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
References
Baettig D, Bondolfi G, Montaldi S, Amey M, Baumann P.
Tricyclic antidepressant plasma levels after augmentation with
citalopram: a case study. Eur J Clin Pharmacol 1993; 44: 403-405.
BNF Joint Formulary Committee.
British National Formulary, Number 35. London: British Medical
Association & Royal Pharmaceutical Society of Great Britain, 1998.
Boehnert MT, Lovejoy FH.
Value of the QRS duration versus the serum drug level in predicting
seizures and ventricular arrhythmias after an acute overdose of
tricyclic antidepressants. N Eng J Med 1985; 313: 474-479.
Bosse GM, Barefoot JA, Pfeifer MP, Rodgers GC.
Comparison of three methods of gut decontamination in tricyclic
antidepressant overdose. J Emerg Med 1995; 13: 203-209.
Buchman AL, Dauer J, Geiderman J.
The use of vasoactive agents in the treatment of refractory
hypotension seen in tricyclic antidepressant overdose. J Clin
Psychopharmacol 1990; 10: 409-413.
Callaham M.
Tricyclic antidepressant overdose. J Am Coll Emerg Phys 1979; 8:
413-425.
Caravati EM, Bossart PJ.
Demographic and electrocardiographic factors associated with severe
tricyclic antidepressant toxicity. J Toxicol Clin Toxicol 1991; 29:
31-43.
Crome P.
Poisoning due to tricyclic antidepressant overdosage: clinical
presentation and treatment. Med Toxicol 1986; 1: 261-285.
Crome P, Braithwaite RA.
Relationship between clinical features of tricyclic antidepressant
poisoning and plasma concentrations in children. Arch Dis Childhood
1978; 53: 902-905.
Dollery C(Ed).
Therapeutic Drugs Volume 1. Edinburgh: Churchill Livingstone, 1991:
208-211.
Dziukas LJ, Vohra J.
Tricyclic antidepressant poisoning. Med J Aust 1991; 154: 344-350.
Frommer DA, Kulig KW, Marx JA, Rumack B.
Tricyclic antidepressant overdose. J Am Med Assoc 1987; 257: 521-526.
Goel KM, Shanks RA.
Amitriptyline and imipramine poisoning in children. Br Med J 1974; 1:
261-263.
Goldstein BJ, Claghorn JL.
An overview of seventeen years of experience with dothiepin in the
treatment of depression in Europe. J Clin Psychiatry 1980; 41: 64-70.
Guy's, Lewisham & St. Thomas' Hospitals Paediatric Formulary, 4th
Edition. London: Guy's & St. Thomas' Hospital Trust, 1997.
Hodes D.
Sodium bicarbonate and hyperventilation in treating an infant with
severe overdose of tricyclic antidepressant. Br Med J 1984; 288:
1800-1801.
Ilett KF, Hackett LP, Dusci LJ, Paterson JW.
Disposition of dothiepin after overdose: effects of repeated-dose
activated charcoal. Ther Drug Monit 1991; 13: 485-489.
Ilett KF, Lebedevs TH, Wojnar-Horton RE, Yapp P, Roberts MJ, Dusci LJ,
Hackett LP.
The excretion of dothiepin and its primary metabolites in breast milk.
Br J Clin Pharmacol 1992; 33: 635-639.
Lipman AG.
Tricyclic antidepressant interactions. Mod Med 1981; 49: 151-152.
Maguire KP, Norman TR, McIntyre I, Burrows GD.
Clinical pharmacokinetics of dothiepin. Clin Pharmacokinetic 1983; 8:
179-185.
Mordel A, Winkler E, Almog S, Tirosh M, Ezra D.
Seizures after flumazenil administration in a case of combined
benzodiazepine and tricyclic antidepressant overdose. Crit Care Med
1992; 20: 1733-1734.
Newton RW.
Physostigmine salicylate in the treatment of tricyclic antidepressant
overdosage. J Am Med Assoc 1975; 231: 941-943.
Noble J, Matthew H.
Acute poisoning by tricyclic antidepressants: clinical features and
management of 100 patients. Clin Toxicol 1969; 2: 403-421.
Nolan L, O'Malley K.
Adverse effects of antidepressants in the elderly. Drugs & Aging 1992;
2: 450-458.
Nyberg G, Martensson E.
