Antidepressant, Anti-anxiety Antidepressant, Anti-anxiety DrugsDrugs

Dr. R. K. DixitDr. R. K. DixitProfessorProfessor

Pharmacology and TherapeuticsPharmacology and TherapeuticsC. S. M. Medical University C. S. M. Medical University

Lucknow, 226003Lucknow, 226003

Classification of Major Affective Classification of Major Affective DisordersDisorders

E pisoda lD epress ion

S easona lA ffec tiveD isorder

A typica lD epress ion

M a jor/E ndogenousD epress ion

M ania Bipola rdepress ion

M a jor A ffec tive D isorders

Episodal (reactive) Episodal (reactive) DepressionDepression

Adverse life events.Adverse life events. Physical illness.Physical illness. Drugs.Drugs. Other psychiatric Other psychiatric disorders.disorders.

Reactive (episodal) Reactive (episodal) DepressionDepression

More than 60% of all depressions.More than 60% of all depressions. Core depressive syndrome: feelings of Core depressive syndrome: feelings of

misery, apathy, inadequacy, pessimism, misery, apathy, inadequacy, pessimism, anxiety, tension, anxiety, tension, guilt.guilt. Ugliness, Low self Ugliness, Low self –esteem, –esteem,

Bodily complaintsBodily complaints

Withdrawn.Withdrawn. Loss of interest in pleasurable Loss of interest in pleasurable

activities.activities. Indecisiveness, loss of motivation.Indecisiveness, loss of motivation. Retardation of thought and action. Retardation of thought and action. Sleep disturbance Sleep disturbance

In severe cases, it is accompanied by In severe cases, it is accompanied by hallucinations and delusions. hallucinations and delusions.

Recurrent suicidal ideation,Recurrent suicidal ideation, a a suicide attempt or a specific suicide suicide attempt or a specific suicide plan.plan.

•significant weight change (without significant weight change (without dieting )dieting )•Psychomotor agitation or retardation.Psychomotor agitation or retardation.

1.1. Has a genetic component.Has a genetic component.

2. Depression can be drug-induced.2. Depression can be drug-induced.

3. Depression can be drug-repressed. 3. Depression can be drug-repressed.

4.4. Depression can be treated with Depression can be treated with drugs.drugs.

5. Depression can be treated with5. Depression can be treated with

Electroconvulsive Therapy (ECT).Electroconvulsive Therapy (ECT).

ManiaMania

Mania alone is rare (10%) and most frequently Mania alone is rare (10%) and most frequently cycles with Major/endogenous depression cycles with Major/endogenous depression

(Manic-Depressive Disease, Bipolar Disorder).(Manic-Depressive Disease, Bipolar Disorder).Core Symptoms:

Characterized by an elevated “high” mood.

Talkative, go on-and-on about the things they will do.

Increased self-esteem.

Auditory hallucinations.

Decrease need to sleep. Expensiveness, unnecessary buying.

Lack judgment, Supermen

The precise cause of affective The precise cause of affective disorders remains elusive.disorders remains elusive.

Evidence implicates alterations in the Evidence implicates alterations in the firing patterns of a subset of biogenic firing patterns of a subset of biogenic amines in the CNS, amines in the CNS,

Norepinephrine (NE) and Serotonin Norepinephrine (NE) and Serotonin (5-HT).(5-HT).

Activity of NE and 5 -HT systemsActivity of NE and 5 -HT systems??..

Almost all NE pathways in the brain originate Almost all NE pathways in the brain originate from the cell bodies of neuronal cells in the from the cell bodies of neuronal cells in the locus coereleus in the midbrain, which send locus coereleus in the midbrain, which send

their axons diffusely to the cortex, their axons diffusely to the cortex, cerebellum and limbic areascerebellum and limbic areas

(hippocampus, amygdala, hypothalamus, (hippocampus, amygdala, hypothalamus, thalamus).thalamus).

MoodMood:: -- higher functions performed by the cortex. -- higher functions performed by the cortex.Cognitive functionCognitive function:: -- function of cortex. -- function of cortex.Drive and motivationDrive and motivation:: -- function of brainstem -- function of brainstemMemory and emotionMemory and emotion:: -- function of the -- function of the

hippocampus and amygdala.hippocampus and amygdala.Endocrine responseEndocrine response:: -- function of -- function of

hypothalamus.hypothalamus.

