Monoamine oxidase inhibitor

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Monoamine oxidase

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 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.[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.

Contents

[edit] Uses

[edit] Therapeutic use

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. MAO inhibitors 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 MAO-A is used in the treatment of clinical depression and anxiety.

[edit] 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.

[edit] 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 When they react with monoamine oxidase, they permanently deactivate it, and the enzyme cannot function until it has been replaced by the body, which can take about two weeks.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 respective concentrations of the substrate and the MAOI.

Harmaline found in Peganum harmala is a "reversible inhibitor of MAO-A (RIMA)."[2]

[edit] 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]

[edit] 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 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.[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.

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.

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 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, 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.

[edit] 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.[5]

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.

[edit] Drug interactions

[edit] List of monoamine oxidase inhibitors

[edit] 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/bbs/topics/NEWS/2006/NEW01326.html. Retrieved on 2007-12-02. 
  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 on 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 on 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. ^ van Broekhoven F, Kan CC, Zitman FG (June 2002). "Dependence potential of antidepressants compared to benzodiazepines". Prog. Neuropsychopharmacol. Biol. Psychiatry 26 (5): 939–43. PMID 12369270. http://linkinghub.elsevier.com/retrieve/pii/S0278-5846(02)00209-9. 
v • d • e
Receptor agonists, antagonists, and reuptake inhibitors
BA/M
AA
ANS
(SANS only—see above for details)
Other RAs
v • d • e
Pharmacology: enzyme inhibition
Class
Substrate
Hydrolase (EC 3)
Lyase (EC 4)
v • d • e
Psychoanaleptics: antidepressants (N06A)
MAOIs
RIs
SSREs
AAs at A2
SAs
MAs
v • d • e
Antiparkinson drugs: dopaminergic agents (N04B)
Dopa and derivatives
Dopamine agonists
Enzyme inhibitors
MAOIs (B)
Multiple/unknown
Combinations
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