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Monoamine oxidase inhibitors (MAOIs) are a class of powerful antidepressant drugs prescribed for the treatment of 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 inhibitors and tricyclic antidepressants) have failed. 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.[1] 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.

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Indications

In the past, MAOIs were prescribed for those resistant to tricyclic antidepressant therapy, but newer MAOIs such as selegiline and moclobemide provide a safer alternative and are now sometimes used as first-line therapy, although these substances are not always as effective as their predecessors.

They are also used for treating agoraphobia or social anxiety. 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.

Mode 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. 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 When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it has been replaced by the body, which can take about two weeks.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. 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, is a "reversible inhibitor of MAO-A (RIMA)."[2]

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, 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.[1][3]

Dangers

When ingested orally, MAOIs inhibit the catabolism of dietary amines. When foods containing tyramine are consumed (so-called "cheese syndrome"), 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.[4] 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[citation needed].

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 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 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. This risk is generally not present with RIMAs. Both kinds of intestinal MAO inhbition 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 fermented substances, such as Chianti and other aged wines, and aged cheeses. Liver is also a well-known source. (See a list of foods containing tyramine). Examples of levodopa-containing foods include broad beans (also known in the United States as fava 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] 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 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.)

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[5], 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. Purely opiate-acting analgesics, such as morphine, and buprenorphine may be used safely with MAOIs, but may require a dosage adjustment.

Nicotine, a substance frequently implicated in tobacco addiction, is not significantly addictive when administered alone.[6] The addictive potential manifests itself after co-administration of an MAOI, which specifically causes sensitization of the locomotor response in rats, a measure of addictive potential.[7] This may be reflected in the difficulty of smoking cessation.

Withdrawal

Antidepressants including MAOIs have some dependence producing effects, most notably 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 or months to minimize or prevent withdrawal symptoms.[8]

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 not easy.

Interactions

The MAOIs are infamous for their numerous drug interactions. Unless the interaction is desired, any drug that falls within the following classifications should be avoided:

Such substances include:

It would be wise to contact a physician or pharmacist before taking any drug while on an MAOI.

List of MAOIs

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 1991 film The Silence of the Lambs, Hannibal Lecter mentions that he once ate the liver of a census taker "with some fava beans and a nice Chianti." This is Lecter's most famous quote. As a psychiatrist, he would know that he had named three of the "forbidden foods" for patients taking MAO inhibitors.

See also

References

  1. ^ a b U.S. Food and Drug Administration (2006-02-28). ""FDA Approves Emsam (Selegiline) as First Drug Patch for Depression."". Press release. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2006/ucm108607.htm. Retrieved 2009-11-19. 
  2. ^ Edward J. Massaro, Handbook of Neurotoxicology
  3. ^ BLTC Research [1] (2006). "Rasagiline: a neuroprotective smart drug?". The Good Drug Guide. http://www.elitenetpharmacy.com/pd_azilect.cfm. Retrieved 2007-12-02. "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." 
  4. ^ Jacob, Giris; Gamboa, Alfredo; Diedrich, André; Shibao, Cyndya; Robertson, David; Biaggioni, Italo (August 2005). "Tyramine-Induced Vasodilation Mediated by Dopamine Contamination: A Paradox Resolved". Hypertension (Lippincott Williams & Wilkins) 46 (2): 358. doi:10.1161/01.HYP.0000172353.62657.8b. PMID 15967868. http://pt.wkhealth.com/pt/re/hyper/pdfhandler.00004268-200508000-00023.pdf. Retrieved 2007-12-02. "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.". 
  5. ^ Pharmacology from H.P. Rang, M.M. Dale, J.M. Ritter, P.K. Moore, year 2003, chapter 38
  6. ^ Guillem K, Vouillac C, Azar MR, et al. (September 2005). "Monoamine oxidase inhibition dramatically increases the motivation to self-administer nicotine in rats". J. Neurosci. 25 (38): 8593–600. doi:10.1523/JNEUROSCI.2139-05.2005. PMID 16177026. 
  7. ^ Villégier AS, Blanc G, Glowinski J, Tassin JP (September 2003). "Transient behavioral sensitization to nicotine becomes long-lasting with monoamine oxidases inhibitors". Pharmacol. Biochem. Behav. 76 (2): 267–74. PMID 14592678. 
  8. ^ van Broekhoven F, Kan CC, Zitman FG (June 2002). "Dependence potential of antidepressants compared to benzodiazepines". Prog. Neuropsychopharmacol. Biol. Psychiatry 26 (5): 939–43. doi:10.1016/S0278-5846(02)00209-9. PMID 12369270. http://linkinghub.elsevier.com/retrieve/pii/S0278-5846(02)00209-9. 

