renal impairment suggests that accumulation of
    active metabolites will occur.

    GENDER:

    Elimination half-lives for dothiepin and nordothiepin are reported to
    be several hours longer in females than in males (Maguire et al.
    1983).

    BREAST MILK

    Dothiepin and its active metabolites are excreted into human breast
    milk.
    In an early study, a patient treated with dothiepin 25 mg three times
    daily for 3 months had milk and serum dothiepin concentrations of
    0.011 and 0.033 mg/L respectively (Rees et al. 1976). These data
    suggest that a baby would ingest less than 0.2% of the maternal
    dothiepin dose based on a daily milk intake of 150 ml/kg, but in this
    study no account was taken of active metabolites.
    A later study considered both the excretion of dothiepin and its
    active metabolites into breast milk. Concentrations of dothiepin,
    nordothiepin, dothiepin-S-oxide and nordothiepin-S-oxide were measured

    in blood and milk samples from five breast feeding women, and in
    plasma samples from their infants. The data show that the mean total
    infant daily dose is 4.5% of the maternal dothiepin dosage in
    dothiepin equivalents (Ilett et al. 1992).

    Toxicokinetics

    Absorption

    Distribution

    Metabolism

    Elimination

    Half life

    Dothiepin: 11-29 hours (Ilett et al. 1991)

    Special populations

    Breast milk

    Summary

    TYPE OF PRODUCT

    A tricyclic antidepressant.

    INGREDIENTS

    Dothiepin capsules: 25 mg
    Dothiepin tablets: 75mg

    SUMMARY OF TOXICITY

    Patients presenting 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.

    Dothiepin overdose should be managed on a clinical basis rather than
    on the amount ingested, but as a guide, doses of 1 g 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.

    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.   Ventricular arrhythmias should be managed with intravenous sodium
         bicarbonate and supportive measures. Where these measures fail
         and an anti-arrhythmic is considered essential, lignocaine is the
         preferred drug.

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

    Clinical Features

    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, Dziukas & Vohra 1991, Noble & Matthews
    1969).

    Severe toxicity: coma, hypotension, convulsions, supraventricular and
    ventricular arrhythmias, hypoxia, metabolic and/or respiratory
    acidosis, and cardiac arrest (Crome 1986, Dziukas & 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
    (Dziukas & Vohra 1991, White 1988).

    INHALATION

    DERMAL

    OCULAR

    OTHER

    CHRONIC

    INGESTION

    INHALATION

    DERMAL

    OCULAR

    OTHER

    At risk groups

    ELDERLY

    There is an increased risk of toxicity resulting from impaired drug
    metabolism and elimination. The elderly are also particularly
    susceptible to the central anticholinergic effects such as confusion,
    disorientation, acute psychosis and hallucinations (Nolan & O'Malley
    1992).

    PREGNANCY

    The safety of dothiepin (or tricyclic antidepressants in general)
    during pregnancy has not been established.
    A handful of cases were reported in the early 1970's linking tricyclic
    antidepressant administration during pregnancy to birth defects,
    particularly limb deformities. Retrospective studies, subsequently
    reported, showed no correlation between tricyclic antidepressant use
    and increased malformations. However, a more recent report of a large

    case-controlled study found a greater occurrence (not quantified) of
    congenital malformation with tricyclic antidepressants than in control
    groups (Schardein 1993).
    Fetal tachyarrhythmia has been reported where dothiepin has been given
    in pregnancy - see case report 1.

    CHILDREN

    Comparison with other tricyclic antidepressants would suggest that
    ingestions in children result in symptoms typical of tricyclic
    antidepressant overdose in adults (Crome & Braithwaite 1978, Goel &
    Shanks 1974).
    See case report 2 for clinical details of dothiepin ingestion in a
    young child.

    ENZYME DEFICIENCIES

    Dothiepin is metabolised by microsomal enzymes in the liver which may
    be subject to genetic polymorphism.

    ENZYME INDUCED

    The metabolism of dothiepin is likely to be increased in the presence
    of enzyme inducing drugs, but is of doubtful clinical relevance as the
    metabolites formed also have antidepressant activity.

    OCCUPATIONS

    OTHERS

    RENAL IMPAIRMENT: increased risk of toxicity due to accumulation of
    metabolites.
    HEPATIC IMPAIRMENT: increased risk of toxicity due to impaired
    metabolism.
    CARDIAC DISEASE: increased risk of toxicity due to underlying disease.
    EPILEPSY: increased risk of seizures.

    Management

    Decontamination

    If within one hour of ingestion, and more than 300mg has been taken by
    an adult or more than 1mg/kg by a child, activated charcoal should be
    given to reduce the absorption.

