Background

Imipramine or Tofranil is a TCS (tricyclic antidepressant). It is used to treat depression, enuresis, chronic pain syndrome, and panic attacks. This drug inhibits alpha-adrenergic, serotonergic, dopaminergic, GABA-ergic, muscarinic, and histaminergic receptors. It inhibits Na channels and retake of serotonin and norepinephrine. It is an anticholinergic agent. It is effective against urinary incontinence.

Tai has found that desmopressin was preferred instead of imipramine to treat nocturnal enuresis. There are no side effects of desmopressin, and imipramine side effects are low. In one study, about 4 out of 71 children who are treated with imipramine had side effects and 125 children who are treated with desmopressin had no side effects. The response rate is about 81.7% and 77.6 % for imipramine and desmopressin.

The dosage of imipramine is 10 mg, 25 mg, 50 mg tablets, 57 mg, 100mg, 125 mg, and 150 mg caplets. The dosage prescription can vary. The maintenance dosage for outpatients is 50 to 150 mg orally at bedtime, avoid dosage of 300 mg in 24 hours. The starting dosage for inpatients is 100 mg for 24 hours in several doses. Over many weeks, the dosage is subsequently increases to 300 mg in 24 hours. The dosage to treat depression in pediatrics is 1.5 to 5 mg/kg in 24 hours in several dosages as 4 times/day for every day, to treat enuresis, the dosage of imipramine for patients whose age is above 6 years is 10 to 25 mg orally for every night at bedtime, and it can be elevated by 10 to 25 mg for every 1 to 2 weeks to a maximum dosage of 50 mg in patients whose age is 6 years to 12 years and 75 mg for patients whose is above 12 years. The effects of drug needs 1 to 3 weeks to happen.

Toxicity of imipramine can occur at therapeutic levels during the starting phase of drug treatment. The most common side effects of anticholinergic properties like:

Tachycardia

Xerostomia

Urinary retention

Tremor

Constipation

Blurred vision

Postural hypotension

Sedation

Weight gain

Delay in cardiac conduction, particularly elevated QRS, QT, and PR intervals

Imipramine may lead to slate grey pigment in sun exposed area of the body because of the precipitation of drug metabolite melanin complex. It is carried out by oxygen-free radical. This drug can affect the function of hepatic and morphology, which can cause hepatitis and cholestasis. Toxicity of cardiac is linked with a serum drug level, which is increased to 1000 ng/mL.

Fekete has found that dose related level of imipramine is high in adolescence and children than adult in blood. It is same with the other antidepressants like fluvoxamine, clomipramine, and citalopram.

In patients who have imipramine toxicity, treatments like hypertonic saline or, NaHCO3 or sodium bicarbonate is used. Lidocaine is used for ventricular tachydysrhythmias. Class IC, class III, and class IA antiarrhythmics must be avoided in imipramine toxicity.

Imipramine is not used in patients who have recent congestive heart failure, narrow angle glaucoma, myocardial infarction, any history of cardiac arrhythmias or angina or who take MAO inhibitors.

Indications/Applications

This test is used in many clinical settings to monitor the treatment.

To assess the therapeutic drug monitoring (TDM)

To monitor the toxicity: Patients may have symptoms of toxicity like confusion, cardiac arrhythmias, signs of overdose, seizures, and agitation. TCS may lead to life-threatening cardiac effects.

To adjust the dosage: It is used to adjust the dosage of imipramine in patients who have liver impairment, elder patients, or those who are taking multiple medications. Pharmacokinetics differences may change the drug levels and need modifications in dosage.

To evaluate the drug interactions

To manage the overdose: TCS may lead to severe cardiovascular and neurological diseases. Drug level measurement may adjust the proper treatment.

Reference Range

The normal range of desipramine and imipramine is 150 to 350 ng/mL.

Minimum toxic level: 300 ng/mL

Toxic level: 1000 ng/mL

Lethal level: 2 gm

Imipramine (parent medication) has a terminal elimination ½ life is 10 to 16 hours.

Desimpramine (active metabolite) has a terminal elimination ½ life is 12 to 30 hours.

Volume of distribution: 10 to 30 L/kg

Interpretation

Normal level of imipramine indicate that the patients receive the effective dose and there is minimum risk of toxicity. Low levels of imipramine (<150 ng/mL) indicate underdosing, rapid metabolism of drug or poor adhesion to drug.

Toxic level of imipramine have a concern of toxicity which can lead to cardiovascular abnormalities like tachycardia, arrhythmias, or longer QT interval, CNS symptoms like confusion, agitation, seizures, severe anticholinergic effects like urinary retention, blurred vision, dry mouth.

Imipramine level may change by drugs which induce or inhibit the CYP2C19 or CYP2C19 enzymes. Administration with CYP2D6 inhibitors like quinidine, paroxetine, or fluoxetine can elevate the levels of imipramine and risk of toxicity. Inducers like rifampin, carbamazepine can reduce the levels of imipramine and efficacy.

Collection And Panels

Sample type: Serum

Sample collection container: Red top tube (no gel)

Sample collection method: Venipuncture

Sample volume: 3 mL

Sample minimum volume: 1 mL

Considerations: When imipramine test is carried out in patients who are taking medication on regular basis, the sample must be taken immediately before the next dosage of imipramine. Serum must be separated from RBCs in 2 hours of collection of blood. Drug which is released from RBC may lead to false increased levels of drug.

Modifying factors:

Smoking the cigarette reduces the serum level of imipramine. This drug is metabolized by CYP450 enzyme 1A2. Escitalopram, chlorpheniramine, thioridazine, clomipramine, propranolol, norfluoxetine, and citalopram may lead to false increased levels of imipramine. Sertraline has exactly different effects.

References

https://www.ncbi.nlm.nih.gov/books/NBK557656/

https://pubmed.ncbi.nlm.nih.gov/3624505/