Monoamine oxidase inhibitor
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{{redirect|MAOI|the Easter Island statues|Moai}}
[[Image:MonoamineOxidase-1GOS.png|thumb|[[Monoamine oxidase]]]]
'''Monoamine oxidase inhibitors''' ('''MAOIs''') are a class of powerful [[Antidepressant|antidepressant drug]]s prescribed for the treatment of [[clinical depression|depression]]. They are particularly effective in treating [[atypical depression]], and have also shown [[efficacy]] in smoking cessation.
Due to potentially lethal dietary and drug interactions, MAOIs had been reserved as a last line of defense, used only when other classes of antidepressant drugs (for example [[selective serotonin reuptake inhibitor]]s and [[tricyclic antidepressants]]) have been tried unsuccessfully. Recently, however, a patch form of the drug [[selegiline]], called [[Emsam]], was developed. It was approved for use by the FDA on [[February 28]], [[2006]].<ref name="Emsam">{{cite press release
| title = "FDA Approves Emsam (Selegiline) as First Drug Patch for Depression."
| publisher = U.S. [[Food and Drug Administration]]
| date = 2006-02-28
| url = http://www.fda.gov/bbs/topics/NEWS/2006/NEW01326.html
| accessdate = 2007-12-02
}}</ref> When applied transdermally the drug does not enter the gastro-intestinal system as it does when taken orally, thereby decreasing the dangers of dietary interactions associated with MAOI pills.
==Uses==
=== Therapeutic use ===
In the past they were prescribed for those resistant to [[tricyclic antidepressant]] therapy, but newer MAOIs are now sometimes used as first-line therapy. They are also used for treating [[agoraphobia]] or [[social anxiety]]. Currently, the availability of [[selegiline]] and [[moclobemide]] provides a safer alternative, although these substances are not always as effective as their predecessors.
MAO inhibitors can also be used in the treatment of [[Parkinson's disease]] (by affecting [[dopaminergic neuron]]s), as well as providing an alternative for [[migraine]] [[prophylaxis]].
== Mode of action ==
MAOIs act by inhibiting the activity of [[monoamine oxidase]] preventing the breakdown of [[monoamine]] [[neurotransmitter]]s, which increases their availability. There are two [[isoform]]s of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially [[deamination| deaminates]] [[serotonin]], [[melatonin]], [[epinephrine]] and [[norepinephrine]]. MAO-B preferentially deaminates [[phenylethylamine]] and [[trace amine]]s. [[Dopamine]] is equally deaminated by both types. Many formulations have forms of [[fluoride]] attached to assist in permeating the [[blood-brain barrier]], which is suspected as a factor in [[pineal gland]] effects.
=== Reversibility ===
The early MAOIs inhibited monoamine oxidase irreversibly. When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it has been replaced by the body, which can take about two weeks. A few newer MAOIs, notably [[moclobemide]], are reversible, meaning that they are able to detach from the enzyme to facilitate usual [[catabolism]] of the [[Substrate (biochemistry)| substrate]]. The level of inhibition in this way is governed by the respective concentrations of the substrate and the MAOI.
[[Harmaline]] found in ''[[Peganum harmala]]'' is a "reversible inhibitor of MAO-A ([[RIMA]])."<ref>[http://books.google.com/books?id=2c2K-epbCDQC&pg=PA237&lpg=PA237&dq=harmaline+antidepressant&source=web&ots=IrcpVr4R_H&sig=5FvlysKKEN7Hb4_YjfgoZM8rsTg Edward J. Massaro, Handbook of Neurotoxicology]</ref>
=== Selectivity ===
In addition to reversibility, MAOIs differ by their selectivity of the MAO receptor. Some MAOIs inhibit both MAO-A and MAO-B equally, other MAOIs have been developed that target one over the other.
MAO-A inhibition reduces the breakdown of primarily [[serotonin]], [[epinephrine]], and [[norepinephrine]] and thus has a higher risk of [[serotonin syndrome]] and/or a [[hypertensive crisis]]. [[Tyramine]] is broken down by MAO-A, therefore inhibiting its action may result in excessive build up of it, so diet must be monitored for tyramine intake.