Serotonin SystemSerotonin System

As with the NE system, serotonin As with the NE system, serotonin neurons located in the pons and neurons located in the pons and

midbrain midbrain

(in groups known as raphe nuclei) (in groups known as raphe nuclei)

send their projections diffusely to the send their projections diffusely to the cortex, hippocampus, amygdala, cortex, hippocampus, amygdala,

hypothalamus, thalamus, etc. --same hypothalamus, thalamus, etc. --same areas implicated in areas implicated in depressiondepression. .

This system is also involved in:This system is also involved in:• Anxiety.Anxiety.• Sleep.Sleep.• Sexual behavior.Sexual behavior.• Temperature regulation.Temperature regulation.• CSF production.CSF production.

Blocked by antidepressantsBlocked by antidepressants

Serotonin receptorsSerotonin receptors 5–HT5–HT11

subtypessubtypes 5–HT5–HT1A1A, 5–HT, 5–HT1B1B, 5–HT, 5–HT1D1D, 5–, 5–

HTHT1E1E, 5–HT, 5–HT1F1F

primarily responsible for primarily responsible for the the therapeutic therapeutic (antidepressant) effects(antidepressant) effects of of increased intrasynaptic increased intrasynaptic serotoninserotonin

5–HT5–HT22 subtypessubtypes

5–HT5–HT2A2A, 5–HT, 5–HT2B2B, 5–HT, 5–HT2C2C

primarily responsible for primarily responsible for thethe toxic toxic effects of effects of increased intrasynaptic increased intrasynaptic serotoninserotonin

Serotonin receptorsSerotonin receptors

Over all 14 types divided in to 1, 2, Over all 14 types divided in to 1, 2, 3, and 4-7 family3, and 4-7 family

All are G-protein coupled receptors All are G-protein coupled receptors except 3except 3

1- decreases cAMP while 4-7 1- decreases cAMP while 4-7 increaseincrease

3- ligand gated cation channel3- ligand gated cation channel

Alternative TherapiesAlternative Therapies

No way of No way of a prioria priori knowing which knowing which therapy will be best for a patient.therapy will be best for a patient.

Light TherapyLight Therapy Psychological Psychological TreatmentTreatment

ECT ECT (patients with suicidal tendency (patients with suicidal tendency

and for quick action)and for quick action)

St. John’s Wort St. John’s Wort (Plant)(Plant)

AntidepressantsAntidepressants

TCAsTCAs

MAOIs

SS

RIs

TCAs

TCAs

TCAs

TC

As

SSRIs

SSRIs

SS

RIs

SSRIs

MAOIs

MAOIsMAOIs

MAOIs

MAOIs

MAOIs

Venflaxine

Ven

flaxine

Ven

flaxine

MAOIs

MAOIs

maprotiline

Amoxepine

doxepin

isocarboxazide

Nortriptyline

Reversible inhibitor of MAO-AReversible inhibitor of MAO-A (RIMAs)(RIMAs)Moclobemide ,ClorgylineMoclobemide ,Clorgyline

(Isocarboxacid, phenelzine, tranylcypromine.)(Isocarboxacid, phenelzine, tranylcypromine.)

Atypical Atypical antidepressantsantidepressantsTrazodone, MianserineTrazodone, Mianserine

Mirtazapine, Venlafaxine Mirtazapine, Venlafaxine Duloxetine,TianeptineDuloxetine,Tianeptine

Amineptine, BupropionAmineptine, Bupropion

NA + 5 HT reuptake inhibitor

Imipramine, AmitriptylineTrimipramine, DoxepinDothiepin, Clomipramine

Selective serotonin Selective serotonin reuptake inhibitors reuptake inhibitors (SSRIs)(SSRIs)

Fluoxetine, Fluvoxamine Fluoxetine, Fluvoxamine

Paroxetine, SertralineParoxetine, Sertraline

Citalopram, EscitalopramCitalopram, Escitalopram

Predominantly NA reuptake inhibitorDesipramine, NortriptylineAmoxapine, Reboxetine

Tricyclic Tricyclic antideprssants (TCAs)antideprssants (TCAs)

ANT IDEPRES SANT S

•CM

•RITA-Don't- Copy

•Exams-For-PCS

•MAD-Boy-turned-violent

Mechanism of ActionMechanism of Action1. 1. Inhibition of MAO enzymes.Inhibition of MAO enzymes.

(MAOIs).(MAOIs).

