Iprindole Explained

Iprindole, sold under the brand names Prondol, Galatur, and Tertran, is an atypical tricyclic antidepressant (TCA) that has been used in the United Kingdom and Ireland for the treatment of depression but appears to no longer be marketed.[1] [2] [3] It was developed by Wyeth and was marketed in 1967.[4] The drug has been described by some as the first "second-generation" antidepressant to be introduced.[5] However, it was very little-used compared to other TCAs, with the number of prescriptions dispensed only in the thousands.[6]

Medical uses

Iprindole was used in the treatment of major depressive disorder in dosages similar to those of other TCAs.[1] [7]

Contraindications

Iprindole has been associated with jaundice and hepatotoxicity and should not be taken by alcoholics or people with pre-existing liver disease.[4] [8] [9] [10] If such symptoms are encountered iprindole should be discontinued immediately.

Side effects

Anticholinergic side effects such as dry mouth and constipation are either greatly reduced in comparison to imipramine and most other TCAs or fully lacking with iprindole.[11] However, it still has significant antihistamine effects and therefore can produce sedation, though this is diminished relative to other TCAs similarly. Iprindole also lacks significant alpha-blocking properties, and hence does not pose a risk of orthostatic hypotension.

Overdose

See main article: Tricyclic antidepressant overdose.

In overdose, iprindole is much less toxic than most other TCAs and is considered relatively benign.[12] For instance, between 1974 and 1985, only two deaths associated with iprindole were recorded in the United Kingdom, whereas 278 were reported for imipramine, although imipramine is used far more often than iprindole.

Interactions

Iprindole has been shown to be a potent inhibitor of the aromatic hydroxylation and/or N-dealkylation-mediated metabolism of many substances including, but not limited to octopamine, amphetamine, methamphetamine, fenfluramine, phenelzine, tranylcypromine, trimipramine, and fluoxetine, likely via inactivating cytochrome P450 enzymes.[13] [14] [15] [16] [17] It also inhibits its own metabolism.[16]

On account of these interactions, caution should be used when combining iprindole with other drugs. As an example, when administered with amphetamine or methamphetamine, iprindole increases their brain concentrations and prolongs their terminal half-lives by 2- to 3-fold, strongly augmenting both their physiological effects and neurotoxicity in the process.[18] [19] [20]

Pharmacology

Pharmacodynamics

See also: Pharmacology of antidepressants.

Iprindole[21]
Site Ki (nM) Species Ref
1,620–3,300 Human [22] [23]
1,262 Human
6,530 Human
2,800 Human
5-HT2A 217–280 Human/rat [24]
5-HT2C 206 Rat
2,300 Human [25]
8,600 Human
>10,000 Mammal [26]
6,300 Rat [27]
H1 100–130 Human/rat [28]
H2 200–8,300 Guinea pig [29] [30]
2,100 Human [31]
>10,000 Rat [32]
Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

Iprindole is unique compared to most other TCAs in that it is a very weak and negligible inhibitor of the reuptake of serotonin and norepinephrine and appears to act instead as a selective albeit weak antagonist of 5-HT2 receptors; hence its classification by some as "second-generation".[33] [34] [35] Additionally, iprindole has very weak/negligible antiadrenergic and anticholinergic activity and weak although possibly significant antihistamine activity; as such, side effects of iprindole are much less prominent relative to other TCAs, and it is well tolerated. However, iprindole may not be as effective as other TCAs, particularly in terms of anxiolysis.[33] [36] Based on animal research, the antidepressant effects of iprindole may be mediated through downstream dopaminergic mechanisms.[37]

The binding affinities of iprindole for various biological targets are presented in the table to the right. It is presumed to act as an inhibitor or antagonist/inverse agonist of all sites. Considering the range of its therapeutic concentrations (e.g., 63–271 nM at 90 mg/day), only the actions of iprindole on the 5-HT2 and histamine receptors might be anticipated to be of possible clinical significance. However, it is unknown whether these actions are in fact responsible for the antidepressant effects of iprindole. The plasma protein binding of iprindole and hence its free percentage and potentially bioactive concentrations do not seem to be known.

