Monoamine Oxidase Inhibitors Chemische Eigenschaften,Einsatz,Produktion Methoden
Biologische Funktion
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.
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.
Nebenwirkungen
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.
Arzneimittelwechselwirkung
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 Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
