Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of norepinephrine, which can rapidly increase blood pressure to the point of causing hypertensive crisis.
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. [12][11][13]
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.[14][13] 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.
Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects.[9]
Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the hydrazine MAOIs.[9][8]
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.[15] 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.[16][17] Other studies have come to similar conclusions.[9] 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.[12]
Tranylcypromine abuse has been reported at doses ranging from 120 to 600 mg per day.[7][18][9] 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.[9]
Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation.[7]
Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.[7]
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:[11]
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.[19] The clinical relevance of this effect is unknown.
Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations.[20] The clinical relevance of this effect is unknown.
Mechanism of tranylcypromine inhibition of MAO.[21]
Pharmacokinetics
Tranylcypromine reaches its maximum concentration (tmax) within 1–2 hours.[12] After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL.[12] While its half-life is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO.[12]
Metabolites of tranylcypromine include 4-hydroxytranylcypromine, N-acetyltranylcypromine, and N-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself.[12]Amphetamine was once thought to be a metabolite of tranylcypromine, but has not been shown to be.[12][22][11]
Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.[11]
Tranylcypromine was originally developed as an analog of amphetamine.[3][12] Although it was first synthesized in 1948,[24] 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.[25]
The drug was introduced by Smith, Kline and French in the United Kingdom in 1960, and approved in the United States in 1961.[26] 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.[27][12][11]
Research
Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two lysines found on histone H3.[19][12][28] Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1.[28] Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers.[28][29]
Tranylcypromine may have neuroprotective properties applicable to the treatment of Parkinson's disease, similar to the MAO-B inhibitors selegiline and rasagiline.[30][8] 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.[8]
^ abcdefgWilliams DA (2007). "Antidepressants". In Foye WO, Lemke TL, Williams DA (eds.). Foye's Principles of Medicinal Chemistry. Hagerstwon, USA: Lippincott Williams & Wilkins. pp. 590–1. ISBN978-0-7817-6879-5.
^Baker GB, Urichuk LJ, McKenna KF, Kennedy SH (June 1999). "Metabolism of monoamine oxidase inhibitors". Cellular and Molecular Neurobiology. 19 (3): 411–26. doi:10.1023/a:1006901900106. PMID10319194. S2CID21380176.
^ abBaldessarini RJ (2005). "17. Drug therapy of depression and anxiety disorders". In Brunton LL, Lazo JS, Parker KL (eds.). Goodman & Gilman's The Pharmacological Basis of Therapeutics. New York: McGraw-Hill. ISBN978-0-07-142280-2.
^Ulrich S, Ricken R, Buspavanich P, Schlattmann P, Adli M (2020). "Efficacy and Adverse Effects of Tranylcypromine and Tricyclic Antidepressants in the Treatment of Depression: A Systematic Review and Comprehensive Meta-analysis". J Clin Psychopharmacol. 40 (1): 63–74. doi:10.1097/JCP.0000000000001153. PMID31834088. S2CID209343653.
^ abcdefghiGillman PK (February 2011). "Advances pertaining to the pharmacology and interactions of irreversible nonselective monoamine oxidase inhibitors". Journal of Clinical Psychopharmacology. 31 (1): 66–74. doi:10.1097/JCP.0b013e31820469ea. PMID21192146. S2CID10525989.
^Blom-Peters L, Lamy M (1993). "Monoamine oxidase inhibitors and anesthesia: an updated literature review". Acta Anaesthesiologica Belgica. 44 (2): 57–60. PMID8237297.
^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. S2CID145562899.
^ abLee 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. PMID16793513.
^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. doi:10.1016/s0165-0327(99)00188-3. PMID11099737.
^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
^Burger A, Yost WL (1948). "Arylcycloalkylamines. I. 2-Phenylcyclopropylamine". Journal of the American Chemical Society. 70 (6): 2198–2201. doi:10.1021/ja01186a062.
^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. PMID19442174.
^ abcZheng YC, Yu B, Jiang GZ, Feng XJ, He PX, Chu XY, et al. (2016). "Irreversible LSD1 Inhibitors: Application of Tranylcypromine and Its Derivatives in Cancer Treatment". Current Topics in Medicinal Chemistry. 16 (19): 2179–88. doi:10.2174/1568026616666160216154042. PMID26881714.
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