Imipramine

Overview

Imipramine is a tricyclic antidepressant primarily used in dogs and cats for the management of urinary incontinence, narcolepsy, and tricyclic-responsive behavioral disorders. It may also be useful as an adjunctive treatment for chronic pain. Clinical effects may take several weeks to become apparent, and the dose should be tapered gradually when discontinuing therapy.

Mechanism of Action (MOA): Imipramine and its active metabolite, desipramine, inhibit the neuronal reuptake of serotonin and norepinephrine, increasing neurotransmitter concentrations. In addition, imipramine has sedative, central and peripheral anticholinergic, alpha-1 adrenergic receptor antagonist, and histamine H1 receptor antagonist activities. Its antienuretic effect is thought to be primarily related to its anticholinergic properties.

Indications

Imipramine is primarily used in dogs and cats for urinary disorders, neurologic conditions, behavioral disorders, and as an adjunctive analgesic.

• Urinary incontinence: Management of urethral incompetence; in dogs, it may be of use if other medical therapy fails, especially if detrusor hyperreflexia is also suspected.
• Narcolepsy: Adjunctive treatment of narcolepsy.
• Behavioral disorders: Management of tricyclic-responsive behavioral disorders.
• Chronic pain: Adjunctive treatment of chronic pain.

Dosage (Reference)

Dog

Dosage recommendations in dogs vary according to the clinical indication. All reported uses are extra-label.

Cat

Published dosage recommendations in cats are limited. All reported uses are extra-label.

Warnings & Precautions

Imipramine should be used cautiously in patients with conditions that may increase the risk of adverse neurologic, gastrointestinal, urinary, cardiovascular, or ophthalmic effects. Gradual discontinuation is recommended to reduce the risk of withdrawal signs.

• Hypersensitivity: Contraindicated in patients with a known hypersensitivity to imipramine or any other tricyclic antidepressant.
• Monoamine oxidase inhibitors (MAOIs): Concomitant use, or administration within 14 days before or after MAOI therapy, is generally contraindicated.
• Seizure disorders: Use with caution, as imipramine may lower the seizure threshold; one reference lists a history of seizures as a contraindication.
• Anticholinergic effects: Use cautiously in animals with decreased gastrointestinal motility, urinary retention, narrow-angle glaucoma, or increased intraocular pressure; one reference lists glaucoma and a history of urinary retention as contraindications.
• Cardiovascular disease: Use with caution, particularly in patients with cardiac rhythm disturbances.
• Thyroid, renal, or hepatic disease: Use with caution in affected patients; one reference lists severe liver disease as a contraindication.
• Discontinuation: Taper the dose gradually over 2–3 weeks when discontinuing treatment to minimize the risk of withdrawal signs.
• Young animals: Use with caution in young animals.
• Pregnancy and lactation: Imipramine crosses the placenta and is excreted into milk; because safety has not been established in animals, it should only be used when the maternal benefits outweigh the potential risks to offspring.

Drug Interactions

The following interactions have been reported or are theoretical. Concurrent use is not necessarily contraindicated unless otherwise stated, but additional monitoring or dose adjustment may be required.

