Usage
- Nortriptyline is primarily prescribed for the treatment of major depressive disorder (MDD). It is also used off-label for other conditions like chronic neuropathic pain, migraine prophylaxis, nocturnal enuresis (bedwetting), and smoking cessation.
- Pharmacological Classification: Tricyclic antidepressant (TCA).
- Mechanism of Action: Nortriptyline inhibits the reuptake of norepinephrine and serotonin, two neurotransmitters in the brain, increasing their availability in the synaptic cleft and enhancing their mood-regulating effects.
Alternate Names
- Nortriptylini hydrochloridum (Latin)
- Brand Names: Pamelor, Aventyl
How It Works
- Pharmacodynamics: Nortriptyline primarily affects the central nervous system by blocking the reuptake of norepinephrine and, to a lesser extent, serotonin. This action elevates mood, improves sleep, and reduces anxiety and pain perception.
- Pharmacokinetics:
- Absorption: Nortriptyline is well-absorbed orally.
- Metabolism: Extensively metabolized in the liver, primarily by CYP2D6, to its active metabolite, 10-hydroxynortriptyline.
- Elimination: Primarily eliminated through renal excretion. The half-life varies but is generally 21-77 hours (and in elderly patients as high as 100 hours or more), allowing for once-daily dosing.
- Mode of Action: Nortriptyline blocks the presynaptic norepinephrine and serotonin transporters, preventing the reuptake of these neurotransmitters back into the presynaptic neuron. This action increases the concentration of norepinephrine and serotonin in the synaptic cleft, thereby enhancing their effects on postsynaptic receptors.
- Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Inhibits reuptake of norepinephrine and serotonin.
- Elimination Pathways: Primarily renal excretion; hepatic metabolism by CYP2D6.
Dosage
Standard Dosage
Adults:
- Initial: 25 mg three to four times daily.
- Maintenance: 75-100 mg daily, may increase up to 150 mg/day. Administer as a single daily dose or in divided doses.
- Elderly: 30-50 mg daily or in divided doses. Start at a low dose and titrate gradually as needed.
Children:
- Not generally recommended for children under 13 for depression.
- Off-label use for nocturnal enuresis: 6-7 years (20-25 kg): 10 mg daily at bedtime.
- Off-label use for other specific conditions: should only be done by specialists who can administer the drug correctly. Dosing may be calculated as mg/kg of body weight.
Special Cases:
- Elderly Patients: Start with lower doses (30-50 mg/day) and titrate slowly.
- Patients with Renal Impairment: Dosage adjustment may be necessary. Monitor closely.
- Patients with Hepatic Dysfunction: Lower doses are recommended. Titrate cautiously.
- Patients with Comorbid Conditions: Close monitoring and dosage adjustments may be required, particularly in patients with cardiovascular disease.
Clinical Use Cases
Nortriptyline does not have FDA-approved indications for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. Its primary use is in managing depression.
Dosage Adjustments
- Adjust dosage based on individual patient response, tolerability, age, and renal/hepatic function.
- Therapeutic drug monitoring may be beneficial, especially at higher doses.
- Consider genetic polymorphisms affecting CYP2D6 activity, which can influence nortriptyline metabolism.
Side Effects
Common Side Effects:
- Dry mouth, constipation, blurred vision, urinary retention, drowsiness, dizziness, weight gain, tremor, sweating, orthostatic hypotension.
Rare but Serious Side Effects:
- Cardiac arrhythmias, seizures, myocardial infarction, stroke, agranulocytosis, hepatotoxicity, neuroleptic malignant syndrome.
Long-Term Effects:
- Tardive dyskinesia (rare).
Adverse Drug Reactions (ADR):
- Allergic reactions (rash, itching, swelling), serotonin syndrome (with concomitant serotonergic agents), severe hypotension, cardiac conduction abnormalities.
Contraindications
- Hypersensitivity to nortriptyline or other TCAs.
- Recent myocardial infarction.
- Angle-closure glaucoma.
- Concomitant use of MAOIs.
Drug Interactions
- MAOIs: Risk of hypertensive crisis.
- CYP2D6 inhibitors (e.g., fluoxetine, paroxetine): Increased nortriptyline levels.
- CYP2D6 inducers (e.g., barbiturates, rifampin): Decreased nortriptyline levels.
