Tranylcypromine, sold under the brand name Parnate among others, is a

monoamine oxidase inhibitor Monoamine oxidase inhibitors (MAOIs) are a drug class, class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressa ...

(MAOI). More specifically, tranylcypromine acts as nonselective and irreversible

inhibitor Inhibitor or inhibition may refer to: Biology * Enzyme inhibitor, a substance that binds to an enzyme and decreases the enzyme's activity * Reuptake inhibitor, a substance that increases neurotransmission by blocking the reuptake of a neurotransmi ...

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 An anxiolytic (; also antipanic or anti-anxiety agent) is a medication or other intervention that reduces anxiety. This effect is in contrast to anxiogenic agents which increase anxiety. Anxiolytic medications are used for the treatment of anxie ...

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 A cyclic compound (or ring compound) is a term for a compound in the field of chemistry in which one or more series of atoms in the compound is connected to form a ring. Rings may vary in size from three to many atoms, and include examples where ...

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 ...

isopropylamine Isopropylamine (also known as monoisopropyl amine, MIPA, or 2-propylamine) is an organic compound, an amine. It is a hygroscopic colorless liquid with ammonia-like odor. It is miscible with water and flammable. It is a valuable intermediate in c ...

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 A structure is an arrangement and organization of interrelated elements in a material object or system, or the object or system so organized. Material structures include man-made objects such as buildings and machines and natural objects such as ...

as a

substituted phenethylamine Substituted phenethylamines (or simply phenethylamines) are a chemical class of organic compounds that are based upon the phenethylamine structure; the class is composed of all the derivative (chemistry), derivative compounds of phenethylamine ...

and

, or more specifically as a

phenylcyclopropylamine Phenylcyclopropylamines, or 2-phenylcyclopropylamines, also known as phenylcypromines, are phenethylamine and amphetamine derivatives in which the alkyl side chain has been cyclized into a cyclopropyl ring. Examples include the monoamine oxidase ...

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 ''Atypical'' is an American comedy-drama television series created by Robia Rashid for Netflix. The series takes place in Connecticut, and focuses on the life of 18-year-old Samuel "Sam" Gardner ( Keir Gilchrist), who is autistic. The first ...

, 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 Reuptake inhibitors (RIs) are a type of reuptake modulators. It is a drug that inhibits the plasmalemmal transporter-mediated reuptake of a neurotransmitter from the synapse into the pre-synaptic neuron. This leads to an increase in extracel ...

antidepressants, such as the

SSRIs Selective serotonin reuptake inhibitors (SSRIs) are a class of drugs that are typically used as antidepressants in the treatment of major depressive disorder, anxiety disorders, and other psychological conditions. SSRIs primarily work by blo ...

TCAs A traffic alert and collision avoidance system (TCAS), pronounced ), also known as an Airborne Collision Avoidance System (ACAS), is an aircraft collision avoidance system designed to reduce the incidence of mid-air collision (MAC) between aircraf ...

, or

bupropion Bupropion, formerly called amfebutamone, and sold under the brand name Wellbutrin among others, is an atypical antidepressant that is indicated in the treatment of major depressive disorder, seasonal affective disorder, and to support smo ...

. 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 Panic disorder is a mental disorder, specifically an anxiety disorder, characterized by reoccurring unexpected panic attacks. Panic attacks are sudden periods of intense fear that may include palpitations, sweating, shaking, shortness of breath ...

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 antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants. TCAs were discovered in the early 1950s and were marketed later in the decade. They are named after their chemical structure, which contains ...

Contraindications

Contraindications include: *

Porphyria Porphyria ( or ) is a group of disorders in which substances called porphyrins build up in the body, adversely affecting the skin or nervous system. The types that affect the nervous system are also known as Porphyria#Acute porphyrias, acute p ...

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 ...

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 Pheochromocytoma is a rare tumor of the adrenal medulla composed of chromaffin cells and is part of the paraganglioma (PGL) family of tumors, being defined as an intra-adrenal PGL. These neuroendocrine tumors can be sympathetic, where they relea ...

Tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...

, 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 Severely elevated blood pressure (equal to or greater than 180 mmHg systolic or 120 mmHg diastolic) is referred to as a hypertensive crisis (sometimes termed malignant or accelerated hypertension), due to the high risk of complications. People ...

. * Concomitant use of serotonin-enhancing drugs, including

, serotonergic

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 Pethidine, also known as meperidine and sold under the brand name Demerol among others, is a fully synthetic opioid pain medication of the phenylpiperidine class. Synthesized in 1938 as a potential anticholinergic agent by the German chemist Ot ...

