|Systematic (IUPAC) name|
|Metabolism||Liver (by enzymes CYP2A6, CYP2C19, CYP2D6, MAOA, and MAOB)|
|Mol. mass||133.19 g/mol|
|(what is this?)|
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). It is used as an antidepressant and anxiolytic agent in the clinical treatment of mood and anxiety disorders, respectively.
Tranylcypromine was originally developed as an analog of amphetamine. Although it was first synthesized in 1948, 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.
The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961. It was withdrawn from the market in February 1964 due to a number of patient deaths involving hypertensive crises with intracranial bleeding.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.
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. 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.
Tranylcypromine is highly effective in the treatment of anergic depression in comparison to placebo. In comparison to imipramine, tranylcypromine has been shown to be more effective in anergic bipolar depression, and results in fewer patients leaving treatment. As contrasted with alprazolam, carbamazepine, and trifluoperazine, only tranylcypromine was effective in increasing the favorability of patients' self-evaluations in the treatment of women with borderline personality disorder. Tranylcypromine has shown substantial effectiveness in treatment-resistant depression, with, or, at unusually high dosages, without, lithium. However, at normal dosages, tranylcypromine proved no more effective than combination venlafaxine and mirtazapine in treatment-resistant depression, and was associated with more intolerance of side effects.
Therapeutic contraindications of tranylcypromine include:
- Cardiovascular or cerebrovascular disease
- Drug abuse (due to the potential for interactions with certain agents, especially stimulants)
- Low body weight, anorexia, or eating disorders of the sort
- Pre-existing and chronic headaches or migraines
- Psychosis such as schizophrenia or bipolar disorder
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 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.
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.
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.
Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. 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.
See, for example:
- Kaiser, C.; Lester, B. M.; Zirkle, C. L.; Burger, A.; Davis, C. S.; Delia, T. J.; Zirngibl, L. (1962). "2-Substituted Cyclopropylamines. I. Derivatives and Analogs of 2-Phenylcyclopropylamine". Journal of Medicinal and Pharmaceutical Chemistry 5 (6): 1243. doi:10.1021/jm01241a017.
- Zirkle, C. L.; Kaiser, C.; Tedeschi, D. H.; Tedeschi, R. E.; Burger, A. (1962). "2-Substituted Cyclopropylamines. II. Effect of Structure upon Monoamine Oxidase-Inhibitory Activity as Measuredin Vivoby Potentiation of Tryptamine Convulsions". Journal of Medicinal and Pharmaceutical Chemistry 5 (6): 1265. doi:10.1021/jm01241a018.
- Cho, S. J.; Jensen, N. H.; Kurome, T.; Kadari, S.; Manzano, M. L.; Malberg, J. E.; Caldarone, B.; Roth, B. L.; Kozikowski, A. P. (2009). "Selective 5-Hydroxytryptamine 2C Receptor Agonists Derived from the Lead Compound Tranylcypromine: Identification of Drugs with Antidepressant-Like Action". Journal of Medicinal Chemistry 52 (7): 1885–902. doi:10.1021/jm801354e. PMC 2832311. PMID 19284718.
|This article needs additional citations for verification. (August 2009)|
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