2. 2. Inhibition of NE and 5-HT reuptake.Inhibition of NE and 5-HT reuptake. (TCAs, SSRIs,(TCAs, SSRIs, Newer TCAs). Newer TCAs).

3. 3. Prominent alpha blocking and weak 5-HT Prominent alpha blocking and weak 5-HT antagonists.antagonists.

(Nefazodone, trazodone,)(Nefazodone, trazodone,)

4. 4. Serotonin and noradrenalin reuptake Serotonin and noradrenalin reuptake inhibitor (SNRIs)inhibitor (SNRIs)

(venlafaxine, duloxetine)(venlafaxine, duloxetine)5. 5. Noradrenergic and specific serotonergic Noradrenergic and specific serotonergic

antidepressants (NaSSAantidepressants (NaSSA) ) (Mirtazapine)(Mirtazapine)

6. 6. Inhibitor of Dopamine and NoradrenalinInhibitor of Dopamine and Noradrenalin(Bupropion)(Bupropion)

7. 7. Blockade of pre-synaptic alpha 2 Blockade of pre-synaptic alpha 2 receptorsreceptors

(Mianserin)(Mianserin)

8. 8. Increases Increases ratherrather than inhibiting 5-HT than inhibiting 5-HT uptakeuptake

(Tianeptine, Amineptine)(Tianeptine, Amineptine)

ATYPICAL

MAO ( monoamine oxidase) an MAO ( monoamine oxidase) an enzymeenzyme

Two typesTwo typesMAO – AMAO – A

-Peripheral adrenergic -Peripheral adrenergic nerve endingsnerve endings

-Intestinal mucosa-Intestinal mucosa

-Human placenta-Human placenta

-Liver-Liver

-Serotonin , -Serotonin , Noradrenalin and Noradrenalin and dopaminedopamine

-Inhibited by -Inhibited by

moclobemidemoclobemide

and clorgylineand clorgyline

MAO-BMAO-B-brain ( basal ganglia)-brain ( basal ganglia)

-Platelets-Platelets

-Liver-Liver

-Deaminates -Deaminates

dopaminedopamine-Inhibeted by -Inhibeted by

selegiline (deprenyl)selegiline (deprenyl)

Isoniazide, iproniazide, phenelzine, isocarboxazide,tranylcypromine were non selective and irreversible inhibitors (Hit and run drugs) used previously but not used now due to drug drug and drug food

interactions. Linezolide (new drug against MRSA) Cheese and serotonin syndrome

A-B

C-D

Nonselective MAOIs not favorable Nonselective MAOIs not favorable

Cheese ReactionCheese Reaction

Cheese, beer, wine, Cheese, beer, wine,

meat, fish, yeast, meat, fish, yeast,

(contain large amount of (contain large amount of tyramminetyrammine and other and other indirectly indirectly acting acting amines)amines)

Due to irreversible block Due to irreversible block of MAO These escape of MAO These escape degradation in degradation in intestinal wall and intestinal wall and liverliver

Hypertensive Hypertensive crisescrises, CVA, CVA

Medical EmergencyMedical Emergency

Reach to circulation Reach to circulation Displace large amount Displace large amount of noradrenalin from of noradrenalin from loaded nervesloaded nerves

Tt. I.V. Tt. I.V. Phentolamine,Phentolamine, Prazosin Prazosin

Nonselective MAOIs not Nonselective MAOIs not favorablefavorable

Cold and Cough medicines Cold and Cough medicines contain contain EphedrineEphedrine

(Same result as cheese reaction)(Same result as cheese reaction)

Levodopa- excitement and hypertensionLevodopa- excitement and hypertension Tricyclic antidepressants- excitement, Tricyclic antidepressants- excitement,

rise in BP, temperaturerise in BP, temperature

Reversible inhibitor of Reversible inhibitor of MAO-AMAO-A

(RIMAs)(RIMAs) Moclobemide-Moclobemide-

ReversibleReversible and selective MAO-A and selective MAO-A inhibitorinhibitor

Short duration of actionShort duration of actionCompetitive enzyme inhibitionCompetitive enzyme inhibitionTyramine is able to displace itTyramine is able to displace itCheese reaction is less likelyCheese reaction is less likelyDevoid of anticholenergic, sedative, Devoid of anticholenergic, sedative, cognitive, cardiovascular effectscognitive, cardiovascular effects

