nortriptyline

**Class and mechanism:** Secondary-amine TCA. It blocks the presynaptic reuptake transporters for norepinephrine (NET) and, to a lesser degree, serotonin (SERT). This increases synaptic monoamines. It also antagonizes muscarinic (M1), histamine (H1), and alpha-1 adrenergic receptors, and it blocks cardiac fast sodium channels. These off-target effects cause most of the adverse effects.

**Pharmacokinetics:** Nortriptyline is the demethylated active metabolite of amitriptyline (tertiary amine). It is metabolized by hepatic CYP2D6, so poor metabolizers have higher levels and toxicity risk, and CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion, quinidine) raise levels. It is highly lipophilic, highly protein bound, and has a large volume of distribution, so dialysis is ineffective in overdose. It has a narrow therapeutic index, and therapeutic drug monitoring is used (therapeutic window about 50–150 ng/mL).

**Clinical uses:** - Major depressive disorder - Neuropathic pain (diabetic neuropathy, postherpetic neuralgia) - Migraine prophylaxis - Nocturnal enuresis (more classically imipramine) - Smoking cessation (second-line) - Chronic pain and fibromyalgia

**Why nortriptyline is favored in some patients:** Among TCAs, secondary amines (nortriptyline, desipramine) have fewer anticholinergic, antihistaminic, and alpha-1 blocking effects than tertiary amines (amitriptyline, imipramine, clomipramine, doxepin). They cause less sedation, less orthostatic hypotension, and less confusion, so they are preferred in the elderly. Mnemonic: "Nortriptyline is the 'nicer' TCA in older adults" (still on the Beers list, but relatively better tolerated).

**Adverse effects (anticholinergic, antihistamine, alpha-1, sodium channel):** - Dry mouth, constipation, urinary retention, blurred vision, tachycardia, and precipitation of acute angle-closure glaucoma (anticholinergic) - Sedation and weight gain (H1) - Orthostatic hypotension and dizziness (alpha-1) - Cardiac conduction slowing with QRS and QT prolongation - Lowered seizure threshold - Hyperthermia in overdose - Mania induction in bipolar patients

**TCA overdose (high-yield):** - Presents with the 3 C's: Convulsions, Coma, Cardiotoxicity (arrhythmias). - Other findings are anticholinergic toxidrome, hypotension, and respiratory depression. - ECG shows QRS widening (>100 ms predicts seizures, >160 ms predicts ventricular arrhythmias), a terminal R wave in aVR, and sinus tachycardia. - Treatment is IV sodium bicarbonate (serum alkalinization to pH 7.45–7.55), which overcomes sodium channel blockade. Also give benzodiazepines for seizures and norepinephrine for hypotension. Use activated charcoal if the patient presents early. Avoid physostigmine (risk of seizures and asystole) and flumazenil. - Class IA and IC antiarrhythmics are contraindicated.

**Contraindications and cautions:** - Recent MI or conduction block - Concurrent MAOI use (risk of serotonin syndrome and hypertensive crisis) - Narrow-angle glaucoma - BPH or urinary retention - Seizure disorders - Boxed warning: increased suicidality in children, adolescents, and young adults - Dangerous in overdose, so prescribe limited quantities to suicidal patients

**Drug interactions:** Serotonergic drugs (serotonin syndrome), CYP2D6 inhibitors (increased levels), other anticholinergics and CNS depressants (additive effects), and QT-prolonging agents.

**Exam pearls:** - TCAs are classified as tertiary amines (amitriptyline, imipramine, clomipramine, doxepin) or secondary amines (nortriptyline, desipramine). - Clomipramine is used for OCD, and imipramine for enuresis. - Abrupt discontinuation can cause a cholinergic rebound/withdrawal syndrome. - Treatment of TCA-induced orthostasis is usually dose reduction or switching agents. - Amitriptyline is metabolized to nortriptyline, and imipramine to desipramine.