Tranylcypromine

From Wikipedia, the free encyclopedia
Jump to: navigation, search
Tranylcypromine
Tranylcypromine.svg
(1S,2R)-(−)-tranylcypromine (top),
(1R,2S)-(+)-tranylcypromine (bottom)
Clinical data
Trade names originally Parnate, many generics[1]
AHFS/Drugs.com Monograph
MedlinePlus a682088
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
Bioavailability 50%[3]
Metabolism

Liver (MAOA and MAOB)

(CYP2A6)[2]
Biological half-life 2.5 hours[3]
Excretion Urine, Feces[3]
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
ECHA InfoCard 100.005.312
Chemical and physical data
Formula C9H11N
Molar mass 133.19 g/mol
3D model (JSmol)
Chirality Racemic mixture
 NYesY (what is this?)  (verify)

Tranylcypromine (INN, USAN, BAN (contracted from trans-2-phenylcyclopropylamine); original trade name Parnate)[1] is a monoamine oxidase inhibitor (MAOI) — it is a nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).[3][4] It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

Medical uses[edit]

Tranylcypromine is used to treat major depressive disorder, including atypical depression, especially when there is an anxiety component, typically as a second line treatment.[5] It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.[6]

Contraindications[edit]

Contraindications include:[5][6][7]

Dietary restrictions[edit]

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 presure, 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.[2][7]

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.[5]

Adverse effects[edit]

Incidence of adverse effects[8]

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.[8]

Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.[8][6]

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.[9] 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.[10][11] Other studies have come to similar conclusions.[8] 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.[2]

Tranylcypromine abuse has been reported at doses ranging from 120-600 mg per day.[5][12][8] 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.[8]

Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.[5]

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.[5]

Interactions[edit]

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:[7]

Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.[7]

Pharmacology[edit]

Pharmacodynamics[edit]

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase.[3] Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA.[2] 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.[2][7] The clinical relevance of increased trace amine availability is unclear.

It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses.[2] Compared to amphetamine, tranylcypromine shows low potency as a dopamine releasing agent, with even weaker potency for norepinephrine and serotonin release.[2][7]

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.[13] The clinical relevance of this effect is unknown.

Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations.[14] The clinical relevance of this effect is unknown.

Mechanism of tranylcypromine inhibition of MAO.[15]

Pharmacokinetics[edit]

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

Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself.[2] Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.[2][16][7]

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.[7]

Chemistry[edit]

Tranylcypromine 10-mg tablet

Synthesis[edit]

Synthesis of tranylcypromine[17]

History[edit]

Tranylcypromine was originally developed as an analog of amphetamine.[3][2] Although it was first synthesized in 1948,[18] 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.[19]

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.[20] 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.[21][2][7]

Research[edit]

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3.[13][2][22] Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1.[22] Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.[22][23]

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson's disease, similar to the MAO-B inhibitors selegiline and rasagiline.[24][6] 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.[6]

See also[edit]

References[edit]

  1. ^ a b Drugs.com International brands for Tranylcypromine. Page accessed April 17, 2016
  2. ^ a b c d e f g h i j k l m n o Ulrich, S; Ricken, R; Adli, M (August 2017). "Tranylcypromine in mind (Part I): Review of pharmacology.". European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology. 27 (8): 697–713. PMID 28655495. doi:10.1016/j.euroneuro.2017.05.007. 
  3. ^ a b c d e f Williams, David A. (2007). "Antidepressants". In Foye, William O.; Lemke, Thomas L.; Williams, David A. Foye's Principles of Medicinal Chemistry. Hagerstwon, USA: Lippincott Williams & Wilkins. pp. 590–1. ISBN 0-7817-6879-9. 
  4. ^ Baldessarini, Ross J. (2005). "17. Drug therapy of depression and anxiety disorders". In Brunton, Laurence L.; Lazo, John S.; Parker, Keith L. (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. ISBN 0-07-142280-3. 
  5. ^ a b c d e f UK Electronic medicines compendium. Tranylcypromine Llast updated October 28, 2015
  6. ^ a b c d e Riederer, P; Laux, G (March 2011). "MAO-inhibitors in Parkinson's Disease.". Experimental neurobiology. 20 (1): 1–17. PMID 22110357. doi:10.5607/en.2011.20.1.1. 
  7. ^ a b c d e f g h i 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. PMID 21192146. doi:10.1097/JCP.0b013e31820469ea. 
  8. ^ a b c d e f 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 : the journal of the European College of Neuropsychopharmacology. 27 (8): 714–731. PMID 28579071. doi:10.1016/j.euroneuro.2017.04.003. 
  9. ^ 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. PMID 22938842. doi:10.4088/JCP.11m07607. 
  10. ^ Smith, MS; Muir, H; Hall, R (February 1996). "Perioperative management of drug therapy, clinical considerations.". Drugs. 51 (2): 238–59. PMID 8808166. 
  11. ^ Blom-Peters, L; Lamy, M (1993). "Monoamine oxidase inhibitors and anesthesia: an updated literature review.". Acta anaesthesiologica Belgica. 44 (2): 57–60. PMID 8237297. 
  12. ^ 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. 
  13. ^ a b 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. PMID 16793513. doi:10.1016/j.chembiol.2006.05.004. 
  14. ^ 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. PMID 20667828. doi:10.1074/jbc.M110.143313. 
  15. ^ Gaweska, H; Fitzpatrick, PF (1 October 2011). "Structures and Mechanism of the Monoamine Oxidase Family.". Biomolecular concepts. 2 (5): 365–377. PMID 22022344. doi:10.1515/BMC.2011.030. 
  16. ^ 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. PMID 11099737. 
  17. ^ 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 
  18. ^ Burger, A; Yost, WL. "Arylcycloalkylamines. I. 2-Phenylcyclopropylamine". Journal of the American Chemical Society. 70 (6): 2198–2201. doi:10.1021/ja01186a062. 
  19. ^ 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. PMID 19442174. doi:10.2174/138161209788168001. 
  20. ^ Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-536874-6. 
  21. ^ ATCHLEY, DW (September 1964). "Reevaluation of Tranylcypromine Sulfate(Parnate Sulfate)". JAMA. 189: 763–4. PMID 14174054. doi:10.1001/jama.1964.03070100057011. 
  22. ^ a b c 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. PMID 26881714. 
  23. ^ 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. PMID 27077938. doi:10.1080/13543784.2016.1175432. 
  24. ^ Al-Nuaimi, SK; Mackenzie, EM; Baker, GB (November 2012). "Monoamine oxidase inhibitors and neuroprotection: a review.". American journal of therapeutics. 19 (6): 436–48. PMID 22960850. doi:10.1097/MJT.0b013e31825b9eb5.