Good for Good for elderlyelderly with heart diseases with heart diseases

Tricyclic Antidepressants Tricyclic Antidepressants (TCAs)(TCAs) ImipramineImipramine represents the class (Prototype) represents the class (Prototype)

Inhibit monoamine reuptake Inhibit monoamine reuptake (serotonin and noradrenalin) (serotonin and noradrenalin)

Increase the concentration of Increase the concentration of Serotonin Serotonin and NAand NA at synapse and potentiate the action at synapse and potentiate the action (therapeutic effects)(therapeutic effects)

Other receptors acted Other receptors acted (Adverse effects)(Adverse effects) Muscarinic- Anticholinergic side Muscarinic- Anticholinergic side effects (dryness etc.) #effects (dryness etc.) #

Alpha- alpha blocking actions Alpha- alpha blocking actions (postural hypotension etc.) #(postural hypotension etc.) #

Histamine-Antihistaminic (sedation) Histamine-Antihistaminic (sedation) ##

Dopamine- antipsychotic (amoxapine, Dopamine- antipsychotic (amoxapine, maprotiline)maprotiline)

TCAs actions (CNS)TCAs actions (CNS)

In Normal personIn Normal person- TirednessTiredness- Light-headednessLight-headedness- SleepinessSleepiness- Difficulty in thinkingDifficulty in thinking- Difficulty in Difficulty in

concentration, concentration, - Gait disturbancesGait disturbances- Provoke anxietyProvoke anxiety- UnpleasantUnpleasant

In DepressedIn Depressed-Sedation immediately-Sedation immediately

-Elevation of mood -Elevation of mood (2-(2-4Weeks)4Weeks)

-Suppresses REM -Suppresses REM prolongs total sleep prolongs total sleep durationduration

Lower seizure threshold and produce convulsions in overdose Don’t carry abuse potential, Development of dependence is less

TCAs uptake blockade TCAs uptake blockade is is not not directly responsible for directly responsible for

antidepressant action?antidepressant action? Uptake blockade occurs quickly but Uptake blockade occurs quickly but

antidepressant action occurs after monthsantidepressant action occurs after months Initially Initially

Pre synaptic alpha 2 and 5-HT1 Pre synaptic alpha 2 and 5-HT1 auto auto receptors are activatedreceptors are activated by increased amount of by increased amount of NA and Serotonin in synaptic cleft NA and Serotonin in synaptic cleft resulting in resulting in

decreased firingdecreased firing But on long term But on long term

desensitizedesensitize and down regulation of these and down regulation of these receptors and induce receptors and induce adaptive changesadaptive changes in the in the number and sensitivity of receptors and amine number and sensitivity of receptors and amine

turnover turnover leading to leading to enhanced enhanced NA and Serotonin NA and Serotonin transmission required for antidepressant action.transmission required for antidepressant action.

TCAs on other systemsTCAs on other systems

ANSANS Potent Potent

anticholinergicanticholinergic

(dry mouth, blurring of (dry mouth, blurring of vision,, constipation, vision,, constipation, urinary hesitancy)urinary hesitancy)

Weak alpha 1 Weak alpha 1 blockingblocking

(postural hypotension, (postural hypotension, impairment of impairment of ejaculation,)ejaculation,)

H1 antihistaminicH1 antihistaminic

(sedation) (sedation)

CVSCVS TachycardiaTachycardia Postural Postural

hypotensionhypotension Cardiac Cardiac

arrhythmias arrhythmias (T wave suppression (T wave suppression or inversion) due to or inversion) due to intra ventricular intra ventricular conduction conduction interference due to interference due to NA and Anti NA and Anti cholinergic actionscholinergic actionsTolerance to Anticholinergic

and hypotensive actions develop latter on

TCAs (Pharmacokinetics)TCAs (Pharmacokinetics) Good oral absorptionGood oral absorption Highly bound to Proteins (plasma and Highly bound to Proteins (plasma and

tissue)tissue) Metabolized in liver (oxidation, Metabolized in liver (oxidation,

glucuronide conjugation and glucuronide conjugation and CYP2D6, CYP2D6, CYP3A4, CYP1A2CYP3A4, CYP1A2

Many active metabolites may be producedMany active metabolites may be produced Mostly can be given once a day (at bed)Mostly can be given once a day (at bed) Have Have Therapeutic WindowTherapeutic Window

phenomenon (50-200ng/ml of imipramin)phenomenon (50-200ng/ml of imipramin)

