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Amitriptyline
Updated 3/2022

Type of Product
Tricyclic antidepressant. Used primarily for the treatment of neuropathic pain. Other uses include treatment of
depression, migraine prophylaxis, and nocturnal enuresis in children.

Ingredients
Amitriptyline
Tablets - 10 mg, 25 mg, 50 mg
Oral solution (150 mL bottle) - 10 mg/5 mL, 25 mg/5 mL, 50 mg/5 mL

Toxicity
Tricyclic antidepressants are highly toxic by ingestion; fatal cardiac arrhythmias may occur soon after ingestion.
Toxicity is due to a combination of anticholinergic (antimuscarinic, atropine-like) effects at autonomic nerve
endings and in the brain, cardiac sodium channel blockade, and alpha 1 adrenergic receptor blockade. In
addition, tricyclic antidepressants block pre-synaptic uptake of amines and the cardiac delayed rectifier
potassium channel.
Ingestion of 15 mg/kg of amitriptyline would be expected to result in serious, potentially life-threatening
symptoms. Ingestion of one or two tablets by a young child may be sufficient to achieve this dose.
Death has been reported after ingestion of 600 mg amitriptyline by an adult (Bickel, 1975); survival has been
reported after ingestion of 4.25 g by a 27-year-old male (Engels & Davidow, 2010) and 57 mg/kg by an 18-
month-old (Mutlu et al, 2010). Coma and tachycardia were reported in a 6-year-old boy ingesting 6.8 mg/kg
(Spiller et al, 2003).
Studies using poisons centre data have found that children who ingested less than 5 mg/kg usually developed
no, or minor, effects (Rosenbaum & Kou, 2005; McFee et al, 2001; Spiller et al, 2003).
Peak plasma concentrations occur within 4 hours of ingestion. Amitriptyline is metabolised by the cytochrome
P450 enzymes to its major active metabolite nortriptyline. The terminal elimination half-life of amitriptyline is
about 25 hours (Amitriptyline Accord UK SPC, 2021) and may be prolonged in overdose (Martindale, 2010).

TOXIC SUBSTANCE
 All patients who have been exposed to this product as a result of self-harm should be referred for
assessment.
All patients who have exceeded their prescribed daily dose of 2 or more cardio-toxic agents should be
referred for medical assessment irrespective of the dose ingested.
All children who have ingested any amount of a tricyclic antidepressant should be referred for medical
assessment.
Adults who have ingested a toxic dose or more (click here for table), or those who are symptomatic, should
be referred for medical assessment.
Consider discussion with NPIS: In the UK NPIS 0344 892 0111 / in Ireland NPIC (01) 809 2566.
Adults who have accidentally ingested less than a toxic dose (click here for table) and who have no new
symptoms since the time of ingestion do not need to be referred for medical assessment. Patients should be
advised to seek medical attention if symptoms develop.

Tricyclic antidepressants - features and management Updated* 5/2023

Features
Severe toxicity occurs from sodium channel blockade and may cause arrhythmias, cardiovascular collapse,
convulsions and coma.
Features can also include those of anticholinergic toxicity: sinus tachycardia, confusion, drowsiness, hot dry skin,
dry mouth and tongue, dilated pupils, urinary retention and ileus. Ataxia, nystagmus, divergent squint, and
myoclonus may occur.
In severe cases, central nervous system depression may progress rapidly to deep coma, with convulsions,
respiratory depression and respiratory arrest. Acute lung injury and acute respiratory distress syndrome may
develop. Convulsions may herald cardiovascular shock.
ECG features include prolongation of the PR, QRS and QT intervals, non-specific ST segment and T wave
changes, and atrioventricular block. Brugada electrocardiographic pattern has been reported. Prolonged QRS is
a predictor of convulsions and ventricular arrhythmias.
Hypotension, hypokalaemia and metabolic acidosis may occur. Hypothermia and rhabdomyolysis, and
occasionally skin blisters, may occur in patients who have been unconscious.
Increased tone and hyperreflexia may be present with extensor plantar reflexes. In deep coma, all reflexes
(including brain-stem reflexes) may be abolished.
During recovery, confusion, agitation and visual hallucinations may occur.
Serotonin Toxicity
Serotonin toxicity may occur, especially in those exposed to multiple drugs affecting the serotonin system.
Features include CNS effects (including agitation or coma), autonomic instability (including hyperpyrexia), and
neuromuscular excitability (including clonus and raised CK).
Death of patients with serotonin toxicity may be due to hyperpyrexia with associated multi organ failure.
For further information click here.
The cardiovascular and CNS effects in overdose will be potentiated by simultaneous ingestion of alcohol,
cardiovascular agents and other psychotropic drugs.
Clinical features common to cardiac/cardiotoxic agents involved in mixed overdoses may be more severe or
prolonged.

