Generic Name

Amitriptyline

Drug Class

Tricyclic antidepressant (TCA).

Mechanism

Amitriptyline exerts its pharmacologic effects through multiple pathways:
• Serotonin‑Norepinephrine Reuptake Inhibition (SNRI) – Blocks the presynaptic transporters SERT and NET, elevating synaptic serotonin and norepinephrine levels.
• Antimuscarinic activity – Binds muscarinic cholinergic receptors, contributing to dry‑mouth, constipation, and sedation.
• α1‑adrenergic blockade – Causes orthostatic hypotension and additional anticholinergic effects.
• Histamine H1 antagonism – Produces sedation and weight gain.
• Potentiation of opioid receptors – Enhances analgesic actions in neuropathic and central pain disorders.

Pharmacokinetics

• Absorption – Rapid oral absorption; peak plasma concentration within 3–4 h.
• Distribution – Large volume of distribution (~7–9 L/kg); highly lipophilic and cross‑blood‑brain barrier.
• Protein binding – ~80–90% (primarily to albumin); drug–drug interactions are common via CYP pathways.
• Metabolism – Primarily hepatic via CYP2C9, CYP2D6, and CYP3A4 to active N‑desmethyl‑amitriptyline and inactive metabolites.
• Elimination – Renally excreted unchanged (~10 %); half‑life ~16–28 h (longer in the elderly or with hepatic impairment).
• Drug interactions – Inhibition or induction of CYP2C9/CYP2D6 significantly alters levels; caution with MAOIs, SSRIs, and agents prolonging QT.

Indications

• Major depressive disorder – Standard dose 25–150 mg/day (sustained‑release preferred).
• Chronic neuropathic pain – 10–50 mg nightly; gradual titration.
• Migraine prophylaxis – 25–75 mg/day, improved with extended‑release formulations.
• Premature ejaculation – 25–50 mg orally; improves time to ejaculation.
• Fibromyalgia and diffuse arthralgia – 25–50 mg night.
• Insomnia – Low‑dose (10–25 mg) as hypnotic.
• Lichen planus, hand eczema – Topical formulations (20–30 % suspension).

Contraindications

• Absolute contraindications
• Known hypersensitivity to TCAs.
• Acute adrenergic crisis (e.g., hypertensive crisis).
• Concomitant use of monoamine oxidase inhibitors (30‑day washout).
• Relative contraindications
• Recent myocardial infarction, congestive heart failure, arrhythmias, or prolonged QT interval.
• Significant hepatic impairment.
• Advanced renal disease (dose adjustment required).
• Warnings
• Cardiac toxicity – Monitor electrocardiogram (QT, PR, QRS) especially in patients ≥60 yr or with electrolyte abnormalities.
• Anticholinergic burden – Be vigilant in elderly to avoid delirium, fall risk, and confusion.
• Addiction potential – Not addictive, but high doses may cause euphoria.
• Overdose risk – Severe cardiovascular collapse, seizures, respiratory depression; treat with activated charcoal, supportive care, and sodium bicarbonate for cardiotoxicity.

Dosing

• Adults (depression)
• Start 25 mg nightly (sustained‑release).
• Titrate by 25 mg increments every 3–5 days.
• Target 75–150 mg/day.
• Neuropathic pain
• Initial 10 mg at bedtime; titrate to 25, 50 mg/night.
• Migraine prophylaxis
• 25–75 mg/day; gradual increase to 100 mg/day if tolerated.
• Premature ejaculation
• 25 mg 30 min pre‑sex; dose can increase to 50 mg.
• Special populations
• Elderly – Start low (10–25 mg) to reduce anticholinergic effects.
• Pediatrics – Limited data; generally avoided unless benefits outweigh risks.
• Pregnancy/Breastfeeding – Use only if benefits justify; crosses placenta; excreted in breast milk.

Administration: Take with food or a full glass of water to reduce GI irritation. Abrupt discontinuation can precipitate withdrawal symptoms.

Adverse Effects

> *Typical side‑effect profile*
• Anticholinergic: dry mouth, constipation, urinary retention, blurred vision, tachycardia.
• Sedation, weight gain.
• Dizziness, orthostatic hypotension.
• Increased constipation; risk of fecal impaction.

> *Serious, less frequent events*
• Cardiac conduction abnormalities: QRS widening, QT prolongation, torsades de pointes (especially in overdose).
• Seizures in overdose or at high plasma levels.
• Hepatotoxicity (rare, but monitor LFTs).
• Severe anticholinergic syndrome (delirium, hyperthermia).

Monitoring

• Baseline: ECG (baseline QTc, PR, QRS); CBC, CMP (renal/hepatic), serum electrolytes (K⁺, Mg²⁺).
• Therapeutic monitoring:
• Elderly – Repeat ECG after dose titration.
• On polypharmacy – Periodic drug‑drug interaction checks.
• Follow‑up:
• Depression scales (HAM-D, PHQ‑9) at 2–4 weeks.
• Pain scores (VAS) for neuropathic pain.
• Adverse effect surveillance (daily during titration).
• Overdose: Suspect in symptomatic patients; treat with decontamination, cardiac monitoring, supportive measures.

Clinical Pearls

• Extended‑Release Advantage – ER formulations provide smoother troughs, reducing daytime sedation and anticholinergic peaks.
• Overlapping NA Transport Inhibition – When adding SSRIs, monitor for serotonin syndrome; TSAs synergize for pain but may increase SSRI side effects.
• Use for Insomnia – Low‑dose (10–25 mg) can be an effective short‑term hypnotic, but taper after 4–6 weeks to avoid rebound.
• Dose‑Response for Nausea – Higher doses (>75 mg) are often needed for migraine prophylaxis; benefit may outweigh nausea in predisposed patients.
• Renal Impairment – Reduce dose to 25 mg/day or consider alternative due to prolonged half‑life.
• Alcohol Interaction – Avoid concurrent alcohol; risk of pronounced CNS depression and orthostatic hypotension.
• Drug–Drug Alert – Fluoxetine can increase amitriptyline levels; consider monitoring or dose adjustment.

*Reference‑friendly quick facts for rapid review:*
• Drug class: Tricyclic antidepressant (TCA).
• Key targets: SERT, NET, muscarinic ACh, α1‑adrenergic, H1 histamine.
• Cardiac risk: Evaluate QTc < 440 ms in men, < 450 ms in women before initiating therapy.
• Recommendation: Start low, go slow; beneficial for multidimensional pain and insomnia beyond conventional antidepressants.

--
• This concise drug card serves as a practical reference for medical students and clinicians seeking a comprehensive, SEO‑friendly overview of Amitriptyline.