Imipramine, sold under the brand name Tofranil, among others, is a tricyclic antidepressant (TCA) mainly used in the treatment of depression.It is also effective in treating anxiety and panic disorder.Imipramine is taken by mouth.
Common side effects of imipramine include dry mouth, drowsiness, dizziness, low blood pressure, rapid heart rate, urinary retention, and electrocardiogram changes.Overdose of the medication can result in death.Imipramine appears to work by increasing levels of serotonin and norepinephrine and by blocking certain serotonin, adrenergic, histamine, and cholinergicreceptors.
Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and TCAs other than amitriptyline (which, at least in the U.K., is prescribed comparatively as frequently as SSRIs) have decreased in prescription frequency with the rise of SSRIs—which have fewer inherent side effects and are far safer in overdose.Regardless of its caveats, imipramine retains importance in psychopharmacology and pediatrics (e.g., with childhood enuresis).[5][6]
Medical uses
Imipramine is primarily used for the treatment of depression and certain anxiety disorders, including acute post-traumatic stress reactions. A significant amount of research regarding its efficacy on acute post-traumatic stress in children and adolescents has focused on trauma resulting from burn-injuries.[7][8][9] Although evidence for its efficacy in the treatment of chronic post-traumatic stress disorder appears to be less robust,[10] it remains a viable treatment.[11] Here, it may share a similar efficacy with the monoamine oxidase inhibitorphenelzine.
Caution is needed in prescribing imipramine (and its commercially available metabolite, desipramine) in children and youth/adolescents (whether they suffer with, e.g., bed-wetting, recurrent panic attacks, acute trauma or, in the case of desipramine
Contraindications
Combining it with alcohol consumption may cause more drowsiness, necessitating greater caution when drinking.[21] It may be unsafe during pregnancy.[1]
Many MAOIs are known to have serious interactions with imipramine. It is often contraindicated during their use or in the two weeks following their discontinuation. This category includes medications such as isocarboxazid, linezolid, methylene blue, phenelzine, selegiline, moclobemide, procarbazine, rasagiline, safinamide, and tranylcypromine.[21][22]
Side effects
These side effects can be contributed to the multiple receptors that imipramine targets such as serotonin, norepinephrine, dopamine, acetylcholine, epinephrine, histamine. Those listed in italics below denote common side effects, separated by the organ systems that are affected.[23] Some side effects may be beneficial in some cases, e.g. reduction of hyperactive gag reflex; reduced random or physical strain-linked urinary leakage.
Like other tricyclic antidepressants, imipramine has many medication interactions. Many MAOIs have serious interactions with this medication. Other categories of medications that may interact with imipramine include blood thinners, antihistamines, muscle relaxants, sleeping pills, thyroid medications, and tranquilizers.Some medications used for various conditions such as high blood pressure, mental illness, nausea, Parkinson's disease, asthma, colds, or allergies.[21]
Certain medications increase the risk of serotonin syndrome, including selective serotonin reuptake inhibitors (SSRIs), St. John's Wort, and drugs such as ecstasy. Other prescription drugs decrease the body's ability to eliminate imipramine. These include barbiturates, some antiarrhythmic medications, some antiepileptic drugs, and certain HIV drugs (protease inhibitors).Others may cause changes in the heart rhythm, such as QT prolongation.[22]
Alcohol and tobacco
Pharmacology
Pharmacodynamics
Imipramine affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, attention-deficit hyperactivity disorder (ADHD), enuresis and numerous other mental and physical conditions. Imipramine is similar in structure to some muscle relaxants, and has a significant analgesic effect and, thus, is very useful in some pain conditions.
The mechanisms of imipramine's actions include, but are not limited to, effects on:
Serotonin: very strong reuptake inhibition. Imipramine is a tertiary TCA, and is a potent inhibitor of serotonin reuptake, and to a greater extent than secondary amine TCAs such as nortriptyline and despiramine.[48]
Norepinephrine: strong reuptake inhibition. Desipramine has more affinity to norepinephrine transporter than imipramine.
Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[60] Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine).[60][61] Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine.[62][63] Other tertiary amine TCAs include amitriptyline,
History
The parent compound of imipramine, 10,11-dihydro-5H-dibenz [ b,f ] azepine (dibenzazepine), was first synthesized in 1899, but no pharmacological assessment of this compound or any substitutedderivatives was undertaken until the late 1940s.[66][67][68] Imipramine was first synthesized in 1951, as an antihistamine.[69][70] The antipsychotic effects of chlorpromazine were discovered in 1952,[71] and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia
Society and culture
Generic names
Imipramine is the English and French generic name of the drug and its INN, BAN, and DCF, while imipramine hydrochloride is its USAN, USP, BANM, and JAN.[79][80][81][82] Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum.[80][82]
3.Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: increasing the power of bioavailability tests Journal of Pharmacokinetics and Biopharmaceutics, June 1979
In the treatment of depression, it has demonstrated similar efficacy to the MAOI moclobemide.[16] It has also been used to treat nocturnal enuresis because of its ability to shorten the time of delta wave stage sleep, where wetting occurs.[17] In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions.[18][19] It is also used for separation anxiety in dogs and cats.Blood levels between 150 and 250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy.[20]
Acetylcholine: imipramine is, to a certain extent, an antimuscarinic, specifically a relative antagonist of the muscarinic acetylcholine receptors. The attendant side-effects (e.g., blurry vision, dry mouth, constipation), however, are somewhat less common with imipramine than amitriptyline and protriptyline, which tend to cause antimuscarinic side-effects more often. All-in-all, however, it is prescribed with caution to the elderly and with extreme caution to those with psychosis, as the general brain activity enhancement in combination with the "dementing" effects of anticholinergics increases the potential of imipramine to cause hallucinations, confusion and delirium in this population. "Anti-cholinergic" side-effects, including urinary hesitancy/retention, may be treated/reversed with bethanechol and/or other acetylcholine-agonists.[51][52][53]Bethanechol may also be able to alleviate the sexual-dysfunction symptoms which may occur in the context of tricyclic-antidepressant treatment.[54][55][56]
Epinephrine: imipramine antagonizes adrenergic receptors, thus sometimes causing orthostatic hypotension.
Sigma receptor: activity on sigma receptors is present, but it is very weak (Ki = 520 nM) and it is about half that of amitriptyline (Ki = 300 nM).
Histamine: imipramine is an antagonist of the histamine H1 receptors.
BDNF: BDNF is implicated in neurogenesis in the hippocampus, and studies suggest that depressed patients have decreased levels of BDNF and reduced hippocampal neurogenesis. It is not clear how neurogenesis restores mood, as ablation of hippocampal neurogenesis in murine models do not show anxiety related or depression related behaviours. Chronic imipramine administration results in increased histone acetylation (which is associated with transcriptional activation and decondensed chromatin) at the hippocampal BDNF promoter, and also reduced expression of hippocampal HDAC5.[57][58]
Pharmacokinetics
Imipramine has a varied absolute oral bioavailability ranging from 22% to 77%, leading to significant variability in pharmacokinetics. While the drug has rapid and complete absorption after oral administration, much of the drug is affected by first pass metabolism. Food has no effect on absorption, peak drug concentration, or time to peak drug concentration.[59]
Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.[59]
of imipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine and its
free base
form has a
chemical formula
of C19H24N2 with a
molecular weight
of 280.407 g/mol.
The drug is used commercially mostly as the hydrochloridesalt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used.
The CAS Registry Number of the free base is 50-49-7, of the hydrochloride is 113-52-0, and of the embonate is 10075-24-8.
In the late 1950s, imipramine was the first TCA to be developed (by Ciba).At the first international congress of neuropharmacology in Rome, September 1958 Dr Freyhan from the University of Pennsylvania discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them diagnosed as "depressive psychosis". The patients were selected for this study based on symptoms such as depressive apathy, kinetic retardation and feelings of hopelessness and despair. In 30% of all patients, he reported optimal results, and in around 20%, failure. The side effects noted were atropine-like, and most patients experienced dizziness. Imipramine was first tried for treating psychotic disorders such as schizophrenia, but proved ineffective. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression.[77] It is not surprising, therefore, that imipramine may cause a high rate of manic and hypomanic reactions in hospitalized patients with pre-existing bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania.[78] Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.
