Nortriptyline

Generic Name: Nortriptyline
Brand Names: Pamelor (US), Aventyl (discontinued in some countries), Allegron (AU/NZ), Norpress

Drug Class: Tricyclic Antidepressant (TCA)
Pharmacological Class: Secondary amine tricyclic antidepressant
Chemical Structure: Dibenzocycloheptadiene derivative
Formulations:

• Oral capsules (10 mg, 25 mg, 50 mg, 75 mg)

• Oral solution (10 mg/5 mL or 25 mg/5 mL depending on country)
  Route of Administration: Oral

---

1. Mechanism of Action

Nortriptyline acts as a tricyclic antidepressant, primarily by inhibiting the reuptake of norepinephrine and, to a lesser extent, serotonin (5-HT) in the presynaptic neuron. This increases their synaptic availability, which contributes to its antidepressant and analgesic effects.

It has relatively less affinity for serotonin transporters compared to tertiary amines (e.g., amitriptyline), and less anticholinergic activity, making it somewhat more tolerable in older adults.

Other mechanisms contributing to clinical effects and side effects:

• Antagonism of muscarinic receptors (anticholinergic effects)

• Blockade of histamine H1 receptors (sedation, weight gain)

• Blockade of alpha-1 adrenergic receptors (orthostatic hypotension)

• Modulation of sodium channels (linked to anti-pain effects and overdose cardiotoxicity)

---

2. Therapeutic Indications

Approved indications:

• Major depressive disorder (MDD) – especially with melancholic features

• Depression in the elderly (more suitable than amitriptyline)

Off-label indications:

• Neuropathic pain (diabetic neuropathy, postherpetic neuralgia)

• Chronic tension-type headache and migraine prophylaxis

• Fibromyalgia

• Attention-deficit hyperactivity disorder (ADHD) (limited use)

• Nocturnal enuresis in children (rare use today)

• Smoking cessation (off-label adjunct)

• Irritable bowel syndrome (IBS) – low-dose for pain modulation

---

3. Dosage and Administration

For Depression (Adults):

• Initial dose: 25 mg/day, preferably at bedtime

• Titration: Increase by 25 mg every 1–2 weeks based on response and tolerability

• Typical maintenance dose: 75–100 mg/day, in single or divided doses

• Maximum dose: 150 mg/day

• Elderly or adolescents: Start at 10–25 mg/day, target dose 30–50 mg/day

For Neuropathic Pain / Migraine / Fibromyalgia (off-label):

• Start: 10–25 mg at bedtime

• Titrate slowly (every 3–7 days)

• Effective dose: 25–75 mg/day

• Lower doses (10–30 mg) often adequate for pain conditions

Note: Steady-state plasma concentrations usually reached within 7 days.

---

4. Pharmacokinetics

• Absorption: Rapid, oral bioavailability ~45–65%

• Peak plasma levels: 7–10 hours

• Plasma protein binding: ~90%

• Half-life: 18–90 hours (average ~30 hrs); prolonged in elderly

• Metabolism: Hepatic via CYP2D6, leading to active metabolites

• Elimination: Primarily renal (as metabolites)

Pharmacogenomics:

• Poor metabolizers of CYP2D6 have ↑ serum levels and side effect risk

• Therapeutic drug monitoring (TDM) is sometimes used to optimize levels (therapeutic range: 50–150 ng/mL)

---

5. Contraindications

• Recent myocardial infarction (MI)

• Arrhythmias, especially conduction disorders

• Concurrent use of MAO inhibitors (within 14 days) – risk of hypertensive crisis or serotonin syndrome

• Hypersensitivity to nortriptyline or other TCAs

• Severe liver disease (relative)

• Children <6 years (contraindicated for any use)

---

6. Warnings and Precautions

• Suicidality: Increased risk of suicidal ideation and behavior in children, adolescents, and young adults during initial treatment

• Cardiotoxicity: Risk of QT prolongation, arrhythmias, and sudden death in overdose

• Anticholinergic effects: Caution in patients with glaucoma, BPH, urinary retention

