Imipramine Hydrochloride

• Major Depressive Disorder (MDD): Treatment of endogenous, reactive, or neurotic depression in adults.
• Childhood Nocturnal Enuresis: Short-term management in children aged six years and older, after exclusion of organic causes.
• Panic Disorder: Reduction in frequency and severity of panic attacks.
• Off-label uses:
• Neuropathic pain management
• Attention Deficit Hyperactivity Disorder (ADHD) refractory to stimulants
• Irritable Bowel Syndrome (IBS) symptoms relief
• Migraine and chronic tension headache prophylaxis
• Bulimia nervosa adjunct therapy

• Route: Oral administration.
• Adults:
• Initial: 75 mg daily, divided or single bedtime dose.
• Maintenance: 50–150 mg/day; may increase up to 300 mg/day in severe cases.
• Children (Nocturnal Enuresis):
• 6–8 years: 25 mg at bedtime.
• 9–12 years: 25–50 mg at bedtime.
• 13–18 years: 50–75 mg at bedtime.
• Maximum: 2.5 mg/kg/day.
• Elderly: Start at 25–50 mg daily; increase cautiously with monitoring.
• Renal/Hepatic Impairment: No formal adjustment guidelines; initiate at low doses with close monitoring.
• Duration: Typically several weeks to months depending on indication.

Imipramine hydrochloride is a tricyclic antidepressant that inhibits the reuptake of norepinephrine and serotonin at presynaptic neurons, increasing their availability in the synaptic cleft and enhancing mood and emotional regulation. It also exhibits antagonistic effects on muscarinic cholinergic, histaminergic, and alpha-adrenergic receptors, contributing to both therapeutic effects and side effect profiles. These actions underpin its efficacy in depression, enuresis, and various off-label indications.

• Absorption: Well absorbed orally; peak plasma levels in 1–2 hours.
• Bioavailability: Moderate due to first-pass metabolism.
• Distribution: Widely distributed; crosses blood-brain barrier; ~90% plasma protein bound.
• Metabolism: Extensively hepatic via CYP2D6, forming active metabolite desipramine.
• Elimination: Primarily renal excretion of metabolites.
• Half-life: Imipramine 11–25 hours; desipramine 12–46 hours.
• Steady-state: Achieved within 7–10 days of dosing.

• Pregnancy: FDA Category D. Evidence of fetal risk exists; use only if benefit justifies risk.
• Lactation: Excreted in breast milk; possible infant sedation or feeding issues. Use caution.
• Recommendation: Avoid unless necessary; monitor infant if breastfeeding.

• Primary Class: Tricyclic Antidepressant (TCA)
• Subclass: Dibenzazepine derivative
• Other Activity: Functional serotonin-norepinephrine reuptake inhibitor (SNRI-like effects)

• Hypersensitivity to Imipramine or other tricyclic antidepressants
• Recent myocardial infarction (acute phase)
• Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing an MAOI
• Severe liver disease
• Narrow-angle glaucoma
• Untreated urinary retention
• Use in children for depression
• Epilepsy (uncontrolled)

• Suicidality Risk:
  Increased risk of suicidal thinking and behavior in children, adolescents, and young adults. Monitor closely during early treatment.
• Cardiovascular Risk:
  May cause arrhythmias, tachycardia, conduction abnormalities, and orthostatic hypotension. ECG monitoring advised for elderly or those with cardiac disease.
• Anticholinergic Effects:
  Dry mouth, constipation, urinary retention, and blurred vision—caution in elderly and prostatic hypertrophy.
• Seizure Threshold Reduction:
  Use with caution in epileptic patients or with drugs that lower seizure threshold.
• Hepatic Monitoring:
  Periodic liver function testing recommended in long-term use.
• Withdrawal Symptoms:
  Abrupt discontinuation can cause nausea, headache, insomnia, irritability, or malaise. Taper dose gradually.

Major Drug-Drug Interactions:

• MAOIs: Risk of hypertensive crisis or serotonin syndrome; contraindicated
• SSRIs (e.g., fluoxetine, paroxetine): May increase plasma levels and toxicity of Imipramine
• CNS depressants (e.g., alcohol, benzodiazepines): Additive sedative effects
• Antiarrhythmic drugs (e.g., quinidine): Increased cardiotoxicity risk
• CYP2D6 inhibitors: May reduce Imipramine metabolism and increase toxicity

Drug-Food Interactions:

• Alcohol: Potentiates CNS depression and hypotension
• Tyramine-rich foods: Caution when transitioning from MAOIs

Enzyme Systems:

• CYP2D6: Major metabolic pathway; subject to genetic polymorphism
• Poor metabolizers may exhibit higher drug levels

• FDA Black Box Warning Reaffirmed:
  Ongoing emphasis on monitoring for suicidal ideation in younger populations
• Preferred Use in Enuresis Decreased:
  Guidelines now recommend behavioral therapy and desmopressin as first-line; Imipramine is reserved for resistant cases
• Genetic Testing (CYP2D6):
  Recommended in some guidelines to individualize dosing and reduce adverse effects in poor metabolizers
• Depression Treatment Updates:
  TCAs, including Imipramine, are now considered second- or third-line therapies due to side effect profile

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Humidity & Light: Protect from moisture and direct sunlight
• Handling: Keep in tightly closed containers
• Reconstitution: Not applicable (oral tablet or capsule)