TCAs Adverse effectsTCAs Adverse effects AnticholinergicAnticholinergic- dry moth, bad taste, - dry moth, bad taste,

constipation, epigastric fullness, urinary constipation, epigastric fullness, urinary retention (more common in elderly male), retention (more common in elderly male), blurred vision, palpitationblurred vision, palpitation

SedationSedation, mental confusion, weakness, mental confusion, weakness Increased appetite and weightIncreased appetite and weight Sweating, fine tremorsSweating, fine tremors Precipitation of seizuresPrecipitation of seizures Postural hypotensionPostural hypotension Cardiac arrhythmiasCardiac arrhythmias Rashes and jaundiceRashes and jaundice

TCAs (Acute Poisoning)TCAs (Acute Poisoning) Usually Usually suicidalsuicidal

attemptattempt Presents asPresents as

Excitement Excitement delirium, delirium, Anticholinergic Anticholinergic

symptoms like symptoms like atropine atropine poisoningpoisoning

Muscle spasmMuscle spasm ConvulsionsConvulsions Respiratory Respiratory

depressiondepression ComaComa

TreatmentTreatment Gastric lavageGastric lavage I.V. line I.V. line OxygenOxygen Maintenance of BP Maintenance of BP

and Temperatureand Temperature Diazepam ivDiazepam iv Propranolol / Propranolol /

lignocainlignocain

TCAs (Interactions)TCAs (Interactions) Potentiation of sympathomimetics Potentiation of sympathomimetics (direct acting)(direct acting) Reduce action of sympathomimetics Reduce action of sympathomimetics (indirect (indirect

acting)acting) Reduce antihypertensive action of guanethidine and Reduce antihypertensive action of guanethidine and

clonidine ( by preventing their transport in to clonidine ( by preventing their transport in to neurons)neurons)

Potentiate other CNS sedativesPotentiate other CNS sedatives SSRIs inhibit metabolism of TCAsSSRIs inhibit metabolism of TCAs With MAO inhibitors dangerous hypertensive crisis With MAO inhibitors dangerous hypertensive crisis

with excitement and hallucinations with excitement and hallucinations Retard the absorption of other drugsRetard the absorption of other drugs Phenytoin, Phenytoin, phenylbutazonephenylbutazone, chlorpromazine, , chlorpromazine,

aspirin, displace TCAs and produce toxicityaspirin, displace TCAs and produce toxicity PhenobarbitonePhenobarbitone induce metabolism and inhibit the induce metabolism and inhibit the

effect of the drugeffect of the drug

MiscellaneousMiscellaneous

AmoxapineAmoxapine Tetra cyclic Tetra cyclic

compoundcompound Blocks D2Blocks D2

reuptake alsoreuptake also Has mixed Has mixed

antidepressant antidepressant and neuroleptic and neuroleptic effectseffects

Good for psychotic Good for psychotic depressiondepression

ReboxetineReboxetine Selective NA Selective NA reuptake reuptake blockerblocker

Weak action Weak action on 5-HT on 5-HT mechanismmechanism

AnticholinergAnticholinergic effects are ic effects are minimalminimal

Selective Serotonin Reuptake Selective Serotonin Reuptake Inhibitors (SSRIs)Inhibitors (SSRIs)

Limitations of TCAsLimitations of TCAs Anticholinergic effectsAnticholinergic effects Alpha blocking actionAlpha blocking action Cardio toxicityCardio toxicity Sedation, seizures pptSedation, seizures ppt Low safety marginLow safety margin Weight gainWeight gain Therapeutic windowTherapeutic window Overdose poisoning Overdose poisoning

commoncommon Lag of 1 month periodLag of 1 month period Incomplete response to Incomplete response to

TtTt

Answers may be given by Answers may be given by SSRIsSSRIs

Selectively Selectively inhibit membrane inhibit membrane associated SERT (serotonin associated SERT (serotonin transporter)transporter)

More tolerability and better More tolerability and better acceptabilityacceptability

Used in depression as well as in Used in depression as well as in OCD, phobiasOCD, phobias

No sedation, No seizure pptNo sedation, No seizure ppt No alpha blocking actionNo alpha blocking action Less chances of arrhythmiaLess chances of arrhythmia No weight gainNo weight gain Now 1Now 1stst choice for choice for OCD, Panic OCD, Panic

disorders, Social Phobia, disorders, Social Phobia, Eating disorders, Premenstrual Eating disorders, Premenstrual syndrome, Post traumatic syndrome, Post traumatic stressstress

