Anti Depressants Final

8/2/2019 Anti Depressants Final

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Anti-DepressantsDr Nauman


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Increased morbidity and mortality.

Disrupts marital, familial, social life.

Affects work, leads to job related problems.

Increased incidence of medical

illnesses,accidents.Risk of suicide.


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Monoamine hypothesis of

depression

Depression is caused by a

functional insufficiency ofmonoamine neurotransmitters

(norepinephrine, serotonin or

both)


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In any case, Reversal of DepressionIn any

case, Reversal of Depression

Should be possible byShould be possible by

Increasing

Increasing

5HT5HT NANACNS Neuronal TransmissionCNS Neuronal Transmission


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Classification

AMINE UPTAKE

INHIBITORS

MAO INHIBITORS


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Amine Uptake Inhibitors

TRICYCLIC ANTIDEPRESSANTS

HETROCYCLICANTIDEPRESSANTS

(ATYPICAL ANTI-DEPRESSANTS)

SSRIs


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Tricyclic Antidepressants

Dibenzazepines

Clomipramine

Imipramine

Desipramine

Trimiparine


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TCAs

Dibenzocycloheptadienes

AmitriptylineProtriptyline

Nortriptyline


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Hetrocyclic or Atypical

AntidepressantsSecond Generation

AmoxapineMaprotiline

TrazodoneBupropion


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Hetrocyclic or Atypical

AntidepressantsThird Generation

Antidepressants

Mirtazepine

Nefazodone

Venlaxafine


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Selective Serotonin Reuptake

Inhibitors (SSRIs)Fluoxetine

ParoxetineCitalopram

Sertarline


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Monoamine Oxidase Inhibitors

Hydrazine Derivatives

PhenelzineIsocarboxazid

Iproniazid

Non-Hydrazine Deratives

Tranylcypromine

Meclobemide


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Tricyclic Antidepressants

Characteristic three ring nucleus.

Most are incompletely absorbed, all

are metabolized in liver => High firstpass effect:

Some have active metabolites

High protein binding, high lipid

solubility.


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Mechanism of Action:

Immediate-Inhibition of NT reuptake

- Immediate action = > NE and 5-HT in synapse

-

But depression is not relievedimmediately

- WHY?


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After 2-4 Weeks

After chronic treatment (2 - 4 weeks)

NE-R and5-HT2R.

NE release and turnover. NE-stimulated cAMP in brain.

Sensitization of 5-HTreceptors.

* Adaptive Responses *

- Takes up to 4 weeks for all TCAantidepressants to have an effect.


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Some have more Effect on NE Uptakethan Serotonin and Vice Versa

More Effect on NE Reuptake

Desipramine

More effect on Serotonin ReuptakeAmitriptyline


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Block of Other Receptors

Muscarinic Receptors

Alpha1 ReceptorsHistamine H1 Receptors

Produce Adverse effects of TCAs


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Actions of TCAs

CNS

In normal peopleClumsiness, sleepiness,

difficulty in concentrating,

unsteady gaitUnpleasant feeling and anxiety


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In depressed People

Little effects at start except sedation

Elevation of mood after 2-3 weeks,

then other symptoms improve


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Decrease Seizure Threshold

AND Produce convulsions inoverdose


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ANS, CVS

All typical features of antimuscarinic

drugs and alpha blockers

Tachycardia, other arrythmias

ECG: T wave suppression


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Tolerance and DEPENDENCE

Tolerance to Anticholinergic,

hypotensive and sedative effects will

develop gradually

Physical dependence occursMalaise, chills, muscle pains


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Know this too !Know this too !

Electro-convulsive therapy

( Shock treatment) forseverely

depressed and suicidal patient


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Uses of TCAs

Major Depression

Bipolar DepressionObsessive Compulsive Disorder

(OCD)

Anxiety Disorders


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Phobias

Panic Disorders Attention Deficit Hyperactivity

Disorder (ADHD)


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Eating Disorders (Anorexia

Nervosa andBulimia Nervosa)

Stress Syndrome(PTSD)

Schizo-affective Disorders

Schizophrenia along with

anti-psychotics


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Non-Psychiatric Uses

Chronic pain syndromes

MigrainePruritis


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Adverse Effects of TCAs

Extension of The actions

ANS

Anticholinergic Effects

CVS

Postural Hypotension

Cardiac ArrhythmiasECG Abnormalities- T Wave inversion

AV Conduction abnormalities


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CNS

Mania or hypomania

Sedation

Increased appetite and weight gain

Lowered seizure threshold

Miscellaneous

Sexual DysfunctionRashes, jaundice rare


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Toxicity-Overdose of TCAs

Life threatening- very serious

Overdose common in already depressed

patients

All above adverse effects are pronounced

Cardiotoxicity, Anticholinergic effects,Respiratory depression, Convulsions

Coma and death may occur


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Treatment of Toxicity

1. SymptomaticGastric Lavage

Activated Charcoal

Respiratory SupportIV Fluids

Maintain BP

2. DrugsDiazepam- Convulsions

Propranolol, Lignocaine

Na Bicarbonate- Acidosis


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Drug Interactions

Pharmacokinetic Interactions

Phenytoin, phenylbutazone and Aspirin

displace TCAs from Plasma Proteins

Phenobarbitone induces metabolism of

TCAs while Carbamazepine inhibits

metabolism of TCAs

SSRIs inhibit the metabolism of TCAs

leading to toxicity

By their anti-cholinergic properties, the

absorption of drugs may be increased or

decreased


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Pharmacodynamic Interactions

Potentiate actions of directly actingsympathomimetics

Inhibit actions of indirect acting

sympathomimetics Block actions of Guanethedine and

Clonidine by preventing their transport

into adrenergic neurons Potentiate CNS depressants including

alcohol


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With MAOIs may cause

hypertensive crisis

With other Anti-cholinergics, added

Anticholinergic effects

Increases alpha blocking effect withother alpha blockers

Increased sedation with anti-

histamines


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Selective Serotonin Reuptake

Inhibitors (SSRIs)Fluoxetine

Sertraline

Paroxetine

Citalopram


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Mechanism of Action

Specific serotonin uptake inhibitorsincrease 5-HT by inhibiting

reuptake.

