Anti depressant drugs

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Depression

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 Classification

A. Selective Serotonin- Reuptake Inhibitor

B-Serotonin-Norepinephrine Reuptake Inhibitors.

1. Selective serotonin-norepinephrine reuptake
inhibitors
2. Tricyclic antidepressants.

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 Classification

C. 5-HT2 Receptor Modulators.

D-Tetracyclic and Unicyclic Antidepressants.

E. Monoamine Oxidase Inhibitors.

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 Classification

A-Selective serotonin reuptake inhibitors

1-fluoxetine
2-sertraline
3-citalopram
4-Escitalopram
5-paroxetine
6-fluvoxamine
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 Classification

B1 -Selective serotonin norepinephrine reuptake

inhibitors(snri)
• Venlafaxine
• Desvenlafexine
• Duloxetine
Milnacipran.

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 Classification
B2 –Tricyclic antidepressants.
1-imipramine
2-clomipramine
3-amitriptyline
4-desipremine
5-trimipramine
6-nortriptyline
7-protriptylinr
8-doxepin

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Classification

C. 5-HT2 Antagonists.

1. Trazodone
2. Nefazodone

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 Classification

• D-TETRACYCLIC AND UNICYCLIC

ANTIDEPRESSENTS
• Amoxapine
• Maprotiline
• Bupropion
• Mirtazipine

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 Monoamine oxidase inhibitors

• Phenelzine
• Isocarboxazid
• Tranylcypromine
• Selegiline
• Moclobemide

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 Pharmacokinetics of
Anti-Depressants
ADD’s share many ph features:-
• Most have fairly rapid oral absorption
• Achieve peak plasma levels within two to three hours
• Are tightly bound to plasma proteins
• Undergo hepatic metabolism
• Have renal excretion

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 Mechanism of action
selective serotonin reuptake inhibitors

1 Inhibits the reuptake of serotonin by binding with serotonin

transporter proteins (SERT ).the SERT is a glycoprotein
imbedded in the axon terminal and cell body membrane of
serotonergic neurons
2 SSRIs inhibits the transporters by binding the receptor
3 So there is increased availability of serotonin at synaptic and
post synaptic level of neurons
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 Mechanism of action

• Ssri bind with serotonin transporter protein and

inhibit the transport of serotonin from extra to
intracellular site.
• So this inc conc of serotonin at its site of action .

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 Effects of ssris

• Acute increase of serotonergic synaptic activity

• Slower changes in several signaling pathways
• Increase in neurotrophic activity after two weeks
• Antidepressants effects

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 Clinical indications of ssris

Major depression
Generalized anxiety disorder
Panic disorder
Obsessive compulsive disorder
Post traumatic stress disorder
Premenstrual dysphoric disorder
Eating disorders (bulimia)
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 Adverse effects of ssris

Increase risk of suicide in patients under the age of 25

Increase serotonergic activity in the gut is associated
with Nausea
Gastrointestinal upset
Diarrhea
Improve after 1st wk of treatment

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 Adverse effects

• Loss of libido
• Delayed orgasm
• Diminished sexual function
• Persists as long as the pt remain on treatment
• Headache
• Insomnia or hypersomnia
• Discontinuation syndrome 1 or 2 days after dc the Rx
• Dizziness paresthesia
• Flue like symptoms/

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 Paroxetine

• Cardiac septal defects are associated with first

trimester exposures with paroxetine thus paroxetine
is a category D agent.
• SSRI’s are probably associated with post birth
complications including pulmonary hypertension.

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 SNRIS

• Venlafaxine
• Duloxetine
• Desvenlafaxine

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 MECHANISM OF ACTION

SNRI,s
( selective serotonin noradrenalin reuptake inhibitors)
These drugs bind with both (SERT AND NET)and inhibits them as do the
TCAs

HOWEVER UNLIKE THE TCAs SNRIs do not have much affinity forother
receptors

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 MECHANISM OF ACTION OF
SNRIS
• Venlafaxine is a potent inhibitor of serotonin reuptake
• At higher doses it is an inhibitor of norepinephrine
reuptake.
• most drugs of snri,s more inhibitory effect on SERT
than NET.
• Better tolerated than tricyclic drugs bec of no significant
anti collinergic alpha adreno ceptor blocking or
antihistaminic effects.

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 CLINICAL INDICATIONS OF
SNRIS
• MDD
• Generalized anxiety disorder
• Post traumatic stress disorder
• OCD
• Social anxiety disorder
• Panic disorder
• Neuropathic pain
• Back ache
• Muscle ache
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 Pharmacokinetics
SNRIs
• Venlaflexin is met in the liver via cyp2d6 into
desvenaflexine.
• Half life = 11 hrs
• 45% exc unchanged in urine
• Dose =1 od

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 Adverse affects of SNRIS

• Nausea
• Dizziness
• Insomnia
• Sedation
• Constipation
• Somnolence
• sweating
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 Adverse effects

Snri,s
Inc bp, heart rate . Cns activation , insomnia ,anxiety and
agitation .