Important pointsImportant points

TCAs have slightly more efficacy

Some patients not responding to TCAs may respond to SSRIs,

SSRIs preferred in prophylaxis of recurrent depression

In severe depression TCAs appear to be more efficacious

Individual compoundsIndividual compounds FluoxetineFluoxetine

Prototype of Prototype of SSRIsSSRIs

Longest actingLongest acting

FluvoxamineFluvoxamine Short actingShort acting Commonly used Commonly used

in indoor patientsin indoor patients ParoxetineParoxetine

Short actingShort acting More GI side More GI side

effectseffects

SertralineSertraline Less chances of Less chances of

drug interactions drug interactions due to low potency due to low potency to cause cytochrome to cause cytochrome enzyme depressionenzyme depression

Citalopram

•Similar to sertraline but should be avoided in patients attempting suicide

Escitalopram

•Active enantiomer of citalopram side effects are less

SSRIsSSRIs Side effectsSide effects

Gastric upsetGastric upset NauseaNausea Interfere with Interfere with

ejaculationejaculation NervousnessNervousness RestlessnessRestlessness InsomniaInsomnia AnorexiaAnorexia HeadacheHeadache DiarrheaDiarrhea EpistaxisEpistaxis EcchymosisEcchymosis

OthersOthers Inhibit Inhibit cytochrome enzymescytochrome enzymes

and elevate the plasma level of and elevate the plasma level of other drugsother drugs

Other serotonergic drug Other serotonergic drug ( MAOIs) is taken may precipitate ( MAOIs) is taken may precipitate Serotonin SyndromeSerotonin Syndrome manifesting manifesting as agitation, restlessness, as agitation, restlessness, sweating, twitching, convulsionssweating, twitching, convulsions

Atypical AntidepressantsAtypical Antidepressants MianserinMianserin

UniqueUnique not inhibit NA and 5-HT uptake not inhibit NA and 5-HT uptake

Blocks pre-synaptic alpha 2 receptors Blocks pre-synaptic alpha 2 receptors increases release and turnover of NAincreases release and turnover of NA

Antagonist at serotonin 2, 1c, and H1 Antagonist at serotonin 2, 1c, and H1 receptorsreceptors

Has sedative effectHas sedative effect Damages liver and bone marrow Damages liver and bone marrow (Reserve (Reserve

drug)drug)

TrazodoneTrazodone Blocks 5-HT uptake Blocks 5-HT uptake Has prominenent Has prominenent alpha blockingalpha blocking Weak 5-HT2 antagonisticWeak 5-HT2 antagonistic No anticholinergic effectNo anticholinergic effect BradycardiaBradycardia Has anxiolytic action alsoHas anxiolytic action also Prolonged and painful Prolonged and painful penile erection (priaprism)penile erection (priaprism)

Atypical AntidepressantsAtypical Antidepressants Tianeptine / and Tianeptine / and

AmineptineAmineptine IncreasesIncreases rather rather

inhibiting 5-HT uptakeinhibiting 5-HT uptake Neither sedative nor stimulantNeither sedative nor stimulant Effective in anxiodepressive Effective in anxiodepressive

statesstates

Venlafaxine / DuloxetineVenlafaxine / Duloxetine SNRI SNRI selectiveselective in action in action Faster onset of actionFaster onset of action Increases BPIncreases BP Duloxetine increases uretheral Duloxetine increases uretheral

tone used in urinary incontinence tone used in urinary incontinence ( over active bladder)( over active bladder)

Mirtazapine (Mirtazapine (NaSSANaSSA)) Noradrenergic and specific Noradrenergic and specific

serotonergic antidepressantserotonergic antidepressant Blocks Blocks alpha 2 auto receptoralpha 2 auto receptor

(on NA neuron) and hetero- (on NA neuron) and hetero- (on 5-HT neuron) receptors (on 5-HT neuron) receptors increasing both NA and increasing both NA and serotonin release.serotonin release.

