Imipramine

Usage

• Imipramine is primarily prescribed for the treatment of various forms of depression, including major depressive disorder, and nocturnal enuresis (bedwetting) in children. Off-label uses include the management of panic disorder, attention-deficit/hyperactivity disorder (ADHD), chronic and neuropathic pain (including diabetic neuropathy), and post-traumatic stress disorder (PTSD).
• Pharmacological Classification: Tricyclic Antidepressant (TCA)
• Mechanism of Action: Imipramine primarily inhibits the reuptake of norepinephrine and serotonin in the synaptic cleft, increasing their concentration and enhancing neurotransmission. It also exhibits anticholinergic, antihistaminic, and alpha-adrenolytic properties, although these are not its primary therapeutic actions.

Alternate Names

• International Nonproprietary Name (INN): Imipramine
• Brand Names: Tofranil, Tofranil-PM, Pr-Imipramine, JAMP-Imipramine

How It Works

• Pharmacodynamics: Imipramine enhances serotonergic and noradrenergic neurotransmission by inhibiting their reuptake in the presynaptic neuron. The increase in these neurotransmitters within the synaptic cleft is thought to be responsible for its antidepressant effect. Its anticholinergic effects can lead to dry mouth, blurred vision, constipation, and urinary retention.
• Pharmacokinetics:
  • Absorption: Imipramine is well-absorbed after oral administration.
  • Metabolism: Extensively metabolized in the liver, primarily by CYP2D6 and CYP2C19 enzymes, to its active metabolite, desipramine. Genetic polymorphisms in these enzymes can affect drug levels and efficacy.
  • Elimination: Primarily excreted in urine as metabolites. The elimination half-life is variable, ranging from 9 to 25 hours.
• Mode of Action: Binds to presynaptic reuptake transporters for serotonin and norepinephrine, inhibiting their reuptake into the neuron. This increases the concentration of these neurotransmitters in the synaptic cleft. Imipramine also exhibits some receptor-binding activity, including antagonism of histamine H1 receptors, muscarinic acetylcholine receptors, and alpha-adrenergic receptors.
• Elimination Pathways: Hepatic metabolism via CYP2D6 and CYP2C19, followed by renal excretion.

Dosage

Standard Dosage

Adults (Depression):

• Outpatients: Initially, 75 mg orally per day, increased gradually to 150-200 mg/day as needed. Maximum dose: 200 mg/day. Doses may be given in divided doses or as a single dose at bedtime.
• Hospitalized Patients: Initially, 100-150 mg orally per day, increased gradually to 200 mg/day. If no response after two weeks, the dose can be further increased to 250-300 mg/day (maximum). May be given in divided doses or as a single bedtime dose.
• Maintenance: 50-100 mg orally per day.

Children (Enuresis):

• 6 years and older: Initially, 25 mg orally per day 1 hour before bedtime. If needed, the dose can be increased weekly in increments of 25 mg. Maximum dose: 2.5 mg/kg/day or the maximum dose for the age group, whichever is less.
• Younger than 6 years: Not recommended.
• Maximum treatment duration for enuresis: 3 months.

Special Cases:

• Elderly Patients: Initially, 10 mg orally per day, gradually increased to 30-50 mg/day. Maximum: 100 mg/day.
• Patients with Renal Impairment: Use with caution. Data limited.
• Patients with Hepatic Dysfunction: Use with caution. Data limited; contraindicated in severe impairment.
• Patients with Comorbid Conditions: Close monitoring is necessary in patients with cardiovascular disease, seizure disorders, glaucoma, urinary retention, or those receiving other medications.

Clinical Use Cases

• Imipramine does not have standard dosage guidelines specifically for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations. In such clinical settings, the drug is generally not indicated or only used cautiously when the benefits clearly outweigh the risks.

Dosage Adjustments

• Renal/Hepatic Impairment: Exercise caution. Adjust dose based on individual patient response.
• Metabolic Disorders/Genetic Polymorphisms: Consider CYP2D6 and CYP2C19 polymorphisms. Reduce dose in poor metabolizers. Therapeutic drug monitoring may be beneficial.

Side Effects

Common Side Effects:

• Dry mouth, blurred vision, constipation, urinary retention, drowsiness, dizziness, headache, nausea, weight gain, tremor.

Rare but Serious Side Effects:

• Seizures, cardiac arrhythmias, orthostatic hypotension, serotonin syndrome, neuroleptic malignant syndrome, agranulocytosis, jaundice.

Long-Term Effects:

• Tardive dyskinesia (rare).

