Chemistry:Imipramine

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Short description: Antidepressant
Imipramine
Imipramine.svg
Imipramine-3D-balls.png
Clinical data
Trade namesTofranil, Tofranil-PM, others
Other namesMelipramine; G-22355
AHFS/Drugs.comMonograph
MedlinePlusa682389
License data
Pregnancy
category
Routes of
administration		By mouth, intramuscular injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability94–96%[2]
Protein binding86%[3]
MetabolismLiver (CYP1A2, CYP2C19, CYP2D6)[3]
MetabolitesDesipramine[3]
Elimination half-life20 hours[3]
ExcretionKidney (80%), fecal (20%)[3]
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
PDB ligand
Chemical and physical data
FormulaC19H24N2
Molar mass280.415 g·mol−1
3D model (JSmol)
  (verify)

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 cholinergic receptors.

Imipramine was discovered in 1951 and was introduced for medical use in 1957. It was the first TCA to be marketed. Imipramine and the other TCAs (besides amitriptyline, which, at least in the U.K., remains at least just as commonly-prescribed as SSRIs) have decreased in use in recent decades, due to the introduction of the selective serotonin reuptake inhibitors (SSRIs), which, although generally significantly less potent in terms of clinical efficacy per-se, have fewer inherent side effects and are far safer in overdose. Irrespective of these caveats, however, imipramine has an invaluable place in psychiatry and other fields of medicine (e.g., with childhood enuresis), and is, indeed, the “gold standard” for panic disorder.[4][5]

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.[6][7][8] Although evidence for its efficacy in the treatment of chronic post-traumatic stress disorder appears to be less robust,[9] it remains a viable treatment.[10] Here, it may act fairly similarly to monoamine oxidase inhibitor phenelzine.

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, panic attacks, acute trauma or, in the case of desipramine,[11][12] ADHD), owing to possibility of certain side-effects which may be of particular concern in those under a certain age.[13][14]

In the treatment of depression, it has demonstrated similar efficacy to the MAOI moclobemide.[15] 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. In veterinary medicine, imipramine is used with xylazine to induce pharmacologic ejaculation in stallions. Blood levels between 150 and 250 ng/mL of imipramine plus its metabolite desipramine generally correspond to antidepressant efficacy.[16]

Contraindications

Combining it with alcohol consumption may cause more drowsiness, necessitating greater caution when drinking. It may be unsafe during pregnancy.

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.[17]

  • Central nervous system: dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paresthesia
  • Cardiovascular: orthostatic hypotension, ECG changes, tachycardia, hypertension, palpitations, dysrhythmias
  • Eyes, ears, nose and throat: blurred vision, tinnitus, mydriasis
  • Gastrointestinal: dry mouth, nausea, vomiting, paralytic ileus, increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change
  • Genitourinary: urinary retention
  • Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia
  • Skin: rash, urticaria, diaphoresis, pruritus, photosensitivity

Overdose

Interactions

Pharmacology

Pharmacodynamics

Site IMI DSI Species Ref
NET 20–37 0.63–3.5 Human [18][19]
DAT 8,500 3,190 Human [18]
5-HT1A ≥5,800 ≥6,400 Human [20][21][22]
5-HT2A 80–150 115–350 Human [20][22]
5-HT3 970–3,651 ≥2,500 Rodent [21][23]
5-HT6 190–209 ND Rat [24]
5-HT7 >1,000 >1,000 Rat [25]
α1 32 23–130 Human [20][26][19]
α2 3,100 ≥1,379 Human [20][26][19]
β >10,000 ≥1,700 Rat [27][28][29]
D1 >10,000 5,460 Human [21][30]
D2 620–726 3,400 Human [30][21][26]
D3 387 ND Human [21]
H1 7.6–37 60–110 Human [20][26][31]
H2 550 1,550 Human [31]
H3 >100,000 >100,000 Human [31]
H4 24,000 9,550 Human [31]
mACh 46 66–198 Human [20][26]
  M1 42 110 Human [32]
  M2 88 540 Human [32]
  M3 60 210 Human [32]
  M4 112 160 Human [32]
  M5 83 143 Human [32]
α3β4 410–970 ND Human [33]
σ1 332–520 1,990–4,000 Rodent [34][35][36]
σ2 327–2,100 ≥1,611 Rat [37][35][36]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

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. Imipramine hydrochloride | DrugBank Online
  • Norepinephrine: strong reuptake inhibition. Desipramine has more affinity to norepinephrine transporter than imipramine.
  • Dopamine: imipramine blocks D2 receptors.[38] Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively).[39]
  • 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.[40][41][42]

Bethanechol may also be able to alleviate the sexual-dysfunction symptoms which may occur in the context of tricyclic-antidepressant treatment.[43][44][45]

  • 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).[citation needed]
  • 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.[46][47]

Pharmacokinetics

Within the body, imipramine is converted into desipramine (desmethylimipramine) as a metabolite.

Chemistry

Imipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[48] Other dibenzazepine TCAs include desipramine (N-desmethylimipramine), clomipramine (3-chloroimipramine), trimipramine (2′-methylimipramine or β-methylimipramine), and lofepramine (N-(4-chlorobenzoylmethyl)desipramine).[48][49] Imipramine is a tertiary amine TCA, with its side chain-demethylated metabolite desipramine being a secondary amine.[50][51] Other tertiary amine TCAs include amitriptyline, clomipramine, dosulepin (dothiepin), doxepin, and trimipramine.[52][53] The chemical name 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.[54] The drug is used commercially mostly as the hydrochloride salt; the embonate (pamoate) salt is used for intramuscular administration and the free base form is not used.[54][55] 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.[54][55]

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 substituted derivatives was undertaken until the late 1940s.[56][57][58] Imipramine was first synthesized in 1951, as an antihistamine.[59][60] The antipsychotic effects of chlorpromazine were discovered in 1952,[61] and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia.[26][62] The medication was tested in several hundred patients with psychosis, but showed little effectiveness.[63] However, imipramine was serendipitously found to possess antidepressant effects in the mid-1950s following a case report of symptom improvement in a woman with severe depression who had been treated with it.[26][62][64] This was followed by similar observations in other patients and further clinical research.[65][63] Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959.[66] Along with the discovery and introduction of the monoamine oxidase inhibitor iproniazid as an antidepressant around the same time, imipramine resulted in the establishment of monoaminergic drugs as antidepressants.[64][65][63]

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.[67] 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.[68] 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.