BupropionBupropion Inhibits Inhibits DA DA and NA and NA

uptake has excitant uptake has excitant effecteffect

Used to reduce Used to reduce smokingsmoking

Antidepressant usesAntidepressant uses Depression Depression ((ECT ECT may be needed in may be needed in

severely depressed and patients having severely depressed and patients having suicidal tendency)suicidal tendency)

Bipolar affective disorders TCAs and Bipolar affective disorders TCAs and lithium or SSRIs with lithium or valporate/ lithium or SSRIs with lithium or valporate/ lamotriginelamotrigine

SSRIs with atypical antipsychotic in SSRIs with atypical antipsychotic in psychotic depressionpsychotic depression

Obsessive compulsive disorders (SSRI and Obsessive compulsive disorders (SSRI and Clomipramine)Clomipramine)

Eating disordersEating disorders

Anxiety disordersAnxiety disorders Neuropathic painNeuropathic pain Attention deficit hyperactivity Attention deficit hyperactivity

disorder in childrendisorder in children Enuresis- (Enuresis- (Imipramine Imipramine 25mg at night)25mg at night) Overactive bladder (stress Overactive bladder (stress

incontinence)incontinence) Migraine prophylaxisMigraine prophylaxis Pruritus (Topical doxepin)Pruritus (Topical doxepin)

Antianxiety DrugsAntianxiety Drugs Anxiety - Anxiety - emotional state emotional state

- UnpleasantUnpleasant- Associated with uneasinessAssociated with uneasiness- DiscomfortDiscomfort- FearFear- Undefined threatUndefined threat- Fear about futureFear about future

Some amount of anxiety is must for progress

When it becomes excessive, disproportionate, hampers performance

then only

needs treatment

Antianxiety DrugsAntianxiety Drugs Drugs producing restful state of mind Drugs producing restful state of mind withoutwithout

interfering with normal mental or physical interfering with normal mental or physical functions. functions.

Have no effect on thought controlHave no effect on thought control Don’t produce extra pyramidal side effectsDon’t produce extra pyramidal side effects Can Produce physical dependenceCan Produce physical dependence May HaveMay Have abuse potential abuse potential Don’t selectively block conditioned avoidance Don’t selectively block conditioned avoidance

response in animalsresponse in animals

Have anticonvulsant Have anticonvulsant activityactivity

Antianxiety DrugsAntianxiety Drugs

BenzodiazepineBenzodiazepine DiazepamDiazepam ChlordiazepoxideChlordiazepoxide OxazepamOxazepam LorazepamLorazepam AlprazolamAlprazolam

AzapironesAzapirones BuspironeBuspirone GepironeGepirone IspapironeIspapirone

OthersOthers Beta blocker- Beta blocker- PropranololPropranolol Antihistaminics- Antihistaminics-

HydroxyzineHydroxyzine SSRIs and other SSRIs and other

antidepressant drugsantidepressant drugsPHO/BIG/DOCLA

BenzodiazepinesBenzodiazepines

Relieve anxiety at low dose ( higher dose Relieve anxiety at low dose ( higher dose induce sleep and impair performance )induce sleep and impair performance )

Selective taming effectSelective taming effect More selective to More selective to limbiclimbic system system Have low side effects in Antianxiety doseHave low side effects in Antianxiety dose Lorazapam and clonazepam IM for Lorazapam and clonazepam IM for

psychotic and manic patients psychotic and manic patients

Act by Act by facilitatingfacilitating GABAergic GABAergic transmissiontransmission

Benzodiazepine MOABenzodiazepine MOA

α subunit

γ subunit

Othersδεθπ

β subunitGABA

Cl

GABA- A Receptor

Diazepam +DMCM –

Flumazenil- 0

BarbituratesMim

etic

Facilitator

Facili

tato

r

Cl

More Cl- intracellular more polarized more refractory

Intracellular

Extra-tracellular

BenzodiazepinesBenzodiazepines Adverse effectsAdverse effects

SedationSedation Light headednessLight headedness Psychomotor impairmentPsychomotor impairment Cognitive impairmentCognitive impairment VertigoVertigo Confusional stateConfusional state Increased weightIncreased weight Impaired sexual functionsImpaired sexual functions Potential to produce dependencePotential to produce dependence All are almost similar selection is empiricalAll are almost similar selection is empirical

Benzodiazepines Benzodiazepines (Individual drugs)(Individual drugs)

ChlordiazepoxideChlordiazepoxide First BZDFirst BZD Long lasting effectLong lasting effect Chronic anxietyChronic anxiety