Management
 Alert for hospital doctors
This agent is potentially very toxic and clinicians managing patients are encouraged to discuss serious cases
with your poisons information service: in the UK NPIS 0344 892 0111, in Ireland NPIC (01) 809 2566.
Click here for details you may be required to give when telephoning NPIS.

1. Maintain a clear airway and ensure adequate ventilation.

2. Cardiac arrest
In the event of cardiac arrest in hospital or witnessed out of hospital cardiac arrest with prompt bystander
CPR, resuscitation should be usually continued for at least 1 hour and only stopped after discussion with a
senior clinician.
If the patient may have been exposed to a sodium channel antagonist, or if QRS duration had been
prolonged prior to cardiac arrest, administer a rapid bolus of 100 mL of 8.4% sodium bicarbonate urgently,
preferably into a large vein. 8.4% sodium bicarbonate is irritant and should be preceded and followed by a
large fluid flush to confirm cannula position and reduce local contact. Monitor pH and administer further
doses as necessary. Click here for further advice on managing ECG abnormalities.
Prolonged resuscitation, even for several hours, may be appropriate following poisoning as recovery with
good neurological outcome may occur.
3. The benefit of gastric decontamination is uncertain. Consider activated charcoal (charcoal dose: 50 g
for adults; 1 g/ kg for children) if the patient presents within 1 hour of ingestion of (click here for toxic
doses) providing it is safe to do so and the airway can be protected. Efficacy declines rapidly with time since
ingestion but there may be some potential benefit from later use, especially following large ingestions.
4. Monitor vital signs and cardiac rhythm; check the capillary blood glucose.
Check and record pupil size.
5. Perform a 12-lead ECG in all patients who require assessment.
Consider repeating the ECG in ANY OF the following circumstances:

The initial ECG is abnormal

The patient is symptomatic
The recommended observation period (see below) is not yet complete

Check cardiac rhythm, QRS duration and QT interval. Click here for treatment thresholds for toxicology
patients.
If the QRS is prolonged:
These patients need treatment with sodium bicarbonate (see below for doses)

Concentrated bicarbonate is irritant; administer into a large vein (or via a central line where possible). A
bolus should be preceded and followed by a large fluid flush to confirm cannula position and reduce local
contact.
Monitor electrolytes; hypokalaemia, hypocalcaemia or hypernatraemia may occur after large doses of
sodium bicarbonate.
Correct hypoxia, hypercapnia and acidosis.

Monitor QRS duration and aim for a serum pH of 7.5-7.55 (H+ 28-32).

Cardiac arrest, VT or QRS ≥ Administer a rapid bolus of 100 mmol (i.e.100 mL 8.4%) sodium
160 msec bicarbonate urgently.
 A repeat bolus may be administered if there is persistent QRS prolongation
or arrhythmias and the pH is <7.5.

QRS 120-160 msec Administer 50 mmol (i.e. 50 mL 8.4%) sodium bicarbonate.

