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tricyclic antidepressants mechanism pharmacology clinical use toxicity
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Here is a comprehensive overview of Tricyclic Antidepressants (TCAs):
Tricyclic Antidepressants (TCAs)
Structure & History
TCAs are named for their three-ring molecular structure. Imipramine was the first TCA, introduced in the 1950s, and the class remained the primary treatment for depression until SSRIs arrived. They are still used today for specific indications.
Mechanism of Action
TCAs work through multiple receptor mechanisms:
| Mechanism | Effect |
|---|---|
| Block NE & serotonin (5-HT) reuptake | Primary antidepressant/analgesic effect — increases synaptic monoamines |
| Muscarinic (anticholinergic) blockade | Dry mouth, constipation, urinary retention, blurred vision, confusion |
| α₁-adrenergic blockade | Orthostatic hypotension |
| Histamine (H₁) blockade | Sedation, weight gain |
| Sodium channel blockade | Cardiac conduction slowing (QRS widening) |
| Potassium channel blockade | QT prolongation |
Individual Agents
| Drug | Class | Notes |
|---|---|---|
| Amitriptyline | Tertiary amine | Most sedating; significant anticholinergic; QT prolongation |
| Imipramine | Tertiary amine | First TCA; also used for enuresis |
| Clomipramine | Tertiary amine | Used for OCD; greatest QT prolongation risk |
| Doxepin | Tertiary amine | Also substrate of CYP2D6 |
| Nortriptyline | Secondary amine | Less sedating; fewer side effects |
| Desipramine | Secondary amine | Least sedating; weakest CYP2D6 inhibitor; fewest drug interactions |
Tertiary amines (amitriptyline, imipramine, doxepin, clomipramine) have more side effects than secondary amines (nortriptyline, desipramine) and are not recommended in older adults.
Clinical Indications
- Major depression (especially treatment-resistant)
- Anxiety disorders including panic disorder
- OCD (clomipramine specifically)
- Chronic pain / neuropathic pain
- Migraine prophylaxis
- Nocturnal enuresis (imipramine)
- Fibromyalgia
- Trigeminal neuralgia
Drug Interactions
- Metabolized by CYP2C19, CYP1A2 (tertiary amines) and CYP2D6 (doxepin, desipramine, nortriptyline)
- CYP inhibitors can unexpectedly raise TCA serum levels → toxicity
- Combining with MAOIs or SSRIs risks serotonin syndrome
TCA Overdose / Toxicity
Toxicity is life-threatening and progresses rapidly:
Timeline
| Phase | Time | Features |
|---|---|---|
| Early | 0–2 hrs | Anticholinergic syndrome: dry skin, urinary retention, confusion, agitation, tachycardia, hallucinations, seizures |
| Late | 2–6 hrs | Myocardial depression, hypotension, bradycardia, wide QRS, arrhythmias |
ECG Findings
- Sinus tachycardia (earliest sign)
- QRS > 100 ms → predictive of seizures
- QRS > 160 ms → predictive of ventricular dysrhythmias
- R wave in aVR > 3 ms (terminal 40-ms rightward axis shift) — hallmark finding
- QT prolongation (especially clomipramine, amitriptyline)
Differential Diagnosis
Wide QRS also seen with: Class IA antiarrhythmics (quinidine, procainamide), Class IC (flecainide), diphenhydramine, carbamazepine, cocaine
Management of Overdose
- Airway/Breathing — secure airway early; intubate if seizing or obtunded
- Activated charcoal — only if within 1 hr, awake, cooperative, no toxicity signs
- IV fluids — for hypotension (isotonic crystalloid first)
- Vasopressors — norepinephrine or epinephrine for refractory hypotension (direct-acting agents preferred)
- Sodium bicarbonate — key treatment for QRS widening or ventricular dysrhythmias
- Bolus: 1–2 mEq/kg IV push if QRS > 100 ms; repeat in 5–10 min if needed
- Infusion: maintain serum pH 7.50–7.55
- Mechanism: provides Na⁺ to overcome channel blockade + alkalinization reduces TCA binding
- Seizures — IV benzodiazepines (lorazepam 1–4 mg or diazepam 5–10 mg); refractory → phenobarbital 15–20 mg/kg
- Avoid: Class IA/IC antiarrhythmics (worsen sodium channel blockade); physostigmine (risk of asystole with QRS/QT prolongation)
If QRS doesn't respond to maximal alkalinization (pH > 7.55), 3% hypertonic saline can be used.
Sources: Rosen's Emergency Medicine (9th ed.), Braunwald's Heart Disease, Adams & Victor's Principles of Neurology, Stahl's Essential Psychopharmacology — Medical Library
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