Tranylcypromine

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Tranylcypromine
Tranylcypromine-racemate2DCSD.svg
(1R,2S)-tranylcypromine3DanJ.gif(1S,2R)-tranylcypromine3DanJ.gif
Systematic (IUPAC) name
(±)-trans-2-phenylcyclopropan-1-amine
or
(1R*,2S*)-2-phenylcyclopropan-1-amine
Clinical data
Trade namesParnate
AHFS/Drugs.commonograph
MedlinePlusa682088
Pregnancy cat.
Legal status
RoutesOral
Pharmacokinetic data
Bioavailability50%[1]
MetabolismLiver (by enzymes CYP2A6, CYP2C19, CYP2D6, MAOA, and MAOB)
Half-life2.5 hours[1]
ExcretionUrine, Feces[1]
Identifiers
CAS number155-09-9 YesY
ATC codeN06AF04
PubChemCID 19493
DrugBankDB00752
ChemSpider18369 YesY
UNII3E3V44J4Z9 N
ChEMBLCHEMBL1179 N
SynonymsTransamine
Chemical data
FormulaC9H11N 
Mol. mass133.19 g/mol
 N (what is this?)  (verify)
 
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Tranylcypromine
Tranylcypromine-racemate2DCSD.svg
(1R,2S)-tranylcypromine3DanJ.gif(1S,2R)-tranylcypromine3DanJ.gif
Systematic (IUPAC) name
(±)-trans-2-phenylcyclopropan-1-amine
or
(1R*,2S*)-2-phenylcyclopropan-1-amine
Clinical data
Trade namesParnate
AHFS/Drugs.commonograph
MedlinePlusa682088
Pregnancy cat.
Legal status
RoutesOral
Pharmacokinetic data
Bioavailability50%[1]
MetabolismLiver (by enzymes CYP2A6, CYP2C19, CYP2D6, MAOA, and MAOB)
Half-life2.5 hours[1]
ExcretionUrine, Feces[1]
Identifiers
CAS number155-09-9 YesY
ATC codeN06AF04
PubChemCID 19493
DrugBankDB00752
ChemSpider18369 YesY
UNII3E3V44J4Z9 N
ChEMBLCHEMBL1179 N
SynonymsTransamine
Chemical data
FormulaC9H11N 
Mol. mass133.19 g/mol
 N (what is this?)  (verify)

Tranylcypromine (brand names: Parnate, Jatrosom (which is a brand solely sold in Germany)) is a drug of the substituted phenethylamine and amphetamine classes which acts as a monoamine oxidase inhibitor (MAOI)—it is a nonselective and irreversible inhibitor of the enzyme monoamine oxidase (MAO).[1][2] It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.

Clinical use[edit]

Despite their well-established efficacy, indications for monoamine oxidase inhibitors are currently very limited, due to their significant potential for adverse effects, many interactions, and the availability of newer and safer (although not necessarily more efficacious) antidepressants.[2] Tranylcypromine is indicated primarily for the treatment of major depressive disorder, and can also be used in the management of various mood and anxiety disorders, typically as a last resort after conventional antidepressants have been tried without success.

Contraindications[edit]

Therapeutic contraindications of tranylcypromine include:

Dietary restrictions[edit]

Foods high in endogenous monoamine precursors or exogenous monoamine compounds may cause adverse reactions. The most common example, hypertensive crisis, is caused by the ingestion of tyramine, which is found in foods such as 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.

Adverse effects[edit]

Adverse effects of tranylcypromine may include anxiety or nervousness, irritability, anorexia and subsequent weight loss, insomnia, mydriasis, tachycardia, hypertension or hypotension, hyperthermia, increased perspiration, muscle tremors, sexual dysfunction consisting of erectile dysfunction and/or anorgasmia, and orthostatic or postural hypotension.

Tranylcypromine is typically considered to have fewer side effects than the hydrazines, such as phenelzine (Nardil).

At least one case of the abuse of tranylcypromine has been noted. Sequelae included the periodic elimination of REM sleep and substantially elevated nocturnal muscle tone. Attempts to discontinue the medication resulted in nightmares accompanied by prompt and grossly excessive nocturnal REM sleep, and narcolepsy.[3]

Overdose[edit]

Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects. They may include exacerbated anxiety, muscle tremors, tachycardia, hypertension or hypotension, and hyperthermia, among others. Rare cases have been reported of hypertensive crisis, serotonin syndrome, myoclonus, hyperpyrexia, psychosis, and delirium, some of which progressed to coma. Additionally, in sensitive individuals or at extreme dosages, hypotension may lead to shock.

Pharmacology[edit]

Tranylcypromine 10-mg tablets

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase.[1][2] Regarding the isoforms of monoamine oxidase, it shows slight preference for the MAOB isoenzyme over MAOA. In addition, tranylcypromine functions as a norepinephrine and dopamine releasing agent with approximately 1/10 the potency of amphetamine.

As a result of these actions, tranylcypromine considerably boosts the concentrations and activity of the monoamine neurotransmitters serotonin and dopamine, along with paradoxical and varying effects on norepinephrine and epinephrine. It increases the levels of the trace amines phenethylamine, tyramine, octopamine, and tryptamine, as well. Tranylcypromine's action on these neurochemicals are believed to be responsible for its therapeutic efficacy.

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.[4]

History[edit]

Tranylcypromine was originally developed as an analog of amphetamine.[1] Although it was first synthesized in 1948,[5] 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.[6]

The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.[7] 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.[8]

See also[edit]

References[edit]

  1. ^ 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. 
  2. ^ a b c 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. 
  3. ^ 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. 
  4. ^ 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. 
  5. ^ Burger, A; Yost, WL. "Arylcycloalkylamines. I. 2-Phenylcyclopropylamine". Journal of the American Chemical Society 70 (6): 2198–2201. doi:10.1021/ja01186a062. 
  6. ^ 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. 
  7. ^ Shorter, Edward (2009). Before Prozac: the troubled history of mood disorders in psychiatry. Oxford [Oxfordshire]: Oxford University Press. ISBN 0-19-536874-6. 
  8. ^ ATCHLEY, DW (September 1964). "Reevaluation of Tranylcypromine Sulfate(Parnate Sulfate)". JAMA 189: 763–4. doi:10.1001/jama.1964.03070100057011. PMID 14174054.