Before the advent of selective serotonin reuptake inhibitors (SSRIs), its sometimes intolerable side-effect profile was considered more tolerable. Therefore, it became extensively used as a standard antidepressant and later served as a prototypical drug for the development of the later-released TCAs. Since SSRIs are superior in terms of inherent side-effect tolerability (although probably inferior in terms of actual efficacy), it has, as of the 1990s, no longer been used as commonly, but is sometimes still prescribed as a second-line treatment for treating major depression. It has also seen limited use in the treatment of migraines, ADHD, and post-concussive syndrome.Imipramine has additional indications for the treatment of panic attacks, chronic pain, and Kleine-Levin syndrome.In pediatric patients, it is relatively frequently used to treat pavor nocturnus and nocturnal enuresis.
Imipramine is marketed throughout the world mainly under the brand name Tofranil.[80][82] Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.[80][82][83]
Availability
Imipramine is available for medical use widely throughout the world, including in the United States, the United Kingdom, elsewhere in Europe, India, Brazil, South Africa, Australia, and New Zealand.[82]
Prescription trends
Between 1998 and 2017, along with amitriptyline, imipramine was the most commonly prescribed first antidepressant for children aged 5-11 years in England.[84]
5.Behavioral, cognitive, and pharmacological treatments of panic disorder with agoraphobia: critique and synthesis Journal of Consulting and Clinical Psychology, February 1991^
6.History repeats itself: pharmacodynamic trends in the treatment of anxiety disorders Current Pharmaceutical Design, 2005^
7.Imipramine treatment in pediatric burn patients with symptoms of acute stress disorder: a pilot study Journal of the American Academy of Child and Adolescent Psychiatry, July 1999^
8.Early treatment of acute stress disorder in children with major burn injury Pediatric Critical Care Medicine, November 2005^
9.Treating thermally injured children suffering symptoms of acute stress with imipramine and fluoxetine: a randomized, double-blind study Burns, November 2008^
10.Platelet imipramine binding in patients with posttraumatic stress disorder before and after phenelzine treatment Psychiatry Research, July 1996^
11.Pharmacological prevention and early treatment of post-traumatic stress disorder and acute stress disorder: a systematic review and meta-analysis Translational Psychiatry, December 2019^
12.Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment Frontiers in Psychiatry, 2020^
13.A systematic review of the efficacy and safety of desipramine for treating ADHD Current Drug Safety, July 2013^
14.Are one or two dangerous? Tricyclic antidepressant exposure in toddlers The Journal of Emergency Medicine, February 2005^
15.Imipramine and enuresis: never forget its dangers Pediatrics, June 1982^
16.Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies Journal of Affective Disorders, October 1995^
23.Mosby's Nursing Drug Reference Mosby Elsevier, 2010^
24.PDSP Ki Database Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill and the United States National Institute of Mental Health, retrieved 7 May 2022^
25.PDSP Ki Database Psychoactive Drug Screening Program (PDSP), University of North Carolina at Chapel Hill and the United States National Institute of Mental Health, retrieved 7 May 2022^
26.Pharmacological profile of antidepressants and related compounds at human monoamine transporters European Journal of Pharmacology, December 1997^
27.Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites The Journal of Pharmacology and Experimental Therapeutics, December 1997^
28.Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro European Journal of Pharmacology, December 1986^
29.Screening the receptorome yields validated molecular targets for drug discovery Current Pharmaceutical Design, 2006^
30.Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor Psychopharmacology, August 1996^
31.Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications NIDA Research Monograph, March 1998^
32.'[3H]quipazine' degradation products label 5-HT uptake sites European Journal of Pharmacology, November 1989^
33.Cloning and expression of a novel serotonin receptor with high affinity for tricyclic psychotropic drugs Molecular Pharmacology, March 1993^
34.Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype The Journal of Biological Chemistry, August 1993^
35.The dopamine inhibitor GBR 12909: selectivity and molecular mechanism of action European Journal of Pharmacology, August 1989^
36.Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative Biochemical Pharmacology, December 1986^