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 Ras-related protein M-Ras, also known as muscle RAS oncogene homolog and R-Ras3, is a protein that in humans is encoded by the ''MRAS'' gene on chromosome 3. It is ubiquitously expressed in many tissues and cell types. This protein functions as a ...

, including

fenfluramine Fenfluramine, sold under the brand name Fintepla, is a serotonergic medication used for the treatment of seizures associated with Dravet syndrome and Lennox–Gastaut syndrome. It was formerly used as an appetite suppressant in the treat ...

, and

pseudoephedrine Pseudoephedrine, sold under the brand name Sudafed among others, is a sympathomimetic medication which is used as a decongestant to treat nasal congestion. It has also been used off-label for certain other indications, like treatment of lo ...

may cause toxicity via serotonin syndrome or

. * L-DOPA given without

carbidopa Carbidopa, sold under the brand name Lodosyn, is a medication given to people with Parkinson's disease in order to inhibit peripheral metabolism of levodopa. This property is significant in that it allows a greater proportion of administered levo ...

may cause hypertensive crisis.

Dietary restrictions

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 Monoamine oxidase A, also known as MAO-A, is an enzyme ( 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 the oxidative deamin ...

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 Orthostatic hypotension, also known as postural hypotension, is a medical condition wherein a person's blood pressure drops when they are standing up ( orthostasis) or sitting down. Primary orthostatic hypotension is also often referred to as ne ...

(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 Xerostomia, also known as dry mouth, is a subjective complaint of dryness in the mouth, which may be associated with a change in the composition of saliva, reduced salivary flow, or have no identifiable cause. This symptom is very common and is o ...

(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 Edema (American English), also spelled oedema (British English), and also known as fluid retention, swelling, dropsy and hydropsy, is the build-up of fluid in the body's tissue (biology), tissue. Most commonly, the legs or arms are affected. S ...

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 Hyperreflexia is overactive or overresponsive bodily reflexes. Examples of this include twitching and spastic tendencies, which indicate disease of the upper motor neurons and the lessening or loss of control ordinarily exerted by higher brain ...

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 Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...

* Leg cramps *

Myalgia Myalgia or muscle pain is a painful sensation evolving from muscle tissue. It is a symptom of many diseases. The most common cause of acute myalgia is the overuse of a muscle or group of muscles; another likely cause is viral infection, espec ...

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 Suicidal ideation, or suicidal thoughts, is the thought process of having ideas or ruminations about the possibility of dying by suicide.World Health Organization, ''ICD-11 for Mortality and Morbidity Statistics'', ver. 09/2020MB26.A Suicidal i ...

* 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 Weight gain is an increase in body weight. This can involve an increase in muscle mass, fat deposits, excess fluids such as water or other factors. Weight gain can be a symptom of a serious medical condition. Description Weight gain occurs ...

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

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

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 Cytochrome P450 2A6 (abbreviated CYP2A6) is a member of the cytochrome P450 mixed-function oxidase system, which is involved in the metabolism of xenobiotics in the body. CYP2A6 is the primary enzyme responsible for the oxidation of nicotine an ...

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

-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

, which may reduce the metabolism and increase the toxicity of substrates of this enzyme, such as: *

Dexmedetomidine Dexmedetomidine, sold under the brand name Precedex among others, is a medication used for sedation. Veterinarians use dexmedetomidine for similar purposes in treating cats, dogs, and horses. It is also used in humans to treat acute agitation as ...

nicotine Nicotine is a natural product, naturally produced alkaloid in the nightshade family of plants (most predominantly in tobacco and ''Duboisia hopwoodii'') and is widely used recreational drug use, recreationally as a stimulant and anxiolytic. As ...

* 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 Valproate (valproic acid, VPA, sodium valproate, and valproate semisodium forms) are medications primarily used to treat epilepsy and bipolar disorder and prevent migraine headaches. They are useful for the prevention of seizures in those with ...

Norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

s prevent neuronal uptake of

tyramine Tyramine ( ) (also spelled tyramin), also known under several other names, is a naturally occurring trace amine derived from the amino acid tyrosine. Tyramine acts as a catecholamine releasing agent. Notably, it is unable to cross the bl ...

and may reduce its

pressor An antihypotensive, also known as a vasopressor, is an agent that raises blood pressure by constricting blood vessels, thereby increasing systemic vascular resistance. This is different from inotropes which increase the force of cardiac contrac ...

effects.