Pharmacokinetics

Only one study appears to have evaluated the pharmacokinetics of iprindole.[38] A single oral dose of 60 mg iprindole to healthy volunteers has been found to achieve mean peak plasma concentrations of 67.1 ng/mL (236 nmol/L) after 2 to 4 hours. The mean terminal half-life of iprindole was 52.5 hours, which is notably much longer than that of other TCAs like amitriptyline and imipramine. Following chronic treatment with 90 mg/day iprindole for 3 weeks, plasma concentrations of the drug ranged between 18 and 77 ng/mL (63–271 nmol/L). Theoretical steady-state concentrations should be reached by 99% within 15 to 20 days of treatment.

Chemistry

Iprindole is a tricyclic compound, specifically a cyclooctaindole (that is, an indole nucleus joined with a cyclooctyl ring), and possesses three rings fused together with a side chain attached in its chemical structure.[39] It is a tertiary amine TCA, although its ring system and pharmacological properties are very different from those of other TCAs.[40] Other tertiary amine TCAs that are similar to iprindole include butriptyline and trimipramine.[41] [42] The chemical name of iprindole is 3-(6,7,8,9,10,11-hexahydro-5H-cycloocta[''b'']indol-5-yl)-N,N-dimethylpropan-1-amine and its free base form has a chemical formula of C19H28N2 with a molecular weight of 284.439 g/mol. The drug has been used commercially as both the free base and the hydrochloride salt. The CAS Registry Number of the free base is 5560-72-5 and of the hydrochloride is 20432-64-8.

History

Iprindole was developed by Wyeth and was marketed in 1967.[4] [43]

Society and culture

Generic names

Iprindole is the English and French generic name of the drug and its,,, and, while iprindole hydrochloride is its .[44] [45] [46] Its generic name in Spanish and German is iprindol while its generic name in Latin is iprindolum. Iprindole was originally known unofficially as pramindole.

Brand names

Iprindole has been marketed under the brand name Prondol by Wyeth in the United Kingdom and Ireland for the indication of major depressive disorder,[47] and has also been sold as Galatur and Tertran by Wyeth.

Availability

Iprindole was previously available in the United Kingdom and Ireland but seems to no longer be available for medical use in any country.

