Tranylcypromine

Tranylcypromine (sold under the trade name Parnate among others)[1] is a monoamine oxidase inhibitor (MAOI); more specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).[2][5] It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

Tranylcypromine
(1S,2R)-(−)-tranylcypromine (top),
(1R,2S)-(+)-tranylcypromine (bottom)
Clinical data
Trade namesParnate, many generics[1]
Other namestrans-2-phenylcyclopropylamine
AHFS/Drugs.comMonograph
MedlinePlusa682088
Pregnancy
category
  • AU: B2
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • CA: ℞-only
    • UK: POM (Prescription only)
    • US: ℞-only
    • In general: ℞ (Prescription only)
    Pharmacokinetic data
    Bioavailability50%[2]
    MetabolismLiver[3][4]
    Elimination half-life2.5 hours[2]
    ExcretionUrine, Feces[2]
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard100.005.312
    Chemical and physical data
    FormulaC9H11N
    Molar mass133.19 g/mol g·mol−1
    3D model (JSmol)
    ChiralityRacemic mixture
     NY (what is this?)  (verify)

    Tranylcypromine is a propylamine formed from the cyclization of amphetamine's side chain; therefore, it is classified as a substituted amphetamine.

    Medical uses

    Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment.[6] It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.[7]

    Contraindications

    Contraindications include:[6][7][8]

    Dietary restrictions
    Main article: Foods containing tyramine

    Tyramine is a common component in many foods, and is normally rapidly metabolized by MAO-A. Individuals not taking MAOIs may consume at least 2 grams of tyramine in a meal and not experience an increase in blood pressure, whereas those taking MAOIs such as tranylcypromine may experience a sharp increase in blood pressure following consumption of as little as 10 mg of tyramine, which can lead to hypertensive crisis.[9][8]

    Foods containing tyramine include aged cheeses, cured meats, tofu and certain red wines. Some, such as yeast extracts, contain enough tyramine to be potentially fatal in a single serving. Spoiled food is also likely to contain dangerous levels of tyramine.[6]

    Adverse effects

    Incidence of adverse effects[10]

    Very common (>10% incidence) adverse effects include:

    Common (1-10% incidence) adverse effects include:

    Other (unknown incidence) adverse effects include:

    Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.[10]

    Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.[10][7]

    It is generally recommended that MAOIs be discontinued prior to anesthesia; however, this creates a risk of recurrent depression. In a retrospective observational cohort study, patients on tranylcypromine undergoing general anesthesia had a lower incidence of intraoperative hypotension, while there was no difference between patients not taking an MAOI regarding intraoperative incidence of bradycardia, tachycardia, or hypertension.[11] The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended.[12][13] Other studies have come to similar conclusions.[10] Pharmacokinetic interactions with anesthetics are unlikely, given that tranylcypromine is a high-affinity substrate for CYP2A6 and does not inhibit CYP enzymes at therapeutic concentrations.[9]

    Tranylcypromine abuse has been reported at doses ranging from 120–600 mg per day.[6][14][10] It is thought that higher doses have more amphetamine-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine.[10]

    Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.[6]

    Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.[6]

    Interactions

    In addition to contraindicated concomitant medications, tranylcypromine inhibits CYP2A6, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as:[8]

    Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.[8]

    Pharmacology

    Pharmacodynamics

    Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase.[2] Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA.[9] This leads to an increase in the availability of monoamines, such as serotonin, norepinephrine, and dopamine, as well as a marked increase in the availability of trace amines, such as tryptamine, octopamine, and phenethylamine.[9][8] The clinical relevance of increased trace amine availability is unclear.

    It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses.[9] Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.[9][8]

    Tranylcypromine has also been shown to inhibit the histone demethylase, BHC110/LSD1. Tranylcypromine inhibits this enzyme with an IC50 < 2 μM, thus acting as a small molecule inhibitor of histone demethylation with an effect to derepress the transcriptional activity of BHC110/LSD1 target genes.[15] The clinical relevance of this effect is unknown.

    Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations.[16] The clinical relevance of this effect is unknown.

    Mechanism of tranylcypromine inhibition of MAO.[17]

    Pharmacokinetics

    Tranylcypromine reaches its maximum concentration (tmax) within 1–2 hours.[9] After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL.[9] While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.[9]

    Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself.[9] Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.[9][18][8]

    Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.[8]

    Chemistry
    Tranylcypromine 10-mg tablet

    Synthesis
    Synthesis of tranylcypromine[19]

    History

    Tranylcypromine was originally developed as an analog of amphetamine.[2][9] Although it was first synthesized in 1948,[20] its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like isoniazid and iproniazid, a hydrazine derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable therapeutic index than previous MAOIs.[21]

    The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.[22] It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding. However, it was reintroduced later that year with more limited indications and specific warnings of the risks.[23][9][8]

    Research

    Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3.[15][9][24] Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1.[24] Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.[24][25]

    Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson's disease, similar to the MAO-B inhibitors selegiline and rasagiline.[26][7] As of 2017, only one clinical trial in Parkinsonian patients has been conducted, which found some improvement initially and only slight worsening of symptoms after a 1.5 year followup.[7]

    See also

    References
    1. Drugs.com International brands for Tranylcypromine. Page accessed April 17, 2016
    2. Williams, David A. (2007). "Antidepressants". In Foye, William O.; Lemke, Thomas L.; Williams, David A. (eds.). Foye's Principles of Medicinal Chemistry. Hagerstwon, USA: Lippincott Williams & Wilkins. pp. 590–1. ISBN 978-0-7817-6879-5.
    3. "Tranylcypromine". www.drugbank.ca. Retrieved 2019-12-06.
    4. Baker, G. B.; Urichuk, L. J.; McKenna, K. F.; Kennedy, S. H. (June 1999). "Metabolism of monoamine oxidase inhibitors". Cellular and Molecular Neurobiology. 19 (3): 411–426. doi:10.1023/a:1006901900106. ISSN 0272-4340. PMID 10319194.
    5. Baldessarini, Ross J. (2005). "17. Drug therapy of depression and anxiety disorders". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.) (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. ISBN 978-0-07-142280-2.CS1 maint: uses editors parameter (link)
    6. UK Electronic medicines compendium. Tranylcypromine Llast updated October 28, 2015
    7. Riederer, P; Laux, G (March 2011). "MAO-inhibitors in Parkinson's Disease". Experimental Neurobiology. 20 (1): 1–17. doi:10.5607/en.2011.20.1.1. PMC 3213739. PMID 22110357.
    8. Gillman, PK (February 2011). "Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors". Journal of Clinical Psychopharmacology. 31 (1): 66–74. doi:10.1097/JCP.0b013e31820469ea. PMID 21192146.
    9. Ulrich, S; Ricken, R; Adli, M (August 2017). "Tranylcypromine in mind (Part I): Review of pharmacology". European Neuropsychopharmacology. 27 (8): 697–713. doi:10.1016/j.euroneuro.2017.05.007. PMID 28655495.
    10. Ricken, R; Ulrich, S; Schlattmann, P; Adli, M (August 2017). "Tranylcypromine in mind (Part II): Review of clinical pharmacology and meta-analysis of controlled studies in depression". European Neuropsychopharmacology. 27 (8): 714–731. doi:10.1016/j.euroneuro.2017.04.003. PMID 28579071.
