Generic Name

Nortriptyline

Mechanism

• Nortriptyline is a tricyclic antidepressant (TCA) that competitively inhibits presynaptic reuptake of *norepinephrine* and *serotonin*.
• It increases synaptic concentrations of these monoamines, enhancing neurotransmission in cortical and limbic pathways.
• Unlike older TCAs, nortriptyline has minimal anticholinergic, antihistaminic, and anti‑α‑adrenergic activity, reducing sedative and antimuscarinic side effects.

Pharmacokinetics

• Absorption: 30–70 % oral bioavailability; peak plasma levels in 2–4 h.
• Distribution: Large volume of distribution (~3.5 L/kg); highly protein‑bound (≈99 %).
• Metabolism: Hepatic CYP2D6, CYP3A4, and CYP2C19 primarily; metabolic rate slowed in poor CYP2D6 metabolizers.
• Elimination: Renal excretion of inactive metabolites; t½ ≈ 10–20 h, extended to ~24 h in poly‑therapy or hepatic impairment.

Indications

• Major depressive disorder (MDD) – first‑line or adjunct therapy.
• Chronic neuropathic pain (e.g., diabetic neuropathy, post‑herpetic neuralgia).
• Fibromyalgia, tension‑type headaches, and migraine prophylaxis (off‑label).
• Obsessive‑compulsive disorder (limited evidence; used with caution).

Contraindications

• Contraindications: Known hypersensitivity to tricyclics; acute heart failure; cardiac conduction abnormalities; uncontrolled glaucoma; seizures.
• Warnings:
• Cardiac: QT prolongation, arrhythmias, orthostatic hypotension.
• CNS: Increased seizure threshold; risk of hallucinations in elderly or with hepatic disease.
• Drug interactions: MAO inhibitors, SSRIs, SNRIs (serotonin syndrome), CYP2D6 inhibitors (cimetidine, fluoxetine).
• Tapering required to avoid withdrawal (nausea, dizziness).

Dosing

• Administer with food to reduce GI upset.
• Avoid abrupt discontinuation; taper over 4–6 weeks.

Adverse Effects

• Common (≤10 %):
• Dry mouth, constipation, blurred vision, urinary retention.
• Somnolence, weight gain, sexual dysfunction.
• Orthostatic hypotension.
• Serious (≤1 %):
• Cardiotoxicity (arrhythmias, ventricular dysfunction).
• Seizures (especially in overdose).
• Severe anticholinergic syndrome (atypical presentations).
• Severe hyponatremia (especially in elderly).

Monitoring

• Baseline: ECG (QTc), serum electrolytes (Na⁺, K⁺), liver & renal function, weight.
• During Therapy:
• Vital signs, weight, BMI.
• ECG every 4–6 weeks if dose > 150 mg/day.
• Serum Na⁺ each 3–4 weeks for patients > 65 y or taking diuretics.
• Drug Levels: Not routinely required; therapeutic range 200–600 ng/mL for depression, 400–800 ng/mL for neuropathic pain.

Clinical Pearls

• CYP2D6 Genotype Matters – Poor metabolizers may reach supratherapeutic levels with standard dosing; adjust accordingly.
• Elderly Sensitivity – Use the lowest effective dose; monitor for orthostatic hypotension and cognitive changes.
• Pain vs Depression Strategy – For neuropathic pain, start lower (25 mg) to mitigate dizziness; titrate to effect, not merely depression scores.
• Drug‑Drug Check – Avoid concomitant MAOIs or serotonergic agents to prevent serotonin syndrome; consider a 5‑week washout period.
• Withdrawal Symptom Control – Gradual tapering reduces nausea, agitation, and headache; consider substituting short‑acting anticholinergics if dry mouth persists.

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• Keywords: nortriptyline pharmacology, TCA mechanism, nortriptyline dosing, nortriptyline side effects, nortriptyline pain management, nortriptyline ECG monitoring.