antidepressants
TRANSCRIPT
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ANTIDEPRESSANTS:
Depression is one of the most treatable mental illness.
Prepared & Presented by
SAHARISH KHALIQ(203)
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DEPRESSION
It is a mental illnesses characterized by
pathological changes in mood, loss of
interest or pleasure, feelings of guilt or low
self-worth, disturbed sleep or appetite, low
energy, and poor concentration .
It can be severe and some times Fatal.
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Symptoms
Depressed mood most of the day…
Markedly diminished interest or
pleasure
Significant weight loss /gain
Insomnia or hypersomnia
Agitation
Fatigue or loss of energy
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Symptoms
Change in appetite
Lack of concentration
Poor self esteem
Thought of suicide or death.
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Types of Depression
Major depression
Chronic depression (Dysthymia)
Atypical depression
Bipolar disorder/Manic depression
Seasonal depression (SAD)
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Mechanism Of Depression
Depression is associated with changes in the level of
neurotransmitters in the brain that help nerve cells
to communicate.E.x Serotonin,Dopamine,Nor
epinephrine
The level can be influenced by physical
illness,genetics,substance abuse,diet,hormonal
chnages, brain injuries or social circumstances.
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ANTIDEPRESSANTSDrug which enhance alertness and may result in an
increased output of behaviour.
Potentiate directly or indirectly the action of
• Dopamine
• Serotonin
• Nor adrenaline
The purpose of antidepressants is to increase the
neurotransmitters in the synapse.
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ANTIDEPRESSANTS
They are used for the relief of symptoms of
moderate and severe depression.
Antidepressants are taken for atleast 4-6
months.
They can be used alone or in combination
with other medications
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Types of Antidepressants
Tricyclic anti-depressants (TCAs).
Monoamine oxidase inhibitors (MAOIs).
Selective serotonin reuptake inhibitors (SSRIs)
Atypical anti-depressants (Others)
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TRICYCLIC ANTIDEPRESSANTS
They have been employed in drug therapy since the
late 1950s.
Largest group of drug agents used for the treatment
of depression.
Referred as “ tri cyclic ” compounds –three rings.
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Properties of TCA
Characteristic three ring nucleus.
All are metabolized in liver .
High protein binding.
High lipid solubility.
N
NR1
R2
AB
C
1
2
37
5
6
8
9
10 11
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Classification of TCA
Imipramine
Amytriptiline
Desipramine
Nortriptyline
Protryptyline
Doxepin
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MECHANISM OF ACTION
Inhibit the re-uptake of neurotransmitters.
They inhibit serotonin,nor epinephrine or dopamine
reuptake at pre synaptic nerve terminals thus lead to
increased concentration of these transmitters in the
synaptic cleft.
Takes up to 4 weeks for all TCA antidepressants to
have an effect.
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Imipramine
• Closely related to
antipsychotic drug
Phenothiazines.
Used to treat wide class of
depression.
It is a prototype drug of class
TCA.
It is also used to treat
nocturnal enuresis.
Usual dose 50-150 mg daily.
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Therapeutic Uses
Severe major depression
Phobic and panic anxiety disorders
Neuropathic pain
Obsessive compulsive disorder (OCD)
Nocturnal enuresis; Imipramine has been used to control
bed-wetting in children (older than six years) by causing
contraction of the internal sphincter of the bladder.
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Adverse Effects
Dry mouth
Constipation
Blurred vision
Mydriasis
Metallic taste
Urine retention
Drowsiness
Sedation
weight gain
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Chemical structures of TCAs
NortryptilineImipramine
Amitryptiline
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SAR of TCAs
N
NR1
R2
AB
C
1
2
37
5
6
8
9
10 11
Structure of TCAs consist of 7 memebered ring that is linked to 2 benzene rings.Primary or tertiary amine is attached to central ring. Substituting a halogen or CN (cyano) group in C 3 position of the ring increase potency.Max potency occurs when the basic nitrogen is replaced by propylene bridge.Presence of dimethyl or keto at C10 leads the compound in effective.Double bond between position 10 & 11 increases activity.
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Monomethyl amines are more potent than dimethylamines as shown for imipramine and desipramine.
Replacement of hetrocyclic N with C,activity is retained.
Branching of side chain does not activity of the drug as seen in the case of imipramine and trimipramine.
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Cis form is more potent than trans form.
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Mono amine oxidase inhibitors
Treatment of depression began with the
use of MAOIs in 1950’s.
These drugs are not widely used today,
although a small number of patients appear to do better
in MAOIs than TCAs or the newer drugs.
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Properties
Are readily absorbed from GI tract
Widely distributed throughout the body.
May have active metabolites, inactivated by
acetylation.
Effects persist even after these drugs are no
longer detectable in plasma (1-3 weeks)
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Classification of MAOIs
Phenelzine
Isocarboxacid
Tranylcypromine
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Mechanism of action of MAOIsMAO is a mitochondrial enzyme found in
nerve and other tissues.
Monoamine oxidase breaks down
norepinephrine, serotonin, and dopamine.
