monoamine oxidase inhibitors

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MAOIs

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MAOIs

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MAO-I

WordNet

1. a substance that retards or stops an activity
2. a molecule containing one amine group (especially one that is a neurotransmitter)
3. any of the enzymes that catalyze biological oxidation

PrepTutorEJDIC

1. 抑制する人(物) / 化学反応抑制剤

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/08/15 10:16:59」(JST)

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"MAOI" redirects here. For the Easter Island statues, see Moai.

Monoamine oxidase

Monoamine oxidase inhibitors (MAOIs) are chemicals which inhibit the activity of the monoamine oxidase enzyme family. They have a long history of use as medications prescribed for the treatment of depression. They are particularly effective in treating atypical depression.^{[citation needed]} They are also used in the treatment of Parkinson's Disease and several other disorders.

Because of potentially lethal dietary and drug interactions, monoamine oxidase inhibitors have historically been reserved as a last line of treatment, used only when other classes of antidepressant drugs (for example selective serotonin reuptake inhibitors and tricyclic antidepressants) have failed. New research into MAOIs indicate that much of the concern over their dangerous dietary side effects stems from misconceptions and misinformation, and that despite proven effectiveness of this class of drugs, it is underutilized and misunderstood in the medical profession. New research also questions the validity of the perceived severity of dietary reactions, which has historically been based on outdated research.

Indications

In the past, MAOIs were prescribed for those resistant to tricyclic antidepressant therapy.^{[citation needed]} Newer MAOIs such as selegiline (typically used in the treatment of Parkinson's disease) and the reversible MAOI moclobemide provide a safer alternative and are now sometimes used as first-line therapy. However, these substances are not always as effective as their predecessors.^{[citation needed]}

MAOIs have been found to be effective in the treatment of panic disorder with agoraphobia, social phobia, atypical depression or mixed anxiety and depression, bulimia, and post-traumatic stress disorder, as well as borderline personality disorder.^{[citation needed]} There are reports of MAOI efficacy in obsessive-compulsive disorder (OCD), trichotillomania, dysmorphophobia, and avoidant personality disorder, but these reports are from uncontrolled case reports.

MAOIs can also be used in 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 "neurotic depression" complicated by panic disorder or hysteroid dysphoria, which involves repeated episodes of depressed mood in response to feeling rejected.

Mechanism of action

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 phenylethylamine and trace amines. Dopamine is equally deaminated by both types.

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, a notable one being moclobemide, are reversible, meaning that they are able to detach from 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, as well as the Ayahuasca vine, Banisteriopsis caapi, and Passiflora incarnata are reversible inhibitors of MAO-A (RIMA).

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 to target one over 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 or with irreversible and unselective inhibitors (such as older MAOIs), of MAO a hypertensive crisis as a result of tyramine food interactions is particularly problematic with older MAOIs. 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 dietary restrictions associated with this. MAO-B would also metabolize tyramine, as 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. Two MAO-Bi drugs, selegiline and rasagiline have been approved by the FDA without dietary restrictions, except in high-dosage treatment, wherein they lose their selectivity.

Dangers

When ingested orally, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese effect"), the individual may suffer from hypertensive crisis. If foods containing tryptophan are consumed, hyperserotonemia may result. The amount required to cause a reaction varies greatly from individual to individual, 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. 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 crisis

Tyrosine, not tyramine, is the precursor to catecholamines. Tyramine is a breakdown product of tyrosine. In the gut and during fermentation, tyrosine, an amino acid, is decarboxylated to tyramine. Under ordinary circumstances, 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 nerve terminals. Once in the cytoplasmic 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. In general, this risk is not present with RIMAs. Both kinds of intestinal MAO inhibition can cause hyperpyrexia, nausea, and psychosis if foods high in levodopa are consumed.

Examples of foods and drinks with potentially high levels of tyramine include liver and fermented substances, such as alcoholic beverages and aged cheeses. (See a List of foods containing tyramine). Examples of levodopa-containing foods include broad beans. These diet restrictions are not necessary for those taking selective MAO-B inhibitors, unless these are being taken in high dosages, as mentioned above.

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.^{[citation needed]} Presumed 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. However, it is now believed that, used as directed under the care of a qualified psychiatrist, this class of drugs is a viable alternative treatment 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 or medications, and some 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.) The risk of the interaction of MAOI medications with other drugs or certain foods is particularly dangerous because those on the medication who would have to restrict their diets often are depressed patients who "don't care if they live or die."

MAOIs should not be combined with other psychoactive substances (antidepressants, painkillers, stimulants, both legal and illegal etc.) except under expert care. Certain combinations can cause lethal reactions, common examples including SSRIs, tricyclics, MDMA, meperidine, tramadol, and dextromethorphan^{[citation needed]}. Agents with actions on epinephrine, norepinephrine, or dopamine must be administered at much lower doses due to potentiation and prolonged effect.