Delayed mechanisms

Desensitization of 5-HT1A,D,7

Autoreceptors

Decrease in 5-HT2A receptors


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Uses Of SSRIs

Similar to TCAs

They are preferred over TCAS

because of lesser adverse effects

Do not cause toxicity in overdose

They both have same efficacy


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Adverse Effects of SSRIs

Nausea, vomiting, headache

Sexual Dysfunction

Interferes with orgasm or ejaculation

Mild anxiety, restlessness and

insomniaMania or hypomania


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Differences Between SSRIs

and TCAs

SSRIs-Advantages:

Less or no effect on H1 receptors

Less or no effect on Muscarinic Receptors Less effect on Alpha-1 Receptors

No seizure precipitating property

No cardiotoxicity Less weight gain

SSRIs: Disadvantage: are enzyme

inhibitors


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Similarities Between TCAs and

SSRIs

Both have similar uses

Both have similar efficacyBoth cause sexual dysfunction

Both may cause mania or

hypomania


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Drug Interactions of SSRIs

Inhibit drug metabolizing enzymes, thus

cause increased levels of

TCAs Warfarin

Haloperidol Beta Blockers

Clozapine Carbamazepine

Benzodiazepines


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Monoamine Oxidase Inhibitors

(MAOIS)Hydrazine Derivatives

Phenelzine

Isocarboxazid

Iproniazid

Non-Hydrazine DerivativesTranylcypromine

Meclobemide


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X. MAO INHIBITORS

Developed for the treatment of tuberculosis

(iproniazid derivatives) - 1951.

These drugs are not widely used today,

although a small number of patients appear

to do better with MAOIs than TCAs or the

newer drugs.

Effects persist even after these drugs are no

longer detectable in plasma (1-3 weeks).


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Mechanism of Action

MAO enzyme metabolizes catecholamines

Two types:

MAO-A: Metabolizes norepinephrine,serotonin and tyramine

MAO-B: Metabolizes Dopamine

Important way of terminating action of

catecholamines


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MAOIs Inhibit MAO enzymes (non-selective):

1) Irreversible MAO inhibitorsPhenelzine and isocarboxazid =>

hydrazides.

2) Reversible MAO Inhibitors.

Tranylcypromine => non-hydrazide

Prolonged blockade, but reversiblewithin 4hr.

Decrease metabolism of most biogenicamines (NE, 5HT, DA, tyramine)


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Selective MAOIs:

Inhibitors of MAO-A

Meclobemide, ClorgylineInhibitors of MAO-B.

Deprenyl, Selegiline (Used in

Parkinsonism, not depression)


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Mechanism

Acute administration causes:

NE and 5-HT in synaptic terminals in

brain but NE in PNS.

NE synthesis and turnover

Chronic administration causes:

NE-stimulated cAMP in brain.

Down regulation of receptors.

Down regulation of 5-HT2 receptors.


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Figure 31-3: Monoamine

Oxidase Inhibitors:

Mechanism of Action

MenuB F T


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Uses of MAOIs

LESS USED

Depression especially notresponding to SSRIs or TCAs

Atypical Depression

Bulimia

OCD


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Adverse Effects

Sexual Dysfunction

Sedation

Weight gain

Urinary hesitancy

Hepatotoxicity


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Drug Interactions-

Wine-and-Cheese Reaction Fatal interaction with tyramine-containing

foods (fermented foods in particular, such

as wine and cheese). MAO-A => Tyramine in the body

=> NE in circulation => induces

hypertensive crisis => can lead tointracranial bleeding and other organ

damage.


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Foods that Contain Tyramine

cheese,

chicken liver,Tomatoes, ketchup

beer,

red wine


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Smoked/pickled or aged meats,

Many types of fish

Poultry (herring, sausage,

corned beef, salami, pepperoni)Yeast extracts

Italian broad beans (fava beans)


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Thus MAOIs are less used

because of the dietary inhibitions


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Drug Interactions-

Serotonin SyndromeOccurs when combined with SSRIs

Hyperthermia, muscle rigidity, myoclonus,

rapid changes in mental status and vitalsigns.

Treat with BZD or dantrolene


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Drug Interactions-

Hyperexcitation SyndromeInteraction with drugs

metabolized by MAOs (e.g.

Meperidine (opioid analgesics) =>hyperpyrexia orhyperexcitation

syndrome involving high fever,

delirium and hypertension).


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OTHER DRUG INTERACTIONS

Hypertensive crisis when combined with

sympathomimetics (e.g., decongestants

found in OTC cold remedies)Inhibition of Metabolism of many drugs

Thus it is important to wait up to 6 weeks

after medication is stopped, before

starting with another drug.


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Hetrocyclic Anti-depressants

They all have different mechanisms of

action and different adverse effects

Buproprion

Nefazodone

Venlafaxine


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Mechanisms

1) NE reuptake inhibitors

Maprotiline, Amoxapine

2) 5-HT receptor antagonism (5-HT2A or 2C receptors)

Nefazodone, Mirtazepine, 3)Dopamine reuptake Inhibitor

Bupropion


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OverviewOverview

3 Major classes of Anti-

depressants

TCAs

SSRIs

MAOIs

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Anti Depressants Final

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