46-514: Monoamine oxidase inhibitors ( MAOIs ) are a 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 antidepressants , especially for treatment-resistant depression and atypical depression . They are also used to treat panic disorder , social anxiety disorder , Parkinson's disease , and several other disorders. Reversible inhibitors of monoamine oxidase A ( RIMAs ) are
92-552: A gate . Depending on the substrate or bound inhibitor, it can exist in either an open or a closed form, which has been shown to be important in defining the inhibitor specificity of hMAO-B. At the end of the substrate cavity is the FAD cofactor with sites for favorable amine binding about the flavin involving two nearly parallel tyrosyl (398 and 435) residues that form what has been termed an aromatic cage . Like MAO-A, MAO-B catalyzes O 2 -dependent oxidation of primary arylalkyl amines ,
138-403: A hypertensive crisis may result due to tyramine food interactions. Tyramine is broken down by MAO-A and MAO-B, therefore inhibiting this action may result in its excessive build-up, so diet must be monitored for tyramine intake. MAO-B inhibition reduces the breakdown mainly of dopamine and phenethylamine , so there are no associated dietary restrictions. MAO-B would also metabolize tyramine, as
184-424: A hypertensive crisis , which can be fatal. Examples of foods and beverages with potentially high levels of tyramine include cheese, Chianti wine , and pickled fish. Excessive concentrations of tyramine in blood plasma can lead to hypertensive crisis by increasing the release of norepinephrine (NE) , which causes blood vessels to constrict by activating alpha-1 adrenergic receptors . Ordinarily, MAO-A would destroy
230-486: A common molecular mechanism of action modulate the activity of a specific biological target . The definition of a mechanism of action also includes the type of activity at that biological target. For receptors, these activities include agonist , antagonist , inverse agonist , or modulator . Enzyme target mechanisms include activator or inhibitor . Ion channel modulators include opener or blocker . The following are specific examples of drug classes whose definition
276-418: A gradual reduction in dosage over a period of days, weeks or sometimes months to minimize or prevent withdrawal symptoms. MAOIs, as with most antidepressant medication, may not alter the course of the disorder in a significant, permanent way, so it is possible that discontinuation can return the patient to the pre-treatment state. This consideration complicates prescribing between an MAOI and an SSRI, because it
322-475: A hierarchy. For example, fibrates are a chemical class of drugs (amphipathic carboxylic acids) that share the same mechanism of action ( PPAR agonist ), the same mode of action (reducing blood triglyceride levels), and are used to prevent and treat the same disease ( atherosclerosis ). However, not all PPAR agonists are fibrates, not all triglyceride-lowering agents are PPAR agonists, and not all drugs used to treat atherosclerosis lower triglycerides. A drug class
368-674: A reduction in dietary and drug interactions. Moclobemide , was the first reversible inhibitor of MAO-A to enter widespread clinical practice. A transdermal patch form of the MAOI selegiline , called Emsam , was approved for use in depression by the Food and Drug Administration in the United States on 28 February 2006. Linezolid is an antibiotic drug with weak, reversible MAO-inhibiting activity. The antibiotic furazolidone also has MAO-inhibiting activity Methylene blue (methylthioninium chloride),
414-493: A result, the use by medical practitioners of these older MAOIs declined. When scientists discovered that there are two different MAO enzymes (MAO-A and MAO-B), they developed selective compounds for MAO-B, (for example, selegiline , which is used for Parkinson's disease), to reduce the side-effects and serious interactions. Further improvement occurred with the development of compounds ( moclobemide and toloxatone ) that not only are selective but cause reversible MAO-A inhibition and
460-401: A reversible inhibitor of MAO-A (i.e., moclobemide ) or low doses of selective MAO-B inhibitors (e.g., selegiline 6 mg/24 hours transdermal patch ). The most significant risk associated with the use of MAOIs is the potential for drug interactions with over-the-counter, prescription, or illegally obtained medications, and some dietary supplements (e.g., St. John's wort or tryptophan ). It
