Download Monoamine hypothesis of depression

: Monoamine hypothesis of depression 
asserts that depression is caused by
functional insufficiency of monoamine
neurotransmitter (norepinephrine, serotonin
or both).
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Tricyclic antidepressnts
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Monoamine oxidase inhibitors
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Selective serotonin reuptake inhibitors
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Atypical antidepressants
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The tricyclic antidepressants are drugs of first choice
for many patients with major depression. The first
tricyclic agent imipramine was introduced to
psychiatry in the late 1950s.
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The structure of imipramine, consist of tricyclic
nucleus i.e. this drug has 3 rings.
Examples f tricyclic drugs are:Imipramine,
Amitriptyline,Nortriptyline
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Tricyclic antidepressants block monoamine reuptake
(norepinephrine and serotonin) into nerve endings.
By blocking reuptake of these neurotransmitters into
nerve endings, tricyclic antidepressants can intensify
their effects.
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: Tricyclic antidepressants are preferred drugs for
treatment of major depression. These drugs can
elevate mood, increase activity and alertness,
improve appetite and normalize sleep patterns.
Tricyclic antidepressants do not relieve
symptoms immediately. Initial responses take
from 1 to 3 weeks to develop. One or 2 months
may be needed before a maximal response is
achieved. Thus a therapeutic effect should not be
considered a failure until medication has been
administered for at least 1 month without
success.
Bipolar disorder (Manic depressive illness) is
characterized by alternating episodes of
mania and depression. TCAs can be helpful
during the depressive phase of this illness.
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3-Obsessive compulsive disorder.
4-Panic disorder.
5-Enuresis
6-Chronic pain.
1-Orthostatic hypotension
hypotension is due blockade of alpha 1 adrenergic
receptors on blood vessels.
2-Anticholinergic effects
The TCAs block muscarinic cholinergic receptors,
and can thereby cause anticholinegic effects( dry
mouth, blurred vision, photophobia,
constipation, urinary retention, and tachycardia).
3-Sedation
Sedation is a common response to TCAs. The
cause is blockade of histamine receptors in the
CNS.
4-Cardiac toxicity: Tricyclics can adversely affect cardiac ◦
function particularly in overdose or in the presence of
preexisting cardiac impairment.
These drugs affect the heart by: ◦
-Decreasing vagal influence on the heart (secondary to ◦
muscarinic blockade).
- Acting directly on the bundle of His to slow conduction. ◦
Both effects increase the risk of dysrrhythmias.
5- Seizures: TCAs can cause seizure. Caution must be ◦
exercised in patients with epilepsy and other seizure
disorders.
 1-Monoamine oxidase inhibitors:
The combination of a TCA with an MAOI ( causes
accumulation of NE in adrenergic neurons) can lead to severe
hypertension from excessive adrenergic stimulation of the
heart and blood vessels.
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2-Direct acting sympathomimetic drugs:.
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Tricyclics potentiate responses to direct acting
sympathomimetics such as epinephrine and NE that produce
their effects by direct interaction with adrenergic receptors.
Stimulation by these drugs is increased because TCAs block
their uptake into adrenergic terminals, thereby prolonging their
presence in the synaptic space.
3-Indirect acting sympathomimetic drugs: TCAs
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decrease responses to indirect acting sympathomimetics such
as ephedrine and amphetamine that produce their effects by
promoting release of transmitter from adrenergic nerves.
Effects of indirect acting sympathomimetics are reduced
because TCAs block uptake of these agents into adrenergic
nerves, thereby preventing them from reaching their site of
action within the nerve terminal.
4-Anticholinergic agents: Since TCAs exert
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anticholinergic actions of their own, they will intensify the
effects of other medications that have anticholinergic actions.
5-CNS depressants: CNS depression caused by TCAs will
add with CNS depression caused by other drugs such as
alcohol, antihistamines, opioids, benzodiazepines and
barbiturates.
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Fluoxetine, Fluvoxamine, Sertraline ,Paroxetine.
Mechanism of action These drugs produce selective
blockade of serotonin reuptake
, and thereby intensifies transmission at serotonergic synapses.
These drugs are as effective as the TCAs, but do not cause
hypotension, sedation or anticholinergic effects. Moreover,
overdose does not cause cardiotoxicity.
In contrast to the TCAs fluoxetine does not block cholinergic,
histamine or alpha 1 adrenergic receptors, and hence does not
cause anticholinegic effects ,sedation, orthostatic hypotension,
or cardiotoxicity.
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Nausea, headache, weight gain and sexual
dysfunction,
CNS stimulation including nervousness,
insomnia, and anxiety.
by increasing serotonergic transmission in the brainstem and
spinal cord, SSRIs can cause serotonin syndrome. This
syndrome usually begins 2 to 72 hours after initiation of
treatment and is most likely if an SSRI is combined with an
MAOI. Signs and symptoms include altered mental status
(agitation, confusion, anxiety, hallucinations, poor
concentration), excessive sweating, tremor and fever. Death
has occurred. The syndrome resolve spontaneously after
discontinuing the drug.
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Phenelzine , Tranylcypromine
The MAOIs are second or third choice antidepressants
for most patients. Although these drugs are effective as
the tricyclics and SSRIs, they are also more dangerous.
Of particular concern is the risk of hypertensive crisis
in response to eating foods rich in tyramine. With the
advent of SSRIs and other alternatives to TCAs, use of
MAOIs continues to decline.
Antidepressant effects of the MAOIs results from
inhibiting MAO in nerve terminals.
By inhibiting intraneuronal MAO-A, these drugs increase
the amount of NE and serotonin available for release
and thereby intensify transmission at noradrenergic and
serotonergic junctions
Depression
Other uses:
Obsessive compulsive disorders
Panic disorders
Tyramine causes the release of large amounts of stored
catecholamines from nerve terminals, resulting in
occipital headache, stiff neck, tachycardia, nausea,
hypertension, cardiac arrhythmias, seizures, and
possibly, stroke
Drowsiness, orthostatic hypotension, blurred vision, dry
mouth, dysuria, and constipation
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