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| | Monoamine Oxidase Inhibitors Basic information |
| | Monoamine Oxidase Inhibitors Chemical Properties |
| | Monoamine Oxidase Inhibitors Usage And Synthesis |
| Biological Functions | Iproniazid, originally developed for the treatment of tuberculosis,
exhibited mood-elevating properties during
clinical trials in tuberculosis patients with depression.
The distinguishing biochemical feature between iproniazid
and other chemically similar antituberculosis compounds
was the ability of the former to inhibit MAO.
Thus, a series of hydrazine and non–hydrazine-related MAOI agents was synthesized and tested for antidepressant
properties. Three MAOI agents are approved
in the United States for use in major depression: isocarboxazid
(Marplan), phenelzine (Nardil), and tranylcypromine
(Parnate).
The MAOIs are as effective as the heterocyclic antidepressants
and the newer agents, such as the SSRIs.
However, at least two forms of life-threatening toxicity
(hepatotoxicity and dietary tyramine–induced hypertensive
crisis ) have been associated with their chronic
use. For this reason, the MAOIs are not considered firstline
agents in the treatment of depression.They are generally
reserved for treatment of depressions that resist
therapeutic trials of the newer, safer antidepressants.
However, a new transdermal formulation of selegiline
undergoing clinical trials demonstrates antidepressant
efficacy without concerns of liver toxicity or dietary
tyramine-induced hypertension. | | Mechanism of action | Monoamine oxidase exists in the human body in two
molecular forms, known as type A and type B. Each of
these isozymes has selective substrate and inhibitor
characteristics. Neurotransmitter amines, such as norepinephrine
and serotonin, are preferentially metabolized
by MAO-A in the brain.MAO-B is more likely to be involved
in the catabolism of human brain dopamine, although
dopamine is also a substrate for MAO-A.
Isocarboxazid, phenelzine, and tranylcypromine are
irreversible nonselective inhibitors of both MAO-A
and MAO-B. However, it appears that inhibition of
MAO-A, not MAO-B, is important to the antidepressant
action of these agents.
Therapeutic efficacy by selective MAO-A inhibitors
(such as clorgyline or moclobemide) in major depressions
strongly suggests that MAO inhibition at central
serotonin or norepinephrine synapses or both is responsible
for the antidepressant properties of these
agents. However, since complete MAO-A inhibition is
achieved clinically within a few days of treatment, while
the antidepressant effects of these drugs are not observed
for 2 to 3 weeks, suggests that additional actions
must be involved.
In a manner similar to that of the TCAs and SSRIs,
MAOIs are known to induce adaptive changes in the
CNS synaptic physiology over 2 to 3 weeks. These
changes result in both down-regulation of synaptic
transmission mediated through noradrenergic α- and β-
adrenoceptors and up-regulation or enhancement of
synaptic transmission at serotonin synapses (5HT1Areceptors).
This action on serotonin neurotransmission
is the result of desensitized somatodendritic autoreceptors
responsible for the regulation of the firing rate
of serotonin-containing neurons of the forebrain.
Accordingly, these neurons fire at elevated rates, releasing releasing
large quantities of serotonin into the synapse. This
serotonin is protected from degradation by inhibition of
synaptic MAO-A. It is believed that the development of
these physiological changes at norepinephrine and
serotonin synapses, which parallel the time delay associated
with the antidepressant properties of the MAOIs,
is the mechanism of action for these agents in the treatment
of major depression. | | Clinical Use | The MAOIs are indicated in patients with atypical (exogenous) depression and in some patients who are
unresponsive to other antidepressive therapy. They rarely are a drug of first choice. Unlabeled uses have
included bulimia (having characteristics of atypical depression), treatment of cocaine addiction (phenelzine),night terrors, posttraumatic stress disorder; some migraines resistant to other therapies, seasonal affective
disorder (30 mg/day), and treatment of some panic disorders. | | Side effects | The potential for toxicity that is associated with the administration
of the MAOIs restricts their use in major
depression. Hepatotoxicity is likely to occur with isocarboxazid
or phenelzine, since hydrazine compounds
can cause damage to hepatic parenchymal cells. This is
true particularly for patients identified as slow acetylators of hydrazine compounds. Fortunately,
the incidence of hepatotoxicity is low with the
available agents.
A greater concern is the potentially lethal cardiovascular
effects that can occur in patients who do not
comply with their dietary restrictions. Patients who take
a MAOI should not eat food rich in tyramine or other
biologically active amines. Normally, these amines are
rapidly metabolized by MAO-A during gastric absorption
by the mucosal cells of the intestinal wall and by
MAO-A and MAO-B during passage through the liver
parenchyma. If both isozymes of MAO are inhibited, elevated
circulating levels of tyramine will be free to interact
with the sympathetic noradrenergic nerve terminals
innervating cardiac and vascular smooth muscle
tissue to produce a pressor effect. In
these conditions, tyramine can cause an acute elevation
in blood pressure, sometimes leading to a hypertensive
crisis. Cheeses, wine, and a whole host of other foods
rich in tyramine must be avoided. A number of other
bothersome side effects, such as tremors, orthostatic hypotension,
ejaculatory delay, dry mouth, fatigue, and
weight gain, are common at therapeutic doses of
MAOIs. | | Drug interactions | Serious hypertension can occur with concomitant administration
of over-the-counter cough and cold medications
containing sympathomimetic amines. When
switching from a MAOI to another antidepressant, such
as a SSRI, a drug-free period of 2 weeks is required to
allow for the regeneration of tissue MAO and elimination
of the MAOI.When switching from an antidepressant,
such as an SSRI, to a MAOI, sufficient time should
be allowed for the SSRI to be cleared from the body (at
least 5 half-lives) before starting the MAOI. Special
note should be taken of fluoxetine’s long half-life, requiring
at least 5 weeks after discontinuation of fluoxetine
at a 20-mg dose and longer at higher doses, before initiation of MAOI therapy. Coadministration of a
MAOI and an SSRI or venlafaxine can overstimulate
the serotonin receptors in the brainstem and spinal cord
(serotonin syndrome), which can be lethal. Serotonin
syndrome consists of a constellation of psychiatric, neurological,
and cardiovascular symptoms that may include
confusion, elevated or dysphoric mood, tremor,
myoclonus, incoordination, hyperthermia, and cardiovascular
collapse. |
| | Monoamine Oxidase Inhibitors Preparation Products And Raw materials |
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