Nortriptyline

1. Drug Name

• Generic Name: Nortriptyline

• Brand Names: Pamelor, Aventyl, Nortryptaline

2. Drug Classification

• Class: Antidepressant

• Subclass: Tricyclic Antidepressant (TCA)

3. Mechanism of Action

• Nortriptyline is a tricyclic antidepressant (TCA) that works by inhibiting the reuptake of serotonin (5-HT) and norepinephrine (NE) into the presynaptic neuron, thereby increasing the levels of these neurotransmitters in the synaptic cleft, which helps to improve mood and alleviate symptoms of depression.

• Anticholinergic Effects: Similar to other TCAs, nortriptyline has anticholinergic properties, which can lead to side effects like dry mouth, blurred vision, constipation, and urinary retention due to its action on muscarinic receptors.

• Adrenergic Receptor Blockade: Nortriptyline also blocks alpha-1 adrenergic receptors, which can cause orthostatic hypotension.

• Histamine Receptor Antagonism: It has sedative effects due to histamine H1 receptor blockade, although this is less pronounced compared to some other TCAs.

• Lower Sedation: Compared to other TCAs, nortriptyline has a more favorable sedative profile, making it useful for patients who are sensitive to the sedative effects of other tricyclic antidepressants.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Approximately 30–50% due to significant first-pass metabolism in the liver.

  • Peak Plasma Concentration (Tmax): Achieved in 2–8 hours following oral administration.

• Distribution:

  • Volume of Distribution (Vd): Nortriptyline has a high volume of distribution, reflecting its ability to penetrate various tissues, including the brain.

  • Protein Binding: Highly protein-bound (approximately 93%) to plasma proteins, mainly albumin and alpha-1 acid glycoprotein.

• Metabolism:

  • Metabolized primarily in the liver by CYP2D6 enzymes to its active metabolites, including 10-hydroxynortriptyline. Variations in the activity of CYP2D6 (due to genetic polymorphisms) can affect the metabolism of nortriptyline, potentially influencing drug levels and therapeutic response.

• Excretion:

  • Half-life (t½): 18–44 hours, allowing for once-daily dosing.

  • Excretion: Nortriptyline and its metabolites are primarily excreted in the urine.

• Special Considerations:

  • Hepatic Impairment: Reduced clearance may occur in patients with liver dysfunction, requiring dose adjustments.

  • Renal Impairment: Nortriptyline should be used with caution in patients with renal impairment as its metabolites may accumulate.

5. Indications

• Primary Indications:

  • Major Depressive Disorder (MDD): Nortriptyline is approved for the treatment of major depressive disorder, particularly in patients who do not respond to other antidepressants.

  • Chronic Pain: Off-label use for conditions such as neuropathic pain, fibromyalgia, post-herpetic neuralgia, and chronic tension-type headaches.

  • Attention-Deficit/Hyperactivity Disorder (ADHD): Occasionally used off-label for ADHD in adults or children, particularly when other treatments are ineffective.

  • Anxiety Disorders: Off-label use in generalized anxiety disorder and panic disorder.

• Off-label Uses:

  • Migraine Prophylaxis: Used off-label as a preventive treatment for migraines.

  • Irritable Bowel Syndrome (IBS): Off-label use to treat IBS-related pain.

  • Enuresis (Bed-Wetting): Occasionally used in children, particularly when other treatments fail.

6. Dosage and Administration

• Adult Dosing:

  • Major Depressive Disorder: The usual starting dose is 25 mg/day, increasing gradually to 75–150 mg/day (in divided doses or as a single evening dose) depending on the patient's response.

  • Chronic Pain Syndromes: Start with 25 mg/day, titrate up to 50–100 mg/day based on clinical response.

  • Migraine Prophylaxis: 25 mg/day, increasing as needed, up to 100 mg/day.

• Pediatric Dosing:

  • For children 6 years and older with depression, start with 10–25 mg/day, gradually titrating to 50–100 mg/day depending on the child's age and weight.

  • Enuresis (Bed-wetting): Start with 10–25 mg/day, increasing gradually.

• Renal and Hepatic Impairment:

  • Reduced dose or more frequent monitoring is required in patients with liver or kidney impairment due to slower drug clearance.

• Elderly Dosing:

  • In elderly patients, a lower starting dose of 10–25 mg/day is recommended, as they are more sensitive to the side effects.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to nortriptyline or any components of the formulation.

  • Concurrent use with MAO inhibitors (MAOIs) or within 14 days of discontinuing an MAOI due to the risk of serotonin syndrome.

  • Acute recovery phase after a myocardial infarction due to the risk of arrhythmias.

  • Prolonged QT interval, arrhythmias, or cardiac conduction defects.

• Relative Contraindications:

  • Glaucoma (especially narrow-angle) due to anticholinergic effects.

