Tranylcypromine
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Tranylcypromine, sold under the brand name Parnate among others, is a monoamine oxidase inhibitor (MAOI). More specifically, tranylcypromine acts as nonselective and irreversible inhibitor of the
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
monoamine oxidase Monoamine oxidases (MAO) () are a family of enzymes that catalyze the oxidation of monoamines, employing oxygen to clip off their amine group. They are found bound to the outer membrane of mitochondria in most cell types of the body. The fi ...
(MAO). It is used as an
antidepressant Antidepressants are a class of medications used to treat major depressive disorder, anxiety disorders, chronic pain, and addiction. Common side effects of antidepressants include Xerostomia, dry mouth, weight gain, dizziness, headaches, akathi ...
and anxiolytic agent in the
clinic A clinic (or outpatient clinic or ambulatory care clinic) is a health facility that is primarily focused on the care of outpatients. Clinics can be privately operated or publicly managed and funded. They typically cover the primary care needs ...
al treatment of mood and
anxiety disorder Anxiety disorders are a group of mental disorders characterized by significant and uncontrollable feelings of anxiety and fear such that a person's social, occupational, and personal functions are significantly impaired. Anxiety may cause phys ...
s, respectively. It is also effective in the treatment of ADHD. Tranylcypromine is also known as ''trans''-2-phenylcyclopropyl-1-amine and is formed ''pro forma'' from the cyclization of
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
's isopropylamine
side chain In organic chemistry and biochemistry, a side chain is a substituent, chemical group that is attached to a core part of the molecule called the "main chain" or backbone chain, backbone. The side chain is a hydrocarbon branching element of a mo ...
. As a result, it is classified structurally as a substituted phenethylamine and
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
, or more specifically as a phenylcyclopropylamine.


Medical uses

Tranylcypromine is used to treat
major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive depression (mood), low mood, low self-esteem, and anhedonia, loss of interest or pleasure in normally ...
, including atypical depression, especially when there is an anxiety component, typically as a second-line treatment. It is also used in depression that is not responsive to reuptake inhibitor antidepressants, such as the SSRIs, TCAs, or bupropion. In addition to being a recognized treatment for major depressive disorder, tranylcypromine has been demonstrated to be effective in treating obsessive-compulsive disorder and panic disorder.
Systematic review A systematic review is a scholarly synthesis of the evidence on a clearly presented topic using critical methods to identify, define and assess research on the topic. A systematic review extracts and interprets data from published studies on ...
s and
meta-analyses Meta-analysis is a method of synthesis of quantitative data from multiple independent studies addressing a common research question. An important part of this method involves computing a combined effect size across all of the studies. As such, th ...
have reported that tranylcypromine is significantly more effective in the treatment of depression than
placebo A placebo ( ) can be roughly defined as a sham medical treatment. Common placebos include inert tablets (like sugar pills), inert injections (like saline), sham surgery, and other procedures. Placebos are used in randomized clinical trials ...
and has efficacy over placebo similar to that of other antidepressants such as tricyclic antidepressants.


Contraindications

Contraindications include: * Porphyria *
Cardiovascular In vertebrates, the circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the body. It includes the cardiovascular system, or vascular system, that consists of the heart a ...
or
cerebrovascular disease Cerebrovascular disease includes a variety of medical conditions that affect the blood vessels of the brain and the cerebral circulation. Arteries supplying oxygen and nutrients to the brain are often damaged or deformed in these disorders. Th ...
* Pheochromocytoma * Tyramine, found in several foods, is metabolized by MAO. Ingestion and absorption of tyramine causes extensive release of
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
, which can rapidly increase blood pressure to the point of causing hypertensive crisis. * Concomitant use of serotonin-enhancing drugs, including SSRIs, serotonergic TCAs,
dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
, and meperidine may cause
serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...
. * Concomitant use of MRAs, including fenfluramine,
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
, and pseudoephedrine may cause toxicity via serotonin syndrome or hypertensive crisis. * L-DOPA given without carbidopa may cause hypertensive crisis.


