Imipramine
Imipramine
Generic Name
Imipramine
Mechanism
Imipramine exerts its therapeutic effect primarily by:
• Inhibiting reuptake of norepinephrine (NE) and serotonin (5‑HT) at presynaptic nerve terminals, enhancing synaptic neurotransmission in the limbic system.
• Antagonizing histamine H1 receptors, causing sedation and antihistaminic effects.
• Blocking α1‑adrenergic, muscarinic (M1‑M3), and serotonin 5‑HT2 receptors, contributing to its anticholinergic, antihypertensive, and anxiolytic properties.
• Modestly antagonizing dopamine D2 receptors, which may influence motor side effects.
The combined NE/5‑HT uptake inhibition is responsible for mood‑lifting efficacy, while peripheral receptor activity accounts for common side‑effect profile.
Pharmacokinetics
| Parameter | Details |
| Absorption | Oral bioavailability ~15‑30 % (first‑pass hepatic metabolism, high extraction ratio). Peak plasma: 3–5 h (imipramine) or 6–12 h (active metabolite desmethyl‑imipramine). |
| Distribution | Highly lipophilic; extensive tissue binding. 95‑100 % protein‑bound (predominantly α‑1‑acid glycoprotein). |
| Metabolism | Hepatic CYP2D6 → desmethyl‑imipramine and other metabolites. CYP2D6 polymorphism can markedly alter trough concentrations. |
| Elimination | Renally excreted (≈40 % unchanged, remainder as metabolites). Half‑life: 15–20 h (imipramine) → 2–3 day steady‑state trough levels. |
| Drug Interactions | Strong CYP2D6 inhibitors (e.g., fluoxetine) ↑ plasma levels; potent CYP2D6 inducers (e.g., carbamazepine) ↓ levels. MAO inhibitors contraindicated; QT‑prolonging agents additive risk. |
Indications
- Major depressive disorder (MDD) – first‑line or adjunct therapy when patients tolerate anticholinergic side effects.
- Chronic neuropathic pain (e.g., trigeminal neuralgia, diabetic peripheral neuropathy).
- Seasonal affective disorder (inadequate response to SSRIs).
- Panic disorder (used in patients with comorbid depression; not first‑line).
Contraindications
- Absolute Contraindications:
- Current use of non‑selective MAO inhibitors.
- Uncontrolled narrow‑angle glaucoma.
- Acute myocardial infarction or uncontrolled arrhythmia.
- Severe hepatic impairment (due to active metabolism).
- Relative Contraindications/Warnings:
- Known hypersensitivity to tricyclics.
- Concomitant use of other anticholinergic or sedating agents.
- Significant orthostatic hypotension.
- Uncontrolled epilepsy (increasing seizure threshold).
- Pregnancy (category C; use only if benefits outweigh risks).
Safety Monitoring: cardiac conduction, blood pressure, glucose, weight.
Dosing
| Phase | Dosage | Frequency | Notes |
| Initial | 10–25 mg qhs | Once daily (at bedtime) | Start low to assess tolerance. |
| Loading | Increase by 5–10 mg/day | Daily | Can titrate to 100 mg/day within 2 weeks if needed. |
| Maintenance | 75–150 mg/day | 1–2 divided doses | Target trough concentration 50–200 ng/mL for depression. |
| Adjustments | ↓ by 5–10 mg/day | As needed | Taper slowly to reduce withdrawal. |
• Liquid formulation: 25 mg/5 mL oral solution.
• Avoid alcohol and benzodiazepine combinations at onset.
Monitoring
| Parameter | Target | Frequency |
| Serum concentration | 50–200 ng/mL | At steady‑state (day 14) and with dosage changes. |
| ECG | QTc < 450 ms | Baseline, then every 3–4 weeks if on high dose or other QT‑prolonging drugs. |
| Blood pressure | <120/80 mmHg | At each visit until stable. |
| Blood glucose | <140 mg/dL | Every 3 months in diabetics. |
| Weight & BMI | Stable | Every 4–6 weeks. |
| Cognitive and mood scales | Depressive scales (HAM-D, PHQ‑9) | Baseline, then 2–4 weeks. |
| Electrolytes | Na⁺, K⁺, Cl⁻, Mg²⁺, Ca²⁺ | Every 3–6 months for chronic use. |
Clinical Pearls
- Triage for Depression: Ideal for patients with significant anhedonia and neurovegetative symptoms; less suitable for those with active anticholinergic burden (e.g., older adults with benign prostatic hyperplasia).
- Dose Escalation Strategy: Doubling dose every 3–4 days is common; avoid exceeding 150 mg/day unless closely monitored due to QT risk.
- CYP2D6 Genotyping: Poor metabolizers may reach toxic levels; consider lower target trough and avoid CYP2D6 inhibitors.
- Cardiac Monitoring: Baseline ECG is mandatory if patient older than 60 or has CAD.
- Drug‑Drug Interaction (DDI) Check: Avoid concomitant NSAIDs (reduce absorption) and avoid high‑dose antihistamines that can potentiate sedation.
- Pregnancy: Third-trimester dosing often requires careful fetal monitoring; use only if benefits outweigh risks.
- Withdrawal: Discontinuation should be gradual; abrupt stop can precipitate dizziness, nausea, and “taper flu-like syndrome.”
*Tip: For patients requiring both anticholinergic and antihistaminic effects, consider low-dose diphenhydramine rather than increasing imipramine dose to reduce central side effects.*