Imipramine Hydrochloride

Tricyclic Antidepressant (TCA) Dibenzazepine derivative; non-selective monoamine reuptake inhibitor

Dosage & Administration Guidelines

Species Route Dose Frequency Duration & Clinical Notes
Dog PO 2-5 mg/kg q12h (every 12 hours) Duration: For behavioral disorders: 4-8 weeks; for urinary incontinence: may be long-term.
Notes: Start at lower end of dose range and titrate gradually. For urinary incontinence, may be used in combination with phenylpropanolamine if inadequate response.
Cat PO 2.5-5 mg/cat (approximately 0.5-1 mg/kg) q12-24h Duration: For behavioral disorders: 4-8 weeks; adjust based on response.
Notes: Cats are sensitive to anticholinergic effects; use with caution. Monitor for sedation and constipation.
Horse PO 0.5-1 mg/kg q12h Duration: For narcolepsy: long-term; for behavioral: variable.
Notes: Limited data; use with caution. May cause GI upset.
Cattle Not recommended N/A N/A Duration: N/A
Notes: No established dosage; not indicated.
Small Ruminants Not recommended N/A N/A Duration: N/A
Notes: No established dosage; not indicated.
Rabbit PO 1-2 mg/kg q12-24h Duration: Variable; monitor closely.
Notes: Limited evidence; use with caution due to risk of GI stasis.
Bird/Poultry Not recommended N/A N/A Duration: N/A
Notes: No established dosage; not indicated.
Exotic/Other Not recommended N/A N/A Duration: N/A
Notes: No established dosage; not indicated.

Clinical Indications & Species Uses

General Indications
  • Tricyclic antidepressant used for behavioral disorders and urinary incontinence in small animals.
Dog (Canine)
  • Behavioral disorders: separation anxiety, phobias, compulsive disorders (as adjunctive therapy)
  • Urinary incontinence due to urethral sphincter hypotonus (especially in neutered females)
  • Narcolepsy (off-label)
Cat (Feline)
  • Behavioral disorders: inappropriate urination (idiopathic), anxiety-related disorders (off-label)
  • Urinary incontinence (rarely used, but may be considered)
Horse (Equine)
  • Narcolepsy (off-label)
  • Behavioral disorders (limited evidence)

Pharmacology & Mechanism of Action

Drug Class: Tricyclic Antidepressant (TCA) | Pharmacological Group: Dibenzazepine derivative; non-selective monoamine reuptake inhibitor

Mechanism of Action: Imipramine is a tricyclic antidepressant that primarily inhibits the presynaptic reuptake of norepinephrine and serotonin (5-HT) in the central nervous system, thereby increasing their concentrations in the synaptic cleft. It also has anticholinergic, antihistaminic, and alpha-1 adrenergic blocking properties. In veterinary medicine, its therapeutic effects for behavioral disorders are attributed to enhanced monoaminergic neurotransmission, while its anticholinergic effects are utilized for urinary incontinence by increasing bladder sphincter tone and reducing detrusor contractions.

Pharmacodynamics: Imipramine exerts its effects by blocking the reuptake of norepinephrine and serotonin, leading to enhanced noradrenergic and serotonergic activity. It also blocks histamine H1 receptors, muscarinic acetylcholine receptors, and alpha-1 adrenergic receptors, contributing to its sedative, anticholinergic, and hypotensive effects. In the lower urinary tract, it increases urethral resistance and decreases bladder contractility, which is beneficial for urethral sphincter hypotonus. The onset of therapeutic effect for behavioral conditions may take 2-4 weeks, whereas effects on urinary incontinence may be seen within days.

⚡ Pharmacokinetics Summary

Absorption: Imipramine is well absorbed after oral administration. Peak plasma concentrations occur approximately 2-4 hours after dosing in dogs. Food may delay absorption but does not significantly affect overall bioavailability.
Distribution: Imipramine is widely distributed throughout the body, with high affinity for tissues such as brain, liver, and kidney. It crosses the blood-brain barrier and the placenta, and is distributed into milk. The volume of distribution is large, reflecting extensive tissue binding.
Metabolism: Imipramine undergoes extensive hepatic metabolism, primarily via cytochrome P450 enzymes (CYP2D6 in humans, but similar isoenzymes in animals). It is metabolized to desipramine, which is an active metabolite with similar pharmacological activity. Other metabolites include hydroxylated derivatives that are further conjugated.
Excretion: Imipramine and its metabolites are excreted primarily in the urine (approximately 70%) and feces (approximately 30%). Renal excretion involves both glomerular filtration and active tubular secretion. The elimination half-life is variable among species.
Half-Life: Dog: approximately 2-4 hours for imipramine, but active metabolite desipramine has a longer half-life (up to 8 hours). Cat: approximately 4-6 hours. Horse: approximately 2-3 hours. In humans, half-life is 11-25 hours, but this is not directly applicable to veterinary species.
Bioavailability: Oral bioavailability is approximately 40-50% in dogs due to first-pass metabolism. In other species, bioavailability may vary but is generally moderate.
Protein Binding: Imipramine is highly protein-bound (approximately 80-90%) in plasma, primarily to albumin and alpha-1 acid glycoprotein.

