Imipramine

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Not to be confused with Idanpramine or Prazepine.
Imipramine
Imipramine.svg
Imipramine-3D-balls.png
Clinical data
Trade names Tofranil
AHFS/Drugs.com Monograph
MedlinePlus a682389
Pregnancy
category
  • AU: C
  • US: N (Not classified yet)
Routes of
administration
Oral
ATC code N06AA02 (WHO)
Legal status
Legal status
Pharmacokinetic data
Bioavailability 94-96%[1]
Protein binding 86%[2]
Metabolism Hepatic (CYP1A2, CYP2C19, CYP2D6)
Main active metabolite desipramine[2]
Biological half-life 20 hours[2]
Excretion Renal (80%), Faecal (20%) (mostly as inactive metabolites)[2]
Identifiers
Synonyms G 22355
CAS Number 50-49-7 YesY
PubChem (CID) 3696
IUPHAR/BPS 357
DrugBank DB00458 YesY
ChemSpider 3568 YesY
UNII OGG85SX4E4 YesY
KEGG D08070 YesY
ChEBI CHEBI:47499 YesY
ChEMBL CHEMBL11 YesY
ECHA InfoCard 100.000.039
Chemical and physical data
Formula C19H24N2
Molar mass 280.407 g/mol
3D model (Jmol) Interactive image
  (verify)

Imipramine, sold as Tofranil and also known as melipramine, is a tricyclic antidepressant (TCA) of the dibenzazepine group. Imipramine is mainly used in the treatment of major depression and enuresis (inability to control urination).

Imipramine was discovered in 1951.[3] It has also been evaluated for use in panic disorder.[4]

Therapeutic uses[edit]

Imipramine is used in the treatment of depression, such as depression associated with agitation or anxiety. It is similar in efficacy to the antidepressant drug moclobemide.[5] 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.

History[edit]

In the late 1950s, imipramine was the first tricyclic antidepressant to be developed (by Ciba). At the first international congress of neuro-pharmacology 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 suffered from dizziness. Imipramine was first tried against psychotic disorders such as schizophrenia, but proved insufficient. As an antidepressant, it did well in clinical studies and it is known to work well in even the most severe cases of depression.[6] 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.[7] Such powerful antidepressant properties have made it favorable in the treatment of treatment-resistant depression.

Before the advent of 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 tricyclics. Today it is no longer 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.

Mechanism of action[edit]

Imipramine, a tertiary amine, affects numerous neurotransmitter systems known to be involved in the etiology of depression, anxiety, 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 medicinal action include, but are not limited to, effects on:

  • Serotonin (5-HT): very strong reuptake inhibition.
  • Norepinephrine (NE): strong reuptake inhibition. Desipramine has more affinity to NET than imipramine.
  • Dopamine (DA): Imipramine blocks D2 receptors.[8] Imipramine, and its metabolite desipramine, have no appreciable affinity for the dopamine transporter (8,500 and >10,000 KinM respectively).[9]
  • Acetylcholine (ACh): imipramine is an anticholinergic. Thus, 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. Imipramine is an antagonist at M2 muscarinic acetylcholine receptors (see external links).
  • Epinephrine: imipramine antagonizes adreno-receptors (II), thus sometimes causing increased heart rate (contributed to by other effects as well), orthostatic hypotension, and a general decrease in the responsiveness of the central nervous system (hence, a contribution to its potent anti-anxiety properties).[citation needed]
  • σ Receptor and enkephalinase: Activity on σ-receptors is present, but it is very low (Ki of 520 nM on σ-receptors, see references) and it is about half the power of amitryptiline (300 nM).[citation needed]
  • Histamine: imipramine is an antagonist at 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 promotor, and also reduced expression of hippocampal HDAC5.[10][11]
  • μ Receptor: imipramine has been shown to increase the expression of μ-opioid receptors in rat forebrain.[12]

Comparison with other antidepressants[edit]

Binding Profile of popular TCAs towards their cloned human (unless otherwise specified) molecular targets (Ki in nM)[13][14]