506-539: A role in stress-induced cardiac damage. Over- expression and increased levels of MAO-B in the brain have also been linked to the accumulation of amyloid β-peptides ( Aβ ), through mechanisms of the amyloid precursor protein secretase , γ-secretase , responsible for the development of plaques, observed in Alzheimer's and Parkinson's patients. Evidence suggests that siRNA silencing of MAO-B, or inhibition of MAO-B through MAO-B inhibitors ( Selegline , Rasagiline ), slows
SECTION 10
#1733085083269552-554: A subclass of MAOIs that selectively and reversibly inhibit the MAO-A enzyme. RIMAs are used clinically in the treatment of depression and dysthymia . Due to their reversibility, they are safer in single-drug overdose than the older, irreversible MAOIs, and weaker in increasing the monoamines important in depressive disorder. RIMAs have not gained widespread market share in the United States. MAOIs have been found to be effective in
598-557: Is a group of medications and other compounds that share similar chemical structures , act through the same mechanism of action (i.e., binding to the same biological target ), have similar modes of action , and/or are used to treat similar diseases. The FDA has long worked to classify and license new medications. Its Drug Evaluation and Research Center categorizes these medications based on both their chemical and therapeutic classes. In several major drug classification systems, these four types of classifications are organized into
644-501: Is also involved in the catabolism of dopamine . MAO-B has a hydrophobic bipartite elongated cavity that (for the "open" conformation) occupies a combined volume close to 700 Å . hMAO-A has a single cavity that exhibits a rounder shape and is larger in volume than the "substrate cavity" of hMAO-B. The first cavity of hMAO-B has been termed the entrance cavity (290 Å ), the second substrate cavity or active site cavity (~390 Å ) – between both an isoleucine 199 side-chain serves as
690-597: 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 catalyzes the oxidative deamination of biogenic and xenobiotic amines and plays an important role in the catabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. This protein preferentially degrades benzylamine and phenethylamine . Similar to monoamine oxidase A (MAO-A), MAO-B
736-410: Is based on a specific mechanism of action: This type of categorisation of drugs is from a biological perspective and categorises them by the anatomical or functional change they induce. Drug classes that are defined by common modes of action (i.e. the functional or anatomical change they induce) include: This type of categorisation of drugs is from a medical perspective and categorises them by
782-411: Is equally deaminated by both types. The early MAOIs covalently bound to the monoamine oxidase enzymes, thus inhibiting them irreversibly; the bound enzyme could not function and thus enzyme activity was blocked until the cell made new enzymes. The enzymes turn over approximately every two weeks. A few newer MAOIs, a notable one being moclobemide , are reversible, meaning that they are able to detach from
828-412: Is necessary to clear the system completely of one drug before starting another. One physician organization recommends the dose to be tapered down over a minimum of four weeks, followed by a two-week washout period. The result is that a depressed patient will have to bear the depression without chemical help during the drug-free interval. This may be preferable to risking the effects of an interaction between
874-527: Is thus composed by one element ("anti-inflammatory") that designates the mechanism of action, and one element ("nonsteroidal") that separates it from other drugs with that same mechanism of action. Similarly, one might argue that the class of disease-modifying anti-rheumatic drugs (DMARD) is composed by one element ("disease-modifying") that albeit vaguely designates a mechanism of action, and one element ("anti-rheumatic drug") that indicates its therapeutic use. Other systems of drug classification exist, for example
920-493: Is typically defined by a prototype drug , the most important, and typically the first developed drug within the class, used as a reference for comparison. This type of categorisation of drugs is from a chemical perspective and categorises them by their chemical structure. Examples of drug classes that are based on chemical structures include: This type of categorisation is from a pharmacological perspective and categorises them by their biological target. Drug classes that share
