Nortriptyline

TCAs
Tricyclic antidepressants (TCAs)

A secondary-amine tricyclic antidepressant: less sedating than amitriptyline, used for depression and nerve pain. Dangerous in overdose.

Updated Nov 12, 2026

Quick facts

Group: Tricyclic antidepressants (TCAs)
Target: Noradrenaline transporter (NET), and to a lesser degree the serotonin transporter (SERT)
Used for: Depression · Off-label · Off-label
Key effects: Dry mouth · Drowsiness · Fast heart rate and dizziness
Monitor: Mood and suicidal thoughts · ECG and blood pressure
ATC: N06AA10

No doses: the clinician sets them by the current guideline.

Mechanism of action

Noradrenaline transporter (NET), and to a lesser degree the serotonin transporter (SERT)Nortriptyline

The figure shows nortriptyline bound to the dopamine transporter of the fruit fly, a close relative of the human noradrenaline transporter; it blocks the same central site.

Target in 3D: Noradrenaline transporter (NET), and to a lesser degree the serotonin transporter (SERT). PDB structure 4M48 (RCSB PDB, public domain). View the structure at RCSB PDB

Nortriptyline is the demethylated (secondary amine) metabolite of amitriptyline. It blocks reuptake of noradrenaline more than serotonin, so more transmitter stays in the synapse; over weeks, receptor adaptations relieve depression and dampen pain signals in the spinal cord. Like other tricyclics it also blocks muscarinic, histamine H1 and alpha-1 receptors (less than tertiary amines), and cardiac sodium channels, which explains its toxicity in overdose.

Blocks noradrenaline (and some serotonin) reuptake
More transmitter in the synapse; adaptation over weeks
Mood improves; descending pain inhibition is strengthened
Also blocks muscarinic, H1, alpha-1 receptors and Na+ channels

Indications

Depression Major depressive disorder →
Off-label: nerve pain after shingles (post-herpetic neuralgia) Herpes zoster (shingles) →
Off-label: panic disorder Panic disorder →
Off-label: aid to stop smoking Tobacco use disorder →

Adverse effects

Common

Dry mouth, constipation and difficulty passing urine
Drowsiness, weakness or tiredness
Fast heart rate and dizziness
Appetite or weight change; sweating
Changes in sex drive or ability

Contraindications

MAO inhibitors now or within the previous two weeks; starting it during linezolid or intravenous methylene blue
Acute recovery period after a myocardial infarction
Hypersensitivity to tricyclic antidepressants

Key interactions

MAO inhibitors, linezolid, methylene blue and other serotonergic drugs: Risk of serotonin syndrome.
CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine, cimetidine): Higher nortriptyline levels and toxicity; levels are checked when such a drug is added or stopped.
Alcohol: More sedation and a higher risk in overdose.
Guanethidine: Its blood-pressure-lowering effect may be blocked.

What is monitored

Mood and suicidal thoughts, especially early and after dose changes
Plasma nortriptyline level at higher doses (it has a therapeutic window)
ECG and blood pressure in heart disease and older people
Eye examination for angle-closure risk before starting

Administration and safety

Oral capsule or liquid, at the same times each day; started low and increased gradually.
Not stopped suddenly: headache, nausea and weakness can follow; the dose is tapered.
Dispensed in limited quantities when suicide risk is a concern, because of overdose toxicity.
Surgeons and dentists are told that the patient takes it.

Pregnancy and breastfeeding

Safe use in pregnancy is not established; it is used only when the benefit outweighs the possible risk.

Nursing care

Before: ask about heart disease, glaucoma, urinary retention and MAOI use.
During: ask about mood and suicidal thoughts at each contact; involve family.
Check pulse and lying/standing blood pressure; teach to rise slowly.
Teach fluids and fibre for constipation, sun protection and to avoid alcohol.

Pharmacokinetics

Absorption: Oral capsule or liquid.
Metabolism: Liver, mainly by CYP2D6; poor metabolisers reach higher levels.
Onset and duration: Antidepressant benefit takes weeks.

Test yourself

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

Nortriptyline is the active metabolite of which tricyclic?

Amitriptyline (by demethylation).

Why is nortriptyline less sedating and anticholinergic than amitriptyline?

As a secondary amine it binds muscarinic and H1 receptors less strongly.

Which drug group can push nortriptyline levels into the toxic range?

CYP2D6 inhibitors such as quinidine, fluoxetine and paroxetine.

What makes tricyclic overdose lethal?

Sodium-channel block in the heart (wide QRS, arrhythmias), plus seizures and coma.

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Connections

← Back to the class: Tricyclic antidepressants (TCAs)

Educational content on how drugs work; not a prescribing guide and no substitute for a health professional's advice. No doses are given.

Sources: Nortriptyline: MedlinePlus Drug Information (MedlinePlus (U.S. National Library of Medicine), 2017); NORTRIPTYLINE HYDROCHLORIDE capsule (DailyMed (U.S. National Library of Medicine), 2026); X-ray structure of dopamine transporter elucidates antidepressant mechanism (RCSB Protein Data Bank, 2013); ATCDDD - ATC/DDD Index (WHO Collaborating Centre for Drug Statistics Methodology, 2026).

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Representative model, for educational purposes only.