Drug SERT NET DAT α1 α2A D2 H1 M1 M3 5-HT1A 5-HT2A 5-HT2C 5-HT6 5-HT7
imipramine 10.4 51.7 8,500 - 3,100 (Human, Brain) 726 11.0 42 60 >10,000 120 (Rat, Cloned) 120 (Rat, Cloned) 190 (Rat, Cloned) 1,000 (Rat, Cloned)
desipramine 179 2.27 >10,000 130 1,380 (Human, Brain) 1,560 45.6 110 210 >10,000 114 (Rat, Cloned) 496 (Rat, Cloned) - 1,000 (Rat, Cloned)
amitriptyline 3.13 22.4 4,440 24 (Human, Brain) 690 (Human, Brain) 1,460 (Human, Brain) 0.5 14.7 12.8 450 (Human, Brain) 5.60 (Rat, Cortex) 6.15 (Rat, Cloned) 103 114 (Rat, Cloned)
clomipramine 0.21 45.9 2,610 3.2 525 120 31.2 - - >10,000 35.5 64.6 53.8 (Rat, Cloned) 127 (Rat, Cloned)

Metabolism[edit]

Within the body, imipramine is converted to desipramine, another TCA.

Side effects[edit]

Those listed in Italic text below denote common side effects.[15]

See also[edit]

References[edit]

  1. ^ "Bioavailability of imipramine tablets relative to a stable isotope-labelled 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. 
  2. ^ a b c d "PRODUCT INFORMATION TOLERADE® (imipramine hydrochloride)". TGA eBusiness Services. PMIP Pty Ltd. 4 June 2013. Retrieved 16 October 2013. 
  3. ^ Walker, S. R. (2012). Trends and Changes in Drug Research and Development. Springer Science & Business Media. p. 109. ISBN 9789400926592. 
  4. ^ Lepola, U; Arató, M; Zhu, Y; Austin, C (June 2003). "Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder" (PDF). The Journal of Clinical Psychiatry. 64 (6): 654–62. doi:10.4088/JCP.v64n0606. PMID 12823079. 
  5. ^ Delini-Stula, A; Mikkelsen, H; Angst, J (October 1995). "Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies". Journal of Affective Disorders. 35 (1–2): 21–30. doi:10.1016/0165-0327(95)00034-K. PMID 8557884. 
  6. ^ Healy, David (1997). The Antidepressant Era. Harvard University Press. p. 211. 
  7. ^ Bottlender, R; Rudolf, D; Strauss, A; Möller, H. J. (1998). "Antidepressant-associated maniform states in acute treatment of patients with bipolar-I depression". European Archives of Psychiatry and Clinical Neuroscience. 248 (6): 296–300. doi:10.1007/s004060050053. PMID 9928908. 
  8. ^ Smiałowski, A. (1991-05-01). "Dopamine D2 receptor blocking effect of imipramine in the rat hippocampus". Pharmacology, Biochemistry, and Behavior. 39 (1): 105–108. ISSN 0091-3057. PMID 1924491. 
  9. ^ Schulze, David R.; Carroll, F. Ivy; McMahon, Lance R. (2012-08-01). "Interactions between dopamine transporter and cannabinoid receptor ligands in rhesus monkeys". Psychopharmacology. 222 (3): 425–438. doi:10.1007/s00213-012-2661-9. ISSN 0033-3158. PMC 3620032Freely accessible. PMID 22374253. 
  10. ^ Tsankova, N. M.; Berton, O; Renthal, W; Kumar, A; Neve, R. L.; Nestler, E. J. (April 2006). "Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action". Nature Neuroscience. 9 (4): 519–25. doi:10.1038/nn1659. PMID 16501568. 
  11. ^ Krishnan, V; Nestler, E. J. (October 2008). "The molecular neurobiology of depression". Nature. 455 (7215): 894–902. Bibcode:2008Natur.455..894K. doi:10.1038/nature07455. PMC 2721780Freely accessible. PMID 18923511. 
  12. ^ De Gandarias, J. M.; Echevarria, E; Acebes, I; Silio, M; Casis, L (July 1998). "Effects of imipramine administration on mu-opioid receptor immunostaining in the rat forebrain". Arzneimittel-Forschung. 48 (7): 717–9. PMID 9706370. 
  13. ^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 28]. Chapel Hill (NC): University of North Carolina. 1998–2013. Available from: "Archived copy". Archived from the original on November 8, 2013. Retrieved July 5, 2013. 
  14. ^ Brunton L, Chabner B, Knollman B, Goodman and Gilman’s (2010). The Pharmacological Basis of Therapeutics (Twelfth ed.). McGraw Hill Professional. 
  15. ^ Skidmore-Roth, L., ed. (2010). Mosby's Nursing Drug Reference (23rd ed.). St. Louis, MO: Mosby Elsevier. 

External links[edit]