Further reading

Notes and References

  1. Book: Ayd FJ . Iprindole . Lexicon of psychiatry, neurology, and the neurosciences . Lippincott-Williams & Wilkins . Philadelphia, Pa . 2000 . 0-7817-2468-6 . https://books.google.com/books?id=ea_QVG2BFy8C&q=iprindole&pg=PA531.
  2. Book: Dictionary of organic compounds . Chapman & Hall . London . 1996 . 0-412-54090-8 .
  3. Book: McNeal E, Cimbolic P . Antidepressant and Biochemical Theories of Depression. Davison GC, Hooley JM, Neale JM . Readings in Abnormal Psychology . Wiley . New York . 1989 . 0-471-63107-8 . https://archive.org/details/isbn_9780471631071 . 186 . iprindole. .
  4. Jaundice from iprindole (Prondol) . Drug and Therapeutics Bulletin . 9 . 3 . 10–11 . January 1971 . 5548547 . 10.1136/dtb.9.3.10 . 31232918 .
  5. Horn AS, Trace RC . Second generation antidepressants: The pharmacological and clinical significance of selected examples . Drug Development Research . 3 . 3 . 203–211 . January 1983 . 10.1002/ddr.430030302 . 84018071 .
  6. Book: Aronson JK . Tricyclic Antidepressants . Meyler's Side Effects of Psychiatric Drugs. https://books.google.com/books?id=AmYFTSO8jCkC&pg=PA18 . 2009. Elsevier. 978-0-444-53266-4. 18–.
  7. Book: Paykel ES . Treatment for Affective Disorders . Wing L, Wing JK . Psychoses of uncertain aetiology . Cambridge University Press . Cambridge, UK . 1982 . 0-521-28438-4 . https://books.google.com/books?id=QFI4AAAAIAAJ&pg=PA167.
  8. Book: Aronson JK . Meyler's Side Effects of Psychiatric Drugs (Meylers Side Effects) . Elsevier Science . Amsterdam . 2008 . 978-0-444-53266-4 .
  9. Ajdukiewicz AB, Grainger J, Scheuer PJ, Sherlock S . Jaundice due to iprindole . Gut . 12 . 9 . 705–708 . September 1971 . 4106521 . 1411804 . 10.1136/gut.12.9.705 .
  10. Clift AD . Allergy to iprindole (Prondole) with hepatotoxicity . British Medical Journal . 2 . 5763 . 712 . June 1971 . 5556082 . 1796275 . 10.1136/bmj.2.5763.712 .
  11. Launchbury AP . Some recently introduced drugs . Progress in Medicinal Chemistry . 7 . 1 . 1–67 (25) . 1970 . 4250600 . 10.1016/s0079-6468(08)70351-5 . Butterworth-Heinemann. 978-0-408-70013-9 .
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  13. Sedlock ML, Ravitch J, Edwards DJ . The effects of imipramine and iprindole on the metabolism of octopamine in the rat . Neuropharmacology . 24 . 8 . 705–708 . August 1985 . 3939325 . 10.1016/0028-3908(85)90002-4 . 39933551 .
  14. Hegadoren KM, Baker GB, Coutts RT, Dewhurst WG . Interactions of iprindole with fenfluramine metabolism in rat brain and liver . Journal of Psychiatry & Neuroscience . 16 . 1 . 5–11 . March 1991 . 2049371 . 1188281 .
  15. Yamamoto T, Takano R, Egashira T, Yamanaka Y . Metabolism of methamphetamine, amphetamine and p-hydroxymethamphetamine by rat-liver microsomal preparations in vitro . Xenobiotica; the Fate of Foreign Compounds in Biological Systems . 14 . 11 . 867–875 . November 1984 . 6506759 . 10.3109/00498258409151485 .
  16. Coutts RT, Hussain MS, Baker GB . Effect of iprindole on the metabolism of trimipramine in the rat . Journal of Psychiatry & Neuroscience . 16 . 5 . 272–275 . December 1991 . 1797102 . 1188365 .
  17. Aspeslet LJ, Baker GB, Coutts RT, Torok-Both GA . The effects of desipramine and iprindole on levels of enantiomers of fluoxetine in rat brain and urine . Chirality . 6 . 2 . 86–90 . 1994 . 8204417 . 10.1002/chir.530060208 .
  18. Fuller RW, Baker JC, Molloy BB . Biological disposition of rigid analogs of amphetamine . Journal of Pharmaceutical Sciences . 66 . 2 . 271–272 . February 1977 . 839428 . 10.1002/jps.2600660235 .
  19. Fuller RW, Hemrick-Luecke S . Long-lasting depletion of striatal dopamine by a single injection of amphetamine in iprindole-treated rats . Science . 209 . 4453 . 305–307 . July 1980 . 7384808 . 10.1126/science.7384808 . 1980Sci...209..305F .
  20. Peat MA, Warren PF, Gibb JW . Effects of a single dose of methamphetamine and iprindole on the serotonergic and dopaminergic system of the rat brain . The Journal of Pharmacology and Experimental Therapeutics . 225 . 1 . 126–131 . April 1983 . 6187915 .
  21. Web site: PDSP Ki Database . Psychoactive Drug Screening Program (PDSP). Bryan Roth . Roth BL, Driscol J . University of North Carolina at Chapel Hill and the United States National Institute of Mental Health . 7 May 2022 .
