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Amitriptyline

Amitriptyline

Elavil Endep Vanatrip Tryptizol Laroxyl

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Updated: December 06, 2025

Overview

Amitriptyline is a tricyclic antidepressant (TCA) primarily used to treat major depressive disorder. It also has FDA-approved and off-label uses for chronic pain conditions, migraine prophylaxis, and other psychiatric disorders. As a tertiary amine TCA, amitriptyline exhibits strong sedative properties compared to other antidepressants. It works by modulating neurotransmitter systems in the central nervous system. Despite its efficacy, its use is often limited by anticholinergic side effects and potential cardiac toxicity.

Drug Class

Tricyclic antidepressant (TCA) Dibenzocycloheptene derivative Serotonin-norepinephrine reuptake inhibitor

Mechanism of Action

Inhibits presynaptic reuptake of serotonin and norepinephrine Blocks histamine H1 receptors (sedative effect) Blocks muscarinic acetylcholine receptors (anticholinergic effects) Blocks alpha-1 adrenergic receptors (orthostatic hypotension) Sodium channel blockade (cardiac effects)

Pharmacokinetics

Absorption: Well absorbed from GI tract (bioavailability ~50%) Distribution: Highly protein-bound (95%), Vd 10-15 L/kg Metabolism: Hepatic via CYP2C19, CYP2D6, and CYP3A4 to active metabolite nortriptyline Excretion: Primarily renal (18% unchanged), some biliary excretion Half-life: 10-28 hours (prolonged in elderly)

Pharmacodynamics

Antidepressant effects: Develop over 2-4 weeks Analgesic effects: Independent of antidepressant action Cardiac effects: QTc prolongation at high doses Anticholinergic effects: Immediate onset

Indications

• Major depressive disorder: For treatment of depression with melancholic features • Neuropathic pain: FDA-approved for chronic pain management • Migraine prophylaxis: Reduces frequency and severity • Fibromyalgia: Off-label use for pain relief • Nocturnal enuresis: In children >6 years (secondary indication)

Contraindications

Absolute: • Recent myocardial infarction • MAOI use within 14 days • Known hypersensitivity • Concurrent use of cisapride Relative: • Narrow-angle glaucoma • Urinary retention • Severe liver disease • Bipolar disorder (may induce mania)

Dosage & Administration

Major depressive disorder: Start 25-50 mg QHS, titrate by 25 mg weekly (max 300 mg/day) Neuropathic pain: Start 10-25 mg QHS, maintain at 25-100 mg/day Migraine prophylaxis: 10-25 mg QHS, max 150 mg/day Geriatric patients: Start 10 mg QHS, max 100 mg/day

Special Populations

Pediatric: Not approved for depression <12 years; enuresis dose 10-20 mg QHS Geriatric: Reduce dose by 30-50%, monitor for falls Renal impairment: CrCl <30 mL/min: reduce dose by 25-50% Hepatic impairment: Reduce dose by 50%, monitor LFTs

Adverse Effects

Common (>10%): • Sedation (40-50%) • Dry mouth (80-100%) • Constipation (30%) • Weight gain (20%) • Orthostatic hypotension (20%) Serious (<1%): • QTc prolongation/torsades • Seizures • Neuroleptic malignant syndrome • Hepatic necrosis • Agranulocytosis

Drug Interactions

• MAOIs: Risk of serotonin syndrome • SSRIs: Increased TCA levels via CYP inhibition • Anticholinergics: Additive adverse effects • Warfarin: Increased anticoagulant effect • Quinidine: Dangerous QTc prolongation • Alcohol: Enhanced CNS depression

Warnings & Precautions

• Black Box Warning: Suicidality in children/young adults • May lower seizure threshold • Requires gradual taper (reduce by 25% weekly) • ECG monitoring recommended in high-risk patients • Paradoxical worsening of anxiety initially • Discontinue 48 hours before surgery

Pregnancy & Lactation

Pregnancy: FDA Category C (risk cannot be ruled out) Neonatal withdrawal symptoms reported Consider risks vs benefits Lactation: Excreted in breast milk (milk:plasma ratio 1:1) AAP considers compatible with breastfeeding Monitor infant for sedation

Monitoring Parameters

• ECG at baseline and dose escalation • Serum levels (therapeutic window 100-250 ng/mL) • Mental status and suicidality • Weight/BMI quarterly • Blood pressure (orthostasis) • Liver function tests annually

Patient Counseling

• Take at bedtime to minimize daytime sedation • Avoid abrupt discontinuation • Report chest pain/palpitations immediately • Use caution when driving/operating machinery • Maintain good oral hygiene • Avoid alcohol and OTC sleep aids • May take 2-4 weeks for full effect

Storage & Stability

Store at 20-25°C (68-77°F) Protect from light Keep container tightly closed Stable in oral liquid formulations for 30 days at room temperature

Clinical Pearls

• Start low (10 mg) in elderly patients • Often more effective for pain at lower doses than for depression • Therapeutic drug monitoring improves outcomes • Consider divided dosing if daytime sedation wanes • Excellent choice for depression with insomnia • Taper over 4 weeks minimum to prevent withdrawal

References

• Goodman & Gilman's: The Pharmacological Basis of Therapeutics, 13th Ed • Lexicomp Drug Information Handbook, 27th Ed • UpToDate: Amitriptyline Drug Information • Stahl's Essential Psychopharmacology, 4th Ed • FDA Prescribing Information for Elavil