Adverse Drug Reactions (ADR):

• Serotonin syndrome, neuroleptic malignant syndrome, severe cardiac arrhythmias, agranulocytosis.

Contraindications

• Hypersensitivity to imipramine or other TCAs.
• Recent myocardial infarction.
• Concomitant or recent use of MAOIs (within 14 days).
• Severe hepatic impairment.

Drug Interactions

• MAOIs: Risk of hypertensive crisis, seizures, or death.
• CYP2D6 and CYP2C19 inhibitors or inducers: Can alter imipramine levels.
• CNS depressants (alcohol, benzodiazepines): Additive sedative effects.
• Anticholinergics: Additive anticholinergic effects.
• QT-prolonging drugs: Increased risk of QT prolongation and torsades de pointes.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: C (older categorization system). Weigh risks and benefits. Limited human data; potential for fetal harm.
• Breastfeeding: Imipramine is excreted in breast milk. Neonatal side effects are possible. Consider alternative safer options or monitor infant closely.

Drug Profile Summary

• Mechanism of Action: Inhibits norepinephrine and serotonin reuptake.
• Side Effects: Dry mouth, blurred vision, constipation, drowsiness, dizziness. Serious: cardiac arrhythmias, seizures, serotonin syndrome.
• Contraindications: Hypersensitivity, recent MI, concomitant MAOI use, severe hepatic impairment.
• Drug Interactions: MAOIs, CYP450 inhibitors/inducers, CNS depressants.
• Pregnancy & Breastfeeding: Use with caution; weigh risks and benefits.
• Dosage: Varies based on indication and patient population. See detailed dosage guidelines.
• Monitoring Parameters: Blood pressure, heart rate, ECG, mental status, liver function tests, complete blood count.

Popular Combinations

• It is not common practice to combine imipramine with other antidepressants. Generally, combination with other drugs is not recommended unless it is specifically indicated and under strict monitoring by a doctor.

Precautions

• General Precautions: Careful monitoring of cardiovascular and mental status, especially in elderly patients.
• Specific Populations: Use cautiously in patients with cardiovascular disease, seizure disorders, urinary retention, glaucoma, or other medical conditions. Closely monitor infants exposed via breastfeeding.
• Lifestyle Considerations: Avoid alcohol, limit activities requiring alertness (driving, operating machinery) until response to treatment is known.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Imipramine?

A: The dosage varies depending on the age of the patient and the condition being treated. For adults with depression, the starting dose is typically 75 mg per day, gradually increased to 150-200 mg/day. For children with enuresis, the starting dose is 25 mg at bedtime. Elderly patients should start at a lower dose (10 mg/day) and increase gradually.

Q2: What are the common side effects of Imipramine?

A: Common side effects include dry mouth, blurred vision, constipation, urinary retention, drowsiness, dizziness, and headache.

Q3: What are the serious side effects of Imipramine?

A: Serious side effects, although rare, include seizures, cardiac arrhythmias, orthostatic hypotension, and serotonin syndrome. Immediate medical attention is required if these occur.

Q4: What are the contraindications for Imipramine?

A: Imipramine is contraindicated in patients with a hypersensitivity to the drug, recent myocardial infarction, concomitant MAOI use, or severe hepatic impairment.

Q5: What are the drug interactions associated with Imipramine?

A: Imipramine interacts with MAOIs (risk of hypertensive crisis), CYP450 inhibitors/inducers (altered drug levels), CNS depressants (increased sedation), and anticholinergics (additive effects).

Q6: Can Imipramine be used during pregnancy and breastfeeding?

A: Imipramine should be used with caution during pregnancy and breastfeeding. The risks and benefits should be carefully weighed. The drug is excreted in breast milk, potentially causing adverse effects in infants.

Q7: How long does it take for Imipramine to start working for depression?

A: The antidepressant effects of Imipramine may not be fully apparent for 2-4 weeks, even at an optimal dose.

Q8: What should patients know about taking Imipramine?

A: Patients should be advised about potential side effects, drug interactions, and the importance of adherence to prescribed dosage. They should avoid alcohol and activities requiring alertness until their response to the medication is established. Report any unusual symptoms to their doctor immediately.

Q9: What are the symptoms of Imipramine overdose?

A: Symptoms of overdose can include confusion, agitation, hallucinations, seizures, cardiac arrhythmias, severe hypotension, and coma.

Q10: How is an Imipramine overdose treated?

A: Treatment is symptomatic and supportive. There’s no specific antidote. Management focuses on stabilizing vital signs and preventing further absorption of the drug.