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Imipramine
Imipramine.svg
Imipramine3DanBS.gif
Systematic (IUPAC) name
3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N,N-dimethylpropan-1-amine
Clinical data
Trade names Tofranil
AHFS/Drugs.com monograph
MedlinePlus a682389
Pregnancy cat.
Legal status
Routes Oral
Pharmacokinetic data
Bioavailability 94-96%[1]
Protein binding 86%[2]
Metabolism Hepatic (CYP1A2, CYP2C19, CYP2D6)
Main active metabolite desipramine[2]
Half-life 20 hours[2]
Excretion Renal (80%), Faecal (20%) (mostly as inactive metabolites)[2]
Identifiers
CAS number 50-49-7 YesY
ATC code N06AA02
PubChem CID 3696
IUPHAR ligand 357
DrugBank DB00458
ChemSpider 3568 YesY
UNII OGG85SX4E4 YesY
KEGG D08070 YesY
ChEBI CHEBI:47499 YesY
ChEMBL CHEMBL11 YesY
Chemical data
Formula C19H24N2 
Mol. mass 280.407 g/mol
 YesY (what is this?)  (verify)

Imipramine (G 22355), 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).

It has also been evaluated for use in panic disorder.[3]

Therapeutic uses[edit]

Imipramine is used in the treatment of depression, such as depression associated with agitation or anxiety and has similar efficacy to the antidepressant drug moclobemide.[4] 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.

History[edit]

Imipramine was, in the late 1950s, 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, USA, discussed as one of the first clinicians the effects of imipramine in a group of 46 patients, most of them were 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 classified as ' 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.[5] It is not surprising, therefore, that Imipramine may cause a high rate of manic and hypomanic reactions in hospitalized patients with preexisting bipolar disorder, with one study showing that up to 25% of such patients maintained on Imipramine switched into mania or hypomania.[6] 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. It is not as commonly used today, but is sometimes used to treat major depression as a second-line treatment. 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. Imipramine has the second highest attraction for the serotonin transporter (SERT) in the tricyclic antidepressant class behind clomipramine. This provides a very strong and proportional effect on the blockade of serotonin reuptake. Moderating this effect, however, is imipramine's continual conversion in the body to its metabolite desipramine, which has extremely strong and relatively selective noradrenergic effects. This blend of imipramine and desipramine circulating together within the body provides a powerful one-two punch in simultaneously blockading both serotonin and norepinephrine reuptake.
  • Dopamine (DA): Reuptake and release at D1 and D2 receptors. Similar but less potent than psychostimulants, dopamine agonists, and the atypical antidepressant bupropion on dopaminergic mechanisms (increase in release and blockade of reuptake inhibition). While this effect is much less than the primary effects on NE, SER and ACh, it is nonetheless significant and is partially responsible for the therapeutic benefits of treatment with Imipramine. Enhancement of brain dopamine activity has been implicated in Imipramine's ability to stimulate motor activity and prolong time spent in escape in mice. Regarding dopamine uptake, imipramine is far less potent than most other antidepressants (for example, it has only 5% of the potency of amitriptyline or paroxetine, see the table below).[citation needed]
  • 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). The blockade of cholinergic (muscarine) receptors is known to cause euphoria, potentially contributing to the mood lifting effects of Imipramine as well. Antimuscarinic effect is also responsible for rapid heart rate (tachycardia).
  • 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).
  • 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).
  • Histamine: Imipramine is an antagonist at histamine H1 receptors. This contributes to the acute sedative effect that it has in most people. In turn, its anti-histaminergic and general calming effects take place immediately, and, thus, Imipramine is sometimes prescribed as a sleep aid in low doses.
  • 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.[7][8]
  • μ receptor: Imipramine has been shown to increase the expression of μ-opioid receptors in rat forebrain.[9]

Comparison with other antidepressants[edit]

Binding Profile of popular TCAs towards their cloned human (unless otherwise specified) molecular targets (Ki in nM)[10][11]

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. Those listed in bold text denote life-threatening side effects.[12]

  • Central Nervous System: Dizziness, drowsiness, confusion, seizures, headache, anxiety, tremors, stimulation, weakness, insomnia, nightmares, extrapyramidal symptoms in geriatric patients, increased psychiatric symptoms, paresthesia
  • 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,

Overdose[edit]

The symptoms and the treatment of an imipramine overdose are largely the same as for the other tricyclic antidepressants. Cardinal symptoms are cardiac (tachycardia, widened QRS complex) and neurological disturbances. Any ingestion by children should be considered as serious and potentially fatal.

Synthesis[edit]

Imipramine synthesis:[13][14] U.S. Patent 2,554,736

See also[edit]

References[edit]

  1. ^ Heck, HA; Buttrill, JE Jr; Flynn, NW; Dyer, RL; Anbar, M; Cairns, T; Dighe, S; Cabana, BE (June 1979). "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. 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. ^ Lepola U, Arató M, Zhu Y, Austin C (June 2003). "Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder". J Clin Psychiatry 64 (6): 654–62. doi:10.4088/JCP.v64n0606. PMID 12823079. 
  4. ^ Delini-Stula A, Mikkelsen H, Angst J (October 1995). "Therapeutic efficacy of antidepressants in agitated anxious depression--a meta-analysis of moclobemide studies". J Affect Disord 35 (1–2): 21–30. doi:10.1016/0165-0327(95)00034-K. PMID 8557884. 
  5. ^ Healy, David: The Antidepressant Era, page 211. Harvard University Press, 1997.
  6. ^ Bottlender R, Rudolf D, Strauss A, Möller HJ (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. 
  7. ^ Tsankova NM, Berton O, Renthal W, Kumar A, Neve RL, Nestler EJ (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. 
  8. ^ Krishnan V, Nestler EJ (October 2008). "The molecular neurobiology of depression". Nature 455 (7215): 894–902. Bibcode:2008Natur.455..894K. doi:10.1038/nature07455. PMC 2721780. PMID 18923511. 
  9. ^ de Gandarias, JM; 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. 
  10. ^ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 28]. Chapel Hill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php
  11. ^ Brunton L, Chabner B, Knollman B. Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Twelfth Edition. McGraw Hill Professional; 2010.
  12. ^ Skidmore-Roth, L.(ed.). (2010). Mosby's Nursing Drug Reference (23rd ed.). St. Louis, MO: Mosby Elsevier.
  13. ^ Schindler, W.; h�Fliger, F. (1954). "�ber Derivate des Iminodibenzyls". Helvetica Chimica Acta 37 (2): 472. doi:10.1002/hlca.19540370211.  edit
  14. ^ Schmolka, S. J.; Zimmer, H. (1984). "N-Dimethylaminopropylation in a Solid-Liquid Two Phase System: Synthesis of Chlorpromazine, its Analogs, and Related Compounds". Synthesis 1984: 29. doi:10.1055/s-1984-30719.  edit

External links[edit]


Original courtesy of Wikipedia: http://en.wikipedia.org/wiki/Imipramine — Please support Wikipedia.
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