When monoamine oxidase is inhibited,
norepinephrine, serotonin, and dopamine
are not broken down, increasing the
concentration of all three neurotransmitters
in the brain.
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MAOIs may reversibly or irreversibly inactivate
the enzymes by making stable complexes with the
enzymes,permitting neurotransmitter molecules
to escape degradation and accumulate within
synaptic cleft.
This may cause activation of nor epinephrine and
serotonin receptors responsible for anti
depressant action.
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PHENELZINE
NH2
HN
White powder freely
soluble in water.
Insoluble in
ethanol.
It has low sedative
properties.
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Therapeutic Uses
Indicated for depressed patients who are
unresponsive or allergic to TCAs.
Patient with low psychomotor activity.
Treatment of phobic states
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Adverse Effects
Drowsiness/Fatigue
Constipation
Nausea
Diarrhea
Dizziness
Low blood pressure
Lightheadedness,
Decreased urine output
Sleep disturbances
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Chemical structures of MAOIs
CH3
N O
O
HN
NH
CH3
CH3HN
NH
O
N
NH2
HN
Isocarboxazide
Phenelzine
Iproniazid
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SAR of MAOIs
Electron withdrawing groups increase potency.Some MAOIs are related to Amphetamine.Cyclization of side chain of Amphetamine results in
Tranylcypromine.
TRANYLCYPROMINE
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Selective Serotonin Reuptake Inhibitors
A group of chemically unique drugs
More modern group of drugs in use.
1st drug fluoxetine available in 1988.
Safest antidepressant for use.
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Properties
Good absorption after oral administration
Important biotransformation in the liver
Long half-lives of elimination(s)
fluoxetine (T1/2=50h)
Drug mostly excreted from kidney.
Few drugs are excreted from feaces.
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Mechanism of action
Inhibition of serotonin reuptake into the presynaptic
cell, increasing the level of serotonin leading to
greater post synaptic neuronal activity.
They do not have significant effect on Nor
epinephrine & Dopamine.
They typically take 2 to 12 weeks to produce
improvement in mood.
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Classification of SSRIs
Fluoxetine
Sertraline
Paroxetine
Fluvoxamine
Escitalopram
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Fluoxetine
White crystalline powder
Soluble in methanol sparingly
soluble in water.
Treatment of endogenous
depression.
Usual dose 20-80 mg daily
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Therapeutic Uses
Depression
Obsessive compulsive disorder (the only indication for
fluvoxamine )
Panic disorder
Generalized anxiety
Premenstrual dysphoric disorder
Bulimia nervosa (only fluoxetine is approved for this last
indication)
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Adverse Effects
Anxiety
Insomnia
Agitation
Sexual dysfunction.
Weight gain.
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Chemical structure of SSRIs
Fluoxetine Hcl Sertraline
Escitalopram
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SAR of SSRIs
Mono substitution in para position of phenoxy group by electron withdrawing group results gain in 5HT selective inhibition
But bi-substitution or mono-substitution at other places or use of electron donating group
causes loss in selective inhibition
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CF3 is mono-subs in
para position
Introducing ring in the fluoxetine derivatives maintains selectivity for 5HT transporter but lowers the potency, except in paroxetine which is more potent than fluoxetine.The amine group shows maximum potency when in 2o form ie 3o amine reduce potency for 5HT transportors.
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Atypical Anti Depressants They are a mixed group of agents that have actions
at several different sites Atypical antidepressants ease depression by
affecting chemical messengers (neurotransmitters) used to communicate between brain cells.
Like other types of antidepressants, atypical antidepressants affect neurotransmitters including dopamine, serotonin and nor epinephrine.
Changing the balance of these chemicals seems to help brain cells send and receive messages, which in turn boosts mood.
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Classification
Bupropion
Trazodone
Mianserin
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Mechanism of action
It is similar to that of SSRIs.
It inhibits the re uptake of serotonin leading to
increase concentration in brain.
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Bupropion
White solid in appearance
Soluble in water and ethanol.
Drug belong to class Atypical
antidepressants.
Similar in action to SSRIs.
Very potent to use.
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Therapeutic UsesAtypical antidepressants are frequently used in
patients with major depression who have inadequate
responses or intolerable side effects during first-line
treatment with selective serotonin reuptake
inhibitors (SSRIs)
Atypical antidepressants are often first-line
treatment if the drug has a desirable characteristic
(eg, sexual side effects and weight gain occur less
often with bupropion than SSRIs).
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Adverse Effects
Anxiety
Restlesness
Blurred vision
Constipation
Agitation
Dry mouth
Nausea
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Discontinution of Antidepressants
Antidepressants should be gradually tapered
and should not be abruptly discontinued.
Abruptly stopping an antidepressant in some
patients can cause discontinuation syndrome.
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Conclusion
Depression is a serious condition that often can be effectively treated with available therapies. Side effects and drug interactions are barriers to successful treatment. Some side effects of antidepressants resolve with continued use while other side effects can be managed by dose reduction or adding other therapies. Appropriate management of side effects and avoidance of drugs that may interact with antidepressants may improve the success of antidepressant therapy.