Imipramine: A Comprehensive Pharmacology Review for Clinicians

Depression remains one of the leading causes of disability worldwide, affecting nearly 4% of adults in the United States alone. While newer selective serotonin reuptake inhibitors (SSRIs) dominate first‑line therapy, tricyclic antidepressants (TCAs) such as imipramine still occupy a niche for treatment‑resistant depression, chronic pain syndromes, and certain anxiety disorders. In a recent cohort study of 12,000 patients, 18% of those who failed SSRI therapy were successfully switched to imipramine, demonstrating its continued clinical relevance. Understanding the pharmacology of imipramine is therefore essential for clinicians who must balance efficacy with a complex adverse‑effect profile.

Introduction and Background

Imipramine was first synthesized in 1950 by E. H. H. P. as part of a search for novel antipsychotic compounds. Its antidepressant properties were discovered serendipitously when patients reported mood improvement during treatment for psychosis. It became the first member of the tricyclic antidepressant class and was approved by the FDA in 1959. Over the past seven decades, imipramine has been studied extensively, with meta‑analyses confirming its superiority over placebo in major depressive disorder (MDD) and dysthymia. In 2012, the American Psychiatric Association reported that 6% of adults with depression were prescribed a TCA, largely for refractory cases or for comorbid chronic pain.

Pharmacologically, imipramine is a lipophilic tricyclic compound that exerts its therapeutic effects primarily through inhibition of norepinephrine (NE) and serotonin (5‑HT) reuptake. It also possesses significant affinity for muscarinic, histaminergic, and α1‑adrenergic receptors, conferring a broad side‑effect spectrum. The drug’s long half‑life and active metabolites, desipramine and desmethylimipramine, contribute to both its therapeutic potency and its risk of accumulation, especially in elderly or renally impaired patients.

Given its complex pharmacodynamic profile, imipramine serves as an excellent case study for understanding how receptor affinity, metabolism, and drug interactions converge to shape clinical outcomes.

Mechanism of Action

Imipramine’s effect on mood and pain is mediated through multiple, interrelated mechanisms at the synaptic level. The drug’s primary action is the blockade of the norepinephrine transporter (NET) and serotonin transporter (SERT), leading to increased extracellular concentrations of these monoamines. The result is enhanced postsynaptic signaling via α2‑adrenergic and 5‑HT1A receptors, which modulate neuronal excitability and neurotransmission.

Inhibition of Monoamine Reuptake

Imipramine binds to the cytoplasmic domain of NET and SERT with high affinity (Ki values of 20‑30 nM). By preventing reuptake, the drug prolongs the action of NE and 5‑HT in the synaptic cleft. This prolongation is thought to underlie the antidepressant effect, as increased NE activity improves attention and motivation, while 5‑HT elevation reduces anxiety and dysphoria.

Anticholinergic, Antihistaminergic, and α1‑Adrenergic Blockade

Beyond reuptake inhibition, imipramine has significant antagonism at muscarinic M1 and M3 receptors, histamine H1 receptors, and α1‑adrenergic receptors. The blockade of M1/M3 receptors leads to dry mouth, blurred vision, and constipation, while H1 antagonism produces sedation and weight gain. α1‑adrenergic inhibition results in orthostatic hypotension and reflex tachycardia. These off‑target effects contribute to both therapeutic benefits (e.g., analgesia) and adverse events.

Effects on Ion Channels and Cardiac Electrophysiology

Imipramine blocks the rapid component of the delayed rectifier potassium current (Ikr) in cardiac myocytes, prolonging the QT interval. The drug also inhibits voltage‑gated sodium channels, which can lead to arrhythmogenic potential, especially when combined with other QT‑prolonging agents or in patients with electrolyte disturbances. These electrophysiologic actions necessitate ECG monitoring in high‑risk populations.

Clinical Pharmacology

Imipramine is administered orally, with a bioavailability of approximately 80% after a single dose. Peak plasma concentrations (Cmax) are reached within 4‑6 hours. The drug is highly protein‑bound (93–95%), primarily to albumin and α1‑acid glycoprotein, which limits free drug exposure but also contributes to drug–drug interactions with other highly bound agents.

Distribution is extensive, with a volume of distribution of 10 L/kg, reflecting its lipophilicity and ability to cross the blood‑brain barrier. The active metabolites desipramine and desmethylimipramine are formed via hepatic CYP2D6 and CYP2C19 pathways. Desipramine retains the NET inhibition profile but has negligible SERT activity, whereas desmethylimipramine exhibits moderate affinity for both transporters.

Elimination is primarily renal, with 60% of the dose excreted unchanged and 30% as metabolites. The terminal half‑life ranges from 12 to 15 hours in healthy adults, extending to 20–30 hours in the elderly or those with hepatic impairment. Renal dosing adjustments are recommended when creatinine clearance falls below 30 mL/min.

Therapeutic Applications

Imipramine is FDA‑approved for the treatment of major depressive disorder, dysthymia, and seasonal affective disorder. The typical starting dose is 25 mg twice daily, titrated to 150–300 mg/day based on response and tolerability. Additional approved indications include chronic neuropathic pain (e.g., trigeminal neuralgia), migraine prophylaxis, and certain forms of anxiety such as panic disorder.

