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# Tricyclic antidepressants (TCAs)

Older antidepressants that block serotonin and norepinephrine reuptake but also many receptors. Effective, still used for pain, but dangerous in overdose.

Updated 2026-11-01

## What they are

The older generation of antidepressants, named after their three-ring structure. Today they are used less for depression and more for neuropathic pain, migraine prevention and, for clomipramine, obsessive-compulsive disorder. Overdose can be fatal, so the amount a person at risk of suicide has access to matters.

## Mechanism of action

TCAs block the norepinephrine transporter (NET) and the serotonin transporter (SERT). They also block muscarinic receptors (dry mouth, constipation, urinary retention, confusion), histamine H1 receptors (sedation, weight gain) and alpha-1 receptors (orthostatic hypotension). At toxic levels they block fast sodium channels in the heart, which widens the QRS complex.

Target: Norepinephrine and serotonin transporters (NET, SERT); also muscarinic, H1 and alpha-1 receptors and cardiac sodium channels

## Key points

- Overdose: the «3 Cs»: convulsions, coma and cardiotoxicity (QRS widening, arrhythmias), with anticholinergic signs and hypotension. A wide QRS is the key danger sign.
- Treatment of cardiotoxicity: intravenous sodium bicarbonate (alkalinisation and sodium load reverse sodium-channel block); class IA and IC antiarrhythmics are avoided.
- Anticholinergic effects make them risky in older adults, prostatic hypertrophy, narrow-angle glaucoma and after a recent myocardial infarction.
- Contraindicated with MAO inhibitors (hyperpyrexia, seizures, death); SSRIs that inhibit CYP2D6 (fluoxetine, paroxetine) can raise TCA levels sharply.
- Tertiary amines (amitriptyline, imipramine, clomipramine) are more anticholinergic and sedating than secondary amines (nortriptyline, desipramine).

## Drugs in this class

- [**Amitriptyline** A classic tricyclic antidepressant on the WHO list, now often used for nerve pain and migraine prevention. Sedating… Norepinephrine transporter (NET) and serotonin transporter (SERT)](https://durgical.com/en/pharmacology/amitriptyline/)
- [**Clomipramine** A strongly serotonergic tricyclic on the WHO list for obsessive-compulsive disorder. Seizures are its main risk, plus… Serotonin transporter (SERT)](https://durgical.com/en/pharmacology/clomipramine/)

## Others in the class

- Nortriptyline
- Imipramine
- Desipramine
- Doxepin

## Test yourself

Think of the answer, then tap the question to see it.

## A patient arrives after a large tricyclic overdose with a QRS that is getting wider. What is the key treatment, and why does it work?

Intravenous sodium bicarbonate. Raising serum pH and giving sodium reduces the tricyclic's block of cardiac fast sodium channels, which narrows the QRS and protects against arrhythmias.

## Which receptor blockade explains the dry mouth, constipation and urinary retention of TCAs?

Muscarinic acetylcholine receptor blockade (anticholinergic effect).

## Why are class IA antiarrhythmics such as procainamide avoided in TCA poisoning?

They also block sodium channels and prolong conduction, so they add to the tricyclic's cardiotoxicity.

## Why is a tricyclic given alongside fluoxetine or paroxetine a risk?

Both SSRIs inhibit CYP2D6, which metabolises tricyclics, so tricyclic levels can rise to toxic values.

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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](https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=4e520c63-1cf6-40f6-a51c-3f9b0e181342) (DailyMed (U.S. National Library of Medicine), 2026); [ATCDDD - ATC/DDD Index](https://atcddd.fhi.no/atc_ddd_index/?code=N06AA) (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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