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. 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. 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 Very common (>10% incidence) adverse effects include: * Dizziness secondary to orthostatic hypotension (17%) Common (1-10% incidence) adverse effects include: *
Tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ...
(5–10%) *
Hypomania Hypomania (literally "under mania" or "less than mania") is a Psychiatry, psychiatric Abnormality (behavior), behavioral syndrome characterized essentially by an apparently non-contextual elevation of Mood (psychology), mood (i.e., euphoria) th ...
(7%) *
Paresthesia Paresthesia is a sensation of the skin that may feel like numbness (''hypoesthesia''), tingling, pricking, chilling, or burning. It can be temporary or Chronic condition, chronic and has many possible underlying causes. Paresthesia is usually p ...
(5%) * Weight loss (2%) * Confusion (2%) * Dry mouth (2%) * Sexual function disorders (2%) *
Hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
(1–2 hours after ingestion) (2%) * Rash (2%) *
Urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include urinary incont ...
(2%) Other (unknown incidence) adverse effects include: * Increased/decreased appetite * Blood dyscrasias * Chest pain *
Diarrhea Diarrhea (American English), also spelled diarrhoea or diarrhœa (British English), is the condition of having at least three loose, liquid, or watery bowel movements in a day. It often lasts for a few days and can result in dehydration d ...
* Edema *
Hallucination A hallucination is a perception in the absence of an external stimulus that has the compelling sense of reality. They are distinguishable from several related phenomena, such as dreaming ( REM sleep), which does not involve wakefulness; pse ...
s * Hyperreflexia *
Insomnia Insomnia, also known as sleeplessness, is a sleep disorder where people have difficulty sleeping. They may have difficulty falling asleep, or staying asleep for as long as desired. Insomnia is typically followed by daytime sleepiness, low ene ...
* Jaundice * Leg cramps * Myalgia *
Palpitations Palpitations occur when a person becomes aware of their heartbeat. The heartbeat may feel hard, fast, or uneven in their chest. Symptoms include a very fast or irregular heartbeat. Palpitations are a sensory symptom. They are often described as ...
* Sensation of cold * Suicidal ideation * Tremor Of note, there has not been found to be a correlation between sex and age below 65 regarding incidence of adverse effects. Tranylcypromine is not associated with weight gain and has a low risk for hepatotoxicity compared to the
hydrazine Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly hazardous unless handled in solution as, for example, hydraz ...
MAOIs. It is generally recommended that MAOIs be discontinued prior to
anesthesia Anesthesia (American English) or anaesthesia (British English) is a state of controlled, temporary loss of sensation or awareness that is induced for medical or veterinary purposes. It may include some or all of analgesia (relief from or prev ...
; 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 Bradycardia, also called bradyarrhythmia, is a resting heart rate under 60 beats per minute (BPM). While bradycardia can result from various pathological processes, it is commonly a physiological response to cardiovascular conditioning or due ...
, tachycardia, or hypertension. The use of indirect sympathomimetic drugs or drugs affecting serotonin reuptake, such as meperidine or
dextromethorphan Dextromethorphan, sold under the brand name Robitussin among others, is a cough suppressant used in many cough and Common cold, cold medicines. In 2022, the US Food and Drug Administration (FDA) approved the combination dextromethorphan/bupropi ...
poses a risk for
hypertension Hypertension, also known as high blood pressure, is a Chronic condition, long-term Disease, medical condition in which the blood pressure in the artery, arteries is persistently elevated. High blood pressure usually does not cause symptoms i ...
and
serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain Serotonin, serotonergic medications or Recreational drug use, drugs. The symptoms can range from mild to severe, and are potentially fatal. Symptoms in mild c ...
respectively; alternative agents are recommended. Other studies have come to similar conclusions. 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. Tranylcypromine
abuse Abuse is the act of improper usage or treatment of a person or thing, often to unfairly or improperly gain benefit. Abuse can come in many forms, such as: physical or verbal maltreatment, injury, assault, violation, rape, unjust practices, ...
has been reported at doses ranging from 120 to 600 mg per day. It is thought that higher doses have more
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
-like effects and abuse is promoted by the fast onset and short half-life of tranylcypromine. Cases of suicidal ideation and suicidal behaviours have been reported during tranylcypromine therapy or early after treatment discontinuation. Symptoms of tranylcypromine overdose are generally more intense manifestations of its usual effects.


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: * Dexmedetomidine * nicotine * TSNAs (found in cured tobacco products, including
cigarette A cigarette is a narrow cylinder containing a combustible material, typically tobacco, that is rolled into Rolling paper, thin paper for smoking. The cigarette is ignited at one end, causing it to smolder; the resulting smoke is orally inhale ...
s) * Valproate Norepinephrine reuptake inhibitors prevent neuronal uptake of tyramine and may reduce its pressor effects.