Nicotine, a substance frequently implicated in tobacco addiction, has been shown to have "relatively weak" addictive properties when administered alone. The addictive potential increases dramatically after co-administration of an MAOI, which specifically causes sensitization of the locomotor response in rats, a measure of addictive potential. This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally-occurring MAOI compounds in addition to the nicotine.

Withdrawal

Antidepressants including MAOIs have some dependence-producing effects, the most notable one being a withdrawal syndrome, which may be severe especially if MAOIs are discontinued abruptly or over-rapidly. However, the dependence-producing potential of MAOIs or antidepressants in general is not as significant as benzodiazepines. For example, antidepressants have significantly less abuse potential than benzodiazepines. Withdrawal symptoms can be managed by a gradual reduction in dosage over a period of weeks, months or years to minimize or prevent withdrawal symptoms.

MAOIs, as with any antidepressant medications, do not alter the course of the disorder, so it is possible that discontinuation can return the patient to the pre-treatment state.

This consideration greatly complicates switching a patient between a MAOI and a SSRI, because it is necessary to clear the system completely of one drug before starting another. If one also tapers dosage gradually, the result is that for weeks 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 the two drugs, but it is often not easy for the patient^{[citation needed]}.

Interactions

The MAOIs are infamous for their numerous drug interactions, including the following kinds of substances:

• Substances that are metabolized by monoamine oxidase, as they can be boosted by up to several-fold.
• Substances that increase serotonin, norepinephrine, or dopamine activity, as too much of any of these neurochemicals can result in severe acute consequences, including serotonin syndrome, hypertensive crisis, and psychosis, respectively.

Such substances include:

• Phenethylamines: 2C-B, Mescaline, Phenethylamine (PEA), etc.
  • Amphetamines: Amphetamine, MDMA, Dextroamphetamine, Methamphetamine, DOM, etc.
• Tryptamines: DMT, Psilocin/Psilocybin ("Magic Mushrooms"), etc.
  • Lysergamides: Ergolines/LSA, LSD ("Acid"), etc.
• Serotonin, Norepinephrine, and/or Dopamine Reuptake Inhibitors:
  • Selective Serotonin Reuptake Inhibitors (SSRIs): Citalopram, Dapoxetine, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline.
  • Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs): Desvenlafaxine, Duloxetine, Milnacipran, Venlafaxine.
  • Norepinephrine-Dopamine Reuptake Inhibitors (NDRIs): Amineptine, Bupropion, Methylphenidate, Nomifensine.
  • Norepinephrine Reuptake Inhibitors (NRIs): Atomoxetine, Mazindol, Reboxetine.
  • Tricyclic Antidepressants (TCAs): Amitriptyline, Butriptyline, Clomipramine, Desipramine, Dosulepin, Doxepin, Imipramine, Lofepramine, Nortriptyline, Protriptyline, Trimipramine.
  • Tetracyclic Antidepressants (TeCAs): Amoxapine, Maprotiline.
  • Phenylpiperidine derivative Opioids: Meperidine/Pethidine, Tramadol, Methadone, Fentanyl, Dextropropoxyphene, Propoxyphene.
  • Others: Brompheniramine, Chlorpheniramine, Cocaine, Cyclobenzaprine, Dextromethorphan (DXM), Ketamine, MDPV, Nefazodone, Phencyclidine (PCP), Pheniramine, Sibutramine, Trazodone.
• Serotonin, Norepinephrine, and/or Dopamine Releasers: 4-Methylaminorex (4-MAR), Amphetamine, Benzphetamine, Cathine, Cathinone, Diethylcathinone, Ephedrine, Levmetamfetamine, Lisdexamfetamine, MDMA ("Ecstasy"), Methamphetamine, Pemoline, Phendimetrazine, Phenethylamine (PEA), Phentermine, Propylhexedrine, Pseudoephedrine, Phenylephrine, Tyramine.
• Serotonin, Norepinephrine, and/or Dopamine Supplemental Precursors: 5-HTP, L-DOPA, L-Phenylalanine, L-Tryptophan, L-Tyrosine.
• Local and General anesthetic in surgery and dentistry in particular those containing Epinephrine. There is no universally taught or accepted practice regarding dentistry and use of MAOIs such as Phenelzine and it is, therefore, vital to inform all clinicians especially dentists of the potential effect of MAOIs and Local Anesthesia. In preparation for dental work, withdrawal from Phenelzine is specifically advised, however since this takes two weeks it is not always a desirable or practical option. Dentists using Local Anesthesia are advised to use a non-epinephrine anesthetic such as Carbocaine at a level of 3%. Specific attention should be paid to blood pressure during the procedure and the level of the anesthetic should be regularly and appropriately topped up since non-epinephrine anestetics take longer to come into effect and wear off faster. Patients taking Phenelzine are advised to notify their Psychiatrist prior to any dental treatment.
• Certain Other Supplements: Hypericum perforatum ("St John's Wort"), Inositol, Rhodiola rosea, S-Adenosyl-L-Methionine (SAMe), L-Theanine.
• Other Monoamine Oxidase Inhibitors.