  22. Tatsumi M, Groshan K, Blakely RD, Richelson E . Pharmacological profile of antidepressants and related compounds at human monoamine transporters . European Journal of Pharmacology . 340 . 2–3 . 249–258 . December 1997 . 9537821 . 10.1016/s0014-2999(97)01393-9 .
  23. Wander TJ, Nelson A, Okazaki H, Richelson E . Antagonism by antidepressants of serotonin S1 and S2 receptors of normal human brain in vitro . European Journal of Pharmacology . 132 . 2–3 . 115–121 . December 1986 . 3816971 . 10.1016/0014-2999(86)90596-0 .
  24. Pälvimäki EP, Roth BL, Majasuo H, Laakso A, Kuoppamäki M, Syvälahti E, Hietala J . Interactions of selective serotonin reuptake inhibitors with the serotonin 5-HT2c receptor . Psychopharmacology . 126 . 3 . 234–240 . August 1996 . 8876023 . 10.1007/bf02246453 . 24889381 .
  25. Richelson E, Nelson A . Antagonism by antidepressants of neurotransmitter receptors of normal human brain in vitro . The Journal of Pharmacology and Experimental Therapeutics . 230 . 1 . 94–102 . July 1984 . 6086881 .
  26. Bylund DB, Snyder SH . Beta adrenergic receptor binding in membrane preparations from mammalian brain . Molecular Pharmacology . 12 . 4 . 568–580 . July 1976 . 8699 .
  27. Book: Baker GB, Greenshaw AJ . Analysis of Psychiatric Drugs . In Vitro and Ex Vivo Neurochemical Screening Procedures for Antidepressants, Neuroleptics, and Benzodiazepines. 10. 1988. 327–378. 10.1385/0-89603-121-7:327. 0-89603-121-7.
  28. Tran VT, Chang RS, Snyder SH . Histamine H1 receptors identified in mammalian brain membranes with [3H]mepyramine . Proceedings of the National Academy of Sciences of the United States of America . 75 . 12 . 6290–6294 . December 1978 . 282646 . 393167 . 10.1073/pnas.75.12.6290 . free . 1978PNAS...75.6290T .
  29. Tsai BS, Yellin TO . Differences in the interaction of histamine H2 receptor antagonists and tricyclic antidepressants with adenylate cyclase from guinea pig gastric mucosa . Biochemical Pharmacology . 33 . 22 . 3621–3625 . November 1984 . 6150708 . 10.1016/0006-2952(84)90147-3 .
  30. Kanba S, Richelson E . Antidepressants are weak competitive antagonists of histamine H2 receptors in dissociated brain tissue . European Journal of Pharmacology . 94 . 3–4 . 313–318 . October 1983 . 6140176 . 10.1016/0014-2999(83)90420-x .
  31. El-Fakahany E, Richelson E . Antagonism by antidepressants of muscarinic acetylcholine receptors of human brain . British Journal of Pharmacology . 78 . 1 . 97–102 . January 1983 . 6297650 . 2044798 . 10.1111/j.1476-5381.1983.tb17361.x .
  32. Largent BL, Gundlach AL, Snyder SH . Psychotomimetic opiate receptors labeled and visualized with (+)-[3H]3-(3-hydroxyphenyl)-N-(1-propyl)piperidine . Proceedings of the National Academy of Sciences of the United States of America . 81 . 15 . 4983–4987 . August 1984 . 6087359 . 391617 . 10.1073/pnas.81.15.4983 . free . 1984PNAS...81.4983L .
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  34. Jaramillo J, Greenberg R . Comparative pharmacological studies on butriptyline and some related standard tricyclic antidepressants . Canadian Journal of Physiology and Pharmacology . 53 . 1 . 104–112 . February 1975 . 166748 . 10.1139/y75-014 .
  35. Horn AS, Trace RC . Structure-activity relations for the inhibition of 5-hydroxytryptamine uptake by tricyclic antidepressants into synaptosomes from serotoninergic neurones in rat brain homogenates . British Journal of Pharmacology . 51 . 3 . 399–403 . July 1974 . 4451753 . 1776771 . 10.1111/j.1476-5381.1974.tb10675.x .
  36. Rickels K, Chung HR, Csanalosi I, Sablosky L, Simon JH . Iprindole and imipramine in non-psychotic depressed out-patients . The British Journal of Psychiatry . 123 . 574 . 329–339 . September 1973 . 4583430 . 10.1192/bjp.123.3.329 . 23126539 .
  37. Berettera C, Invernizzi R, Pulvirenti L, Samanin R . Chronic treatment with iprindole reduces immobility of rats in the behavioural 'despair' test by activating dopaminergic mechanisms in the brain . The Journal of Pharmacy and Pharmacology . 38 . 4 . 313–315 . April 1986 . 2872301 . 10.1111/j.2042-7158.1986.tb04576.x . 27863022 .
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