Available Formulations & Strengths

Oral Tablet 10 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg (PO)
Oral Capsule 25 mg, 50 mg, 75 mg, 100 mg, 125 mg, 150 mg (PO)
Injectable Solution (for human use; not commonly used in veterinary) 12.5 mg/mL (1 mL ampules) (IM)

Contraindications & Clinical Warnings

Contraindications:
  • Hypersensitivity to imipramine or other tricyclic antidepressants
  • Concurrent use of monoamine oxidase inhibitors (MAOIs) - risk of severe serotonin syndrome
  • Recent myocardial infarction or cardiac conduction abnormalities
  • Severe hepatic or renal impairment
  • Angle-closure glaucoma (due to anticholinergic effects)
  • Urinary retention or prostatic hypertrophy (due to anticholinergic effects)
Warnings & Clinical Precautions:
  • Use with caution in patients with cardiovascular disease, seizure disorders, or thyroid disease.
  • May cause sedation and anticholinergic effects; monitor for constipation, urinary retention, and dry mouth.
  • In cats, may cause hyperexcitability or agitation in some individuals.
  • Do not discontinue abruptly; taper dose to avoid withdrawal effects.
  • Use with caution in geriatric patients due to increased sensitivity to anticholinergic effects.
  • May lower seizure threshold; use with caution in epileptic patients.
  • Safety in pregnant or lactating animals has not been established; use only when clearly needed.
  • For food animals, observe withdrawal times; extra-label use is prohibited in some countries.

Adverse Effects & Reactions

Common:

  • Sedation
  • Dry mouth
  • Constipation
  • Urinary retention
  • Mydriasis
  • Tachycardia
  • Vomiting
  • Diarrhea

Serious / Severe:

  • Cardiac arrhythmias (e.g., QT prolongation, AV block)
  • Seizures
  • Severe hypotension
  • Hepatotoxicity
  • Serotonin syndrome (when combined with other serotonergic drugs)
  • Bone marrow suppression (rare)

Rare:

  • Agranulocytosis
  • Cholestatic jaundice
  • Skin reactions
  • Photosensitivity
  • Paradoxical aggression or agitation

Key Drug Interactions

Interacting Drug / Class Clinical Effect & Mechanism Severity
Monoamine oxidase inhibitors (MAOIs) Risk of severe serotonin syndrome, hyperthermia, and cardiovascular collapse. High
Selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) Additive serotonergic effects, increased risk of serotonin syndrome. High
Sympathomimetics (e.g., phenylpropanolamine, epinephrine) Increased risk of hypertension and cardiac arrhythmias. High
Anticholinergic drugs (e.g., atropine) Additive anticholinergic effects, leading to severe constipation, urinary retention, and tachycardia. Moderate
Cimetidine Inhibits hepatic metabolism of imipramine, increasing plasma levels and toxicity risk. Moderate
Fluoxetine or other CYP2D6 inhibitors Increased imipramine levels due to enzyme inhibition. Moderate
Anticoagulants (e.g., warfarin) May increase anticoagulant effect due to inhibition of metabolism. Moderate
Tramadol Increased risk of seizures and serotonin syndrome. High

Overdose & Toxicity Management

Signs of Toxicity:

  • Severe anticholinergic effects: agitation, hallucinations, hyperthermia, mydriasis
  • Cardiac toxicity: arrhythmias, QT prolongation, hypotension, cardiac arrest
  • CNS depression: coma, respiratory depression
  • Seizures
  • Vomiting

Emergency Treatment Protocol: Treatment is symptomatic and supportive. Induce emesis if recent ingestion and no contraindications. Administer activated charcoal to reduce absorption. Provide IV fluids for hypotension. Use sodium bicarbonate for cardiac arrhythmias (especially QRS widening). Treat seizures with diazepam or barbiturates. Monitor ECG and vital signs closely. Physostigmine may be used for severe anticholinergic signs but with caution. No specific antidote; supportive care is essential.

Food Animal Withdrawal Times

Imipramine is not approved for use in food animals. Extra-label use in food animals is prohibited in many countries. If used in an emergency, a withdrawal time of at least 30 days for meat and 7 days for milk is recommended, but consult regulatory authorities.

Storage, Handling & Regulatory Information

Storage Temperature: Store at controlled room temperature 20-25°C (68-77°F), excursions permitted between 15-30°C (59-86°F).

Light Sensitivity: Light-sensitive — protect from direct exposure.

Handling & Special Conditions: Protect from light and moisture. Keep in a tightly closed container.

Dispensing Status: Prescription Required (Rx Only)

Approval Status: Imipramine is not FDA-approved for veterinary use; it is used extra-label in animals. It is approved for human use in the US.

Extra-Label (Off-Label) Use: In the US, extra-label use of imipramine in animals is permitted under AMDUCA (Animal Medicinal Drug Use Clarification Act) provided there is a valid veterinarian-client-patient relationship, and no approved animal drug is available. However, extra-label use in food animals is prohibited if the drug is not approved for food animals and may cause residues. In the EU, similar rules apply under Regulation (EC) No 470/2009.

Clinical Pearls & Practice Notes

💡 Clinical Insights: Imipramine is a tricyclic antidepressant used in veterinary medicine primarily for behavioral disorders (e.g., separation anxiety, compulsive behaviors) and for urethral sphincter hypotonus causing urinary incontinence, especially in spayed female dogs. It is often used as an adjunct to behavioral modification. The drug has a slow onset of action for behavioral effects (2-4 weeks), so patience is required. For urinary incontinence, it may be used alone or in combination with phenylpropanolamine. Side effects are common, especially anticholinergic effects like dry mouth, constipation, and urinary retention. Cardiac effects are a concern, so baseline ECG is recommended in animals with pre-existing heart disease. Imipramine should be used with caution in animals with seizure disorders. It is contraindicated with MAOIs and should not be used concurrently with other serotonergic drugs. Dosing should be individualized, and gradual tapering is necessary to avoid withdrawal. In cats, dosing is lower and monitoring is essential. For food animals, imipramine is not approved and extra-label use is restricted. Always consult the latest veterinary drug references for updated information.

References & Literature

  • 📚 Plumb's Veterinary Drug Handbook
  • 📚 Papich Veterinary Pharmacology and Therapeutics
  • 📚 Compendium of Veterinary Products (CVP)