    11. van Haelst, IM; van Klei, WA; Doodeman, HJ; Kalkman, CJ; Egberts, TC; MAOI Study, Group. (August 2012). "Antidepressive treatment with monoamine oxidase inhibitors and the occurrence of intraoperative hemodynamic events: a retrospective observational cohort study". The Journal of Clinical Psychiatry. 73 (8): 1103–9. doi:10.4088/JCP.11m07607. PMID 22938842.
    12. Smith, MS; Muir, H; Hall, R (February 1996). "Perioperative management of drug therapy, clinical considerations". Drugs. 51 (2): 238–59. doi:10.2165/00003495-199651020-00005. PMID 8808166.
    13. Blom-Peters, L; Lamy, M (1993). "Monoamine oxidase inhibitors and anesthesia: an updated literature review". Acta Anaesthesiologica Belgica. 44 (2): 57–60. PMID 8237297.
    14. Le Gassicke, J; Ashcroft, GW; Eccleston, D; Evans, JI; Oswald, I; Ritson, EB (1 April 1965). "The Clinical State, Sleep and Amine Metabolism of a Tranylcypromine ('Parnate') Addict". The British Journal of Psychiatry. 111 (473): 357–364. doi:10.1192/bjp.111.473.357.
    15. Lee, MG; Wynder, C; Schmidt, DM; McCafferty, DG; Shiekhattar, R (June 2006). "Histone H3 lysine 4 demethylation is a target of nonselective antidepressive medications". Chemistry & Biology. 13 (6): 563–7. doi:10.1016/j.chembiol.2006.05.004. PMID 16793513.
    16. Mast, N; Charvet, C; Pikuleva, IA; Stout, CD (8 October 2010). "Structural basis of drug binding to CYP46A1, an enzyme that controls cholesterol turnover in the brain". The Journal of Biological Chemistry. 285 (41): 31783–95. doi:10.1074/jbc.M110.143313. PMC 2951250. PMID 20667828.
    17. Gaweska, H; Fitzpatrick, PF (1 October 2011). "Structures and Mechanism of the Monoamine Oxidase Family". Biomolecular Concepts. 2 (5): 365–377. doi:10.1515/BMC.2011.030. PMC 3197729. PMID 22022344.
    18. Sherry, RL; Rauw, G; McKenna, KF; Paetsch, PR; Coutts, RT; Baker, GB (December 2000). "Failure to detect amphetamine or 1-amino-3-phenylpropane in humans or rats receiving the MAO inhibitor tranylcypromine". Journal of Affective Disorders. 61 (1–2): 23–9. doi:10.1016/s0165-0327(99)00188-3. PMID 11099737.
    19. A US patent 4016204 A, Vithal Jagannath Rajadhyaksha, "Method of synthesis of trans-2-phenylcyclopropylamine", published 1977-04-05, assigned to Nelson Research & Development Company
    20. Burger, A; Yost, WL (1948). "Arylcycloalkylamines. I. 2-Phenylcyclopropylamine". Journal of the American Chemical Society. 70 (6): 2198–2201. doi:10.1021/ja01186a062.
    21. López-Muñoz, F; Alamo, C (2009). "Monoaminergic neurotransmission: the history of the discovery of antidepressants from 1950s until today". Current Pharmaceutical Design. 15 (14): 1563–86. doi:10.2174/138161209788168001. PMID 19442174.
    22. Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 978-0-19-536874-1.
    23. ATCHLEY, DW (September 1964). "Reevaluation of Tranylcypromine Sulfate(Parnate Sulfate)". JAMA. 189 (10): 763–4. doi:10.1001/jama.1964.03070100057011. PMID 14174054.
    24. Zheng, YC; Yu, B; Jiang, GZ; Feng, XJ; He, PX; Chu, XY; Zhao, W; Liu, HM (2016). "Irreversible LSD1 Inhibitors: Application of Tranylcypromine and Its Derivatives in Cancer Treatment". Current Topics in Medicinal Chemistry. 16 (19): 2179–88. doi:10.2174/1568026616666160216154042. PMID 26881714.
    25. Przespolewski, A; Wang, ES (July 2016). "Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia". Expert Opinion on Investigational Drugs. 25 (7): 771–80. doi:10.1080/13543784.2016.1175432. PMID 27077938.
    26. Al-Nuaimi, SK; Mackenzie, EM; Baker, GB (November 2012). "Monoamine oxidase inhibitors and neuroprotection: a review". American Journal of Therapeutics. 19 (6): 436–48. doi:10.1097/MJT.0b013e31825b9eb5. PMID 22960850.
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