History

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 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 a reduction in dietary and drug interactions.

Irreversible MAOIs were the first antidepressants to be discovered, but they fell out of favour with the advent of the discovery of safer antidepressants; these newer antidepressant drug classes have fewer adverse effects, especially the dangerous irreversible MAOI food interaction with tyramine, sometimes referred to as the 'cheese syndrome', which leads to dangerous hypertension. However, reversible MAOIs lack these hypertensive adverse effects. Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice; its reversible inhibitory features give it a number of advantages over the older irreversible MAO inhibitors.

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 February 28, 2006.

List of MAOIs

• Plant extracts
  • Selective MAO-A Inhibitors
    • Harmala alkaloids (found in Coffee, Syrian rue,
    • Resveratrol (found in Japanese knotweed and skin of red grapes)
  • Nonselective MAO-A/MAO-B Inhibitors
    • Curcumin (found in Turmeric)
    • Rhodiola rosea (active constituent(s) unknown)
    • Ruta graveolens (active constituent(s) unknown)
    • Ginkgo biloba
    • Anthocyanins
    • Proanthocyanidin
  • Selective MAO-B inhibitors
    • Epicatechin
    • Emodin (found in Fo-Ti)
    • Gentiana lutea (active constituent(s) unknown)

• Pharmaceutical Drugs
  • Nonselective MAO-A/MAO-B Inhibitors
    • Hydrazines
      • Benmoxin (Nerusil, Neuralex)
      • Hydralazine (Apresoline)
      • Iproclozide (Sursum)
      • Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida)
      • Isocarboxazid (Marplan)
      • Isoniazid (Laniazid, Nydrazid)
      • Mebanazine (Actomol)
      • Nialamide (Niamid)
      • Octamoxin (Ximaol, Nimaol)
      • Phenelzine (Nardil, Nardelzine)
      • Pheniprazine (Catron)
      • Phenoxypropazine (Drazine)
      • Pivalylbenzhydrazine (Tersavid)
      • Procarbazine (Matulane, Natulan, Indicarb)
      • Safrazine (Safra)
    • Non-Hydrazines
      • Caroxazone (Surodil, Timostenil)
      • Echinopsidine (Adepren)
      • Furazolidone (Furoxone, Dependal-M)
      • Linezolid (Zyvox, Zyvoxam, Zyvoxid)
      • Tranylcypromine (Parnate, Jatrosom)
    • Antibiotics with MAO inhibiting activity
      • Linezolid
  • Selective MAO-A Inhibitors
    • Brofaromine (Consonar)
    • Metralindole (Inkazan)
    • Minaprine (Cantor)
    • Moclobemide (Aurorix, Manerix)
    • Pirlindole (Pirazidol)
    • Toloxatone (Humoryl)
  • Selective MAO-B Inhibitors
    • Lazabemide (Pakio, Tempium)
    • Pargyline (Eutonyl)
    • Rasagiline (Azilect)
    • Selegiline (Deprenyl, Eldepryl, Emsam)

• Research Compounds
  • Nonselective MAO-A/MAO-B Inhibitors
    • Hydrazines
      • Metfendrazine
  • Selective MAO-A Inhibitors
    • Amiflamine
    • Bazinaprine
    • Befloxatone
    • Cimoxatone
    • Clorgyline
    • Esuprone
    • Eprobemide (Befol)
    • Methylene Blue
    • Pirlindole
    • Sercloremine
    • Tetrindole
    • Thesputiaint
    • CX157 (Tyrima)
  • Selective MAO-B Inhibitors
    • D-Deprenyl
    • Ladostigil
    • Milacemide
    • Mofegiline

• Antiparasitic
  • Invertebrate MAO Inhibitors
    • Amitraz antiparasitic used in animals for ticks, mites (sarcoptes, demodex) and lice. Used on plants as an insecticide against mites, aphids, etc.

Various tryptamine and phenethylamine/amphetamine derivatives such as αET, αMT, amphetamine (itself), methamphetamine, MDMA, 4-MTA, PMA, 2C-T-7, and 2C-T-21 may also have weak to strong MAOI effects at high doses. Many other unlisted hydrazines like hydrazine (itself), monomethylhydrazine, and phenylhydrazine have some MAOI properties as well.

Cultural references

• In the episode "The Late Shaft" of the TV detective drama Castle, Bobby Mann was taking an MAO inhibitor. His killer used this fact to trigger a negative interaction with the drug, leading to Bobby's death through what seemed to be a normal heart attack.