- Anticholinergic drugs: Additive anticholinergic effects.
- CNS depressants: Additive sedative effects.
- Alcohol: Increased sedation and impaired cognitive function.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Nortriptyline is classified as Pregnancy Category D. Use only if the potential benefits outweigh the risks to the fetus.
- Fetal Risks: Increased risk of congenital malformations, particularly cardiovascular defects.
- Breastfeeding: Nortriptyline is excreted in breast milk and can cause adverse effects in infants. Consider the risks and benefits before using during breastfeeding.
Drug Profile Summary
- Mechanism of Action: Inhibits norepinephrine and serotonin reuptake.
- Side Effects: Dry mouth, constipation, blurred vision, drowsiness, dizziness, cardiac arrhythmias (rare).
- Contraindications: Hypersensitivity, recent MI, angle-closure glaucoma, concomitant MAOI use.
- Drug Interactions: MAOIs, CYP2D6 inhibitors/inducers, anticholinergics, CNS depressants.
- Pregnancy & Breastfeeding: Use with caution; potential fetal risks; excreted in breast milk.
- Dosage: Adults: 75-100 mg/day; Elderly: 30-50 mg/day.
- Monitoring Parameters: ECG (especially in the elderly or those with cardiac conditions), blood pressure, mental status, nortriptyline plasma levels (at higher doses).
Popular Combinations
Nortriptyline is sometimes used in combination with other antidepressants or mood stabilizers for treatment-resistant depression. However, combining with other serotonergic medications can increase the risk of serotonin syndrome. Combining it with other drugs with anticholinergic properties can result in undesirable additive effects.
Precautions
- General Precautions: Monitor for suicidal ideation, cardiac function, and anticholinergic effects.
- Specific Populations:
- Pregnant Women: Use only if potential benefits outweigh risks.
- Breastfeeding Mothers: Use with caution; consider the risks and benefits.
- Children & Elderly: Start with lower doses and titrate slowly.
- Lifestyle Considerations: Limit alcohol intake; avoid driving or operating machinery if drowsiness occurs.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Nortriptyline?
A: Adults: Initial dose is typically 25 mg three to four times a day, increasing gradually to a usual maintenance dose of 75-100 mg daily, up to a maximum of 150 mg daily. Elderly: Start with a lower dose of 30-50 mg daily and titrate carefully.
Q2: What are the common side effects of Nortriptyline?
A: Common side effects include dry mouth, constipation, blurred vision, urinary retention, drowsiness, dizziness, tremor, and orthostatic hypotension.
Q3: How does Nortriptyline differ from other TCAs?
A: Nortriptyline has a more selective effect on norepinephrine reuptake compared to other TCAs like amitriptyline, which also strongly inhibits serotonin reuptake. This selectivity may result in fewer anticholinergic and sedative side effects.
A: Serious side effects include cardiac arrhythmias, seizures, myocardial infarction, stroke, and neuroleptic malignant syndrome.
Q5: Can Nortriptyline be used during pregnancy?
A: Nortriptyline is a Pregnancy Category D drug and should be used during pregnancy only if the potential benefits outweigh the risks to the fetus.
Q6: How should Nortriptyline be discontinued?
A: Nortriptyline should be tapered gradually to minimize withdrawal symptoms. Abrupt discontinuation can lead to symptoms such as nausea, headache, and malaise.
Q7: What should I monitor in patients taking Nortriptyline?
A: Monitor for suicidal ideation, cardiovascular function (especially in the elderly), and anticholinergic side effects. Therapeutic drug monitoring of nortriptyline plasma levels can be useful at higher doses.
Q8: Does Nortriptyline interact with other medications?
A: Yes, Nortriptyline has several clinically significant drug interactions. Avoid concomitant use with MAOIs. It interacts with CYP2D6 inhibitors and inducers, as well as alcohol, CNS depressants, and anticholinergic medications.
A: Nortriptyline is primarily metabolized by CYP2D6 in the liver. Genetic variations in CYP2D6 activity can affect nortriptyline levels and therapeutic response.
Q10: Are there any dietary restrictions while taking Nortriptyline?
A: While no specific dietary restrictions are mandatory, advise patients to limit alcohol intake as it can potentiate the sedative effects of Nortriptyline.
