Imipramine

Source: Wikipedia, the free encyclopedia.
Imipramine
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%[3]
Protein binding86%[4]
MetabolismLiver (CYP1A2, CYP2C19, CYP2D6)[4]
MetabolitesDesipramine[4]
Elimination half-life20 hours[4]
ExcretionKidney (80%), fecal (20%)[4]
Identifiers
  • 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
JSmol)
  • CN(C)CCCN1c2ccccc2CCc2ccccc21
  • InChI=1S/C19H24N2/c1-20(2)14-7-15-21-18-10-5-3-8-16(18)12-13-17-9-4-6-11-19(17)21/h3-6,8-11H,7,12-15H2,1-2H3 checkY
  • Key:BCGWQEUPMDMJNV-UHFFFAOYSA-N checkY
  (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

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 considered the "gold standard" for panic disorder.[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 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,[12][13] ADHD), owing to possibility of certain side-effects which may be of particular concern in those under a certain age.[14][15]

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. 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.[17]

Contraindications

Combining it with

drowsiness, necessitating greater caution when drinking.[18] 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.[18][19]

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.[20]

  • 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,
    paralytic ileus
    , increased appetite, cramps, epigastric distress, jaundice, hepatitis, stomatitis, constipation, taste change
  • Genitourinary: urinary retention
  • Hematological: agranulocytosis, thrombocytopenia, eosinophilia, leukopenia
  • Skin: rash,
    pruritus
    , photosensitivity

Overdose

Main articles: Tricyclic antidepressant § Overdose, and Tricyclic antidepressant overdose

Interactions

Main article: Tricyclic antidepressant § Interactions

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

allergies.[18]

Certain medications increase the risk of

QT prolongation.[19]

Alcohol and tobacco may interact with imipramine. Tobacco may decrease the medication's effectiveness.[18]

Pharmacology

Pharmacodynamics

See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Imipramine (and metabolite)[21][22]
Site IMI DSITooltip Desipramine Species Ref
SERTTooltip Serotonin transporter 1.3–1.4 17.6–163 Human [23][24]
NETTooltip Norepinephrine transporter 20–37 0.63–3.5 Human [23][24]
DATTooltip Dopamine transporter 8,500 3,190 Human [23]
5-HT1A ≥5,800 ≥6,400 Human [25][26][27]
5-HT2A 80–150 115–350 Human [25][27]
5-HT2C 120 244–748 Human/rat [28][29][26]
5-HT3 970–3,651 ≥2,500 Rodent [26][30]
5-HT6 190–209 ND Rat [31]
5-HT7 >1,000 >1,000 Rat [32]
α1 32 23–130 Human [25][33][24]
α2 3,100 ≥1,379 Human [25][33][24]
β
 >10,000 ≥1,700 Rat [34][35][36]
D1
 >10,000 5,460 Human [26][37]
D2
 620–726 3,400 Human [37][26][33]
D3
 387 ND Human [26]
H1 7.6–37 60–110 Human [25][33][38]
H2 550 1,550 Human [38]
H3 >100,000 >100,000 Human [38]
H4 24,000 9,550 Human [38]
mAChTooltip Muscarinic acetylcholine receptor 46 66–198 Human [25][33]
  M1 42 110 Human [39]
  M2 88 540 Human [39]
  M3 60 210 Human [39]
  M4 112 160 Human [39]
  M5 83 143 Human [39]
α3β4 410–970 ND Human [40]
σ1 332–520 1,990–4,000 Rodent [41][42][43]
σ2 327–2,100 ≥1,611 Rat [21][42][43]
hERG
Tooltip human Ether-à-go-go-Related Gene		 3,400 ND Human [44]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Imipramine affects numerous

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.[45]
  • Norepinephrine: strong reuptake inhibition. Desipramine has more affinity to norepinephrine transporter than imipramine.
  • D2 receptors.[46] Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (Ki = 8,500 and >10,000 nM, respectively).[47]
  • 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.[48][49][50]

Bethanechol may also be able to alleviate the sexual-dysfunction symptoms which may occur in the context of tricyclic-antidepressant treatment.[51][52][53]

  • 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]
  • 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.[54][55]

Pharmacokinetics

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

Chemistry

Imipramine is a

embonate (pamoate) salt is used for intramuscular administration and the free base form is not used.[62][63] 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.[62][63]

History

The

derivatives was undertaken until the late 1940s.[64][65][66] Imipramine was first synthesized in 1951, as an antihistamine.[67][68] The antipsychotic effects of chlorpromazine were discovered in 1952,[69] and imipramine was then developed and studied as an antipsychotic for use in patients with schizophrenia.[33][70] The medication was tested in several hundred patients with psychosis, but showed little effectiveness.[71] 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.[33][70][72] This was followed by similar observations in other patients and further clinical research.[73][71] Subsequently, imipramine was introduced for the treatment of depression in Europe in 1958 and in the United States in 1959.[74] 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.[72][73][71]

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.[75] 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.[76] Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression
.

