(1S,2R)-(−)-tranylcypromine (top), (1R,2S)-(+)-tranylcypromine (bottom) | |
Clinical data | |
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Trade names | Parnate, many generics[1] |
Other names | trans-2-phenylcyclopropylamine |
AHFS/Drugs.com | Monograph |
MedlinePlus | a682088 |
Pregnancy category |
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Routes of administration | Oral |
ATC code | |
Legal status | |
Legal status | |
Pharmacokinetic data | |
Bioavailability | 50%[2] |
Metabolism | Liver[3][4] |
Elimination half-life | 2.5 hours[2] |
Excretion | Urine, Feces[2] |
Identifiers | |
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CAS Number | |
PubChem CID | |
DrugBank | |
ChemSpider | |
UNII | |
KEGG | |
ChEBI | |
ChEMBL | |
ECHA InfoCard | 100.005.312 |
Chemical and physical data | |
Formula | C9H11N |
Molar mass | 133.194 g·mol−1 |
3D model (JSmol) | |
Chirality | Racemic mixture |
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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 is a propylamine formed from the cyclization of amphetamine's side chain; therefore, it is classified as a substituted amphetamine.
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 include:[6][7][8]
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]
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 to 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]
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]
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.
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]
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]
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]