Tranylcypromine

Source: Wikipedia, the free encyclopedia.
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
Routes of
administration
Oral
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability50%[4]
MetabolismLiver[5][6]
Elimination half-life2.5 hours[4]
ExcretionUrine, Feces[4]
Identifiers
  • (±)-trans-2-phenylcyclopropan-1-amine
    or
    rel-(1R,2S)-2-phenylcyclopropan-1-amine
JSmol)
ChiralityRacemic mixture
  • c1cccc(c1)[C@@H]2C[C@H]2N
  • InChI=1S/C9H11N/c10-9-6-8(9)7-4-2-1-3-5-7/h1-5,8-9H,6,10H2/t8-,9+/m0/s1 checkY
  • Key:AELCINSCMGFISI-DTWKUNHWSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Tranylcypromine, sold under the brand name Parnate among others,

irreversible inhibitor of the enzyme monoamine oxidase (MAO).[4][7] It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders
, respectively.

Tranylcypromine is a

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.[8] It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion.[9] In addition to being a recognized treatment for major depressive disorder, tranylcypromine has been demonstrated to be effective in treating

obsessive compulsive disorder[10][11][12] and panic disorder.[13][14]

Systematic reviews and meta-analyses have reported that tranylcypromine is significantly more effective in the treatment of depression than placebo and has efficacy over placebo similar to that of other antidepressants such as tricyclic antidepressants.[15][16]

Contraindications

Contraindications include:[8][9][17]

Dietary restrictions

Tyramine is a biogenic amine produced as a (generally undesirable) byproduct during the fermentation of certain tyrosine-rich foods. It is rapidly metabolized by MAO-A in those not taking MAO-inhibiting drugs. Individuals sensitive to tyramine-induced hypertension may experience an uncomfortable, yet fleeting, increase in blood pressure after ingesting relatively small amounts of tyramine. [18][17][19]

Advances in food safety standards in most nations, as well as the widespread use of starter-cultures shown to result in undetectable to low levels of tyramine in fermented products has rendered concerns of serious hypertensive crises rare in those consuming a modern diet.[20][19] Those treated with MAOIs should still exercise caution, particularly at home, if it is unclear whether food has been properly refrigerated. Since tyramine-producing microbes also produce compounds to which humans have a natural aversion, disposal of any questionable food—particularly meats—should be sufficient to avoid hypertensive crises.

Adverse effects

Incidence of adverse effects[15]

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.[15]

Tranylcypromine is not associated with

hydrazine MAOIs.[15][9]

It is generally recommended that MAOIs be discontinued prior to

meperidine or dextromethorphan poses a risk for hypertension and serotonin syndrome respectively; alternative agents are recommended.[22][23] Other studies have come to similar conclusions.[15] 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.[18]

Tranylcypromine abuse has been reported at doses ranging from 120 to 600 mg per day.[8][24][15] 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.[15]

Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.[8]

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.[8]

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:[17]

pressor effects.[17]

Pharmacology

Pharmacodynamics

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase.

The clinical relevance of increased trace amine availability is unclear.

It may also act as a

releasing agent, with even weaker potency for norepinephrine and serotonin release.[18][17]

Tranylcypromine has also been shown to inhibit the

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.[25]
The clinical relevance of this effect is unknown.

Tranylcypromine has been found to inhibit

CYP46A1 at nanomolar concentrations.[26]
The clinical relevance of this effect is unknown.

Mechanism of tranylcypromine inhibition of MAO.[27]

Pharmacokinetics

Tranylcypromine reaches its maximum concentration (tmax) within 1–2 hours.[18] After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL.[18] While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.[18]

Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself.[18] Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.[18][28][17]

Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.[17]

Chemistry

Tranylcypromine 10-mg tablet

Synthesis

Synthesis of tranylcypromine[29]

History

Tranylcypromine was originally developed as an

analog of amphetamine.[4][18] Although it was first synthesized in 1948,[30] 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.[31]

The drug was introduced by

Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.[32] 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.[33][18][17]

Research

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3.[25][18][34] Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1.[34] Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.[34][35]

Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson's disease, similar to the MAO-B inhibitors selegiline and rasagiline.[36][9] 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.[9]

See also

References

  1. ^ a b Drugs.com International brands for Tranylcypromine. Page accessed April 17, 2016
  2. FDA
    . Retrieved 22 Oct 2023.
  3. ^ 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.
  4. ^ .
  5. ^ "Tranylcypromine". www.drugbank.ca. Retrieved 2019-12-06.
  6. S2CID 21380176
    .
  7. ^ .
  8. ^ a b c d e UK Electronic medicines compendium. Tranylcypromine Llast updated October 28, 2015
  9. ^
    PMID 22110357
    .
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  11. ^ Marques C, Nardi A, Mendlowicz M, Figueira I, Versiani M (1994-01-01). "The tranylcypromine in the treatment of obsessive-compulsive disorder: Report of six cases". ResearchGate. pp. 400–403.
  12. .
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  14. – via www.aafp.org.
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  20. ^ Gillman PK (2016). "Monoamine oxidase inhibitors: a review concerning dietary tyramine and drug interactions" (PDF). PsychoTropical Commentaries. 1: 1–90.
  21. PMID 22938842
    .
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  29. ^ 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 
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