Continuing Education Activity

Imipramine is a medication used in the treatment of depression and anxiety. It is a tertiary amine tricyclic antidepressant. This activity reviews the indications, contraindications, activity, adverse events, and other key elements of imipramine therapy in the clinical setting as continuous monitoring of the drug and the acute management of tricyclic overdose. These factors will be clinically relevant and essential for interprofessional team members in taking care of patients on imipramine therapy.

Objectives:

• Describe common adverse effects associated with imipramine.
• Explain the need for monitoring of imipramine to ensure maintaining the therapeutic level and avoid the toxic effects of imipramine.
• Review the interventions for an imipramine overdose.
• Summarize how collaboration and effective communication among healthcare providers can promote patient care when monitoring the dose of imipramine and prompt treatment in imipramine overdose.

Indications

Imipramine is a tertiary amine tricyclic antidepressant. Tricyclic antidepressants (TCAs) had been approved by the Food and Drug Administration (FDA) as antidepressants in the 1950s. Although it is FDA approved for the treatment of depression, it is a second-line treatment, notably in severe depression with melancholic and atypical features due to its undesirable side effects and its toxicity in overdose. Imipramine is an adjunctive therapy in nocturnal enuresis in children above six years of age. There are other off-label uses of imipramine as in the treatment of chronic neuropathic pain and panic disorder.[1][2][3][4]

Mechanism of Action

Imipramine blocks the reuptake of norepinephrine and serotonin. Since imipramine is a tertiary amine, it has a greater affinity for serotonin, and it has more anticholinergic side effects, which can prove helpful in treating enuresis. Imipramine blocks D-2 receptors. Additionally, imipramine and other tricyclics have different effects on other receptors. It blocks antimuscarinic receptors, thus, producing anticholinergic adverse effects. It also blocks alpha 1 and 2 adrenergic and H1 receptors.[5] 

Administration

Imipramine is available both in tablets and in capsules. The tablets are available in doses of 10, 25, 50 mg, while the capsules are available in doses of 75, 100, 125, 150 mg. Due to the side effects associated with imipramine and with other tricyclic antidepressants, the recommendation is to initiate treatment at a lower dose and then titrate up gradually to higher doses. Some metal ions such as copper, zinc, and magnesium can affect the efficiency of passive and active transport of imipramine.[6][7]

Adverse Effects

Since imipramine acts on various receptors in the body, it can cause adverse effects on some organs and systems. In the central and autonomic nervous system, the antihistaminic effects of imipramine can lead to dizziness, sedation, confusion, delirium, seizures, increased appetite, and weight gain.

The anticholinergic properties of imipramine can produce undesired side effects such as blurred vision, constipation, tachycardia, confusion, dry mouth, urinary retention, delirium, and narrow-angle glaucoma. Therefore, it is crucial to use imipramine cautiously in patients with acute angle glaucoma, paralytic ileus, urinary retention, and benign prostatic hypertrophy. The cardiovascular side effects include cardiac arrhythmia, which is the leading cause of death in tricyclic antidepressant overdose. Other adverse effects include GI upset, mild elevation of liver enzymes, sexual dysfunction, and diaphoresis. TCAs may rarely cause bone marrow suppression. Diaphoresis and orthostatic hypotension are mainly caused by noradrenergic receptor manipulation, while sexual dysfunction is due to serotonergic effects such as impaired arousal and orgasms.

Serotonin syndrome is a life-threatening condition, and it occurs with concurrent use of other serotonergic drugs as SSRI, triptans, tramadol, lithium, St John's wort, and tryptophan. Patients will present with altered mental state, autonomic changes as tachycardia, and neuromuscular changes as tremor, rigidity, and myoclonus. Imipramine can worsen suicidal ideation during the initial period of taking this medication in patients under the age of 24. Imipramine and other antidepressants can lead to the precipitation of a manic or mixed episode in a bipolar patient.[7][8] Therefore, it is essential to obtain pertinent history to rule out bipolar disorder in patients with a history of depression before prescribing imipramine.

Contraindications

Imipramine is contraindicated in hypersensitivity to the drug, especially in cross-reactivity with other dibenzodiazepines, in acute recovery from myocardial infarction, and when used concurrently with MOAI or within 14 days of discontinuing either imipramine or MOAI as this may precipitate hypertensive crisis. Contraindications to imipramine also include its use with linezolid or IV methylene blue as both have MOAI properties.[5]

Monitoring

It is highly recommended to closely monitor patients for their clinical condition, their response to the medication, and during periods of dose adjustment. Family and caregivers should be encouraged to observe their patients and to contact their psychiatrist if needed. The therapeutic index of TCAs is narrow. Therefore, regular drug monitoring is required to ensure the therapeutic blood level and, at the same time to avoid to toxic effects of imipramine. 

