Desipramine

Not to be confused with depramine.
Desipramine
Skeletal formula of desipramine
Ball-and-stick model of the desipramine molecule
Clinical data
Trade namesNorpramin, Pertofrane, others
Other namesDesmethylimipramine; Norimipramine; EX-4355; G-35020; JB-8181; NSC-114901[1][2][3]
AHFS/Drugs.comMonograph
MedlinePlusa682387
Routes of
administration		Oral, intramuscular injection
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability60–70%[6]
Protein binding91%[6]
MetabolismLiver (CYP2D6)[7]
Elimination half-life12–30 hours[6]
ExcretionUrine (70%), feces[6]
Identifiers
  • 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.000.037 Edit this at Wikidata
Chemical and physical data
FormulaC18H22N2
Molar mass266.388 g·mol−1
3D model (JSmol)
  • c1cc3c(cc1)CCc2c(cccc2)N3CCCNC
  • InChI=1S/C18H22N2/c1-19-13-6-14-20-17-9-4-2-7-15(17)11-12-16-8-3-5-10-18(16)20/h2-5,7-10,19H,6,11-14H2,1H3 checkY
  • Key:HCYAFALTSJYZDH-UHFFFAOYSA-N checkY
  (verify)

Desipramine, sold under the brand name Norpramin among others, is a tricyclic antidepressant (TCA) used in the treatment of depression.[8] It acts as a relatively selective norepinephrine reuptake inhibitor, though it does also have other activities such as weak serotonin reuptake inhibitory, α1-blocking, antihistamine, and anticholinergic effects. The drug is not considered a first-line treatment for depression since the introduction of selective serotonin reuptake inhibitor (SSRI) antidepressants, which have fewer side effects and are safer in overdose.

Medical uses

Desipramine is primarily used for the treatment of depression.[8] It may also be useful to treat symptoms of attention-deficit hyperactivity disorder (ADHD).[9] Evidence of benefit is only in the short term, and with concerns of side effects its overall usefulness is not clear.[10] Desipramine at very low doses is also used to help reduce the pain associated with functional dyspepsia.[11] It has also been tried, albeit with little evidence of effectiveness, in the treatment of cocaine dependence.[12] Evidence for usefulness in neuropathic pain is also poor.[13]

Side effects

Desipramine tends to be less sedating than other TCAs and tends to produce fewer anticholinergic effects such as dry mouth, constipation, urinary retention, blurred vision, and cognitive or memory impairments.[14]

Overdose

Main article: Tricyclic antidepressant overdose

Desipramine is particularly toxic in cases of overdose, compared to other antidepressants.[15] Any overdose or suspected overdose of desipramine is considered to be a medical emergency and can result in death without prompt medical intervention.

Pharmacology

Pharmacodynamics

See also: Pharmacology of antidepressants and Tricyclic antidepressant § Binding profiles
Desipramine[16]
Site Ki (nM) Species Ref
SERTTooltip Serotonin transporter 17.6–163 Human [17][18]
NETTooltip Norepinephrine transporter 0.63–3.5 Human [17][18]
DATTooltip Dopamine transporter 3,190 Human [17]
5-HT1A ≥6,400 Human [19][20]
5-HT2A 115–350 Human [19][20]
5-HT2C 244–748 Rat [21][22]
5-HT3 ≥2,500 Rodent [22][23]
5-HT7 >1,000 Rat [24]
α1 23–130 Human [19][25][18]
α2 ≥1,379 Human [19][25][18]
β ≥1,700 Rat [26][27]
Cav2.2 410 Human [28]
D1 5,460 Human [29]
D2 3,400 Human [19][25]
H1 60–110 Human [19][25][30]
H2 1,550 Human [30]
H3 >100,000 Human [30]
H4 9,550 Human [30]
mAChTooltip Muscarinic acetylcholine receptor 66–198 Human [19][25]
  M1 110 Human [31]
  M2 540 Human [31]
  M3 210 Human [31]
  M4 160 Human [31]
  M5 143 Human [31]
σ1 1,990–4,000 Rodent [32][33]
σ2 ≥1,611 Rat [16][33]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Desipramine is a very potent and relatively selective norepinephrine reuptake inhibitor (NRI), which is thought to enhance noradrenergic neurotransmission.[34][35] Based on one study, it has the highest affinity for the norepinephrine transporter (NET) of any other TCA,[17] and is said to be the most noradrenergic[36] and the most selective for the NET of the TCAs.[34] The observed effectiveness of desipramine in the treatment of ADHD was the basis for the development of the selective NRI atomoxetine and its use in ADHD.[34]

