indication

For the relief of symptoms of depression and as temporary adjunctive therapy in reducing enuresis in children aged 6 years and older. May also be used to manage panic disorders, with or without agoraphobia, as a second line agent in ADHD, management of eating disorders, for short-term management of acute depressive episodes in bipolar disorder and schizophrenia, and for symptomatic treatment of postherpetic neuralgia.

pharmacology

Imipramine is a tricyclic antidepressant with general pharmacological properties similar to those of structurally related tricyclic antidepressant drugs such as amitriptyline and doxepin. A tertiary amine, imipramine inhibits the reuptake of serotonin more so than most secondary amine tricyclics, meaning that it blocks the reuptake of neurotransmitters serotonin and noradrenaline almost equally. With chronic use, imipramine also down-regulates cerebral cortical β-adrenergic receptors and sensitizes post-synaptic sertonergic receptors, which also contributes to increased serotonergic transmission. It takes approximately 2 - 4 weeks for antidepressants effects to occur. The onset of action may be longer, up to 8 weeks, in some individuals. It is also effective in migraine prophylaxis, but not in abortion of acute migraine attack.

mechanism of action

Imipramine works by inhibiting the neuronal reuptake of the neurotransmitters norepinephrine and serotonin. It binds the sodium-dependent serotonin transporter and sodium-dependent norepinephrine transporter preventing or reducing the reuptake of norepinephrine and serotonin by nerve cells. Depression has been linked to a lack of stimulation of the post-synaptic neuron by norepinephrine and serotonin. Slowing the reuptake of these neurotransmitters increases their concentration in the synaptic cleft, which is thought to contribute to relieving symptoms of depression. In addition to acutely inhibiting neurotransmitter re-uptake, imipramine causes down-regulation of cerebral cortical beta-adrenergic receptors and sensitization of post-synaptic serotonergic receptors with chronic use. This leads to enhanced serotonergic transmission.

toxicity

Oral, rat LD₅₀: 355 to 682 mg/kg. Toxic signs proceed progressively from depression, irregular respiration and ataxia to convulsions and death. Antagonism of the histamine H₁ and α₁ receptors can lead to sedation and hypotension. Antimuscarinic and anticholinergic side effects such as blurred vision, dry mouth, constipation and urine retention may occur. Cardiotoxicity may occur with high doses of imipramine. Cardiovascular side effects in postural hypotension, tachycardia, hypertension, ECG changes and congestive heart failure. Psychotoxic effects include impaired memory and delirium. Induction of hypomanic or manic episodes may occur in patients with a history of bipolar disorder. Withdrawal symptoms include GI disturbances (e.g. nausea, vomiting, abdominal pain, diarrhea), anxiety, insomnia, nervousness, headache and malaise.

biotransformation

Exclusively metabolized by the liver. Imipramine is converted in the liver by various CYP isoenzymes (e.g. CYP1A2, CYP2D6, CYP3A4, CYP2C9) to active metabolites desipramine and 2-hydroxydesipramine.

absorption

Rapidly and well absorbed after oral administration. Bioavailability is approximately 43%. Peak plasma concentrations usually attained 1 - 2 hours following oral administration. Absorption is unaffected by food.

half life

Imipramine - 8-20 hours; Desipramine (active metabolite) - up to 125 hours

route of elimination

Approximately 40% of an orally administered dose is eliminated in urine within 24 hours, 70% in 72 hours. Small amounts are eliminated in feces via the biliary elimination.

drug interactions

Altretamine: Risk of severe hypotension

Artemether: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Atazanavir: Atazanavir may increase the effect and toxicity of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if atazanavir if initiated, discontinued or dose changed.

Butabarbital: Barbiturates like butabarbital may increase the metabolism of tricyclic antidepressants like imipramine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Butalbital: Barbiturates such as butalbital may increase the metabolism of tricyclic antidepressants such as imipramine. Monitor for decreased therapeutic effects of tricyclic antidepressants if a barbiturate is initiated/dose increased, or increased effects if a barbiturate is discontinued/dose decreased. The tricyclic antidepressant dosage will likely need to be increased during concomitant barbiturate therapy, and reduced upon barbiturate discontinuation.

Carbamazepine: Carbamazepine may decrease the serum concentration of the tricyclic antidepressant, imipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if carbamazepine is initiated, discontinued or dose changed.

Cimetidine: Cimetidine may increase the effect of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if cimetidine is initiated, discontinued or dose changed.

Cisapride: Increased risk of cardiotoxicity and arrhythmias

Clonidine: The tricyclic antidepressant, imipramine, decreases the effect of clonidine.

Desvenlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Dihydroquinidine barbiturate: Dihydroquinidine barbiturate increases the effect of the tricyclic antidepressant, imipramine.

Dobutamine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of dobutamine.

Donepezil: Possible antagonism of action

Dopamine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of dopamine.

Duloxetine: Possible increase in the levels of this agent when used with duloxetine

Ephedra: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of ephedra.

Ephedrine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of ephedrine.

Epinephrine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of epinephrine.

Fenoterol: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of fenoterol.

Fluconazole: Fluconazole may increase the effect and toxicity of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Additive QTc-prolonging effects may also occur. Monitor for changes in the therapeutic and adverse effects of imipramine if fluconazole is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Fluoxetine: The SSRI, fluoxetine, may increase the serum concentration of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of imipramine if fluoxetine is initiated, discontinued or dose changed.

Fluvoxamine: The SSRI, fluvoxamine, may increase the serum concentration of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Additive modulation of serotonin activity also increases the risk of serotonin syndrome. Monitor for development of serotonin syndrome during concomitant therapy. Monitor for changes in the therapeutic and adverse effects of imipramine if fluvoxamine is initiated, discontinued or dose changed.

