Drug reference

Amitriptyline

TCA · Antidepressant

Also known as Amitriptyline hydrochloride, Laroxyl, Tryptanol

START

Confirm depression or neuropathic pain. Baseline ECG (QTc), liver function. Screen for bipolar disorder (may induce mania). Start 25-50 mg at bedtime.

TYPICAL MAX

300 mg/day (adults); 100 mg/day (elderly). Do not exceed without cardiology consultation.

STOP IF

QTc >500 ms, syncope, seizures, severe anticholinergic toxicity, serotonin syndrome, jaundice

WATCH

ECG (baseline and periodically), mood/suicidality (especially first 4 weeks), orthostatic BP, anticholinergic side effects, weight

CDSCO approvedSchedule HJan AushadhiATC N06AA09

Dose laddermg/d

Renal dose adjustmenteGFR mL/min/1.73m²

KDIGO 2024 + manufacturer label

Pharmacokineticsplasma · t hours

ONSET: 1.3h · absorption onset
PEAK: 5h · 4-6 h (oral)
t½: 20h · 10-50 h (mean 15-28 h); CYP2D6 dependent
DURATION: 1d · 24 h (bedtime dosing)

EXCRETION

~18% renal (metabolites); hepatic CYP2C19/CYP2D6/CYP3A4

route + CYP

INTERACTIONS

12 major

incl. contraindicated

PREGNANCY

FDA PLLR: Animal studies showed adverse effects. Limited human data. Use only if benefit clearly outweighs risk. May cause neonatal withdrawal symptoms if used in third trimester.

FDA category + note

Top interactionssee all 12 →

MoclobemideContraindicatedTextbookG&G 14e
Mao InhibitorsContraindicatedDatabaseKimi deep-research + Cla
Monoamine Oxidase Inhibitors (maois)ContraindicatedDatabase
EpinephrineSevereTextbook-citedKDT 7e · p950

Available in India

356 branded formulations and 220 fixed-dose combinations. Look up specific brands in the Drugs workspace.

Jan Aushadhi — generic available at GoI pharmacies

Mechanism

Amitriptyline is a tricyclic antidepressant (TCA) that exerts its therapeutic effects through multiple mechanisms. Its primary antidepressant action involves inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake transporters (SERT and NET), increasing synaptic concentrations of these monoamines. Additionally, it is a potent antagonist at muscarinic acetylcholine receptors (M1-M5), histamine H1 receptors, and alpha-1 adrenergic receptors. It also has sodium channel blocking activity (class IA antiarrhythmic-like effect) and antagonizes NMDA receptors. This broad receptor profile accounts for both its antidepressant efficacy and its extensive side effect profile (anticholinergic, sedative, orthostatic hypotension, and cardiotoxicity in overdose).

Indications

Major depressive disorder (MDD)Neuropathic pain (diabetic neuropathy, postherpetic neuralgia)Chronic tension-type headache prophylaxisMigraine prophylaxisFibromyalgiaIrritable bowel syndrome (IBS — low-dose, off-label)Insomnia (low-dose, off-label)Post-traumatic stress disorder (PTSD — off-label)

Dosing

Adult: Depression: 25-50 mg PO at bedtime initially; titrate by 25-50 mg every 3-7 days; usual 100-200 mg/day at bedtime; max 300 mg/day. Neuropathic pain: 10-25 mg PO at bedtime initially; titrate to 25-75 mg/day. Elderly: start 10-25 mg at bedtime; max 100 mg/day.
Pediatric: Not recommended <12 years (increased suicidality risk).
Renal adjustment: No specific adjustment required.
Hepatic adjustment: Start at low dose (10-25 mg); titrate slowly. Monitor for sedation and cardiotoxicity.
Geriatric: Start 10-25 mg at bedtime; max 100 mg/day. Increased risk of falls, confusion, orthostatic hypotension, cardiotoxicity. Beers Criteria: potentially inappropriate (anticholinergic, sedating).
Max dose: 300 mg/day (adults); 100 mg/day (elderly)

Pharmacokinetics

Onset

Antidepressant effect: 2-4 weeks. Analgesic effect: 1-2 weeks.

Peak effect

Oral: peak plasma at 4-6 hours.

Duration

24 hours (supports once-daily bedtime dosing).

Half-life

10-50 hours (mean 15-28 hours; highly variable due to CYP2D6 polymorphism). Nortriptyline (active metabolite): 18-44 hours.

Bioavailability

~45-55% (oral; significant first-pass metabolism).

Protein binding

~95% (bound to albumin, alpha-1-acid glycoprotein, and lipoproteins).