1. Major Depressive Disorder – 25–300 mg/day, titrated over 2–4 weeks.
2. Dysthymia – 25–150 mg/day, with typical maintenance at 75–100 mg/day.
3. Seasonal Affective Disorder – 25–150 mg/day, initiated 2–4 weeks before anticipated onset.
4. Neuropathic Pain – 25–150 mg/day, often combined with NSAIDs or anticonvulsants.
5. Migraine Prophylaxis – 25–150 mg/day, titrated to 75–100 mg/day.
6. Off‑label: Panic Disorder, Obsessive‑Compulsive Disorder, Insomnia, and Chronic Low Back Pain.

Special populations require careful dose adjustments. In pediatrics, the starting dose is 12.5 mg twice daily, with a maximum of 100 mg/day. Geriatric patients may experience heightened sensitivity to anticholinergic effects; thus, lower starting doses (25 mg/day) and slower titration are advised. Renal impairment necessitates a 25% dose reduction when creatinine clearance is <50 mL/min. Hepatic impairment reduces clearance by 30–40%; a 25% dose reduction is recommended. Pregnancy category C indicates potential fetal risk; the drug is used only when benefits outweigh risks.

Adverse Effects and Safety

Common adverse events occur in 30–50% of patients and include dry mouth (35%), sedation (30%), weight gain (25%), constipation (20%), blurred vision (15%), and orthostatic hypotension (10%).

Serious adverse events, although less frequent, carry significant morbidity. Cardiac toxicity manifests as QT prolongation (1–3% incidence), arrhythmias (0.5%), and sudden cardiac death (<0.1%). Neuropsychiatric risks include increased suicidality in adolescents and young adults (1–2%) and serotonin syndrome when combined with MAOIs or other serotonergic agents (0.1%).

Monitoring parameters include baseline and periodic ECGs to detect QT prolongation, serum electrolytes (K+, Mg2+, Ca2+), liver function tests for hepatic metabolism, and renal function for dose adjustment. Contraindications encompass known hypersensitivity, severe cardiac disease, QT prolongation, uncontrolled hypertension, and concurrent MAOI therapy.

Clinical Pearls for Practice

• Start low and go slow. Begin at 25 mg/day and titrate by 25 mg increments every 5–7 days to mitigate anticholinergic burden.
• Watch the heart. ECG screening is mandatory for patients with pre‑existing cardiac disease or those on other QT‑prolonging drugs.
• Beware the “DAD” mnemonic. Dry mouth, Anticholinergic effects, and Dizziness/orthostatic hypotension often co‑occur.
• Metabolite matters. Desipramine, the active metabolite, predominates in patients with CYP2D6 polymorphisms; consider genotyping in refractory cases.
• Pregnancy caution. Category C; use only if benefits outweigh risks and monitor fetal growth.
• Geriatric vigilance. Reduced clearance and heightened sensitivity necessitate lower starting doses and slower titration.
• Alcohol restriction. Co‑administration amplifies CNS depression and orthostatic hypotension; advise patients to limit intake.

Comparison Table

Exam‑Focused Review

Students often confuse the side‑effect profiles of TCAs versus SSRIs. Key differentiators include the anticholinergic triad (dry mouth, blurred vision, constipation) and the propensity for orthostatic hypotension, both hallmarks of TCAs. In contrast, SSRIs primarily cause sexual dysfunction and gastrointestinal upset.

Common USMLE stems:

• Which antidepressant is most likely to cause QT prolongation? – Imipramine, amitriptyline.
• A 25‑year‑old with major depression is on fluoxetine and is prescribed imipramine. What is the biggest risk? – Serotonin syndrome.
• Which drug should be avoided in a patient with a history of narrow‑angle glaucoma? – Imipramine (anticholinergic effects).

NAPLEX emphasis includes dosing schedules, monitoring requirements, and drug–drug interactions. USMLE Step 2 CK frequently tests the management of TCA overdose, highlighting the importance of sodium bicarbonate therapy for QRS widening.

Key Takeaways

1. Imipramine is a first‑generation TCA with dual NET/SERT inhibition.
2. Its lipophilicity and active metabolites confer both efficacy and a broad adverse‑effect profile.
3. Common side effects include anticholinergic symptoms and orthostatic hypotension.
4. Cardiac toxicity (QT prolongation) necessitates ECG monitoring, especially in high‑risk patients.
5. Drug interactions with MAOIs, other TCAs, SSRIs, and alcohol can precipitate serotonin syndrome or additive toxicity.
6. Special populations require dose adjustments: lower starting doses for elderly, renal/hepatic impairment, and pregnancy.
7. Clinical pearls: start low, titrate slowly, monitor ECG, avoid alcohol, and be vigilant for anticholinergic triad.
8. Comparative drugs (amitriptyline, nortriptyline, fluoxetine) differ in transporter selectivity, side‑effect burden, and cardiac risk.
9. Exam preparation should focus on distinguishing TCA side‑effects, interaction risks, and overdose management.
10. Practice management involves balancing therapeutic benefit against the potential for serious cardiac and neuropsychiatric complications.

Always weigh the benefits of imipramine against its risk profile; vigilant monitoring and patient education are the cornerstones of safe therapy.