• Seizure threshold reduction: Dose-dependent risk

• CNS effects: May impair judgment, alertness, and coordination

• Hyponatremia, SIADH: Rare but possible

• Mania: May unmask bipolar disorder

• Withdrawal symptoms: Abrupt cessation may cause nausea, headache, malaise, irritability, sleep disturbance

---

7. Adverse Effects

Very Common (>10%)

• Drowsiness

• Dry mouth

• Constipation

• Dizziness

• Weight gain

Common (1–10%)

• Blurred vision

• Urinary retention

• Palpitations, tachycardia

• Increased appetite

• Orthostatic hypotension

• Tremors

• Sexual dysfunction

• Confusion (especially in elderly)

• Sweating

• Anxiety or agitation

Uncommon to Rare (<1%)

• Arrhythmias

• Seizures

• Hepatotoxicity (elevated LFTs)

• Agranulocytosis

• Galactorrhea

• Photosensitivity reactions

• Serotonin syndrome (if combined with serotonergic agents)

---

8. Overdose Risk and Management

Toxicity may occur with >500 mg ingestion, but even lower doses may be dangerous in vulnerable individuals.

Toxic effects:

• Cardiac conduction delays (wide QRS, QT prolongation)

• Seizures

• Coma

• Respiratory depression

• Hypotension

• Anticholinergic syndrome (delirium, hyperthermia)

Management:

• Supportive care

• Activated charcoal (if within 1 hour)

• Cardiac monitoring (especially ECG changes)

• Sodium bicarbonate for QRS prolongation or arrhythmia

• Benzodiazepines for seizures

• ICU admission for serious toxicity

---

9. Drug Interactions

Pharmacodynamic interactions:

• MAO inhibitors: contraindicated – serotonin syndrome risk

• SSRIs (e.g., fluoxetine, paroxetine): ↑ nortriptyline levels via CYP2D6 inhibition

• CNS depressants (alcohol, benzodiazepines): additive sedation

• Clonidine, guanethidine: TCAs may blunt antihypertensive effect

• Anticholinergics: ↑ risk of anticholinergic toxicity

• QT-prolonging drugs: additive risk (e.g., amiodarone, sotalol, erythromycin)

Pharmacokinetic interactions:

• CYP2D6 inhibitors (bupropion, quinidine, SSRIs): ↑ nortriptyline exposure

• Barbiturates, carbamazepine, phenytoin: ↓ nortriptyline levels via enzyme induction

• Anticoagulants (warfarin): monitor INR – risk of potentiation

---

10. Use in Special Populations

Elderly:

• Increased sensitivity to side effects (confusion, falls, cardiac effects)

• Start low (10–25 mg/day); monitor closely

• Increased risk of QT prolongation

Pregnancy:

• Category C (US): Risk not ruled out

• Animal studies show adverse effects; use only if clearly needed

• Possible neonatal withdrawal symptoms if used near delivery

Lactation:

• Excreted in breast milk; low concentrations

• Monitor infant for drowsiness, poor feeding

Hepatic Impairment:

• Metabolized hepatically; start with lower dose, monitor LFTs

Renal Impairment:

• No major issues reported; monitor elderly or comorbid patients

---

11. Monitoring Parameters

• Mental status: depression severity, suicidal ideation

• ECG: baseline in elderly or cardiac disease

• Plasma levels: therapeutic range 50–150 ng/mL (optional)

• Blood pressure and heart rate

• Signs of toxicity (especially in elderly)

• Weight gain and metabolic effects

• Liver function tests (LFTs) if prolonged use

---

12. Tapering and Discontinuation

• Avoid abrupt cessation after long-term use

• Gradually taper dose over several weeks to reduce withdrawal symptoms:

  • Nausea

  • Headache

  • Malaise

  • Irritability

  • Rebound insomnia or depression

---

13. Patient Counseling Points

• Take at bedtime due to sedative effects

• Do not drive or operate machinery until individual response is known

• Avoid alcohol and CNS depressants

• Report any suicidal thoughts, palpitations, or visual changes

• Effects on mood may take 2–4 weeks to become evident

• Dry mouth: use sugar-free gum or saliva substitutes

• Constipation: increase fluid and fiber intake

• Do not stop abruptly

• Inform all healthcare providers (e.g., before surgery)