Generic Name

Doxepin

Mechanism

• Serotonin and norepinephrine reuptake inhibition: ↓ synaptic reuptake → ↑ monoamine levels.
• Strong H1‑histamine antagonism: causes pronounced sedation, making it ideal for insomnia.
• Partial α1‑adrenergic blockade: leads to vasodilation and orthostatic hypotension.
• Muscarinic M1–M3 blockade: produces anticholinergic symptoms (dry mouth, blurred vision).

Overall, the combination of monoamine inhibition and antihistamine activity yields a sedative effect distinct from other TCAs.

Pharmacokinetics

• Absorption: ~70–80 % orally, peak plasma at ~2–3 h.
• Distribution: highly protein‑bound (~80 %‑90 %) with large volume of distribution.
• Metabolism: primarily hepatic CYP2D6 → demethylated N‑desmethyl‑doxepin (active).
• Half‑life: 12–20 h (oral), 25–37 h for metabolites.
• Excretion: renal (~50 %) and fecal; caution in hepatic/renal impairment.

Indications

• Short‑term insomnia (≤ 4–8 weeks): 10–50 mg nightly.
• Generalized anxiety disorder: 120–200 mg/day (split dosing).
• Obsessive‑compulsive disorder: 120–200 mg/day.
• Topical anti‑pruritic: 20 % 2‑4 % cream for severe pruritus, eczema, and severe rosacea.
• Pediatric use (in rare cases) for anxiety and insomnia after careful risk‑benefit assessment.

Contraindications

• Cardiac conduction abnormalities (QT prolongation, arrhythmias).
• Severe hepatic or renal disease.
• Acute narrow‑angle glaucoma.
• Severe dementia, advanced cerebro‑vascular disease, or severe constipation (anticholinergic load).
• Pregnancy/Breast‑feeding: category D; avoid unless benefit > risk.
• Concurrent use with MAO inhibitors: avoid due to serotonin syndrome risk.

Dosing

Titration: Begin at lowest effective dose; increase by 10 mg increments every 3–5 days.

Duration: Short‑term (<8 weeks) for insomnia; longer‑term for anxiety/OC but titrate.

Adverse Effects

• Common: Sedation, dry mouth, constipation, weight gain, blurred vision, orthostatic hypotension.
• Serious: Cardiotoxicity (arrhythmia, hypotension), seizures, hepatotoxicity, severe anticholinergic crisis, neuropsychiatric symptoms (hallucinations, confusion).

Rare but severe: Sudden death in overdose; treat with activated charcoal, correct electrolytes, and cardiac monitoring.

Monitoring

Topical: Monitor for skin irritation or contact dermatitis; discontinue if severe.

Clinical Pearls

• Hydrophobicity matters: Doxepin’s high lipophilicity enhances CNS penetration → strong sedation but also accumulates in tissues.
• “Low‑dose sedation” rule: Use the minimal effective dose for insomnia (10 mg) to limit anticholinergic load.
• Avoid caffeine 2–4 h pre‑dose; may counterbalance sedative effects.
• Elderly caution: Use 5 mg initial dose and titrate slowly due to prolonged half‑life and heightened sensitivity.
• Topical 20 %: Use under 8 weeks; longer durations raise systemic absorption risk.
• Cardiac patients: Routine ECG monitoring; consider alternatives (e.g., trazodone) if conduction issues suspected.
• Drug interactions: Strong inhibition of CYP2D6; caution with other CYP2D6 substrates (e.g., paroxetine, metoprolol).

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• *For more in‑depth information, consult the latest prescribing information and relevant clinical guidelines.*