37.Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding Cellular and Molecular Neurobiology, August 1999^
38.Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram European Journal of Pharmacology, December 2007^
39.Binding of antidepressants to human brain receptors: focus on newer generation compounds Psychopharmacology, May 1994^
40.Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro The Journal of Pharmacology and Experimental Therapeutics, July 1984^
41.Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics Naunyn-Schmiedeberg's Archives of Pharmacology, February 2012^
42.Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics Biochemical Pharmacology, June 1993^
43.Different interaction between tricyclic antidepressants and mecamylamine with the human alpha3beta4 nicotinic acetylcholine receptor ion channel Neurochemistry International, March 2010^
44.1,3-Di(2-[5-3H]tolyl)guanidine: a selective ligand that labels sigma-type receptors for psychotomimetic opiates and antipsychotic drugs Proceedings of the National Academy of Sciences of the United States of America, November 1986^
45.Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered Human Psychopharmacology, April 2010^
46.Evaluation of sigma (σ) receptors in the antidepressant-like effects of ketamine in vitro and in vivo European Neuropsychopharmacology, April 2012^
47.Inhibition of the current of heterologously expressed HERG potassium channels by imipramine and amitriptyline British Journal of Pharmacology, September 1999^
49.Dopamine D2 receptor blocking effect of imipramine in the rat hippocampus Pharmacology, Biochemistry, and Behavior, May 1991^
50.Interactions between dopamine transporter and cannabinoid receptor ligands in rhesus monkeys Psychopharmacology, August 2012^
51.Muscarinic cholinergic receptor subtype on frog esophageal peptic cells: binding and secretion studies The Journal of Pharmacology and Experimental Therapeutics, September 1988^
52.The use of bethanechol chloride with tricyclic antidepressants The American Journal of Psychiatry, November 1975^
53.Treatment of nortriptyline's side effects in elderly patients: a double-blind study of bethanechol The American Journal of Psychiatry, August 1993^
54.Bethanechol chloride can reverse erectile and ejaculatory dysfunction induced by tricyclic antidepressants and mazindol: case report The Journal of Clinical Psychiatry, April 1986^
55.Reversal by bethanechol of imipramine-induced ejaculatory dysfunction The American Journal of Psychiatry, September 1987^
56.Bethanecol chloride for treatment of clomipramine-induced orgasmic dysfunction in males Revista do Hospital das Clinicas, December 2004^
57.Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action Nature Neuroscience, April 2006^
58.The molecular neurobiology of depression Nature, October 2008^
59.Clinical pharmacokinetics of imipramine and desipramine Clinical Pharmacokinetics, May 1990^
60.Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies Springer Science & Business Media, 15 February 2013^
61.Foye's Principles of Medicinal Chemistry Lippincott Williams & Wilkins, 2008^
62.Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology John Wiley & Sons, 20 September 1994^
63.Metabolism of Drugs and Other Xenobiotics John Wiley & Sons, 23 February 2012^
64.Pharmacology Secrets Elsevier Health Sciences, 2002^
65.Shorter Oxford Textbook of Psychiatry OUP Oxford, 9 August 2012^
66.Antidepressant drugs: imipramine, mianserin and trazodone Comparative Biochemistry and Physiology. C, Comparative Pharmacology and Toxicology, 1987^
67.Pharmacotherapy of mental illness--a historical analysis Progress in Neuro-Psychopharmacology & Biological Psychiatry, May 2001^
68.Synthesis of substituted 10,11-dihydro-5H-dibenz[b,f]azepines; key synthons in syntheses of pharmaceutically active compounds Journal of Heterocyclic Chemistry, 1999^
69.Trends and Changes in Drug Research and Development Springer Science & Business Media, 2012^
70.Histaminergic Neurons: Morphology and Function CRC Press, 22 February 1991^
71.History of the Synapse CRC Press, 21 April 2014^
73.Understanding Depression: Volume 2. Clinical Manifestations, Diagnosis and Treatment Springer, 2 January 2018^
74.The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation? Pharmacology & Therapeutics, October 2018^
75.Seminars in General Adult Psychiatry RCPsych Publications, April 2007^
76.Forensic Toxicology: Controlled Substances and Dangerous Drugs Springer Science & Business Media, 6 December 2012^
78.Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression European Archives of Psychiatry and Clinical Neuroscience, 1998^
84.Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998-2017: A population-based cohort study PLOS Medicine, July 2020^