MAO-B inhibition reduces the breakdown mainly of [[dopamine]] and [[phenethylamine]] so there are no dietary restrictions associated with this. Two such drugs, [[selegiline]] and [[rasagiline]] have been approved by the FDA without dietary restrictions, except in high dosage treatment where they lose their [[Selectivity (pharmacology)| selectivity]].<ref name="Emsam"/><ref>{{cite web
| url = http://www.elitenetpharmacy.com/pd_azilect.cfm
| title = Rasagiline: a neuroprotective smart drug?
| accessdate = 2007-12-02
| author = [[BLTC Research]] [http://www.bltc.com/]
| year = 2006
| work = The Good Drug Guide
| quote = At dosages above around 2 mg per day, rasagiline loses its selectivity for MAO type B and also inhibits MAO type A. An MAO-B selective regimen does not cause significant [[tyramine]] [[potentiation]], the dreaded 'cheese effect' common to users of older unselective and irreversible MAOIs who eat tyramine-rich foods. Thus low-dosage rasagiline demands no special dietary restrictions.
}}</ref>
== Dangers ==
When ingested orally, MAOIs inhibit the catabolism of dietary amines. Sufficient intestinal MAO-A inhibition can lead to [[hypertensive crisis]], when foods containing [[tyramine]] are consumed (so-called "[[cheese syndrome]]"), or [[serotonin syndrome|hyperserotonemia]] if foods containing [[tryptophan]] are consumed. The amount required to cause a reaction exhibits great individual variation and depends on the degree of inhibition, which in turn depends on dosage and selectivity.
The exact mechanism by which tyramine causes a hypertensive reaction is not well understood, but it is assumed that tyramine displaces norepinephrine from the storage vesicles.<ref>{{cite journal
| last = Jacob
| first = Giris
| coauthors = Gamboa, Alfredo; Diedrich, André; Shibao, Cyndya; Robertson, David; Biaggioni, Italo
| year = 2005
| month = August
| title = Tyramine-Induced Vasodilation Mediated by Dopamine Contamination: A Paradox Resolved
| journal = Hypertension
| volume = 46
| issue = 2
| pages = 358
| publisher = Lippincott Williams & Wilkins
| doi = 10.1161/01.HYP.0000172353.62657.8b
| url = http://pt.wkhealth.com/pt/re/hyper/pdfhandler.00004268-200508000-00023.pdf
| accessdate = 2007-12-02
| quote = Tyramine displaces norepinephrine from neuronal vesicles into the axoplasm, and it is likely that some of it is converted to DHPG, and only a portion reaches the circulation.
| pmid = 15967868
}}</ref> This may trigger a cascade in which excessive amounts of norepinephrine can lead to a hypertensive crisis. Another theory suggests that proliferation and accumulation of [[catecholamines]] causes hypertensive crises.
[[Tyrosine]] is the precursor to catecholamines, not tyramine. Tyramine is a breakdown product of tyrosine. In the gut and during fermentation tyrosine, an amino acid, is [[Decarboxylation|decarboxylated]] to tyramine. Ordinarily, tyramine is deaminated in the [[liver]] to an inactive metabolite, but when the hepatic MAO (primarily MAO-A) is inhibited, the "first-pass" clearance of tyramine is blocked and circulating tyramine levels can climb. Elevated tyramine competes with tyrosine for transport across the blood-brain barrier (via aromatic amino acid transport) where it can then enter [[adrenergic receptor|adrenergic nerve terminals]]. Once in the [[cytoplasm]]ic space, tyramine will be transported via the [[vesicular monoamine transporter]] (VMAT) into synaptic vesicles thereby displacing norepinephrine. The mass transfer of norepinephrine from its vesicular storage space into the extracellular space via mass action can precipitate the hypertensive crisis. Hypertensive crises can sometimes result in stroke or cardiac arrhythmia if not treated. This risk is generally not present with [[RIMA]]s. Both kinds of intestinal MAO inhbition can cause [[hyperpyrexia]], nausea and [[psychosis]] if foods high in [[levodopa]] are consumed.