Before the advent of

pavor nocturnus and nocturnal enuresis
.

Society and culture

Generic names

Imipramine is the English and French

Latin is imipraminum.[63][78] The embonate salt is known as imipramine pamoate.[63][78]

Brand names

Imipramine is marketed throughout the world mainly under the brand name Tofranil.[63][78] Imipramine pamoate is marketed under the brand name Tofranil-PM for intramuscular injection.[63][78][79]

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.[78]

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.[80]

See also

References

  1. ^ a b "Imipramine Use During Pregnancy". Drugs.com. 28 August 2019. Retrieved 7 February 2020.
  2. ^ Anvisa (2023-03-31). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 2023-04-04). Archived from the original on 2023-08-03. Retrieved 2023-08-16.
  3. S2CID 23232584
    .
  4. ^ a b c d e "Product Information Tolerade (imipramine hydrochloride)". TGA eBusiness Services. PMIP Pty Ltd. 4 June 2013. Archived from the original on 10 December 2019. Retrieved 16 October 2013.
  5. ^ 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.
  6. ^ 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.
  7. PMID 10405506
    .
  8. S2CID 43261789
    .
  9. PMID 18675519
    .
  10. S2CID 11314379
    .
  11. PMID 31819037
    .
  12. PMID 32982805
    .
  13. PMID 23914752
    .
  14. PMID 15707813
    .
  15. S2CID 29104331
    .
  16. PMID 8557884
    .
  17. PMID 2683251
    .
  18. ^ a b c d "Imipramine: MedlinePlus Drug Information". medlineplus.gov. Retrieved 2024-04-01.
  19. ^ a b "Imipramine Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing - WebMD". www.webmd.com. Retrieved 2024-04-01.
  20. ^ Skidmore-Roth L, ed. (2010). Mosby's Nursing Drug Reference (23rd ed.). St. Louis, MO: Mosby Elsevier.
  21. ^ a b Roth BL, Driscol J. "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.
  22. ^ Roth BL, Driscol J. "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.
  23. ^
    PMID 9537821
    .
  24. ^
    PMID 9400006
    .
  25. ^
    S2CID 21236268
    .
  26. ^
    PMID 9686407
    .
  27. ^
    PMID 3816971
    .
  28. PMID 16712488
    .
  29. S2CID 24889381
    .
  30. PMID 2533080
    .
  31. PMID 7680751
    .
  32. PMID 8394362
    .
  33. ^
    PMID 6086881
    .
  34. PMID 2530094
    .
  35. PMID 3790168
    .
  36. S2CID 19490821
    .
  37. ^
    PMID 17850785
    .
  38. ^
    S2CID 14274150
    .
  39. ^
    PMID 8100134
    .
  40. S2CID 29461221
    .
  41. PMID 2877462
    .
  42. ^
    S2CID 26491662
    .
  43. ^
    S2CID 24494428
    .
  44. PMID 10510461
    .
  45. ^ Imipramine hydrochloride | DrugBank Online
  46. S2CID 36818141
    .
  47. PMID 22374253
    .
  48. PMID 2901489
    .
  49. PMID 1166898
    .
  50. PMID 8101048
    .
  51. PMID 3957884
    .
  52. PMID 3631333
    .
  53. PMID 15654489
    .
  54. S2CID 21547891
    .
  55. PMID 18923511
    .
  56. ^
    ISBN 978-94-007-5805-6
    .
  57. ISBN 978-0-7817-6879-5
    .
  58. ISBN 978-0-471-95052-3
    .
  59. ISBN 978-3-527-64632-6
    .
  60. ISBN 1-56053-470-2
    .
  61. ISBN 978-0-19-162675-3
    .
  62. ^
    ISBN 978-1-4757-2085-3
    .
  63. ^
    ISBN 978-3-88763-075-1
    .
  64. PMID 2882911
    .
  65. S2CID 20630716
    .
  66. ISSN 0022-152X
    .
  67. ISBN 9789400926592
    .
  68. ISBN 978-0-8493-6425-9
    .
  69. ISBN 978-1-4822-8417-1
    .
  70. ^
    ISBN 978-1-4381-0192-7
    .
  71. ^
    ISBN 978-981-10-6577-4
    .
  72. ^
    PMID 29803629
    .
  73. ^
    ISBN 978-1-904671-44-2
    .
  74. ISBN 978-1-4684-3444-6
    .
  75. ISBN 9780674039575
    .
  76. S2CID 25542287
    .
  77. ISBN 978-94-011-4439-1
    .
  78. ^ a b c d e f "Imipramine Uses, Side Effects & Warnings". Drugs.com.
  79. ISBN 978-1-58562-660-1
    .
  80. PMID 32697803
    .

Further reading