Venlafexine overdose= cardiac toxicity

Duloxetin=hepato toxicity
Discontinuation syndrome
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 Contraindications

• Duloxetine is metabolized in the liver to many

metabolites duloxetine should not be administered to
patients with hepatic insufficiency
• Metabolites are excreted in urine so duloxetine is not
recommended in patients with end stage renal disease

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 Tricyclic antidepressants
• Dominant class of antidepressants until the introduction of
SSRIS in 1980s and 1990s.
• Nine TCAs are available all have a tricyclic core.
• The TCAs block SERT and NET.also have antimuscirinic,alpha
blocking and antihistaminic activity.
Prototype drug is imipramine.
• They all have similar therapeutic efficacy
• Choice of drug depends on patient tolerance of side effect
• At present TCAs are used in depression unresponsive to SSRIs
and SNRIs .
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 pharmacokinetics

Tricyclic anti depressents

• Half life = long
• Dose 1 od
• Exc = only 5 % from urine .

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 Clinical indication of TCAs

• Major Depression
• Panic disorders
• Nocturnal enuresis imipramine is used by causing
contraction of internal sphincter of the bladder
• Chronic pain (neuropathic pain) amitriptyline.

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 TCA,S
• Anticolinergic effects
• Dry mouth
Adverse effects • Constipation
• Uri retention
• Blurred vision
• Confusion
• Orthostatic
hypotension
• Wt gain
• Sedation
• Arrhythmia
• Sexual side effects
• Discontinuation 36

syndrome .
 MECHANISM OF ACTION

5-HT2 ANTAGONISTS
Trazodone and nefazodone = antagonists on 5HT RECEPTORS.
Inhibition of this recptors=antidepressant and anti anxiety
effects .
Lsd ( lysergic acid diethylamide) and mescaline = agonists to
these receptors and cause anxiety and hallucinations.

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 MECHANISM OF ACTION

• Nafazodone and trazodone primary metabolite m-

cpp is a potent 5HT2 antagonist

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.nefazodone is aweak inhibitor of both SERT and NET

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 Pharmacokinetics

• Goes through extensive hepatic metabolism

• Half life = small so split dosing is req .
• Trazodone = only 5- HT2 antagonist given in single
dose.

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 Adverse effects

5HT2antagonists

Sedation
Gi disturbances
Orthostatic hypotension
Hepatotoxicity – hep failure

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 Monoamine oxidase inhibitors.

• MAOIs act inhibiting the actions of monoamine oxidase

in the neuron and increasing monoamine levels.
• There are 2 forms of monoamine oxidase A and B
• MAO/A is present primarily in the brain , gut , placenta
and liver
• MAO/B is found primarily in serotonergic and
histaminergic neurons distributed in brain , liver , and
platelets.

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 Pharmacokinetics
Mao inhibitors
Diff mao inhibitors = met via diff pathways
they have extenive first pass effect so their bioavalibility is
decreased.
Bec of prominenet first pass effect and their tendency to inhibit mao
in the gut alternative routes of administration are being developed
These routes decrease the risk of food interactions and provide
increased bio avaliabity.
Selegeline is available in transdermal and sublingual routes , so it
bypass both gut and liver.

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 Adverse effects
MOA

Orthostatic hypotension
Wt gain
Sexual side effects
Activation
Insomnia
Restlessness
Confusion
Sudden discontinuation = delirium like effects e.g. psychosis and confusion
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 Tetra cyclic and uni cyclic
antidepressants
• Bupropion=pre synaptic releaase of NE and has no
direct effect on serotonin system.
• Mirtazipine= antagonists on alpha adrenoreceptors=
releases noradrenalin and serotonin.
• It also has antagonist effect on 5HT2 and 5HT3
receptors.
• Also acts as antagonist on H1 receptors so it has
sedative effect.
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 pharmacokinetics

Tetracyclic and unicyclic agents

Bupropion is rapidly absorbed
Protein binding =85%
Met = hepatic

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 pharmacokinetics
• Excretion = biphasic
ist phas = I hr
2nd phase = 14 hrs
Amoxapine = rapidly absorbed
Protein binding =85%
Half life =variable
Drug given =divided doses
Metabolisim = hepatic .
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 Tetra cyclic and uni cyclic
antidepressants
• Maprotiline and amoxapine=acts like tricyclic
antidepressants. Both inhibit NET more than SERT
• AMOXAPINE moderate inhibitor of post synaptic
D2 RECEPTORS
• So amoxapine possesses some antipsychotic
properties. .