Chronic use of MAOIs may provide some antidepressant effects that are thought to be mediated by metabolism of tyramine to [[octopamine]], a reaction catalyzed by [[phenyl-N-methyl transferase]] that normally converts dopamine to norepinephrine. Octopamine may then act as a "false transmitter" in that it is stored and released like the endogenous transmitter norepinephrine. However, it is a poor agonist of postsynaptic adrenoceptors while retaining agonist activity at presynaptic autoreceptors. This action reduces adrenergic transmission by diminishing postsynaptic receptor activation and by a presynaptic autoinhibitory effect. Finally, octopamine may serve as an agonist at a novel "trace amine" receptor expressed at low levels throughout the brain.
Examples of foods and drinks with potentially high levels of [[tyramine]] include fermented substances, such as [[Chianti]] and other aged [[wine]]s, and aged [[cheese]]s. [[Liver]] is also a well-known source. (See a [[list of foods containing tyramine]]). Examples of levodopa-containing foods include [[Vicia faba|broad beans]] (also known in the United States as fava beans). These diet restrictions are not necessary for those taking selective MAO-B inhibitors.
It deserves separate mention that some meat extracts and yeast extracts ([[Bovril]], [[Marmite]], [[Vegemite]]) contain extremely high levels of tyramine, and should not be used with these medications.
When MAOIs were first introduced, these risks were not known, and over the following four decades, fewer than 100 people have died from hypertensive crisis.{{Fact|date=December 2007}} Presumably due to the sudden onset and violent appearance of the reaction, MAOIs gained a reputation for being so dangerous that, for a while, they were taken off the market in America entirely. It is now known that, used as directed under the care of a qualified psychiatrist, this class of drugs remains a safe alternative for intermediate- to long-term use.
The most significant risk associated with the use of MAOIs, is the potential for interactions with over-the-counter and prescription medicines, illicit drugs and certain supplements (e.g. [[St. John's Wort]]). It 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 dosage should be reduced by 75%, and duration is extended)
MAOIs should not be combined with other psychoactive substances (antidepressants, illicit drugs, painkillers, stimulants, etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including [[Selective serotonin reuptake inhibitor|SSRI]]s, [[Tricyclic antidepressant|tricyclic]]s, [[MDMA]], [[meperidine]], [[tramadol]], and [[dextromethorphan]]. Agents with actions on epinephrine, norepinephrine or dopamine must be administered at much lower doses due to potentiation and prolonged effect. Purely opiate-acting [[analgesic]]s, such as [[morphine]] and [[buprenorphine]] may be used safely with MAOIs, but may require a dosage adjustment.
===Drug interactions===
{{unreferencedsection|date=December 2007}}
*Sympathomimetics (e.g. [[pseudoephedrine]] in cold remedies)
**Risk of hypertensive crisis
*[[Reserpine]], [[guanethidine]], [[tricyclic antidepressant]]s
**Excitement
**Increase in blood pressure and body temperature
*[[Levodopa]] (L-DOPA)
**Excitement
**Hypertension
*[[Anticholinergic]]s (Henbane, Datura)
**Risk of hallucination
*[[Antihistamine]]s, [[barbiturate]]s, [[ethanol]], [[opioid]]s
**Action of these drugs prolonged - risk of respiratory depression
*[[Pethidine]] (Demerol)
**Risk of high fever, sweating, excitement, delirium, convulsions, respiratory depression (MAOIs retard metabolism of pethidine, but not its demethylation, therefore excess norpethidine is formed).
*[[Methylenedioxymethamphetamine]] (MDMA, "Ecstasy")
**Risk of hypertensive crisis
**[[Serotonin syndrome]]
*[[Dextromethorphan]] (DXM, cough-syrup)
**[[Serotonin syndrome]]
*[[Imitrex]]/Sumatriptan, Migraine Medicine
*[[Dimethyltryptamine]]
**Increases oral activity
**Action of this drug is greatly prolonged
**Dimethyltryptamine is often intentionally combined with MAOIs, and can be found in the psychoactive decoction [[ayahuasca]]
