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 34.7°C, 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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