Simple English

[[File:|thumb|Monoamine oxidase]] Monoamine oxidase inhibitors (MAOIs) and reversible monoamine oxidase inhibitors (RIMAs) are a type of antidepressant drugs given for the treatment of depression. They are good at treating atypical depression, Parkinson's disease, anxiety disorders, social phobia and have also shown to help people to stop smoking tobacco.

As MAOIs drugs can be fatal people if they take too much, they are often only ever given when other antidepressant drugs have failed. Some newer drugs such as selegiline and moclobemide have proven to be safer than the older MAOIs and are prescribed by physicians in the first instance.

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Uses

MAOIs and RIMAs are used to provide a second line of treatment for certain psychiatric illnesses, most commonly types of hard to treat depression with not normal symptoms and anxiety disorders (with or without panic attacks. They may also be used for social phobia. MAO-B inhibitors are used to treat Parkinson's disease. Certain MAOIs have been shown to help people to stop smoking tobacco.

How they work

Monoamine oxidase inhibitors work by stopping the action of an enzyme called monoamine oxidase. This enzyme breaks down a group of brain signalling chemicals called the monoamine neurotransmitters. There are two types of the enzyme, MAO-A and MAO-B. Each type breaks apart different chemicals in the group. MAO-A breaks down melatonin, serotonin, epinephrine and norepinephrine. MAO-B breaks down phenylethylamine and the trace amines. These chemicals (neurotransmitters) are used in the brain for signalling purposes. Dopamine, for example, is a chemical that affects motivation and pleasure. Effectively, they work on balancing the brain's chemistry.

Side effects

Like all drugs, MAOIs and RIMAs can have effects that are not intended and are not part of the treatment that the drugs provide. In this class of drug, these include a risk of a hypertensive crisis. This can be caused by high levels of tyramine; such as by eating cheese (except cream or cottage cheese, meat extracts such as Bovril, yeast extract, stock cubes, fermented soya bean products, alcohol (especially fortified wine (port, sherry), beer and chainti wine. Also preserved fish, preserved poultry, offal, avocado, banana skins, broad bean pods and pickled or smoked herring must be avoided. Certain medications can also cause a hypertensive crisis with MAOIs and RIMAs, such as; amphetamine, fenfluramine, ephedrine, phenlyephrine, phenylpropanolamine, nasal decongestants, L-dopa, pethidine and tricyclic antidepressants. Use of a RIMA rather than a MAOI can reduce these side-effects, however tyramine rich foods should still be avoided.

List of MAOIs

  • 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)
    • 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)
  • Herbal Drugs
    • Selective MAO-A Inhibitors
      • Resveratrol (found in skin of red grapes)[1]
    • Nonselective MAO-A/MAO-B Inhibitors
      • Curcumin (found in turmeric)
      • Harmala alkaloids (found in tobacco, syrian rue, passion flower, ayahausca, and Tribulus terrestris)
        • Harmine, Harmaline, Tetrahydroharmine, Harmalol, Harman, Norharman, etc
      • Rhodiola Rosea (active consituent(s) unknown)
    • Selective MAO-B inhibitors
      • Catechin (found in the tea plant, cocoa, and cat's claw)
      • Desmethoxyyangonin (found in kava)
      • Epicatechin (also found in the tea plant, cocoa, and cat's claw)
      • Fo-Ti (active constituent(s) unknown)
      • Hydroxytyrosol (found in olive oil)
      • Piperine (found in pepper)
    • Unknown Selectivity
      • Ginkgo Biloba (active constituent(s) unknown)
      • Liquorice (active constituent(s) unknown)
      • Myristicin (found in nutmeg, parsley, and dill)
      • Siberian Ginseng (active constituent(s) unknown)
      • St. John's Wort (active constituent(s) unknown)
      • Yerba Mate (active constituent(s) unknown)
      • Yohimbe (active constituent(s) unknown)
  • Research Compounds
    • Nonselective MAO-A/MAO-B Inhibitors
    • Selective MAO-A Inhibitors
      • Amiflamine
      • Bazinaprine
      • Befloxatone
      • Befol
      • Cimoxatone
      • Clorgyline
      • Esuprone
      • Methylene Blue
      • Sercloremine
      • Tetrindole
      • Tyrima
    • Selective MAO-B Inhibitors
      • D-Deprenyl
      • Ladostigil
      • Milacemide
      • Mofegiline

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Notes

  1. Antioxidant Activity of Resveratroi Closely Correlates with Its Monoamine oxidase-A Inhibitory Activity, Yong Nam Han, Shi Yong Ryu and Byung Hoon Han, Natural Products Research Institute, Seoul National University, Seoul 110-460, Korea (Received February 27, 1990), Arch. Pharm. Res. 13(2), 132-135 (1990), http://www.springerlink.com/content/mtmu568441508047/fulltext.pdf?page=1








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