Pharmacology

Pharmacodynamics

Tranylcypromine acts as a nonselective and irreversible inhibitor of monoamine oxidase. Regarding the

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...

s of monoamine oxidase, it shows slight preference for the

MAOB Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyze ...

isoenzyme In biochemistry, isozymes (also known as isoenzymes or more generally as multiple forms of enzymes) are enzymes that differ in amino acid sequence but catalyze the same chemical reaction. Isozymes usually have different kinetic parameters (e.g. di ...

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 Monoamine neurotransmitters are neurotransmitters and neuromodulators that contain one amino group connected to an aromaticity, aromatic ring by a two-carbon chain (such as -CH2-CH2-). Examples are dopamine, norepinephrine and serotonin. All m ...

, 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, ...

, 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 Tryptamine is an indolamine metabolite of the essential amino acid tryptophan. The chemical structure is defined by an indole—a fused benzene and pyrrole ring, and a 2-aminoethyl group at the second carbon (third aromatic atom, with the firs ...

octopamine Octopamine (OA), also known as ''para''-octopamine and norsynephrine among synonyms, is an organic chemical closely related to norepinephrine, and synthesized biologically by a homologous pathway. Octopamine is often considered the major "fig ...

, and

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

. The clinical relevance of increased trace amine availability is unclear. It may also act as a

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epinep ...

at higher therapeutic doses. Compared to

, tranylcypromine shows low potency as a

releasing agent A monoamine releasing agent (MRA), or simply monoamine releaser, is a drug that induces the release of one or more monoamine neurotransmitters from the presynaptic neuron into the synapse, leading to an increase in the extracellular concentrati ...

, with even weaker potency for

and

release. Tranylcypromine has also been shown to inhibit the

histone In biology, histones are highly basic proteins abundant in lysine and arginine residues that are found in eukaryotic cell nuclei and in most Archaeal phyla. They act as spools around which DNA winds to create structural units called nucleosomes ...

demethylase, BHC110/

LSD1 Lysine-specific histone demethylase 1A (LSD1) also known as lysine (K)-specific demethylase 1A (KDM1A) is a protein that in humans is encoded by the ''KDM1A'' gene. LSD1 is a flavin-dependent monoamine oxidase, which can demethylate mono- and ...

. 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. Tranylcypromine-MAO-inhibiton

Pharmacokinetics

Tranylcypromine reaches its maximum concentration (t_max) 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

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 Analog or analogue may refer to: Computing and electronics * Analog signal, in which information is encoded in a continuous variable ** Analog device, an apparatus that operates on analog signals *** Analog electronics, circuits which use analog ...

. Although it was first synthesized in 1948, its MAOI action was not discovered until 1959. Precisely because tranylcypromine was not, like

isoniazid Isoniazid, also known as isonicotinic acid hydrazide (INH), is an antibiotic used for the treatment of tuberculosis. For active tuberculosis, it is often used together with rifampicin, pyrazinamide, and either streptomycin or ethambutol. F ...

and

iproniazid Iproniazid (Marsilid, Rivivol, Euphozid, Iprazid, Ipronid, Ipronin) is a non-selective, irreversible inhibition, irreversible monoamine oxidase inhibitor (MAOI) of the hydrazine (antidepressant), hydrazine class. It is a xenobiotic that was origi ...

, a

derivative, its clinical interest increased enormously, as it was thought it might have a more acceptable

therapeutic index The therapeutic index (TI; also referred to as therapeutic ratio) is a quantitative measurement of the relative safety of a drug with regard to risk of overdose. It is a comparison of the amount of a therapeutic agent that causes toxicity to the ...

than previous MAOIs. The drug was introduced by

Smith, Kline and French Smith, Kline & French (SKF) was an American pharmaceutical company that is now a part of the British group GSK plc. History In 1830, John K. Smith opened a drugstore in Philadelphia, and his younger brother, George, joined him in 1841 to form J ...

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

, 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 Monoamine oxidase B (MAO-B) is an enzyme that in humans is encoded by the ''MAOB'' gene. The protein encoded by this gene belongs to the flavin monoamine oxidase family. It is an enzyme located in the outer mitochondrial membrane. It catalyze ...

inhibitors

selegiline Selegiline, also known as L-deprenyl and sold under the brand names Eldepryl, Zelapar, and Emsam among others, is a medication which is used in the treatment of Parkinson's disease and major depressive disorder. It has also been studied and us ...

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.

References

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

Medical uses

Contraindications

Dietary restrictions

Adverse effects

Interactions

Pharmacology

Pharmacodynamics

Pharmacokinetics

Chemistry

Synthesis

History

Research

See also

References