Desipramine has the weakest antihistamine and anticholinergic effects of the TCAs.[37][36][38] It tends to be slightly activating/stimulating rather than sedating, unlike most others TCAs.[36] Whereas other TCAs are useful for treating insomnia, desipramine can cause insomnia as a side effect due to its activating properties.[36] The drug is also not associated with weight gain, in contrast to many other TCAs.[36] Secondary amine TCAs like desipramine and nortriptyline have a lower risk of orthostatic hypotension than other TCAs,[39][40] although desipramine can still cause moderate orthostatic hypotension.[41]

Pharmacokinetics

Desipramine is the major metabolite of imipramine and lofepramine.[42]

Chemistry

Desipramine is a tricyclic compound, specifically a dibenzazepine, and possesses three rings fused together with a side chain attached in its chemical structure.[43] Other dibenzazepine TCAs include imipramine (N-methyldesipramine), clomipramine, trimipramine, and lofepramine (N-(4-chlorobenzoylmethyl)desipramine).[43][44] Desipramine is a secondary amine TCA, with its N-methylated parent imipramine being a tertiary amine.[45][46] Other secondary amine TCAs include nortriptyline and protriptyline.[47][48] The chemical name of desipramine is 3-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)-N-methylpropan-1-amine and its free base form has a chemical formula of C18H22N2 with a molecular weight of 266.381 g/mol.[1] The drug is used commercially mostly as the hydrochloride salt; the dibudinate salt is or has been used for intramuscular injection in Argentina (brand name Nebril) and the free base form is not used.[1][2] The CAS Registry Number of the free base is 50-47-5, of the hydrochloride is 58-28-6, and of the dibudinate is 62265-06-9.[1][2][49]

History

Desipramine was developed by Geigy.[50] It first appeared in the literature in 1959 and was patented in 1962.[50] The drug was first introduced for the treatment of depression in 1963 or 1964.[50][51]

Society and culture

Generic names

Desipramine is the generic name of the drug and its INNTooltip International Nonproprietary Name and BANTooltip British Approved Name, while desipramine hydrochloride is its USANTooltip United States Adopted Name, USPTooltip United States Pharmacopeia, BANTooltip British Approved Name, and JANTooltip Japanese Accepted Name.[1][2][52][3] Its generic name in French and its DCFTooltip Dénomination Commune Française are désipramine, in Spanish and Italian and its DCITTooltip Denominazione Comune Italiana are desipramina, in German is desipramin, and in Latin is desipraminum.[2][3]

Brand names

Desipramine is or has been marketed throughout the world under a variety of brand names, including Irene, Nebril, Norpramin, Pertofran, Pertofrane, Pertrofran, and Petylyl among others.[2][3]