**Dimethyltryptamine is extremly low in toxicity and the interaction is only as dangerous as the MAOI by itself.
== List of MAOIs ==
Monoamine oxidase inhibitors include:
* [[Isocarboxazid]] (Marplan)
* [[Moclobemide]] (Aurorix, Manerix, Moclodura)
* [[Phenelzine]] (Nardil)
* [[Tranylcypromine]] (Parnate contents 5 mg, Jatrosom contents 10 mg)
* [[Selegiline]] (Selegiline, Eldepryl), and [[Emsam]]
* [[Rasagiline]] (Azilect)
* [[Nialamide]]
* [[Iproniazid]] (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida)
* [[Iproclozide]]
* [[Toloxatone]]
* [[Linezolid]] (Zyvox, Zyvoxid), an [[antibiotic]] of the [[oxazolidinone]] family, is a reversible, nonselective MAOI which has been known to induce serotonin syndrome post SSRI ingestion. Zyvox requires the same dietary precautions as other MAOI's
* Many tryptamines have MAOI properties. [[Harmala|Harmine]] (present in [[Harmal]], ''[[Banisteriopsis caapi]]'', and [[tobacco]]) is a powerful MAOI, which is often used as one of the ingredients of [[ayahuasca]]. Certain synthetic tryptamines such as [[Alphamethyltryptamine|AMT]], [[5-MeO-DMT]] or [[5-MeO-AMT]] produce only minor MAO inhibition. The phenethylamine derivatives substituted with a sulfur at the 4-position, such as [[2C-T-7]] are quite potent MAO-A inhibitors,<ref>PMID 17521909 (2007): "Human and rat monoamine oxidase-A are differentially inhibited by (S)-4-alkylthioamphetamine derivatives: insights from molecular modeling studies."</ref> which makes them potentially dangerous when taken in large doses, or when combined with stimulants such as [[ephedrine]] or [[MDMA]]. Some deaths have occurred from such combinations.
* Dienolide [[Kavalactone|kavapyrone]] desmethoxyyangonin (MAOI-B)<ref>PMID 9832350 (1998): "Inhibition of platelet MAO-B by kava pyrone-enriched extract from Piper methysticum Forster (kava-kava)."</ref>
* [[Dextroamphetamine]] [http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2043671]
===Reversible type B selective MAOIs===
====Research [[Lead compound|prototypes]]====
*[[Safinamide]],<ref>PMID 17824599 (2007): "Solid-phase synthesis and insights into structure-activity relationships of safinamide analogues as potent and selective inhibitors of type B monoamine oxidase."</ref> in [[clinical study#Phase III|phase III]] for [[Parkinson's disease]]<ref>PMID 17199024 (2007)</ref>
*Certain [[coumarine]]s ([[umbelliferone]]s)<ref>PMID 17915852 (2007): "Structures of human monoamine oxidase B complexes with selective noncovalent inhibitors: safinamide and coumarin analogs."</ref><ref>PMID 16884303 (2006): "Structural insights into monoamine oxidase inhibitory potency and selectivity of 7-substituted coumarins from ligand- and target-based approaches."</ref> including [[geiparvarin]]<ref>PMID 12443774 (2002): "Natural and synthetic geiparvarins are strong and selective MAO-B inhibitors. Synthesis and SAR studies"</ref>
*5''H''-[[Indane|Indeno]][1,2-c][[pyridazine|pyridazin]]-5-ones<ref>PMID 17910428 (2007): "Synthesis and Monoamine Oxidase Inhibitory Activity of New Pyridazine-, Pyrimidine- and 1,2,4-Triazine-Containing Tricyclic Derivatives"</ref><ref>PMID 12467619 (2003): "Rational approaches towards reversible inhibition of type B monoamine oxidase. Design and evaluation of a novel 5H-Indeno[1,2-c]pyridazin-5-one derivative."</ref><ref>PMID 17034132 (2006): "Impact of Species-Dependent Differences on Screening, Design, and Development of MAO B Inhibitors"</ref>
==References==
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{{Antidepressants}}
{{Enzyme inhibition}}
[[Category:Antidepressants]]
[[Category:Monoamine oxidase inhibitors|*]]
[[de:Monoaminooxidase-Hemmer]]
[[fr:Inhibiteur des monoamine oxydases]]
[[he:מונואמין אוקסידאז]]
[[nl:Monoamino-oxidaseremmer]]
[[ja:モノアミン酸化酵素阻害薬]]
[[pl:Inhibitory monoaminooksydazy]]
[[pt:Antidepressor inibidor da MAO]]
[[fi:Monoamiinioksidaasi-inhibiittori]]