Transcript 3-II (MAOIs & atypic..

Monoamine Oxidase
Inhibitors
Monoamine oxidase inhibitors


Monoamine Oxidase Inhibitors (MAOIs)
are a class of powerful antidepressant
drugs. They are particularly effective in
treating atypical depression, panic
disorders, social phobia
Due to potentially lethal dietary and drug
interactions, MAOIs had been reserved
as a last line of Rx, used only when
other classes of antidepressant drugs
(e.g. SSRIs and TCAs) have failed
What is Monoamine Oxidase?
MAO is a mitochondrial enzyme found in most
tissues; NS, liver, gut (presynaptic nerves).
 The enzyme is responsible for the degradation
of monoamine neurotransmitters


There are two forms of monoamine
oxidase; MAO-A and MAO-B
MAO-A is responsible for NE, 5-HT &
tyramine metabolism
 MAO-B is more selective for dopamine
metabolism

Mechanism of action
 MAOIs
act by inhibiting the
activity of MAO thus
preventing the breakdown of
monoamine neurotransmitters
and thereby increasing their
availability in the synaptic cleft
Site of Action of MAOIs

The early MAOIs inhibited MAO
irreversibly. i.e 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function until it has been replaced by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, moclobemide,
are reversible, they are able to
detach from the enzyme.
Classification of MAOIs
According to Reversibility,
MAOIs can be classified
into:
1-Irreversible agents;
Tranylcypromine, phenelzine
irreversibly combine with the enzyme
& have a prolonged action
2- Reversible agents;
- Moclobemide
.
Classification of MAOIs
According to selectivity, MAOIs can
be classified into:
1-Non selective agents;
Phenelzine,Tranylcypromine
They inhibit MAO A, MAO B
2- Selective agents;
-Moclobemide, (MAO-A)I
-Selegiline, (MAO-B)I
.
 Many foods containing tyramine is normally
degraded in the gut by MAO-A
 Since the enzyme is inhibited by MAOIs,
tyramine from ingested food is absorbed, and
then taken up into adrenergic neurons.
 It is converted into octopamine - a false
transmitter which causes massive release of
NE and may result in hypertensive crisis
-.
People
taking
MAOI’s should
avoid foods rich
in tyramine
 e.g.aged wine ,
aged cheese,
liver, sausages,
fish
 Some meat and
yeast extracts
Drug Interactions
1-The use of MAO inhibitors
with TCAs causes elevated
levels of NE and hypertensive
crisis
2-Concurrent use of a MAOI and
fluoxetine may lead to the
serotonin syndrome
Drug Interactions
3-Local anaesthetics or cold medications
contain (pseudoephedrine, ephedrine) have
synergistic effects with the increased levels
of catecholamines caused by MAOIs
5-MAOIs with pethidine may lead to abnormal
syndrome characterized by hyperpyrexia,
irritability, hypotension and coma due to an
abnormal pethidine metabolite resulting from
the inhibition of the normal demethylation
pathway of pethidine by MAOIs
Current use of MAOIs
They are not the first-line drugs because of
the great drug interaction risks & the
complicated dietary restrictions required
 The reversible selective MAO-A inhibitor
moclobemide & the selective MAO-B
inhibitor selegiline have a greater safety
margin
 Newer MAOIs are used for the treatment
of atypical depression ( + severe anxiety
or panic attacks, marked obesity) and
depression resistant to therapy

Selegiline Patch (Emsam™)
 Selective
MAO-B Inhibitor
 Bioavailability
Orally: 4%
Transdermally: 74%
 Avoid first pass GI exposure
 Much less inhibition of gut & liver MAOA
Mixed - Action &
Atypical
Antidepressants
Mixed-Action
Antidepressants
 Selective
serotonin- norepinephrine
reuptake inhibitors ( SNRIs)
 Norepinephrine reuptake inhibitors
(NRIs)
 Norepinephrine-dopamine reuptake
inhibitors (NDRIs)
Serotonin-norepinephrine
reuptake inhibitors (SNRIs)
SNRIs are a newer form of antidepressants that work on both 5-HT
(SSRI-plus) and weak NE reuptake
blockade
 They have similar side effects to the
SSRIs except increased risk of
hypertension
 Examples : Venlafaxine

Venlafaxine
Potent inhibitor of
serotonin, NE reuptake
transporter (SNRIs)
 Unlike, TCAs, has little
activity at adrenergic,
histaminic and
muscarinic receptors
(fewer side effects
than TCAs)

Reboxetine
 Na
reuptake
inhibitor
[ NARIs ]
No affinity
for 5HT, DA,
H, muscarinic
receptors

Reboxetine
 Has
a positive effect on the
concentration and motivation in
particular
 Safe to combine with SSRIs
 Minimal side effects only related
to activation of adrenergic system
as tremor, tachycardia
Mirtazapine
 Belongs to a newer class of
antidepressants
 acts by blocking presynaptic
central alpha-2 adrenergic
receptors leading to increased
release of NE and serotonin
 + blocking serotonin receptors
(5HT3 , 5HT2 receptors)------- >
lower incidence of adverse effects
such as anxiety, insomnia, and
nausea
 has only minimal activity at
dopaminergic and muscarinic
receptors.
Mirtazapine
Does not cause anti-muscarinic side
effects , less sexual dysfunction
 Side effects include sedation
(antihistaminic effect) and weight gain

Mirtazapine is preferred in
cancer patients because:
Improves appetite
 nausea & vomiting ( 5-HT3 blocking)
  body weight
 Sedation (antihistaminic)
 Less sexual dysfunction (5-HT2 blocking)
 Has no anti-muscarinic effect

Norepinephrine-dopamine reuptake
inhibitors (NDRIs)
 Bupropion
(Wellbutrin ) is a
unique drug that has been shown
to possess significant potency as
NE and dopamine reuptake
inhibitor in the brain with no
direct action on the serotonin
system
Therapeutic uses:
1- Treatment of major depression and
bipolar depression
2-Can be used in smoking cessation as it
reduces the severity of nicotine craving
& withdrawal symptoms
Advantages:
 No sexual dysfunction
 No weight gain (as no serotonin effect)
 No orthostatic hypotension
Side effects: ppt seizures :it 
threshold of neuronal firing