A repeat bolus may be administered if there is persistent QRS prolongation

Children with QRS Administer 1-2 mL/kg 8.4% (centrally) or 2-4 mL/kg 4.2% (peripherally):
prolongation If cardiac arrest or VT – as a bolus
If prolonged QRS alone – over 20 minutes

Patients may additionally need treatment with magnesium if the QT is prolonged. Click here for further
advice on ECG interpretation in poisoned patients.
Discuss with your local poisons information service: in the UK NPIS 0344 892 0111, in Ireland NPIC (01)
809 2566.
Click here for details you may be required to give when telephoning NPIS.
6. In all patients who require assessment check U&Es, FBC and LFTs.
Check serum CK in patients who have been unconscious and immobile for some time.
7. Ensure adequate hydration to maintain a good urine output (0.5 mL/kg/hour) and perfusion.
8. Consider arterial/venous blood gas analysis in patients who have a reduced level of consciousness, reduced
oxygen saturation on pulse oximetry or metabolic disturbance.
9. All patients who require assessment should be observed for at least 6 hours after exposure.
Following mixed overdoses involving cardiac/cardiotoxic agents, asymptomatic patients should be monitored
for at least the longest period recommended in any of the individual TOXBASE entries.
Check pulse and blood pressure. Monitor cardiac rhythm. Repeat ECGs should be performed. In
symptomatic patients, or patients with an abnormal ECG, consider early discussion with HDU/ITU.
Asymptomatic patients with a normal ECG after 6 hours can be considered for discharge with advice to
return if symptoms develop.
10. Metabolic acidosis
If metabolic acidosis persists despite correction of hypoxia and adequate fluid resuscitation consider
correction with intravenous sodium bicarbonate. Rapid correction is particularly important if there is
prolongation of the QRS interval. Ensure serum potassium is within normal range as administration of
sodium bicarbonate may worsen hypokalaemia.
Adults: an initial dose of 50-100 mmol sodium bicarbonate (e.g. 50-100 mL 8.4% or 100-200 mL 4.2%) may
be given and repeated as necessary, guided by arterial blood gas monitoring (aim for a pH of 7.5-7.55 [H+
28-32]). The volumes for different concentrations of sodium bicarbonate to achieve a dose of 50-100 mmol
in adults are shown here.
Children: Give 1-2 mmol/kg sodium bicarbonate (1-2 mL/kg 8.4% or 2-4 mL/kg 4.2%) over 20 minutes.
Repeat as necessary to achieve pH of 7.5-7.55 (H+ 28-32).
Since 4.2% and 8.4% bicarbonate are irritant to veins, and can rarely cause local necrosis in cases of
extravasation, administer into a large vein (or via a central line where possible). A bolus should be
preceded and followed by a large flush to confirm cannula position and to reduce local contact.
Adults and children: Recheck acid base status after administration of sodium bicarbonate.
Click here for further information on metabolic acidosis
11. Convulsions
Give oxygen; check blood glucose, U&Es, calcium, magnesium, phosphate and blood gases. Correct acid
 base and metabolic disturbances as required.

Single brief convulsions do not require treatment.

Control convulsions that are frequent or prolonged with intravenous diazepam (10-20 mg in adults; 0.1-0.3
mg/kg body weight in children), lorazepam (4 mg in adults; 0.1 mg/kg in children), or midazolam (5-10 mg in
adults; 0.05-0.15 mg/kg in children).

Further doses of benzodiazepines may be needed in adults; refer to intensive care. In children seek
consultant paediatric input.