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.[54][55][69][70] Its generic name in Spanish and Italian and its DCIT are imipramina, in German is imipramin, and in Latin is imipraminum.[55][70] The embonate salt is known as imipramine pamoate.[55][70]

Brand names

Imipramine is marketed throughout the world mainly under the brand name Tofranil.[55][70] Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.[55][70][71]

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.[70]

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.[72]

References

  1. ↑ "Imipramine Use During Pregnancy". 28 August 2019. https://www.drugs.com/pregnancy/imipramine.html. 
  2. ↑ "Bioavailability of imipramine tablets relative to a stable isotope-labeled internal standard: increasing the power of bioavailability tests". Journal of Pharmacokinetics and Biopharmaceutics 7 (3): 233–248. June 1979. doi:10.1007/BF01060015. PMID 480146. 
  3. ↑ 3.0 3.1 3.2 3.3 3.4 "Product Information Tolerade (imipramine hydrochloride)". TGA eBusiness Services. PMIP Pty Ltd. 4 June 2013. https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-07434-3. 
  4. ↑ Michelson, L.K. and Marchione, K., 1991. Behavioral, cognitive, and pharmacological treatments of panic disorder with agoraphobia: critique and synthesis. Journal of Consulting and Clinical Psychology, 59(1), p.100.
  5. ↑ Schwartz, T.L., Nihalani, N., Simionescu, M. and Hopkins, G., 2005. History repeats itself: pharmacodynamic trends in the treatment of anxiety disorders. Current pharmaceutical design, 11(2), pp.255-263.
  6. ↑ "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 38 (7): 873–882. July 1999. doi:10.1097/00004583-199907000-00018. PMID 10405506. 
  7. ↑ "Early treatment of acute stress disorder in children with major burn injury". Pediatric Critical Care Medicine 6 (6): 676–681. November 2005. doi:10.1097/01.pcc.0000165562.04157.da. PMID 16276335. 
  8. ↑ "Treating thermally injured children suffering symptoms of acute stress with imipramine and fluoxetine: a randomized, double-blind study". Burns 34 (7): 919–928. November 2008. doi:10.1016/j.burns.2008.04.009. PMID 18675519. 
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  19. ↑ 19.0 19.1 19.2 Cite error: Invalid <ref> tag; no text was provided for refs named pmid9400006
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  21. ↑ 21.0 21.1 21.2 21.3 21.4 Cite error: Invalid <ref> tag; no text was provided for refs named pmid9686407
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  62. ↑ 62.0 62.1 "Introduction, History, and Brain Basics". Antidepressants. Infobase Publishing. 2009. p. 15. ISBN 978-1-4381-0192-7. https://books.google.com/books?id=Duy5_XAD-vgC&pg=PA15. 
  63. ↑ 63.0 63.1 63.2 "Ketamine: A Promising Rapid-Acting Antidepressant". Understanding Depression: Volume 2. Clinical Manifestations, Diagnosis and Treatment. Springer. 2 January 2018. p. 224. ISBN 978-981-10-6577-4. https://books.google.com/books?id=rCdFDwAAQBAJ&pg=PA224. 
  64. ↑ 64.0 64.1 "The neurobiology of depression, ketamine and rapid-acting antidepressants: Is it glutamate inhibition or activation?". Pharmacology & Therapeutics 190: 148–158. October 2018. doi:10.1016/j.pharmthera.2018.05.010. PMID 29803629. 
  65. ↑ 65.0 65.1 "Drug Treatment of Depression". Seminars in General Adult Psychiatry. RCPsych Publications. April 2007. p. 71. ISBN 978-1-904671-44-2. https://books.google.com/books?id=6PGzHFuS1xkC&pg=PA71. 
  66. ↑ "Controlled and Non-controlled but Commonly Abused Substances". Forensic Toxicology: Controlled Substances and Dangerous Drugs. Springer Science & Business Media. 6 December 2012. p. 248. ISBN 978-1-4684-3444-6. https://books.google.com/books?id=szDnBwAAQBAJ&pg=PA248. 
  67. ↑ The Antidepressant Era. Harvard University Press. 1997. p. 211. ISBN 9780674039575. https://archive.org/details/antidepressanter00heal. 
  68. ↑ "Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression". European Archives of Psychiatry and Clinical Neuroscience 248 (6): 296–300. 1998. doi:10.1007/s004060050053. PMID 9928908. 
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  70. ↑ 70.0 70.1 70.2 70.3 70.4 70.5 "Imipramine Uses, Side Effects & Warnings". https://www.drugs.com/mtm/imipramine.html. 
  71. ↑ Handbook of Essential Psychopharmacology. American Psychiatric Publishing. 2 April 2007. p. 79. ISBN 978-1-58562-660-1. https://books.google.com/books?id=5XCKY-s6OVIC&pg=PA79. 
  72. ↑ "Incidence and prevalence of primary care antidepressant prescribing in children and young people in England, 1998-2017: A population-based cohort study". PLOS Medicine 17 (7): e1003215. July 2020. doi:10.1371/journal.pmed.1003215. PMID 32697803. 

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