966-839: Is vital that a doctor supervise such combinations to avoid adverse reactions. For this reason, many users carry an MAOI-card, which lets emergency medical personnel know what drugs to avoid (e.g. adrenaline [epinephrine] dosage should be reduced by 75%, and duration is extended). Tryptophan supplements can be consumed with MAOIs, but can result in transient serotonin syndrome . MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, including prescribed, OTC and illegally acquired drugs, etc.) except under expert care. Certain combinations can cause lethal reactions; common examples include SSRIs , tricyclics , MDMA , meperidine , tramadol , and dextromethorphan , whereas combinations with LSD , psilocybin , or DMT appear to be relatively safe. Drugs that affect
SECTION 20
#17330850832691012-732: The Biopharmaceutics Classification System which determines a drugs' attributes by solubility and intestinal permeability. Monoamine oxidase B 1GOS , 1OJ9 , 1OJA , 1OJC , 1OJD , 1S2Q , 1S2Y , 1S3B , 1S3E , 2BK3 , 2BK4 , 2BK5 , 2BYB , 2C64 , 2C65 , 2C66 , 2C67 , 2C70 , 2C72 , 2C73 , 2C75 , 2C76 , 2V5Z , 2V60 , 2V61 , 2VRL , 2VRM , 2VZ2 , 2XCG , 2XFN , 2XFO , 2XFP , 2XFQ , 2XFU , 3PO7 , 3ZYX , 4A79 , 4A7A , 4CRT 4129 109731 ENSG00000069535 ENSMUSG00000040147 P27338 Q8BW75 NM_000898 NM_172778 NP_000889 NP_766366 Monoamine oxidase B ( MAO-B )
1058-507: The gastrointestinal tract . In 2021, it was discovered that MAO-A completely or almost completely mediates striatal dopamine catabolism in the rodent brain and that MAO-B is not importantly involved. In contrast, MAO-B appears to mediate γ-aminobutyric acid (GABA) synthesis from putrescine in the striatum, a minor and alternative metabolic pathway of GABA synthesis, and this synthesized GABA in turn inhibits dopaminergic neurons in this brain area. MAO-B specifically mediates
1104-650: The nicotine . While safer than general MAOIs, RIMAs still possess significant and potentially serious drug interactions with many common drugs; in particular, they can cause serotonin syndrome or hypertensive crisis when combined with almost any antidepressant or stimulant , common migraine medications, certain herbs, or most cold medicines (including decongestants , antihistamines , and cough syrup ). Ocular alpha-2 agonists such as brimonidine and apraclonidine are glaucoma medications which reduce intraocular pressure by decreasing aqueous production. These alpha-2 agonists should not be given with oral MAOIs due to
1150-441: The transformations of putrescine into γ-aminobutyraldehyde (GABAL or GABA aldehyde) and N -acetylputrescine into N -acetyl-γ-aminobutyraldehyde ( N -acetyl-GABAL or N -acetyl-GABA aldehyde). These findings may warrant a rethinking of the actions of MAO-B inhibitors in the treatment of Parkinson's disease . Alzheimer's disease (AD) and Parkinson's disease (PD) are both associated with elevated levels of MAO-B in
1196-440: The 2 isoenzymes of MAO has led to the development of selective MAOIs that may have a more favorable side-effect profile. The older MAOIs' heyday was mostly between the years 1957 and 1970. The initial popularity of the 'classic' non-selective irreversible MAO inhibitors began to wane due to their serious interactions with sympathomimetic drugs and tyramine -containing foods that could lead to dangerous hypertensive emergencies. As
1242-530: The anti-aging effects of selegiline in animals are due to its catecholaminergic activity enhancer actions rather than MAO-B inhibition. While people lacking the gene for MAO-A display intellectual disabilities and behavioral abnormalities, people lacking the gene for MAO-B display no abnormalities except elevated phenethylamine levels in urine. Newer research indicates the importance of phenethylamine and other trace amines , which are now known to regulate catecholamine and serotonin neurotransmission through
1288-589: The antidote indicated for drug-induced methemoglobinemia on the World Health Organization's List of Essential Medicines , among a plethora of other off-label uses, is a highly potent, reversible MAO inhibitor. The Food and Drug Administration (FDA) has approved these MAOIs to treat depression: Marketed pharmaceuticals Other pharmaceuticals Naturally occurring RIMAs in plants Only reversible phytochemical MAOIs have been characterized. Research compounds Drug class A drug class