If unresponsive to the above measures, the patient should be referred urgently to critical care. The NPIS
recommends barbiturates as second line therapy and avoidance of phenytoin.
Click here for further management
12. Hypotension
Ensure adequate fluid resuscitation. Treat brady and tachyarrhythmias appropriately.
Consider early referral to critical care for patients with fluid-resistant hypotension, as these patients can
deteriorate extremely rapidly.
Sodium bicarbonate administration may be of benefit in fluid resistant hypotension in the context of sodium
channel blocker toxicity, especially if there is QRS prolongation. Consider administration of 50 mmol (i.e. 50
mL 8.4%) sodium bicarbonate. Repeat doses may be required. Aim for a serum pH of 7.5 - 7.55 (H+ 28-
32).
Invasive vascular monitoring and echocardiography may help determine the likely relative benefits of
inotropes and vasopressors because reduced cardiac output and vasodilation often co-exist in severe or
mixed poisoning.
There have been very occasional reports of worsening of hypotension associated with adrenaline treatment,
thought to be due to beta-receptor agonist effects.
Vasopressors and inotropes can be initiated in an emergency through peripheral venous access. THIS
SHOULD ONLY BE DONE UNDER THE DIRECTION OF AN EXPERIENCED PHYSICIAN (SpR AND
ABOVE). Click here for further advice on doses.
Contact the NPIS for further advice about patients who remain in refractory shock despite the above
treatments; in the UK NPIS 0344 892 0111, in Ireland NPIC (01) 809 2566
13. High Dose Insulin
In patients with severe impairment of myocardial contractility an insulin and dextrose infusion has been
shown to improve systemic perfusion. It is particularly useful in the presence of acidosis.
Give dextrose and insulin as per protocol. Monitor for hypoglycaemia and hypokalaemia.
For a suitable protocol click here.
Discuss with your local poisons information service: in the UK NPIS 0344 892 0111, in Ireland NPIC (01)
809 2566.
Click here for details you may be required to give when telephoning NPIS.
14. Glucagon - severe hypotension
Glucagon is a treatment option for severe hypotension, heart failure or cardiogenic shock.
In adults:
A bolus of 5-10 mg IV in adults should be administered over 1-2 minutes, followed by an infusion of 50-150
micrograms/kg/hour, titrated to clinical response. Infusion is an off-label method of glucagon administration.
Limited evidence is available for the use of doses in excess of 10 mg/hour. If haemodynamic improvement is
not achieved with this dose consider the use of additional treatments for hypotension.
The reconstituted solution for IV infusion can be administered without further dilution, or may be diluted with
glucose 5%.
 In children:
A bolus of 50-150 micrograms/kg IV should be administered over 1-2 minutes (Shepherd, 2006), followed by
an infusion of 50 micrograms/kg/hour, titrated to clinical response.
Note: Beware adverse effects of intravenous administration, in particular vomiting, hyperglycaemia,
hypokalaemia and hypocalcaemia.
Consider prophylactic treatment with an antiemetic.
Note: Glucagon must be used immediately following reconstitution, do not prepare well in advance. Be
aware that glucagon should be stored in a fridge, rather than within the antidotes cupboard.
Calcium-containing solutions (e.g. Hartmann's) and sodium chloride are not suitable dilutents as
precipitation may occur. The use of water as a diluent has been associated with thrombophlebitis. Cloudy
solutions must not be used.
There is no recommended final volume/concentration for dilution; for adults, it is usually convenient to dilute
in 100 mL or 250 mL, but smaller or larger infusion volumes can be used.
Reference

15. In cardiac arrest or life-threatening cardiotoxicity where other therapies have been ineffective, consider the
use of intravenous lipid emulsion therapy, but the evidence of benefit is weak.
Click here for doses
16. Mechanical Cardiac Support
Mechanical adjuncts may be a bridge to recovery in patients with life-threatening haemodynamic instability
where other measures have failed. Options include:

vaECMO (veno-arterial extracorporeal membrane oxygenation) or cardiac bypass. Click here for further
information on VA-ECMO.
intra-aortic balloon pump (for those patients without severe rhythm disturbance).

