Pharmacology · Tricyclic antidepressants (TCAs)
Amitriptyline !
A classic tricyclic antidepressant on the WHO list, now often used for nerve pain and migraine prevention. Sedating, anticholinergic, dangerous in overdose.
Updated 2026-11-01
The figure shows amitriptyline bound to human NET in an outward-open state.
Mechanism of action
Amitriptyline blocks the membrane pumps that take norepinephrine and serotonin back into neurons. It also blocks muscarinic, histamine H1 and alpha-1 adrenergic receptors, which explains much of its adverse-effect profile, and at high levels it blocks cardiac fast sodium channels.
- Amitriptyline blocks NET and SERT
- Norepinephrine and serotonin act longer in the synapse
- It also blocks muscarinic, H1 and alpha-1 receptors
- In overdose it blocks cardiac sodium channels and widens the QRS
Pharmacokinetics
- Absorption
- Rapidly absorbed by mouth
- Metabolism
- In the liver by N-demethylation and hydroxylation; CYP2D6 poor metabolisers and CYP2D6 inhibitors raise tricyclic levels
- Elimination
- Almost entirely as metabolites in the urine
- Onset and duration
- Sedation appears early; the antidepressant effect takes weeks
Indications
- Depression
- Post-herpetic neuralgia (pain after shingles) Herpes zoster (shingles) →
- Migraine prevention Migraine →
- Symptom control in palliative care (WHO list)
Adverse effects
Common
- Dry mouth, constipation, blurred vision, urinary retention (anticholinergic)
- Sedation and weight gain (H1 block)
- Orthostatic hypotension and dizziness (alpha-1 block)
- Tachycardia and ECG changes
- Confusion, especially in older adults
Contraindications
- MAO inhibitors, or within 14 days of stopping one (hyperpyrexia, convulsions, deaths)
- Acute recovery phase after myocardial infarction
- Cisapride (QT prolongation)
- Hypersensitivity to amitriptyline
Key interactions
- MAO inhibitors, linezolid, intravenous methylene blue
- Serotonin syndrome and hyperpyretic crises
- CYP2D6 inhibitors (fluoxetine, paroxetine, quinidine), cimetidine
- Higher tricyclic levels and toxicity
- Other anticholinergic drugs
- Paralytic ileus, urinary retention, hyperthermia
- Alcohol and other CNS depressants
- Additive sedation and respiratory depression
- Sympathomimetics, including epinephrine in local anaesthetics
- Exaggerated pressor and cardiac effects; close supervision needed
What is monitored
- ECG in older adults or heart disease
- Orthostatic blood pressure and falls
- Anticholinergic effects: bowel habit, urination, confusion
- Mood and suicidal thoughts; plasma levels when combined with CYP2D6 inhibitors
Administration and safety
- Given by mouth; because of its sedation, the label prefers a bedtime dose for maintenance
- People at risk of suicide get the smallest practical supply, because a large overdose can be fatal
- Stopped gradually; abrupt cessation can cause nausea, headache and malaise
- Stopped several days before elective surgery when possible (label)
Nursing care
- Check orthostatic blood pressure and fall risk, especially in older adults
- Ask about constipation, urinary retention and blurred vision; teach fluids, fibre and when to report
- Assess suicide risk and limit the amount of medicine available at home
- Know the overdose signs: drowsiness, confusion, dilated pupils, tachycardia, seizures and a wide QRS on the ECG
- Warn about alcohol and driving while drowsy
Pregnancy and breastfeeding
Crosses the placenta; there are a few reports of problems in exposed infants without proven cause, so it is used only when the benefit justifies the possible risk.
Test yourself
Think of the answer, then tap the question to see it.
What ECG finding is the best marker of severity in tricyclic overdose, and what treats it?
Widening of the QRS complex (sodium-channel block). Intravenous sodium bicarbonate is given to alkalinise and load sodium, which narrows the QRS.
Which receptor blocks explain amitriptyline's dry mouth, sedation and orthostatic hypotension?
Muscarinic block (dry mouth, constipation, urinary retention), H1 block (sedation, weight gain) and alpha-1 block (orthostatic hypotension).
Which two non-depression uses of amitriptyline are most common?
Post-herpetic neuralgia and migraine prevention; it is also on the WHO list for symptom control in palliative care.
Why is amitriptyline avoided right after a myocardial infarction?
It can cause arrhythmias, conduction changes and tachycardia; the label excludes the acute recovery phase after infarction.
Related drugs
Related conditions
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Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.
Sources: DailyMed - AMITRIPTYLINE HYDROCHLORIDE tablet, film coated (DailyMed (U.S. National Library of Medicine), 2026); Amitriptyline: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2024); eEML - Electronic Essential Medicines List (World Health Organization, 2025); 8Y93: Structure of NET-Amitriptyline in outward-open state (RCSB Protein Data Bank, 2024).
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Representative model, for educational purposes only.