References

  1. ^ a b c d e Elks J (14 November 2014). The Dictionary of Drugs: Chemical Data: Chemical Data, Structures and Bibliographies. Springer. pp. 363–. ISBN 978-1-4757-2085-3.
  2. ^ a b c d e f Index Nominum 2000: International Drug Directory. Taylor & Francis. 2000. pp. 304–. ISBN 978-3-88763-075-1.
  3. ^ a b c d "Desipramine - Drugs.com". drugs.com.
  4. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
  5. ^ 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.
  6. ^ a b c d Lemke TL, Williams DA (24 January 2012). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 588–. ISBN 978-1-60913-345-0.
  7. ^ Sallee FR, Pollock BG (May 1990). "Clinical pharmacokinetics of imipramine and desipramine". Clinical Pharmacokinetics. 18 (5): 346–364. doi:10.2165/00003088-199018050-00002. PMID 2185906. S2CID 37529573.
  8. ^ a b Brunton L, Chabner B, Knollman B (2010). Goodman and Gilman's The Pharmacological Basis of Therapeutics (12th ed.). New York: McGraw-Hill Professional. ISBN 978-0-07-162442-8.
  9. ^ Ghanizadeh A (July 2013). "A systematic review of the efficacy and safety of desipramine for treating ADHD". Current Drug Safety. 8 (3): 169–174. doi:10.2174/15748863113089990029. PMID 23914752.
  10. ^ Otasowie J, Castells X, Ehimare UP, Smith CH (September 2014). "Tricyclic antidepressants for attention deficit hyperactivity disorder (ADHD) in children and adolescents". The Cochrane Database of Systematic Reviews. 9 (9): CD006997. doi:10.1002/14651858.CD006997.pub2. PMC 11236426. PMID 25238582.
  11. ^ "UpToDate". www.uptodate.com.
  12. ^ Pani PP, Trogu E, Vecchi S, Amato L (December 2011). "Antidepressants for cocaine dependence and problematic cocaine use". The Cochrane Database of Systematic Reviews (12): CD002950. doi:10.1002/14651858.CD002950.pub3. PMID 22161371.
  13. ^ Hearn L, Moore RA, Derry S, Wiffen PJ, Phillips T (September 2014). Hearn L (ed.). "Desipramine for neuropathic pain in adults". The Cochrane Database of Systematic Reviews. 2014 (9): CD011003. doi:10.1002/14651858.CD011003.pub2. PMC 6804291. PMID 25246131.
  14. ^ "Desipramine Hydrochloride". Martindale: The Complete Drug Reference. London, UK: Pharmaceutical Press. 13 December 2013. Retrieved 17 July 2014.
  15. ^ White N, Litovitz T, Clancy C (December 2008). "Suicidal antidepressant overdoses: a comparative analysis by antidepressant type". Journal of Medical Toxicology. 4 (4): 238–250. doi:10.1007/BF03161207. PMC 3550116. PMID 19031375.
  16. ^ 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.
  17. ^ a b c d Tatsumi M, Groshan K, Blakely RD, Richelson E (December 1997). "Pharmacological profile of antidepressants and related compounds at human monoamine transporters". European Journal of Pharmacology. 340 (2–3): 249–258. doi:10.1016/s0014-2999(97)01393-9. PMID 9537821.
  18. ^ a b c d Owens MJ, Morgan WN, Plott SJ, Nemeroff CB (December 1997). "Neurotransmitter receptor and transporter binding profile of antidepressants and their metabolites". The Journal of Pharmacology and Experimental Therapeutics. 283 (3): 1305–1322. PMID 9400006.
  19. ^ a b c d e f g Cusack B, Nelson A, Richelson E (May 1994). "Binding of antidepressants to human brain receptors: focus on newer generation compounds". Psychopharmacology. 114 (4): 559–565. doi:10.1007/bf02244985. PMID 7855217. S2CID 21236268.