Discuss with your local poisons information service: in the UK NPIS 0344 892 0111, in Ireland NPIC (01)
809 2566.
Click here for details you may be required to give when telephoning NPIS.
17. Agitation and delirium/psychosis
Where available, follow local guidelines for treatment of agitation and delirium.
The primary goal of management is to keep patient and staff safe while allowing continued evaluation.
Ensure other causes are excluded (e.g. hypoxia, infection, hypoglycaemia and raised ICP). Attempt de-
escalation by reducing environmental stimuli (e.g. quiet room) and providing basic needs (e.g. a close
relative, a warm blanket and food (if appropriate)).
For pharmacotherapy in adults:
Give an initial dose of oral or IV diazepam (10-20 mg) or lorazepam (1-2 mg). Further boluses, given IV, may
be administered if the patient remains agitated, provided there is no impairment of respiratory function.
If oral and IV routes are not available give lorazepam IM (1-2 mg) or midazolam IM (5-10 mg) repeated as
necessary.
Patients with severe agitation may need high doses of intravenous diazepam (total dose in excess of 100
mg given incrementally). These patients need urgent referral to critical care.
Haloperidol (5-10 mg IM) may be an adjunct when agitation remains resistant to two or more
benzodiazepine doses as described above. Antipsychotics should be avoided in patients with Parkinson’s
disease or Lewy body dementia.
Ketamine has also been used for uncontrolled agitation but must be used by a practitioner experienced in
its use in an appropriate clinical environment with equipment for intubation if necessary.
 Click here for pharmacotherapy in children:
18.
Hypothermia
Rewarm slowly using conventional methods.
19. Hyperthermia
Mild to moderate hyperthermia may respond to conventional cooling measures such as:
● Mist and fan techniques
● Ice packs to groin and axillae
● External cooling devices.
When rising body temperature exceeds 38.5°C, urgent cooling measures with regular monitoring of core
temperature, at least every 30 minutes, should be employed according to local protocols. Such measures
include:
● Ice-baths (may achieve rapid cooling but caution in elderly/comorbidities)
● Internal/invasive measures - cold fluid lavage (gastric, bladder, peritoneal), intravascular cooling
techniques.
Sedation should be employed where it can be safely performed (diazepam 10-20 mg in adults; 0.25 mg/kg
body weight in children).
Patients with severe hyperthermia may need high doses of intravenous diazepam (total dose in excess of
100 mg given incrementally). These patients need urgent referral to critical care.
Severe hyperthermia carries a high mortality rate, urgent intervention is recommended.
Rapid sequence intubation with paralysis is usually warranted when the temperature is rising rapidly and is
not controlled by the above measures.
If hyperkalaemia is likely, avoid suxamethonium.
On-going neuromuscular paralysis, and sedation with a benzodiazepine infusion, is recommended in
addition to cooling measures (see above) as per local protocols.
Dantrolene may be considered where there is muscular hyperactivity (initially 2-3 mg/kg by intravenous
injection, to a maximum of 10 mg/kg. For further information click here).
In patients with pyrexia, monitor renal function and CK activity. Ensure adequate hydration and monitor urine
output carefully.
Consider other causes as hyperthermia may be caused by conditions other than poisoning.
If serotonin toxicity is present click here for management.
If neuroleptic malignant syndrome is present click here for management.
If hyperthermia persists despite the above measures discuss with your local poisons information service: in
the UK NPIS 0344 892 0111, in Ireland NPIC (01) 809 2566.
Click here for details you may be required to give when telephoning NPIS.
20. For features and management of serotonin toxicity click here.
21. Forced diuresis, haemodialysis and haemoperfusion are of no value due to the large volume of distribution
of tricyclic antidepressants. Dialysis and haemoperfusion are not recommended for tricyclic overdoses
(EXTRIP).
22. Other measures as indicated by the patient's clinical condition.
Patients should be advised on discharge to seek medical attention if symptoms subsequently develop.

Adverse drug reactions can be reported to the MHRA via the Yellow Card scheme. For more
information and to make a report click here.
Additional Information
Activated charcoal
Serotonin Syndrome
References
Amitriptyline in pregnancy
Tricyclic antidepressants in pregnancy

All material on TOXBASE® is subject to Crown copyright protection. This document grants no rights to use such content other than
as an information resource to be used by healthcare professionals in the management of poisoning. For any other use of material
you must apply for permission in writing from NPIS Edinburgh, Royal Infirmary of Edinburgh, EH16 4SA or via [email protected]