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 Adverse effects

TETRACYCLIC AND UNICYCLIC

ANTIDEPRESSENTS
SEDATION
SEIZURES
AGITATION
INSOMNIA
ANXIETY.

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 Clinical pharmacology

Social anxiety disoder

Severe anxiety in social gatherings to the extent that daily life
suffers,
Rx = ssri,s and venlafexine

Ptsd( post traumatic stress disorder)

Any trauma or life threatening event results in anxiety
provoking thoughts .Rx= ssri,s and psychotherapy .
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 Clinical pharmacology

• So MAINTANANCE THERAPY may be given to

prevent the disease .
Maintanace therapy = 5 years
Ssri , snri or tca given as maintanance therapy for its
protective effects .
If 2 or more serious mdd episodes in 5 years=
maintenance therapy indicated.
ADD given for all subtypes of depression
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 Clinical pharmacology

• ADDs if given with psychotherapy ( cog behav

therapy ) = more effective.

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 Clinical pharmacology

• it antagonize nic receptors.

Eating disorder
• bulimia ( food binges followed by ritualistic purging
by emesis )
• Hupokalemia may occur which could be dangerous

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 Clinical pharmacology
• Rx = fluoxitin.
• bupropion = RX of obesity and smoking cessation.

Other conditions
• Urinary stress incontinence = snri,s given
• Vasomotor symp of peri menupause= desvenlafexine
• Ssri.s
• Nefazodone .
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 Choice of anti depressant drug .

• Older pt,s are sensitive to TCAs

• Females respond to SSRIs better than SNRIS or
TCAs.
MDD SSRIs = safe tolerable .inexpensive so are
first line treatment for treating depression.s

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 Choice of anti depressant drug

• Bupropion and mirtazipine also ist line Rx for MDD

bec of lil or no side effects .
• TCA and MOA = 2nd or 3rd line for MDD due to
lethal overdose , serious adv effects and serious drug
interactions
• Used only in resistant depression .

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 dose

SSRIs and SNRIS

• Rx starts with therapeutic dose
• If no benefit – 4 weeks than higher dose given and
dose is titrated to its max level.

TCA and MAO .

Req titration dose for lethal side effects .

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 Overdose
• Suicide is unfortunate and serious consequent in dep patients
• 15 % risk of suiside in all kinda dep
• Reason= overdose
• TCA frequently involved.
• Overdose lead to lethal arrhythmias vent tachycardia and vent
arrhythmias
• Altered mental status eg seizures and bp changes seen in TCA
overdose
• 1500 mg of imipramine or amytriptyline is enough to cause
overdose and lethal in many pts.
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 Overdose
• Todellers =100mg dose causes toxicity .
• Rx=cardiac. monitorring
• airway support
• gastric lavage
• Sodium bicabonate is often adm to uncouple TCA from
cardiac sodium channel.
MAO
OVERDOSE = autoimune instability , hyper androgenic
symp,psychotic symp, confusion , delerium , fever , seizures.
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 Overdose
• Rx=cardiac monitorring
• vit sign support
• gastric lavage.

• ssri
• Over dose is uncommon
• Snri also safe
• Vanlafexine = may = cardiac toxicity.
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 Overdose

• Bupropion= seizures
• If ant dep +ALCOHOL = fatal dose
• rx = emptying of gas tic contents .

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 Drug interactions
• Sedative effects of antidepressants can be potentiates with other
sedatives , eg alcohol , barbiturates, benzodiazepines…

• MAO inhibitors , should not be given along with tyramine

containing food , eg cheese , red beer and other fermented food.

• Tyramine is normally destroyed by mao enzymes present in the

intestines. 61
 Drug interactions
• MAO INHIBITTORS prevent the destruction of tyramine that
will cause the release of NE from adrenergic nerve endings ….

• NE will cause HTN in the pt s.

• Similarly other indirectly acting sympatho mimetics such as

EPHEDRINE , PHENYLPROPRANOLAMINE should be
avoided along with MAO inhibitors , as they may also cause
HTN with MAO inhibitors. 62
 DRUG INTERACTIONS

• Combination of MAOIs with a serotenergic agent

may result in life threatening SEROTONIN
SYNDROME.
• Delirium,coma.
• Hypertention,tachycardia,diaphoresis.
• Myoclonus,hyperreflexia,tremor effects.

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 Drug interactions

• NEFAZODONE , and FLUVOXAMINE , inhibits the

metabolism of terfenadine , astemizole and cisapride.
• An inc concentration of these drugs in the body leads to cardiac
arrhythmias so these drugs should be avoided along with the
nefazodone and fluvoxamine..

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THANK YOU
………
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