         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 MANAGEMENT OF THE SYMPTOMATIC PATIENT

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

    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
    CONTRA-INDICATED (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 THE SYMPTOMATIC PATIENT

    1. 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 intravenous 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 lignocaine 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 dothiepin 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).

    2. COMA
    Good supportive care is essential.

    3. HYPOTENSION
    Hypotension should be managed by the administration of intravenous
    fluids and by physical means. The majority of patients ingesting
    dothiepin 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) (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).

    4. 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.

    5. OTHER
    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-
    30mg two-hourly in adults).

    Monitoring

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

    Observe for a minimum of 6 hours post-ingestion where:

         i) more than 1mg/kg has been ingested by a child,
         ii) more than 300 mg is known to have been ingested by an adult,
         iii) the patient is symptomatic.

    Antidotes

    None available

    Elimination techniques

    Dialysis and haemoperfusion are ineffective as means of promoting drug
    or metabolite elimination.

    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 the tricyclics 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
    suggested, 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, 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
    (Sener 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).

    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 - Fetal tachyarrhythmia attributed to maternal drug
    treatment with dothiepin.
    A 26 year old woman was started on dothiepin 50 mg daily during the
    first trimester of pregnancy. This was increased to 75 mg daily at
    about 16 weeks of gestation and subsequently reduced to 50 and 25 mg
    daily at 30 and 34 weeks respectively. At 37 weeks there had been
    little growth over the previous three weeks, the patients weight
    remaining the same. The fetal heart rate was irregular with over 180
    beats per minute. An ultrasound scan showed a normally grown fetus
    with no evidence of cardiac failure. The dothiepin was stopped after a
    few days. The frequency and the duration of the tachyarrhythmias
    decreased and within four days no abnormalities of the fetal heart
    rate were detected. At subsequent review in antenatal clinics no
    abnormalities were noted, and the patient delivered a healthy infant
    at term (Prentice & Brown 1989).

    CASE REPORT 2 - Dothiepin ingestion in an infant.
    An 11-month-old child weighing 9.7 kg ingested about 13 dothiepin 75
    mg tablets (100 mg/kg). She was drowsy, had muscle twitching and a
    generalised convulsion. On admission to hospital one and a half hours
    later she was comatose and convulsing. Her pulse was 160 beats/minute,
    blood pressure 80/50 mm Hg, respirations regular, and pupils fixed and
    dilated. Electrocardiography showed sinus tachycardia. Her convulsions
    were controlled with 10 mg IV diazepam and 4 ml IM paraldehyde. She
    was intubated and her stomach emptied. She suddenly became bradycardic
    (pulse 50 beats/minute, blood pressure unrecordable), with wide QRS
    complexes showing on the ECG. Cardiac massage and assisted ventilation
    were started. She was unresponsive to IV atropine, and was given
    5 mmol sodium bicarbonate and 50 ml plasma protein fraction. Blood gas
    analysis showed hypoxia with metabolic and respiratory acidosis.
    Further sodium bicarbonate was given (30 mmol) and hyperventilation
    started. One hour later blood gas analysis showed correction of her
    acidosis, her pulse returned to 104 beats/minute, and her blood
    pressure was 75 mm Hg systolic. Over the next few hours there was
    narrowing of the QRS complexes, some ST depression, and ventricular
    ectopic beats. She was responsive to pain ten hours after ingestion,
    and made an uneventful recovery (Hodes 1984).

    Analysis

    Agent/toxin/metabolite

    There is no clear relationship between plasma dothiepin 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

    Optimum storage

    Transport of samples

    Interpretation of data

    There is considerable variation in plasma concentration of dothiepin
    between individuals.
    As a guide, it has been suggested that therapeutic effect is
    associated with plasma dothiepin concentrations in excess of 0.1 mg/L
    (Rees 1981).
    Forensic studies have found lethal tricyclic antidepressant levels
    ranging from 1.1 mg/L to 21.8 mg/L (Frommer et al. 1987).

    Conversion factors

    1 mg/L = 3.013 micromoles/L
    1 micromole/L = 0.332 mg/L

    The molecular weight of dothiepin hydrochloride is 331.9

    Other recommendations

    Prevention of poisoning

    Other toxicological data

    Carcinogenicity

    Genotoxicity

    Mutagenicity

    Reprotoxicity

    Teratogenicity

    Relevant animal data

    Animal tests show no evidence of carcinogenicity, teratogenicity,
    genotoxicity, or reprotoxicity (Dollery 1991, Goldstein & Claghorn
    1980).

    Relevant in vitro data

    Laboratory tests involving mammalian cells, human lymphocytes, and
    bacteria show no evidence of genotoxicity (Dollery 1991).

    Other regulatory standards

    NA

    Environment

    NA

    Hazard

    NA

    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 October 1996
    Updated May 1998

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    See Also:
       Toxicological Abbreviations