Galantamine: Possible antagonism of action

Grepafloxacin: Increased risk of cardiotoxicity and arrhythmias

Guanethidine: The tricyclic antidepressant, imipramine, may increase the sympathomimetic effect of guanethidine.

Isocarboxazid: Possibility of severe adverse effects

Isoproterenol: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of isoproterenol.

Ketoconazole: Ketoconazole, a moderate CYP2D6 inhibitor, may increase the serum concentration of imipramine by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if ketoconazole is initiated, discontinued or dose changed.

Lumefantrine: Additive QTc-prolongation may occur. Concomitant therapy should be avoided.

Mephentermine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of mephentermine.

Mesoridazine: Increased risk of cardiotoxicity and arrhythmias

Metaraminol: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of metaraminol.

Methoxamine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of methoxamine.

Moclobemide: Possible severe adverse reaction with this combination

Norepinephrine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of norepinephrine.

Orciprenaline: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of orciprenaline.

Phenelzine: Possibility of severe adverse effects

Phenylephrine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of phenylephrine.

Phenylpropanolamine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of phenylpropanolamine.

Pirbuterol: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of pirbuterol.

Procaterol: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of procaterol.

Pseudoephedrine: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of pseudoephedrine.

Quinidine: Additive QTc-prolonging effects may occur. Quinidine may also increase the serum concentration of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if quinidine is initiated, discontinued or dose changed. Monitor for the development of torsades de pointes during concomitant therapy.

Quinidine barbiturate: Quinidine barbiturate increases the effect of tricyclic antidepressant, imipramine.

Rasagiline: Possibility of severe adverse effects

Rifabutin: The rifamycin, rifabutin, may decrease the effect of the tricyclic antidepressant, imipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if rifabutin is initiated, discontinued or dose changed.

Rifampin: The rifamycin, rifampin, may decrease the effect of the tricyclic antidepressant, imipramine, by increasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if rifampin is initiated, discontinued or dose changed.

Ritonavir: Ritonavir may increase the effect and toxicity of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if ritonavir if initiated, discontinued or dose changed.

Rivastigmine: Possible antagonism of action

Salbutamol: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of salbutamol.

Sibutramine: Increased risk of CNS adverse effects

Sparfloxacin: Increased risk of cardiotoxicity and arrhythmias

Tacrine: The therapeutic effects of the central acetylcholinesterase inhibitor, Tacrine, and/or the anticholinergic, Imipramine, may be reduced due to antagonism. The interaction may be beneficial when the anticholinergic action is a side effect. Monitor for decreased efficacy of both agents.

Tacrolimus: Additive QTc-prolongation may occur increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Tamoxifen: Imipramine may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Consider alternate therapy.

Tamsulosin: Imipramine, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Imipramine is initiated, discontinued, or dose changed.

Terbinafine: Terbinafine may increase the effect and toxicity of the tricyclic antidepressant, imipramine, by decreasing its metabolism. Monitor for changes in the therapeutic and adverse effects of imipramine if terbinafine is initiated, discontinued or dose changed.

Terbutaline: The tricyclic antidepressant, imipramine, increases the sympathomimetic effect of terbutaline.

Terfenadine: Increased risk of cardiotoxicity and arrhythmias

Thioridazine: Increased risk of cardiotoxicity and arrhythmias

Thiothixene: May cause additive QTc-prolonging effects. Increased risk of ventricular arrhythmias. Consider alternate therapy. Thorough risk:benefit assessment is required prior to co-administration.

Ticlopidine: Ticlopidine may decrease the metabolism and clearance of Imipramine. Consider alternate therapy or monitor for adverse/toxic effects of Imipramine if Ticlopidine is initiated, discontinued or dose changed.

Toremifene: Additive QTc-prolongation may occur, increasing the risk of serious ventricular arrhythmias. Consider alternate therapy. A thorough risk:benefit assessment is required prior to co-administration.

Tramadol: Tramadol increases the risk of serotonin syndrome and seizures. Imipramine may decrease the effect of Tramadol by decreasing active metabolite production.

Tranylcypromine: Increased risk of serotonin syndrome. Concomitant therapy should be avoided. A significant washout period, dependent on the half-lives of the agents, should be employed between therapies.

Trazodone: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Trimethobenzamide: Trimethobenzamide and Imipramine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Trimipramine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome. QTc-prolongation may also occur, increasing the risk of serious ventricular arrhythmias. Concomitant therapy should be used with caution.

Triprolidine: Triprolidine and Imipramine, two anticholinergics, may cause additive anticholinergic effects and enhance their adverse/toxic effects. Additive CNS depressant effects may also occur. Monitor for enhanced anticholinergic and CNS depressant effects.

Trospium: Trospium and Imipramine, two anticholinergics, may cause additive anticholinergic effects and enhanced adverse/toxic effects. Monitor for enhanced anticholinergic effects.

Venlafaxine: Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.

Voriconazole: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Vorinostat: Additive QTc prolongation may occur. Consider alternate therapy or monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).

Ziprasidone: Additive QTc-prolonging effects may increase the risk of severe arrhythmias. Concomitant therapy is contraindicated.

Zolmitriptan: Use of two serotonin modulators, such as zolmitriptan and imipramine, increases the risk of serotonin syndrome. Consider alternate therapy or monitor for serotonin syndrome during concomitant therapy.

Zuclopenthixol: Additive QTc prolongation may occur. Consider alternate therapy or use caution and monitor for QTc prolongation as this can lead to Torsade de Pointes (TdP).