Antipsychotic Agents PPT

8/12/2019 Antipsychotic Agents PPT

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SECOND

GENERATION

ANTIPSYCHOTICS

CHAIR PERSONS:

PROF.Dr.V.GEETHANJALI, M.D(PSY) DCHASST.PROF.DR.G.AMUDHA, M.D.(PSY) DCH


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ATYPICAL ANTIPSYCHOTICS

Low EPS good for negative symptoms Serotonin-dopamine antagonist D2 antagonist with rapid dissociation.

D2 Partial agonist Serotonin partial agonist at 5HT1A receptor


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The Mesolimbic Dopamine

Hypothesis of Positive Symptoms

of Schizophrenia


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negative

symptom

s

affective

symptom

s

Mesocortical Pathway to VMPFC


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The Mesocortical Dopamine

Hypothesis of Cognitive, Negative,

and Affective Symptoms of

Schizophrenia


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What makes an antipsychotic

atypical?


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D2 antagonism and anticholinergic

agents


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5HT1A autoreceptors


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Atypical antipsychotics and prolactin


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Dopamine receptor o tp t


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Dopamine receptor output


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Histamine H1 Combined with Serotonin 2C Antagonism May


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Histamine H1 Combined with Serotonin 2C Antagonism May

Stimulate Appetite


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CLASSIFICATION

Dibenzodiazepines

Clozapine

Substituted Benzamides

Amisulpride

Sulpride

Benzisoxazoles

Iloperidone

Paliperidone Risiperidone

Benzisothiazolyl

ziprasidone


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CLASSIFICATION

Thienobenzodiazepine

Olanzapine

Dibenzothiazepine

Quetiapine

Partial Agonists

Aripiprazole

BifeprunoxDibenzothiepin

Zotepine

Dibenzooxepinopyrrole

Asenapine


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RISPERIDONE

Benzisoxizole derivative Bio-availability 70%

9-hydroxy risperidone half life 3-20 hrs 5-HT 2A ,D2,-1, -2,H1 antagonism Weak affinity 5-HT 1C ,5-HT 1D Metabolised by CYP 2D6


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Therapeutic Ind-R

Acute psychosis Maintenance treatment Sczh.

Bipolar maniaAutism PTST Treatment resistant depression Bor.PD

Lesch-Nyhan syndrome


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Therapeutic Ind-R

Treatment refractory OCD Tourettessyndrome

Conduct disorder MR with beh.prob.(.01-.06 mg/kg/day)AIDS related dementia Drug induced psychosis (.25-3 mg/day) Huntingtons disease


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DOSAGE-R

Starting dose 0.5-1mg b.d Increase by 0.5-2mg b.d on days 2 and 3,with

further dose increases thereafter by 0.5-1mg Sczh. - adult 8mg/day, adolescents-3mg/day Bipolar maniaadult-6mg/day , adolescents-

2.5mg/dayAutism- < 20kg -.25mg/day, >20kg-0.5mg/day


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R-CYP 2D6

Fluoxetine,Paroxetine,Bupropion,Quinidine

CBZ, Phenytoin, Phenobarbital,

Valproate by 20%


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RISPERIDONE SIDE EFFECTS

Elderly patient - risk CVA Neuroleptic Malignant Syndrome Tardive dyskinesiaD2 blockade in basal ganglia

12% wt. gain Diabetes Mellitus Orthostatic hypertension and syncope

sedation., somnolence

Hyperprolactinemia Erectile dysfunction


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R- SPL. GROUP

Pregnancy category C 3% congenital malformation

16% spontaneous abortion Perinatal syndrometremor , EPS, irritability,

somnolence, feeding problems

Lactation2-4% of maternal dose Infertility -sperm motility in adults Pituitary gland adenoma, mammary gland

adenocarcinoma , pancreas adenoma-prolactin


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DOSE RANGE -R

2-8 mg/day max.16mg Available1,2,3,4mg tablets

1mg/ml oral solution

Long acting risperidone microspheres-I.M. aqueoussuspensionglycolic acid lactate polymer

Drug release commences 3 weeks after inj.