  20. ^ a b Wander TJ, Nelson A, Okazaki H, Richelson E (December 1986). "Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro". European Journal of Pharmacology. 132 (2–3): 115–121. doi:10.1016/0014-2999(86)90596-0. PMID 3816971.
  21. ^ Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J (August 1996). "Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor". Psychopharmacology. 126 (3): 234–240. doi:10.1007/bf02246453. PMID 8876023. S2CID 24889381.
  22. ^ a b Toll L, Berzetei-Gurske IP, Polgar WE, Brandt SR, Adapa ID, Rodriguez L, et al. (March 1998). "Standard binding and functional assays related to medications development division testing for potential cocaine and opiate narcotic treatment medications". NIDA Research Monograph. 178: 440–466. PMID 9686407.
  23. ^ Schmidt AW, Hurt SD, Peroutka SJ (November 1989). "'[3H]quipazine' degradation products label 5-HT uptake sites". European Journal of Pharmacology. 171 (1): 141–143. doi:10.1016/0014-2999(89)90439-1. PMID 2533080.
  24. ^ Shen Y, Monsma FJ, Metcalf MA, Jose PA, Hamblin MW, Sibley DR (August 1993). "Molecular cloning and expression of a 5-hydroxytryptamine7 serotonin receptor subtype". The Journal of Biological Chemistry. 268 (24): 18200–18204. doi:10.1016/S0021-9258(17)46830-X. PMID 8394362.
  25. ^ a b c d e Richelson E, Nelson A (July 1984). "Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro". The Journal of Pharmacology and Experimental Therapeutics. 230 (1): 94–102. PMID 6086881.
  26. ^ Muth EA, Haskins JT, Moyer JA, Husbands GE, Nielsen ST, Sigg EB (December 1986). "Antidepressant biochemical profile of the novel bicyclic compound Wy-45,030, an ethyl cyclohexanol derivative". Biochemical Pharmacology. 35 (24): 4493–4497. doi:10.1016/0006-2952(86)90769-0. PMID 3790168.
  27. ^ Sánchez C, Hyttel J (August 1999). "Comparison of the effects of antidepressants and their metabolites on reuptake of biogenic amines and on receptor binding". Cellular and Molecular Neurobiology. 19 (4): 467–489. doi:10.1023/A:1006986824213. PMID 10379421. S2CID 19490821.
  28. ^ Benjamin ER, Pruthi F, Olanrewaju S, Shan S, Hanway D, Liu X, et al. (September 2006). "Pharmacological characterization of recombinant N-type calcium channel (Cav2.2) mediated calcium mobilization using FLIPR". Biochemical Pharmacology. 72 (6): 770–782. doi:10.1016/j.bcp.2006.06.003. PMID 16844100.
  29. ^ Deupree JD, Montgomery MD, Bylund DB (December 2007). "Pharmacological properties of the active metabolites of the antidepressants desipramine and citalopram". European Journal of Pharmacology. 576 (1–3): 55–60. doi:10.1016/j.ejphar.2007.08.017. PMC 2231336. PMID 17850785.
  30. ^ a b c d Appl H, Holzammer T, Dove S, Haen E, Strasser A, Seifert R (February 2012). "Interactions of recombinant human histamine H₁R, H₂R, H₃R, and H₄R receptors with 34 antidepressants and antipsychotics". Naunyn-Schmiedeberg's Archives of Pharmacology. 385 (2): 145–170. doi:10.1007/s00210-011-0704-0. PMID 22033803. S2CID 14274150.
  31. ^ a b c d e Stanton T, Bolden-Watson C, Cusack B, Richelson E (June 1993). "Antagonism of the five cloned human muscarinic cholinergic receptors expressed in CHO-K1 cells by antidepressants and antihistaminics". Biochemical Pharmacology. 45 (11): 2352–2354. doi:10.1016/0006-2952(93)90211-e. PMID 8100134.
  32. ^ Weber E, Sonders M, Quarum M, McLean S, Pou S, Keana JF (November 1986). "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. 83 (22): 8784–8788. Bibcode:1986PNAS...83.8784W. doi:10.1073/pnas.83.22.8784. PMC 387016. PMID 2877462.