• Alpha-2 adrenergic agonists (e.g., clonidine, dexmedetomidine, xylazine): May increase the risk of CNS and respiratory depression, hypertension, and bradycardia. Tricyclic antidepressants may also reduce the antihypertensive effects of alpha-2 agonists; use cautiously.
• Antihypertensive agents (e.g., amlodipine, enalapril, telmisartan): Increased risk of hypotension.
• Albuterol: May increase the risk of cardiotoxicity.
• Alprazolam: May increase plasma concentrations of imipramine.
• Anticholinergic agents (e.g., atropine, glycopyrrolate, oxybutynin): Additive anticholinergic effects; use cautiously.
• Antihistamines (e.g., cetirizine, chlorpheniramine, diphenhydramine, hydroxyzine): May increase CNS depression and anticholinergic effects. Avoid the combination or monitor for sedation, tachycardia, ileus, mydriasis, or constipation.
• Azole antifungals (e.g., itraconazole, ketoconazole): Increased risk of QT interval prolongation.
• Cimetidine: May inhibit imipramine metabolism and increase the risk of toxicity; one reference says imipramine should not be used with drugs metabolized by cytochrome P450 2D6, including cimetidine.
• CNS depressants (e.g., cannabidiol, diazepam, methocarbamol, pregabalin): Additive CNS depression; use cautiously.
• Cyclobenzaprine or dextromethorphan: Increased risk of serotonin syndrome.
• Cyproheptadine: May antagonize the serotonergic effects of tricyclic antidepressants.
• Flumazenil: In animals with suspected tricyclic antidepressant overdose, may increase the risk of seizures and arrhythmias.
• Metoclopramide: May increase the risk of extrapyramidal reactions or neuroleptic malignant syndrome. This combination is considered contraindicated in humans.
• Mirtazapine: May increase the risk of constipation, urinary retention, CNS depression, and serotonin syndrome.
• Monoamine oxidase inhibitors (e.g., amitraz, linezolid, possibly selegiline): Concurrent use within 14 days is generally contraindicated because of the risk of serotonin syndrome.
• NSAIDs (e.g., carprofen, meloxicam): May increase the risk of bleeding.
• Opioids (e.g., buprenorphine, butorphanol, fentanyl, methadone, morphine, tramadol): May increase the risk of urinary retention, constipation, paralytic ileus, CNS and respiratory depression, and serotonin syndrome.
• Phenobarbital or rifampin: May decrease tricyclic antidepressant blood concentrations.
• Phenothiazines (e.g., acepromazine): May increase the risk of cardiotoxicity.
• QT-prolonging agents (e.g., amiodarone, cisapride, procainamide, quinidine, sotalol): Increased risk of QT interval prolongation and tricyclic antidepressant adverse effects.
• Selective serotonin reuptake inhibitors (SSRIs; e.g., fluoxetine, paroxetine, sertraline): Increased risk of serotonin syndrome; avoid concurrent use.
• Sympathomimetic agents (e.g., epinephrine, phenylpropanolamine): May increase the risk of cardiac effects (arrhythmias, hypertension) and hyperpyrexia.
• Thyroid agents (e.g., levothyroxine): May increase the risk of cardiac arrhythmias.
• Trazodone and other serotonergic agents: Generally avoid because of the risk of serotonin syndrome; one reference says trazodone may be considered in exceptional cases with careful monitoring for serotonin syndrome.

Side Effects & Overdose

Side Effects

Most adverse effects of imipramine are associated with its anticholinergic and sedative properties, although multiple organ systems may also be affected.

• Anticholinergic effects: Dry mouth, constipation, tachycardia, hyperexcitability, and tremors.
• CNS effects: Sedation, CNS stimulation, and seizures.
• Cardiovascular: Cardiac dysrhythmias.
• Hematologic: Bone marrow suppression.
• Gastrointestinal: Diarrhea and vomiting.
• Endocrine: Glycemic changes and hyponatremia; total and free T4 concentrations may decrease in dogs.
• Renal: Delayed micturition.

Overdose

Tricyclic antidepressant overdose can be life-threatening and requires prompt treatment.

• Oral LD₅₀ (dogs): 100–215 mg/kg.
• Clinical signs: Arrhythmias, cardiorespiratory collapse, seizures, CNS depression, and coma.
• Management: Perform standard decontamination measures when appropriate; induce emesis only within 15 minutes of exposure and not in a patient already showing clinical signs, and keep asymptomatic patients under observation in the clinic for at least 6 hours.
• IV lipid emulsion: Has been used successfully in humans and may be beneficial in veterinary patients; a 20% emulsion is given at 1.5 mL/kg IV as a bolus followed by 0.25 mL/kg/min for 1 hour, and can be repeated in 4–6 hours if the serum is not lipemic and the response is poor.
• Sodium bicarbonate: Used to maintain blood pH at 7.55; if acid-base status is not being monitored, start with 2–3 mEq/kg IV over 15–30 minutes in a symptomatic patient.
• Drugs to avoid: Do not use atropine (it worsens the anticholinergic effects), trazodone (it can cause serotonin syndrome when given concurrently), magnesium sulfate as a cathartic (it can cause magnesium toxicity when GI motility is reduced) or beta-blockers for tachycardia (they can worsen hypotension).

Key Notes

• Delayed response: Clinical improvement may require several weeks before the full therapeutic effect is observed.
• Long-term therapy: Treatment should be continued long enough to adequately assess the patient’s response before considering dose adjustments or alternative therapy.
• Individual variation: Response to imipramine may vary considerably among patients; therapy should be individualized.
• Behavioral disorders: Imipramine is generally reserved for selected cases when a tricyclic antidepressant is considered appropriate.
• Monitoring: Obtain a CBC, serum chemistry profile, urinalysis and thyroid testing at baseline, 1 month after starting and yearly thereafter, and a baseline ECG; monitor heart rate and rhythm.