Pharmacology


Pharmacodynamics

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 Monoamine oxidase A, also known as MAO-A, is an enzyme (Enzyme classification, E.C. 1.4.3.4) that in humans is encoded by the ''MAOA'' gene. This gene is one of two neighboring gene family members that encode mitochondrial enzymes which catalyze ...
. This leads to an increase in the availability of monoamines, such as
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
,
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
, and
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
,
epinephrine Adrenaline, also known as epinephrine, is a hormone and medication which is involved in regulating visceral functions (e.g., respiration). It appears as a white microcrystalline granule. Adrenaline is normally produced by the adrenal glands a ...
as well as a marked increase in the availability of
trace amine Trace amines are an endogenous group of trace amine-associated receptor 1 (TAAR1) agonists – and hence, monoaminergic neuromodulators – that are structurally and metabolically related to classical monoamine neurotransmitters. Compared to ...
s, such as tryptamine, octopamine, and phenethylamine. The clinical relevance of increased trace amine availability is unclear. It may also act as a norepinephrine reuptake inhibitor at higher therapeutic doses. Compared to
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
, tranylcypromine shows low potency as a
dopamine Dopamine (DA, a contraction of 3,4-dihydroxyphenethylamine) is a neuromodulatory molecule that plays several important roles in cells. It is an organic chemical of the catecholamine and phenethylamine families. It is an amine synthesized ...
releasing agent, with even weaker potency for
norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic compound, organic chemical in the catecholamine family that functions in the brain and human body, body as a hormone, neurotransmitter and neuromodulator. The ...
and
serotonin Serotonin (), also known as 5-hydroxytryptamine (5-HT), is a monoamine neurotransmitter with a wide range of functions in both the central nervous system (CNS) and also peripheral tissues. It is involved in mood, cognition, reward, learning, ...
release. 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. The clinical relevance of this effect is unknown. Tranylcypromine has been found to inhibit CYP46A1 at nanomolar concentrations. The clinical relevance of this effect is unknown.


Pharmacokinetics

Tranylcypromine reaches its maximum concentration (tmax) within 1–2 hours. After a 20 mg dose, plasma concentrations reach at most 50-200 ng/mL. While its
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
is only about 2 hours, its pharmacodynamic effects last several days to weeks due to irreversible inhibition of MAO. Metabolites of tranylcypromine include 4-hydroxytranylcypromine, ''N''-acetyltranylcypromine, and ''N''-acetyl-4-hydroxytranylcypromine, which are less potent MAO inhibitors than tranylcypromine itself.
Amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
was once thought to be a metabolite of tranylcypromine, but has not been shown to be. Tranylcypromine inhibits CYP2A6 at therapeutic concentrations.


Chemistry

Tranylcypromine-10mg-Quarter.jpg, Tranylcypromine 10-mg tablet Tranylcypromine India.jpg, A box of tranylcypromine manufactured in
India India, officially the Republic of India, is a country in South Asia. It is the List of countries and dependencies by area, seventh-largest country by area; the List of countries by population (United Nations), most populous country since ...


Synthesis


History

Tranylcypromine was originally developed as an analog of
amphetamine Amphetamine (contracted from Alpha and beta carbon, alpha-methylphenethylamine, methylphenethylamine) is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, an ...
. 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 Hydrazine is an inorganic compound with the chemical formula . It is a simple pnictogen hydride, and is a colourless flammable liquid with an ammonia-like odour. Hydrazine is highly hazardous unless handled in solution as, for example, hydraz ...
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 The United Kingdom of Great Britain and Northern Ireland, commonly known as the United Kingdom (UK) or Britain, is a country in Northwestern Europe, off the coast of European mainland, the continental mainland. It comprises England, Scotlan ...
in 1960, and approved in the
United States The United States of America (USA), also known as the United States (U.S.) or America, is a country primarily located in North America. It is a federal republic of 50 U.S. state, states and a federal capital district, Washington, D.C. The 48 ...
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.


Research

Tranylcypromine is known to inhibit LSD1, an enzyme that selectively demethylates two
lysine Lysine (symbol Lys or K) is an α-amino acid that is a precursor to many proteins. Lysine contains an α-amino group (which is in the protonated form when the lysine is dissolved in water at physiological pH), an α-carboxylic acid group ( ...
s found on
histone H3 Histone H3 is one of the five main histones involved in the structure of chromatin in eukaryotic cells. Featuring a main globular domain and a long N-terminal end, N-terminal tail, H3 is involved with the structure of the nucleosomes of the 'b ...
. Genes promoted downstream of LSD1 are involved in cancer cell growth and metastasis, and several tumor cells express high levels of LSD1. Tranylcypromine analogues with more potent and selective LSD1 inhibitory activity are being researched in the potential treatment of cancers. Tranylcypromine may have neuroprotective properties applicable to the treatment of
Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...
, similar to the MAO-B inhibitors selegiline and
rasagiline Rasagiline, sold under the brand name Azilect among others, is a medication which is used in the treatment of Parkinson's disease. It is used as a monotherapy to treat symptoms in early Parkinson's disease or as an adjunct therapy in more advan ...
. 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.


See also

* Tranylcypromine/trifluoperazine


References

{{GlaxoSmithKline CYP2D6 inhibitors Monoamine oxidase inhibitors Norepinephrine-dopamine releasing agents Phenylcyclopropylamines Substituted amphetamines Substances discovered in the 1940s