DiazepamDiazepam Has two phase of Has two phase of

metabolismmetabolism Broken in to Broken in to active active

metabolitesmetabolites Long duration of actionLong duration of action

OxazepamOxazepam Polar compoundPolar compound Penetration In brain is slowPenetration In brain is slow No active metaboliteNo active metabolite Used in short lasting Used in short lasting

anxiety stateanxiety state

LorazepamLorazepam Less lipid solubleLess lipid soluble Slow entry in brainSlow entry in brain No active metaboliteNo active metabolite IMIM

Alprazolam-

high potency, mood elevating in depressed pt. less drowsiness

BuspironeBuspirone

Does not produce sedation,Does not produce sedation, cognitive cognitive impairment,impairment,

Does notDoes not interact with BZD receptor interact with BZD receptor or modify GABAergic transmissionor modify GABAergic transmission

No toleranceNo tolerance No physical dependenceNo physical dependence No muscle relaxant No muscle relaxant No anticonvulsant propertyNo anticonvulsant property

BuspironeBuspirone

Relieves mild to moderate generalized Relieves mild to moderate generalized anxietyanxiety

Effects develop Effects develop slowly slowly (not used for acute)(not used for acute) Partial agonist on 5HT1A (pre-synaptic) Partial agonist on 5HT1A (pre-synaptic)

and antagonist on 5HT postsynaptic and antagonist on 5HT postsynaptic receptorsreceptors

Presynaptic auto-receptors stimulated Presynaptic auto-receptors stimulated leading to reduced activity of dorsal raphe leading to reduced activity of dorsal raphe serotonergic neurones serotonergic neurones

Also has Also has weak D2 blockingweak D2 blocking effect effect

HydroxazineHydroxazine H1H1 antihistaminic antihistaminic Sedative, anti -Sedative, anti -

emetic and emetic and spasmolyticspasmolytic

Anti - PruritusAnti - Pruritus

PropranololPropranolol Reduces Reduces

sympathetic sympathetic symptoms like rise symptoms like rise in BP, Tremors, in BP, Tremors, sweating etc.sweating etc.

Performance or Performance or situational anxietysituational anxiety

(like examination (like examination fear, social phobia, fear, social phobia, public lecture)public lecture)

QuestionsQuestions Classify antipsychotic drugsClassify antipsychotic drugs Classify antidepressant drugsClassify antidepressant drugs Pharmacological actions of Pharmacological actions of

chlorpromazinechlorpromazine Pharmacological actions of amitriptylinePharmacological actions of amitriptyline Drug indued parkinsonismDrug indued parkinsonism MOA of antipsychoticMOA of antipsychotic MOA of antidepressantsMOA of antidepressants LithiumLithium

QuestionsQuestions Drug of choice of cheese reaction-PhentolamineDrug of choice of cheese reaction-Phentolamine Moclobemide is reversible and selective MAO-A inhibitorMoclobemide is reversible and selective MAO-A inhibitor All antidepressants don’t inhibit DA uptake except amoxapine, All antidepressants don’t inhibit DA uptake except amoxapine,

maprotiline, Bupropionmaprotiline, Bupropion Antidepressants don’t carry abuse potentialAntidepressants don’t carry abuse potential SSRIs are inhibitor of CYP enzymesSSRIs are inhibitor of CYP enzymes Serotonin syndromeSerotonin syndrome Trazodone – may produce priaprism due to high Trazodone – may produce priaprism due to high αα1 blocking 1 blocking

propertyproperty Mianserin unique not inhibiting NA or 5HT but blocks Pre-Mianserin unique not inhibiting NA or 5HT but blocks Pre-

synaptic synaptic αα2 receptors2 receptors Tianeptine, Amineptine - unique increase 5-HT uptakeTianeptine, Amineptine - unique increase 5-HT uptake Venlafaxine, Duloxetine – SNRIVenlafaxine, Duloxetine – SNRI Mirtazapine- NaSSA- blocks Mirtazapine- NaSSA- blocks αα2 auto and hetro receptors and 2 auto and hetro receptors and

enhance NA and 5HT releaseenhance NA and 5HT release Nocturnal enuresis- ImipramineNocturnal enuresis- Imipramine Benzodiazepines- GABA facilitatoryBenzodiazepines- GABA facilitatory Buspirone- partial agonist at 5HT1A autoreceptors,antagonist at Buspirone- partial agonist at 5HT1A autoreceptors,antagonist at

5HT1A postsynaptic5HT1A postsynaptic DOC of performance or situational anxiety- B-blockersDOC of performance or situational anxiety- B-blockers

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