1334-540: The brain. The normal activity of MAO-B creates reactive oxygen species , which directly damage cells. MAO-B levels have been found to increase with age, suggesting a role in natural age related cognitive decline and the increased likelihood of developing neurological diseases later in life. More active polymorphisms of the MAO-B gene have been linked to negative emotionality , and suspected as an underlying factor in depression . Activity of MAO-B has also been shown to play
1380-607: The enzyme to facilitate usual catabolism of the substrate . The level of inhibition in this way is governed by the concentrations of the substrate and the MAOI. Harmaline found in Peganum harmala , Banisteriopsis caapi , and Passiflora incarnata is a reversible inhibitor of monoamine oxidase A (RIMA). In addition to reversibility, MAOIs differ by their selectivity of the MAO enzyme subtype. Some MAOIs inhibit both MAO-A and MAO-B equally, other MAOIs have been developed to target one over
1426-546: The excess NE; when MAO-A is inhibited, however, NE levels get too high, leading to dangerous increases in blood pressure. RIMAs are displaced from MAO-A in the presence of tyramine , rather than inhibiting its breakdown in the liver as general MAOIs do. Additionally, MAO-B remains free and continues to metabolize tyramine in the stomach, although this is less significant than the liver action. Thus, RIMAs are unlikely to elicit tyramine-mediated hypertensive crisis; moreover, dietary modifications are not usually necessary when taking
Monoamine oxidase inhibitor - Misplaced Pages Continue
1472-499: The imine is hydrolyzed by water, forming ammonia and the aldehyde. MAO-A generally metabolizes tyramine , norepinephrine , serotonin , and dopamine (and other less clinically relevant chemicals). In contrast, MAO-B metabolizes dopamine and β-phenethylamine , as well as other less clinically relevant chemicals. The differences between the substrate selectivity of the two enzymes are utilized clinically when treating specific disorders; MAO-A inhibitors have been typically used in
1518-476: The initial step in the breakdown of these molecules. The products are the corresponding aldehyde , hydrogen peroxide , and ammonia : This reaction is believed to occur in three steps. First, the amine is oxidized to the corresponding imine , with reduction of the FAD cofactor to FADH 2 . Second, O 2 accepts two electrons and two protons from FADH 2 , forming H 2 O 2 and regenerating FAD. Third,
1564-406: The only differences between dopamine, phenethylamine, and tyramine are two phenylhydroxyl groups on carbons 3 and 4. The 4-OH would not be a steric hindrance to MAO-B on tyramine. Selegiline is selective for MAO-B at low doses, but non-selective at higher doses. The knowledge of MAOIs began with the serendipitous discovery that iproniazid was a potent MAO inhibitor (MAOI). Originally intended for
1610-416: The other. MAO-A inhibition reduces the breakdown of primarily serotonin, norepinephrine, and dopamine; selective inhibition of MAO-A allows for tyramine to be metabolised via MAO-B. Agents that act on serotonin, if taken with another serotonin-enhancing agent, may result in a potentially fatal interaction called serotonin syndrome ; if taken with irreversible and unselective inhibitors (such as older MAOIs)
1656-487: The pathology they are used to treat. Drug classes that are defined by their therapeutic use (the pathology they are intended to treat) include: Some drug classes have been amalgamated from these three principles to meet practical needs. The class of nonsteroidal anti-inflammatory drugs (NSAIDs) is one such example. Strictly speaking, and also historically, the wider class of anti-inflammatory drugs also comprises steroidal anti-inflammatory drugs . These drugs were in fact
1702-400: The predominant anti-inflammatories during the decade leading up to the introduction of the term "nonsteroidal anti-inflammatory drugs." Because of the disastrous reputation that the corticosteroids had got in the 1950s, the new term, which offered to signal that an anti-inflammatory drug was not a steroid, rapidly gained currency. The drug class of "nonsteroidal anti-inflammatory drugs" (NSAIDs)