Determination of free fractions of tricyclic antidepressants. Arch
Pharmacol 1984; 327: 260-265.
Ogura C, Kishimoto A, Mizukawa R, Hazama H, Honma H, Kawahara K.
Age differences in effects on blood pressure, flicker fusion
frequency, salivation and pharmacokinetics of single oral doses of
dothiepin and amitriptyline. Eur J Clin Pharmacol 1983; 25: 811-814.
Orr DA, Bramble MG.
Tricyclic antidepressant poisoning and prolonged external cardiac
massage during asystole. Br Med J 1981; 283: 1107-1108.
ONS.
Office for National Statistics. St Catherine's House, 10 Kingsway,
London. Personal communication - 1996.
Pentel P, Peterson CD.
Asystole complicating physostigmine treatment of tricyclic
antidepressant overdose. Ann Emerg Med 1980; 9: 588-590.
Pimentel L, Trommer L.
Cyclic antidepressant overdoses. Emerg Med Clin N Am 1994; 12:
533-547.
Prentice A, Brown R.
Fetal tachyarrhythmia and maternal antidepressant treatment. Br Med J
1989; 298: 190.
Rees JA, Glass RC, Sporne GA.
Serum and breast milk concentrations of dothiepin. Practitioner 1976;
217: 686.
Rees JA.
Clinical interpretation of pharmacokinetic data on dothiepin
hydrochloride (dosulepin, Prothiaden). J Int Med Res 1981; 9: 98-102.
Roy TM , Ossorio MA, Cipolla LM, Fields CL, Snider HL, Anderson WH.
Pulmonary complications after tricyclic antidepressant overdose. Chest
1989; 96: 852-856.
Rudorfer MV, Manji HK, Potter WZ.
Comparative tolerability profiles of the newer versus older
antidepressants. Drug Saf 1994; 10: 18-46.
Schardein JL.
Chemically induced birth defects. 2nd ed. New York:Marcel Dekker,
1993.
Swartz CM, Sherman A.
The treatment of tricyclic antidepressant overdose with repeated
charcoal. J Clin Psychopharmacol 1984; 4: 336-340.
Sener EK, Gabe S, Henry JA.
Response to glucagon in imipramine overdose. J Toxicol Clin Toxicol
1995; 33: 51-53.
Stern TA, O'Gara PT, Mulley AG, Singer DE, Thibault GE.
Complications after overdose with tricyclic antidepressants. Crit Care
Med 1985; 13: 672-674.
Stockley IH.
Drug interactions 4th ed. London: The Pharmaceutical Press, 1996.
Taboulet P, Michard F, Muszynski J, Galliot-Guilley M, Bismuth C.
Cardiovascular repercussions of seizures during cyclic antidepressant
poisoning. Clin Toxicol 1995; 33: 205-211.
Taylor D.
Selective serotonin reuptake inhibitors and tricyclic antidepressants
in combination: interactions and therapeutic uses. Br J Psychiatry
1995; 167: 575-580.
Teba L, Schiebel F, Dedhia HV, Lazzell VA.
Beneficial effect of norepinephrine in the treatment of circulatory
shock caused by tricyclic antidepressant overdose. Am J Emerg Med
1988: 6: 566-568.
Varnell RM, Godwin JD, Richardson ML, Vincent JM.
Adult respiratory distress syndrome from overdose of tricyclic
antidepressants. Radiology 1989; 170: 667-670.
White A.
Overdose of tricyclic antidepressants associated with absent
brain-stem reflexes.Can Med Assoc J 1988; 139: 133-134.
White K, Simpson G.
The combined use of MAOI's and tricyclics. J Clin Psychiatry 1984; 45:
67-69.
Wolfe TR, Caravati EM, Rollins DE.
Terminal 40-ms frontal plane QRS axis as a marker for tricyclic
antidepressant overdose. Ann Emerg Med 1989; 18: 348-351.
Yang KL, Dantzker DR.
Reversible brain death: a manifestation of amitriptyline overdose.
Chest 1991; 99: 1037-1038.
Yu DK , Dimmitt DC, Lanman C, Giesing DH.
Pharmacokinetics of dothiepin in humans: a single dose
dose-proportionality study. J Pharm Sci 1986; 75: 582-585.
See Also:
Toxicological Abbreviations