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Monoamine oxidase inhibitors ( MAOIs) are a class of drug that inhibit the activity of one or both monoamine oxidase : monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). MAOIs are effective due to their specialized function of the inhibition of the enzyme that is responsible for neurotransmitter degradation in the synaptic cleft. This is especially true for treatment-resistant depression, which is a type of depression that is resistant to common treatments of typical depression, such as selective-serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs).
MAOIs are also utilized to treat panic disorder, social anxiety disorder, Parkinson's disease, and several other disorders.
Reversible inhibitors of monoamine oxidase A (RIMAs) are a subclass of MAOIs that selectively and reversibly enzyme inhibitor the MAO-A enzyme. RIMAs are used clinically in the medication 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 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 with dysthymia complicated by panic disorder or hysteroid dysphoria.
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.
Pargyline is a non-selective MAOI that was previously used as an antihypertensive agent to treat hypertension (high 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 a reversible inhibitor of MAO-A (i.e., moclobemide) or low doses of selective MAO-B inhibitors (e.g., Emsam).
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,Pharmacology from H.P. Rang, M.M. Dale, J.M. Ritter, P.K. Moore, year 2003, chapter 38 tramadol, and dextromethorphan, whereas combinations with LSD, psilocybin, or DMT appear to be relatively safe. Drugs that affect 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 the nicotine.
While safer than general MAOIs, 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 , , 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 the risk of hypertensive crisis. Kanski's Clinical Ophthalmology, 8th Edition (2016). Brad Bowling. 978-0-7020-5573-7 p. 332
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 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 the two drugs.
There are two of monoamine oxidase, MAO-A and MAO-B. MAO-A preferentially deamination serotonin, melatonin, epinephrine, and norepinephrine. MAO-B preferentially deaminates phenethylamine and certain other ; in contrast, MAO-A preferentially deaminates other trace amines, like tyramine, whereas dopamine is equally deaminated by both types.
Harmaline found in Peganum harmala, Banisteriopsis caapi, and Passiflora incarnata is a reversible inhibitor of monoamine oxidase A (RIMA).
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) 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 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 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. 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), 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:
Other pharmaceuticals
Naturally occurring RIMAs in plants
Only reversible phytochemical MAOIs have been characterized.
Research compounds
Mechanism of action
MAOIs act by inhibiting the activity of monoamine oxidase. Monoamine oxidase is an enzyme that is responsible for the degradation of monoamine neurotransmitters, such as dopamine, serotonin, and norepinephrine, and prevents these neurotransmitters from remaining in the synaptic cleft for extended periods of time. Monoamine Oxidase Inhibitors are responsible for inhibiting monoamine oxidase, ultimately leading to prevention of the degradation of neurotransmitters in the synaptic cleft, leading to higher concentrations of neurotransmitters to remain in the synaptic cleft for longer periods of time.
Reversibility
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 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.
Selectivity
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 the other.
History
The knowledge of MAOIs began with the serendipitous discovery that iproniazid was a potent MAO inhibitor (MAOI). Originally intended for 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 the 2 isoenzymes of MAO has led to the development of selective MAOIs that may have a more favorable side-effect profile.
List of MAO inhibiting drugs
Marketed MAOIs
MAOIs that have been withdrawn from the market
List of RIMAs
Marketed pharmaceuticals
See also
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