Metabolism

Extensive hepatic via CYP2C19 (N-demethylation to nortriptyline — active metabolite), CYP2D6 (hydroxylation), CYP3A4, and CYP1A2. Nortriptyline is also pharmacologically active. CYP2D6 poor metabolizers have higher amitriptyline and lower nortriptyline levels.

Excretion

Renal: ~18% unchanged and metabolites within 24 hours. Fecal: small amount.

Contraindications

Hypersensitivity to amitriptyline or TCAs
Recent MI (within 6 months) or current ischemic heart disease
Arrhythmias (especially prolonged QT, heart block)
MAOI use within 14 days (serotonin syndrome risk)
Acute angle-closure glaucoma
Urinary retention or severe prostatic hyperplasia (anticholinergic effects)
Severe hepatic impairment

Side effects

Common

Sedation, drowsinessDry mouth (anticholinergic)Constipation (anticholinergic)Blurred vision, mydriasis (anticholinergic)Urinary retention (anticholinergic)Orthostatic hypotension (alpha-1 blockade)Tachycardia, palpitationsWeight gainDizziness

Serious

QT prolongation and torsades de pointes (dose-related; TCA overdose is particularly cardiotoxic)
Seizures (lowers seizure threshold)
Serotonin syndrome (with MAOIs, SSRIs, SNRIs, tramadol)
Agranulocytosis, bone marrow suppression (rare)
Hepatotoxicity (cholestatic jaundice)
Suicidal ideation (black box warning for antidepressants <24 years)
Severe anticholinergic toxicity (delirium, hyperthermia, ileus, urinary retention)
Cardiac conduction abnormalities (heart block, arrhythmias — especially in overdose)

Pregnancy & lactation

Pregnancy

FDA PLLR: Animal studies showed adverse effects. Limited human data. Use only if benefit clearly outweighs risk. May cause neonatal withdrawal symptoms if used in third trimester.

Lactation

Excreted in breast milk (infant dose ~1-3% of maternal). May cause infant sedation, poor feeding. Monitor infant closely. Consider alternative antidepressant if breastfeeding.

Drug interactions

Moclobemide

Contraindicated

Textbook

Increased risk of serotonin syndrome and potentiated sympathomimetic effects.

Should not be used concurrently with MAOIs or within 14 days of stopping MAOIs.

Source: G&G 14e

Mao Inhibitors

Contraindicated

Database

MAOIs + TCAs can precipitate serotonin syndrome, hypertensive crisis, hyperpyrexia, convulsions, and death. Both increase monoamine availability through different mechanisms.

Do NOT use within 14 days of MAOI discontinuation. Wait at least 2 weeks after stopping MAOI before starting amitriptyline.

Source: Kimi deep-research + Cla

Monoamine Oxidase Inhibitors (maois)

Contraindicated

Database

Serotonin syndrome (hyperthermia, rigidity, myoclonus, mental status changes, autonomic instability) and hypertensive crisis.

CONTRAINDICATED. A washout period of at least 14 days is required when switching between amitriptyline and MAOIs (21 days for phenelzine). For moclobemide, a shorter washout may be acceptable, but caution is still advised.

Epinephrine

Severe

Textbook-cited

Exaggerated hypertensive response

Use local anaesthetic without adrenaline in patients on TCAs

Source: KDT 7e · p950

Adrenaline

Severe

Textbook

Potentiation of adrenaline's effects.

Vasoconstrictor (adrenaline) containing LA should be avoided in patients receiving tricyclic antidepressants.

Source: KDT 7e · p365

Artemisinins

Severe

Textbook

Increased risk of cardiac conduction defects.

Source: KDT 7e · p816-835

Meglumine Antimoniate

Severe

Textbook

Increased cardiotoxicity (e.g., QT prolongation).

Source: Harrison 22e · p1740

Alcohol

Severe

Database

Additive CNS depression — enhanced sedation, respiratory depression, impaired cognition, increased fall risk (especially in elderly).

Counsel patient to avoid alcohol. Monitor level of consciousness. Fall precautions in elderly.

Source: Kimi deep-research + Cla

Amiodarone

Severe

Database

Drug interaction classified as: synergy.

Source: DDInter

Amisulpride

Severe

Database

Drug interaction classified as: synergy

Source: DDInter

Anagrelide

Severe

Database

Drug interaction classified as: synergy

Source: DDInter

Anticholinergics (e.g., Atropine, Benztropine, Diphenhydramine)

Severe

Database

Increased risk of severe anticholinergic side effects such as dry mouth, blurred vision, urinary retention, constipation, confusion, and delirium.

Avoid concomitant use if possible. If unavoidable, monitor closely for anticholinergic toxicity and consider reducing doses of one or both drugs. Educate patients on symptoms of anticholinergic toxicity.