Reversible inhibitors of monoamine oxidase A (RIMAs) are a subclass of MAOIs that
selectively and
reversiblyinhibit the MAO-A enzyme. RIMAs are used clinically in the
treatment of
depression and
dysthymia. Due to their reversibility, they are safer in single-drug overdose than the older, irreversible MAOIs,[2] and weaker in increasing the monoamines important in depressive disorder.[3] 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
migraineprophylaxis. Inhibition of both MAO-A and MAO-B is used in the treatment of
clinical depression and
anxiety.
Newer MAOIs such as
selegiline (typically used in the treatment of Parkinson's disease) and the reversible MAOI
moclobemide provide a safer alternative[19] and are now sometimes used as first-line therapy.
Side effects
Hypertensive crisis
People taking MAOIs generally need to change their diets to limit or avoid foods and beverages containing
tyramine, which is found in products such as cheese, soy sauce, and salami.[21] If large amounts of tyramine are consumed, they may develop a
hypertensive crisis, which can be fatal.[22] Examples of
foods and beverages with potentially high levels of tyramine include cheese,
Chianti wine, and pickled fish.[23] Excessive concentrations of tyramine in blood plasma can lead to hypertensive crisis by increasing the release of
norepinephrine (NE), which causes blood vessels to constrict by activating
alpha-1 adrenergic receptors.[24] Ordinarily, MAO-A would destroy the excess NE; when MAO-A is inhibited, however, NE levels get too high, leading to dangerous increases in blood pressure.
RIMAs are displaced from MAO-A in the presence of
tyramine,[25] 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.,
selegiline 6 mg/24 hours transdermal patch).[24][26][27]
Drug interactions
The most significant risk associated with the use of MAOIs is the potential for
drug interactions with over-the-counter, prescription, or illegally obtained medications, and some
dietary supplements (e.g.,
St. John's wort or
tryptophan). 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 [epinephrine] dosage should be reduced by 75%, and duration is extended).[23]
Tryptophan supplements can be consumed with MAOIs, but can result in transient
serotonin syndrome.[28]
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 including
SSRIs,
tricyclics,
MDMA,
meperidine,[29]tramadol,
dextromethorphan,[30] whereas combinations with
LSD,
psilocybin, or
DMT appear to be relatively safe.[31][citation needed] 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.[32][33][34] This may be reflected in the difficulty of smoking cessation, as tobacco contains naturally occurring MAOI compounds in addition to the
nicotine.[32][33][34]
While safer than general MAOIs,
RIMAs 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
decongestants,
antihistamines, and
cough syrup).[citation needed]
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.[35]
Withdrawal
Antidepressants including MAOIs have some
dependence-producing effects, the most notable one being a
discontinuation syndrome, which may be severe especially if MAOIs are discontinued abruptly or too rapidly. The dependence-producing potential of MAOIs or antidepressants in general is not as significant as
benzodiazepines, however. Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of days, weeks or sometimes months to minimize or prevent withdrawal symptoms.[36]
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.[37] 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.[38] 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.[38]
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.[39]
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.
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.[41] 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.[42]Selegiline is selective for MAO-B at low doses, but non-selective at higher doses.
History
The knowledge of MAOIs began with the serendipitous discovery that
iproniazid was a potent MAO inhibitor (MAOI).[43] 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.[44]
The older MAOIs' heyday was mostly between the years 1957 and 1970.[41] 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.[45][46]Moclobemide, was the first reversible inhibitor of MAO-A to enter widespread clinical practice.[47]
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