1748-709: The progression, improves and reverses the symptoms, associated with AD and PD, including the reduction of Aβ plaques in the brain. Transgenic mice that are unable to produce MAO-B are shown to be resistant to a mouse model of Parkinson's disease. They also demonstrate increased responsiveness to stress (as with MAO-A knockout mice ) and increased β-PEA . In addition, they exhibit behavioral disinhibition and reduced anxiety-like behaviors. Treatment with selegiline , an MAO-B inhibitor, in rats has been shown to prevent many age-related biological changes, such as optic nerve degeneration , and extend average lifespan by up to 39%. However, subsequent research suggests that
1794-451: The release or reuptake of epinephrine, norepinephrine, serotonin or dopamine typically need to be administered at lower doses due to the resulting potentiated and prolonged effect. MAOIs also interact with tobacco -containing products (e.g. cigarettes) and may potentiate the effects of certain compounds in tobacco. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally occurring MAOI compounds in addition to
1840-419: The risk of hypertensive crisis. Antidepressants including MAOIs have some dependence -producing effects, the most notable one being a discontinuation syndrome , which may be severe especially if MAOIs are discontinued abruptly or too rapidly. The dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines , however. Discontinuation symptoms can be managed by
1886-661: The treatment of panic disorder with agoraphobia , social phobia , atypical depression or mixed anxiety disorder and depression, bulimia , and post-traumatic stress disorder , as well as borderline personality disorder , and obsessive–compulsive disorder (OCD). MAOIs appear to be particularly effective in the management of bipolar depression according to a retrospective-analysis from 2009. There are reports of MAOI efficacy in OCD, trichotillomania , body dysmorphic disorder , and avoidant personality disorder , but these reports are from uncontrolled case reports. MAOIs can also be used in
Monoamine oxidase inhibitor - Misplaced Pages Continue
1932-470: The treatment of Parkinson's disease by targeting MAO-B in particular (therefore affecting dopaminergic neurons ), as well as providing an alternative for migraine prophylaxis . Inhibition of both MAO-A and MAO-B is used in the treatment of clinical depression and anxiety . MAOIs appear to be particularly indicated for outpatients with dysthymia complicated by panic disorder or hysteroid dysphoria . Newer MAOIs such as selegiline (typically used in
1978-474: The treatment of Parkinson's disease) and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy. Pargyline is a non-selective MAOI that was previously used as an antihypertensive agent to treat hypertension (high blood pressure). People taking MAOIs generally need to change their diets to limit or avoid foods and beverages containing tyramine . If large amounts of tyramine are consumed, they may develop
2024-554: The treatment of depression, whereas MAO-B inhibitors are typically used in the treatment of Parkinson's disease. Concurrent use of MAO-A inhibitors with sympathomimetic drugs can induce a hypertensive crisis as a result of excessive norepinephrine. Likewise, the consumption of tyramine-containing substances, such as cheese, whilst using MAO-A inhibitors also carries the risk of hypertensive crisis. Selective MAO-B inhibitors bypass this problem by preferentially inhibiting MAO-B, which allows tyramine to be metabolized freely by MAO-A in
2070-410: The treatment of tuberculosis, in 1952, iproniazid's antidepressant properties were discovered when researchers noted that the depressed patients given iproniazid experienced a relief of their depression. Subsequent in vitro work led to the discovery that it inhibited MAO and eventually to the monoamine theory of depression . MAOIs became widely used as antidepressants in the early 1950s. The discovery of
2116-527: The two drugs. MAOIs act by inhibiting the activity of monoamine oxidase , thus preventing the breakdown of monoamine neurotransmitters and thereby increasing their availability. There are two isoforms of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deaminates serotonin , melatonin , epinephrine , and norepinephrine . MAO-B preferentially deaminates phenethylamine and certain other trace amines ; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine , whereas dopamine
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