NORTRIPTYLINE HYDROCHLORIDE
Clinical safety rating: caution
Animal studies have proved adverse effects but may be safe for humans
Nortriptyline is a tricyclic antidepressant that inhibits the reuptake of norepinephrine and serotonin at the presynaptic neuronal membrane, increasing their concentrations in the synaptic cleft. It also has anticholinergic, antihistaminic, and alpha-adrenergic blocking properties.
| Metabolism | Primarily hepatic via CYP450 isoenzymes, including CYP2D6 and CYP3A4. Active metabolite: desmethylnortriptyline. Peak plasma levels occur within 7–8.5 hours. |
| Excretion | Primarily renal (70% as metabolites, <5% unchanged) and fecal (30% via biliary elimination). |
| Half-life | Terminal elimination half-life 18-56 hours (mean 28 hours); steady-state reached in 5-7 days. |
| Protein binding | 92-94% bound to albumin, alpha-1-acid glycoprotein, and lipoproteins. |
| Volume of Distribution | 14-21 L/kg; large Vd indicates extensive tissue distribution. |
| Bioavailability | Oral: 46-56% (first-pass metabolism); IM: 100% (not available in US); IV: 100%. |
| Onset of Action | Oral: antidepressant effect 2-4 weeks; analgesic effect 1-7 days at low doses. |
| Duration of Action | 24-48 hours after single dose; continuous therapy required for sustained antidepressant effect. |
25 mg orally three times daily or 75 mg orally once daily at bedtime; initial dose 25 mg at bedtime, titrate up to 75-150 mg/day.
| Dosage form | CAPSULE |
| Renal impairment | No adjustment required for mild to moderate renal impairment; avoid use in severe renal impairment (GFR <30 mL/min) due to anticholinergic effects. |
| Liver impairment | Child-Pugh A: reduce dose by 50%; Child-Pugh B: reduce dose by 75%; Child-Pugh C: contraindicated. |
| Pediatric use | 6-12 years: 10-25 mg/day in divided doses; >12 years: 25-50 mg/day in divided doses; max 150 mg/day. Not recommended in children <6 years. |
| Geriatric use | Initiate at 10-25 mg at bedtime; monitor for orthostatic hypotension, sedation, and anticholinergic effects; maximum 50-100 mg/day. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
MAOIs can cause serotonin syndrome and hyperpyrexia Strong anticholinergic effects may occur with other drugs Increased risk of suicide in children and young adults.
| Breastfeeding | Nortriptyline is excreted into breast milk. M/P ratio approximately 2.0 (range 0.6-3.7). Relative infant dose estimated 2-3% of maternal weight-adjusted dose. Monitor infant for sedation, irritability, poor feeding. Generally considered compatible with breastfeeding at low maternal doses. |
| Teratogenic Risk | First trimester: Limited human data; animal studies show no consistent teratogenicity. Avoid unless benefit outweighs risk. Second/third trimester: Risk of neonatal withdrawal (irritability, respiratory distress) and anticholinergic effects (feeding intolerance, ileus). Use lowest effective dose. |
■ FDA Black Box Warning
Suicidality and Antidepressant Drugs: Nortriptyline may increase the risk of suicidal thinking and behavior in children, adolescents, and young adults with major depressive disorder and other psychiatric disorders. Close monitoring is required during initial treatment.
| Common Effects | Dry mouth |
| Serious Effects |
["Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuation","Recent myocardial infarction (MI)","Hypersensitivity to nortriptyline or any component of the formulation","Use in patients with narrow-angle glaucoma (unless on appropriate therapy)","Use with cisapride (due to risk of QT prolongation)"]
| Precautions | ["Suicide risk: Monitor for clinical worsening and suicidality","Serotonin syndrome: Risk with concomitant serotonergic drugs","Cardiotoxicity: QT prolongation, arrhythmias; use with caution in patients with cardiovascular disease","Anticholinergic effects: Caution in patients with urinary retention, angle-closure glaucoma, or hyperthyroidism","Manic episodes: May precipitate hypomania or mania in predisposed patients","Seizure threshold: Lowered seizure threshold; caution in patients with seizure disorder","Use in pregnancy: Crosses placenta; risk of neonatal withdrawal/toxicity"] |
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| Fetal Monitoring | Maternal: Serum nortriptyline levels (therapeutic range 50-150 ng/mL), ECG for QTc prolongation if risk factors, blood pressure, mental status. Fetal/neonatal: Ultrasound for fetal growth, nonstress test in third trimester; monitor neonate for withdrawal symptoms and anticholinergic effects. |
| Fertility Effects | No known direct effect on fertility. However, hyperprolactinemia and sexual dysfunction (delayed ejaculation, anorgasmia) reported which may impair fertility in some individuals. Depression itself can reduce libido and fertility. |