Treatment with imipramine and other tricyclics usually requires a duration of around 4 to 5 weeks to elicit a good response. Research has shown that increasing the dose of imipramine to greater than 300ng/mL effectively treated severe depression. However, when the drug level greatly exceeds 300ng/mL, it will be more likely to be associated with significant and serious side effects. Extreme precautions are necessary, especially in a patient with cardiovascular disease, including conduction defects, tachycardia, acute myocardial infarction, and hepatic impairment. When coadministering imipramine with a MOAI, it can lead to fatal hypertensive crisis or seizures. When imipramine is co-ingested with SSRI, it can cause serotonin syndrome.[7][5]

Toxicity

The risk of developing toxicity from imipramine and other tricyclics is greater upon increasing the dose. An overdose of imipramine can result in serious side effects, mainly cardiac dysrhythmia, critical hypotension, convulsions, coma, confusion, hyperactive reflexes, and hypothermia. Imipramine has type 1 antiarrhythmic effects as it blocks the fast sodium channel on the myocardium. Therefore, this will lead to inhibition of depolarization of the heart action potential, which will result in QRS prolongation, which can lead to cardiac arrhythmia.

Acute management must begin with an assessment of airway, breathing, and circulation in addition to ECG monitoring and vital signs. The initial management should primarily focus on the correction of hypoxia and acidosis if present. Treatment with sodium bicarbonate will reverse the fast sodium channel function on the myocardium, which will reverse the cardiotoxicity and will also help in increasing the pH, which can enhance the excretion of TCAs. Therefore, continuous monitoring of imipramine is important to prevent cardiotoxicity and to prevent morbidity and mortality. If patients develop seizures, the recommendation is to use benzodiazepines as first-line therapy. However, dose adjustment is necessary for certain medical conditions as hepatic or renal impairment.[9][10][11]

Enhancing Healthcare Team Outcomes

Patients should receive education about the possible side effects profile associated with imipramine and other tricyclics.; this will help patients make better decisions that fit their health. Before initiating imipramine, it is imperative to discuss with the patient regarding its clinical use and side effects of imipramine and other tricyclic antidepressants. Patient education about warning signs and symptoms that warrant a visit to the emergency department, such as suicidal thoughts, confusion, dizziness, severe palpitations, and vision changes, is vital before initiating therapy as well. Additionally, imipramine should be prescribed within the therapeutic dose with gradual titration as it can be fatal in overdose and require close monitoring. Special precautions merit consideration for anyone on this medication. Parents should be urged to keep the drug in a locked cabinet away from the reach of children.[10] 

Managing imipramine therapy requires the efforts of an interprofessional team that includes clinicians, specialists, mid-level practitioners, pharmacists, and psychology professionals, all collaborating and communicating as a cohesive unit and engaging the patient in their own care. Psychoeducation and good interprofessional communication skills between mental and other health providers and patients are of paramount importance for a better outcome. [Level 5]

Review Questions

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References

1.

Hearn L, Derry S, Phillips T, Moore RA, Wiffen PJ. Imipramine for neuropathic pain in adults. Cochrane Database Syst Rev. 2014 May 19;2014(5):CD010769. [PMC free article: PMC6485593] [PubMed: 24838845]

2.

Caldwell PH, Sureshkumar P, Wong WC. Tricyclic and related drugs for nocturnal enuresis in children. Cochrane Database Syst Rev. 2016 Jan 20;2016(1):CD002117. [PMC free article: PMC8741207] [PubMed: 26789925]

3.

Dean L. Imipramine Therapy and CYP2D6 and CYP2C19 Genotype. In: Pratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Malheiro AJ, editors. Medical Genetics Summaries [Internet]. National Center for Biotechnology Information (US); Bethesda (MD): Mar 23, 2017. [PubMed: 28520379]

4.

Giwa A, Oey E. The return of an old nemesis: Survival after severe tricyclic antidepressant toxicity, a case report. Toxicol Rep. 2018;5:357-362. [PMC free article: PMC5977411] [PubMed: 29854605]

5.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Jan 3, 2018. Desipramine. [PMC free article: PMC547852] [PubMed: 31643558]

6.

Opoka W, Kryczyk A, Krakowska A, Piotrowska J, Gdula-Argasińska J, Kała K, Linek M, Muszyńska B. The evaluation of effect of selected metal ions on the efficiency of passive and active transport of imipramine. Psychiatr Pol. 2019 Oct 30;53(5):1169-1179. [PubMed: 31955193]

7.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Apr 27, 2018. Antidepressant Agents. [PMC free article: PMC547852] [PubMed: 31643899]

8.

LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. National Institute of Diabetes and Digestive and Kidney Diseases; Bethesda (MD): Apr 25, 2018. Imipramine. [PMC free article: PMC547852] [PubMed: 31643220]

9.

Dokken K, Fairley P. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 18, 2022. Sodium Channel Blocker Toxicity. [PubMed: 30521265]

10.

Khalid MM, Waseem M. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jul 17, 2023. Tricyclic Antidepressant Toxicity. [PubMed: 28613681]

11.

Güloglu C, Orak M, Ustündag M, Altunci YA. Analysis of amitriptyline overdose in emergency medicine. Emerg Med J. 2011 Apr;28(4):296-9. [PubMed: 20923818]

Disclosure: Rola Fayez declares no relevant financial relationships with ineligible companies.

Disclosure: Vikas Gupta declares no relevant financial relationships with ineligible companies.