  33. ^ a b Hindmarch I, Hashimoto K (April 2010). "Cognition and depression: the effects of fluvoxamine, a sigma-1 receptor agonist, reconsidered". Human Psychopharmacology. 25 (3): 193–200. doi:10.1002/hup.1106. PMID 20373470. S2CID 26491662.
  34. ^ a b c Martin A, Volkmar FR, Lewis M (2007). Lewis's Child and Adolescent Psychiatry: A Comprehensive Textbook. Lippincott Williams & Wilkins. pp. 764–. ISBN 978-0-7817-6214-4.
  35. ^ Janowsky DS, Byerley B (October 1984). "Desipramine: an overview". The Journal of Clinical Psychiatry. 45 (10 Pt 2): 3–9. PMID 6384207.
  36. ^ a b c d e Curtin C (19 January 2016). Pain Management, An Issue of Hand Clinics, E-Book. Elsevier Health Sciences. pp. 55–. ISBN 978-0-323-41691-7.
  37. ^ Gold MS, Carman JS, Lydiard RB (2 July 1984). Advances in Psychopharmacology. CRC Press. pp. 98–. ISBN 978-0-8493-5680-3.
  38. ^ Bayless TM, Diehl A (2005). Advanced Therapy in Gastroenterology and Liver Disease. PMPH-USA. pp. 263–. ISBN 978-1-55009-248-6.
  39. ^ Leigh H (6 December 2012). Biopsychosocial Approaches in Primary Care: State of the Art and Challenges for the 21st Century. Springer Science & Business Media. pp. 108–. ISBN 978-1-4615-5957-3.
  40. ^ Hales RE, Yudofsky SC, Gabbard GO (2011). Essentials of Psychiatry. American Psychiatric Pub. pp. 468–. ISBN 978-1-58562-933-6.
  41. ^ Rakel RE (May 2007). Textbook of Family Medicine E-Book. Elsevier Health Sciences. pp. 313–. ISBN 978-1-4377-2190-4.
  42. ^ Leonard BE (October 1987). "A comparison of the pharmacological properties of the novel tricyclic antidepressant lofepramine with its major metabolite, desipramine: a review". International Clinical Psychopharmacology. 2 (4): 281–297. doi:10.1097/00004850-198710000-00001. PMID 2891742.
  43. ^ a b Ritsner MS (15 February 2013). Polypharmacy in Psychiatry Practice, Volume I: Multiple Medication Use Strategies. Springer Science & Business Media. pp. 270–271. ISBN 978-94-007-5805-6.
  44. ^ Lemke TL, Williams DA (2008). Foye's Principles of Medicinal Chemistry. Lippincott Williams & Wilkins. pp. 580–. ISBN 978-0-7817-6879-5.
  45. ^ Cutler NR, Sramek JJ, Narang PK (20 September 1994). Pharmacodynamics and Drug Development: Perspectives in Clinical Pharmacology. John Wiley & Sons. pp. 160–. ISBN 978-0-471-95052-3.
  46. ^ Anzenbacher P, Zanger UM (23 February 2012). Metabolism of Drugs and Other Xenobiotics. John Wiley & Sons. pp. 302–. ISBN 978-3-527-64632-6.
  47. ^ Anthony PK (2002). Pharmacology Secrets. Elsevier Health Sciences. pp. 39–. ISBN 978-1-56053-470-9.
  48. ^ Cowen P, Harrison P, Burns T (9 August 2012). Shorter Oxford Textbook of Psychiatry. OUP Oxford. pp. 532–. ISBN 978-0-19-162675-3.
  49. ^ Chambers M. "Desipramine dibudinate". ChemIDplus. U.S. National Library of Medicine.
  50. ^ a b c Andersen J, Kristensen AS, Bang-Andersen B, Strømgaard K (July 2009). "Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters". Chemical Communications (25): 3677–3692. doi:10.1039/b903035m. PMID 19557250.
  51. ^ Dart RC (2004). Medical Toxicology. Lippincott Williams & Wilkins. pp. 836–. ISBN 978-0-7817-2845-4.
  52. ^ Morton IK, Hall JM (6 December 2012). Concise Dictionary of Pharmacological Agents: Properties and Synonyms. Springer Science & Business Media. pp. 94–. ISBN 978-94-011-4439-1.