• In the episode "Cut" of Law & Order, a surgeon prescribes painkillers that interact with an MAOI a patient was taking, leading to her death.

• The pilot episode of Law and Order was similar to an actual event. Journalist Sidney Zion questioned the sudden death of his daughter Libby Zion at an ER room in Manhattan on Oct 4, 1984. The cause of death was attributed to "mysterious infection". The father convinced authorities to launch a criminal investigation when it was discovered that several medications, including Demerol, were administered to his daughter, reacting with her Nardil medications. The DA sought charges of murder against a doctor who had approved use of restraints and narcotics when Libby became increasingly agitated. The case prompted many reforms in graduate medical education and limiting number of hours staff can work. Drug abuse was successfully argued as a major factor leading to her death.

See also

• Reversible inhibitor of MAO-A (RIMA)
• Hydrazine (antidepressant)
• MAO, MAO-A, MAO-B

References

UpToDate Contents

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• 1. 成人におけるうつ病治療としてのモノアミン酸化酵素阻害剤（MAOI） monoamine oxidase inhibitors maois for treating depressed adults
• 2. 不安障害および物質使用障害を併発した場合の治療 treatment of co occurring anxiety disorders and substance use disorders
• 3. 成人における単極性うつ病：継続療法および維持療法 unipolar depression in adults continuation and maintenance treatment
• 4. 成人の注意欠陥多動性障害（ADHD）に対する薬物療法 pharmacotherapy for adult adhd
• 5. 成人の古典的ホジキンリンパ腫生存者に対するアプローチの概要 overview of the approach to the adult survivor of classical hodgkin lymphoma

English Journal

• Subnanomolar indazole-5-carboxamide inhibitors of monoamine oxidase B (MAO-B) continued: indications of iron binding, experimental evidence for optimised solubility and brain penetration.

• Tzvetkov NT1, Antonov L2.
• Journal of enzyme inhibition and medicinal chemistry.J Enzyme Inhib Med Chem.2017 Dec;32(1):960-967. doi: 10.1080/14756366.2017.1344980.
• PMID 28726524
• PMID 28097890

• Through scaffold modification to 3,5-diaryl-4,5-dihydroisoxazoles: new potent and selective inhibitors of monoamine oxidase B.

• Meleddu R1, Distinto S1, Cirilli R2, Alcaro S3, Yanez M4, Sanna ML1, Corona A1, Melis C1, Bianco G1, Matyus P5, Cottiglia F1, Maccioni E1.
• Journal of enzyme inhibition and medicinal chemistry.J Enzyme Inhib Med Chem.2017 Dec;32(1):264-270. doi: 10.1080/14756366.2016.1247061.
• PMID 28097874

Japanese Journal

• Design, Synthesis and Inhibitory Activities of 8-(Substituted styrol-formamido)phenyl-xanthine Derivatives on Monoamine Oxidase B

• Hu Suwen,Nian Siyun,Qin Kuiyou [他],Xiao Tong,Li Lingna,Qi Xiaolu,Ye Faqing,Liang Guang,Hu Guoxin,He Jincai,Yu Yinfei,Song Bo
• Chemical and Pharmaceutical Bulletin 60(3), 385-390, 2012
• … Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. … These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease. …
• NAID 130001852426

• ステロイド誘発鶏胚白内障モデルでのsemicarbozide-sensitive monoamine oxidase阻害剤の効果

• 石川 陽平,橋爪 公平,西郡 秀夫 [他],真島 行彦,黒坂 大二郎
• 岩手医学雑誌 63(4), 229-237, 2011-10-01
• NAID 110008665542

• Rapid screening of monoamine oxidase B inhibitors in natural extracts by capillary electrophoresis after enzymatic reaction at capillary inlet

• HU Kun,ZHANG Lichun,LI Xiangtang,ZHAO Shulin
• Journal of chromatography. B, Analytical technologies in the biomedical and life sciences 878(30), 3156-3160, 2010-11-15
• NAID 10028043990

Related Links

• monoamine oxidase inhibitors - definition of monoamine ...

Monoamine Oxidase Inhibitors Definition Monoamine oxidase inhibitors (MAO inhibitors) are medicines that relieve certain types of mental depression. Purpose MAO inhibitors are a type of antidepressant and are used to treat mental ...

• Monoamine oxidase inhibitors (MAOIs) - Mayo Clinic

MAOIs — Learn about the benefits, side effects and risks of these older antidepressants. ... Monoamine oxidase inhibitors (MAOIs) were the first type of antidepressant developed. They're effective, but they've generally been replaced ...

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関連記事	「inhibitor」

「inhibitor」

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• 阻害剤、阻害薬、抑制薬、抑制剤、(内在性物質について)インヒビター、抑制物質

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blocker、depressant、suppressant