  • Urinary retention, especially in patients with benign prostatic hyperplasia (BPH).

  • Bipolar disorder: Use with caution as TCAs can precipitate a manic episode if given alone without a mood stabilizer.

8. Warnings and Precautions

• Black Box Warning:

  • Suicidal Thoughts: There is an increased risk of suicidal thoughts and behavior in children, adolescents, and young adults, especially during the first few weeks of therapy or when doses are adjusted.

• Other Warnings:

  • Anticholinergic Effects: Caution is needed in elderly patients and those with glaucoma, urinary retention, or constipation.

  • Cardiac Effects: Nortriptyline may prolong the QT interval and cause arrhythmias, particularly in patients with pre-existing cardiovascular disease. Regular monitoring of the ECG is recommended, especially in older patients.

  • Seizures: Nortriptyline lowers the seizure threshold, and should be used with caution in patients with a history of seizures.

  • Discontinuation Syndrome: Abrupt discontinuation may lead to withdrawal symptoms such as nausea, headache, insomnia, and irritability. A gradual tapering schedule is recommended.

9. Adverse Effects

• Common Adverse Effects:

  • Sedation: Drowsiness and fatigue due to histamine antagonism.

  • Anticholinergic Effects: Dry mouth, constipation, blurred vision, urinary retention.

  • Weight Gain: Weight gain may occur in some individuals, particularly with long-term use.

  • Orthostatic Hypotension: Due to alpha-1 adrenergic blockade, especially in the elderly.

• Less Common but Clinically Significant:

  • Cardiovascular: Tachycardia, prolonged QT interval, and arrhythmias.

  • Sexual Dysfunction: Decreased libido, ejaculatory delay, and anorgasmia.

• Rare/Serious:

  • Serotonin Syndrome: Symptoms such as hyperthermia, muscle rigidity, tremors, and mental status changes when taken with other serotonergic drugs.

  • Severe Arrhythmias: Cardiac complications, particularly in overdose situations.

  • Hepatotoxicity: Rare liver enzyme abnormalities and jaundice.

10. Drug Interactions

• MAOIs: The combination of nortriptyline with MAOIs (or within 14 days of stopping an MAOI) can cause serotonin syndrome.

• CYP450 Inhibitors: Fluoxetine, paroxetine, and other CYP2D6 inhibitors can increase nortriptyline levels, possibly leading to toxicity.

• CNS Depressants: Additive sedative effects when combined with benzodiazepines, alcohol, or other CNS depressants.

• Anticholinergic Drugs: Additive effects when used with other anticholinergic drugs (e.g., antihistamines, antipsychotics).

• Antihypertensive Drugs: Nortriptyline may reduce the effectiveness of alpha-1 blockers and beta-blockers due to alpha-adrenergic blockade.

11. Clinical Pharmacology

• Pharmacodynamics:

  • Nortriptyline’s therapeutic effects are related to its action on serotonergic and noradrenergic pathways, enhancing mood regulation and improving symptoms of depression.

  • It has a moderate sedative effect, useful for patients with insomnia or agitation due to depression or anxiety.

12. Special Populations

• Pregnancy Category: Category C. Use only if the benefit justifies the potential risk to the fetus.

• Lactation: Excreted in breast milk. Caution is advised when using nortriptyline in breastfeeding women, particularly at higher doses.

• Elderly: Reduced metabolism in the elderly may require dose adjustments, and they are more susceptible to orthostatic hypotension, sedation, and anticholinergic effects.

13. Therapeutic Uses

• First-line Treatment for major depressive disorder in patients who do not respond to SSRIs or when side effects of SSRIs are intolerable.

• Effective in chronic pain syndromes such as neuropathic pain, fibromyalgia, and chronic tension headaches.

14. Monitoring and Follow-Up

• Before: Baseline cardiac evaluation, renal function, liver function tests.

• During: Monitor ECG for QT interval changes, weight, and blood pressure.

• Therapeutic Monitoring: Nortriptyline levels are not routinely monitored, but toxicity should be suspected in overdose situations.

15. Overdose Management

• Symptoms: Severe sedation, tachycardia, arrhythmias, hypotension, seizures, and coma.

• Treatment: Supportive care including airway management, cardiac monitoring, and seizure control. Sodium bicarbonate may be used to treat arrhythmias. Activated charcoal may be used if ingestion occurred within an hour.

16. Patient Counseling Information

• Key Points:

  • Take the medication at night to minimize daytime sedation.

  • Avoid alcohol and other CNS depressants while taking nortriptyline.

  • Gradually taper the medication to avoid withdrawal symptoms.

• Signs to Watch For:

  • Cardiac symptoms such as palpitations, dizziness, or chest pain.

  • Signs of serotonin syndrome such as hyperthermia, agitation, and muscle rigidity.