No test dose required Available dose25,37.5 ,50mg every 2 weeks3,6,>6 mg oral dose

Not suitable for treatment refractory Sczh.


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PALIPERIDONE

Major active metabolite of Risperidone Shares Risperidone receptor profile

Pressure based osmotic release oral system Gradual release without peak Initiation without titration No significant hepatic metabolism Fewer drug interaction


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P-PHARMACOLOGY

P-extended release t - 23 hrs

CYP 2D6 ,CYP 3A4 P 450 isoenzyme -not an inhibitor or inducer


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P-INDICATION

Schizophreniaacute and maintenancetreatment

sleep architecture -stage 2 ,REM,SEI


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P-ADVERSE REACTION

QT prolongation12 msecs

7 % wt. gain Elderly - risk CVA NMS, TD

DM Prolactin

P DOSAGE


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P-DOSAGE

Extended Release3,6,9 mg tablets Starting dose6mg/day Titrationonce in 2-3 days

Maximum 12mg/day Paliperidone palmitate long acting inj. plasma level within a day max.13 days

no oral supplementation

no test dose

no cold storage

bioavailability- 28 %


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P-DOSE AND ADMINISTRATION

Day 1 150 mg i.m deltoid

Day 8 100mg i.m deltoid

Every month 50-150mg

i.m.

Deltoid or

gluteal


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ILOPERIDONE

SDA antagonist 1 antagonismhypotension Treatment of schz.,PCP induced psychosis

Oral dose20 -24 mg/day


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CLOZAPINE

Dibenzodiazepine Only oral preparation

Absorptionpeak plasma level2hrs t - 12hrs Bioavailabilty 27-47% - 1stpass metab.

N-desmethyl clozapinemetabolite M 1 agonist ( cognition)

Clozapine


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p


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CLOZAPINE

Stronger 5-HT2 blockade, D1,D3,D4,1 Less D2 antagonist (40- 50 % occupancy)

fast dissociation

Plasma conc. 10-20 ml/mg/kg

C INDICATION


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C-INDICATION

Treatment resistant Schiz. Suicidal behaviour,hostile,aggresion Severe TD ( spares striatal D2 receptors)

Schiz. + substance abuse Treatment resistant Mania Severe psychotic depression

Huntingtons disease, Idiopathic Parkinsonsdisease Treatment resistant autism, OCD Polydipsia hyponatremia syndrome

C SIDE EFFECTS


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C- SIDE EFFECTS

Most commonsedation HR (vagolytic property of drug)

>25 beats /min >300mg /day dose

QT intervalReversible non specific ST,T wave flatting or

inversion

Idiopathic myocarditis (first 6 weeks), ventriculararrythmias

Blurring, dry mouth, constipation (Muscarinic

Antagonist)

C SIDE EFFECTS


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C- SIDE EFFECTS

Sialorrhea Clonidine 0.1-0.2mgAmitriptyline useful

Wt. gain4kg

Seizures > 600mg dose 4 % risk Add Sodium valproate/opiramate/Gabapentin No CBZ - precipitate neutropenia


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C- SIDE EFFECTS

Agranulocytosis 0.7 %

First 3 monthsBefore therapy WBC > 3500

6monthsweekly monitoring

6-12 monthsevery 2weeks monitoringThen every 4 weeks monitoring

If Pt.s WBC < 3000, Neutro < 1500 stop CLZ.

Total Eosinophils > 4000 discontinue CLZ.


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C-C.I.

WBC < 3500 cells/cu.mm BM disorder

Previous h/o agranulocytosis with CLZtreatment CBZ co-drug

Pregnancy Cat.B drug Excreted in breast milkshould not feed Discontinuing CLZ

Cholinergic rebound taper 2-4 weeks


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C-DRUG INTERACTION

CYP 1A2, 2D6, 3A4 CLOZAPINE

Fluoxetine Fluvoxamine Dupropion, TCA

Caffeine Erythromycin Ciprofloxacin


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C-DRUG INTERACTION Clozapine

Nicotine

CBZ Phenytoin Rifampicin

Lithium ppt. seizure,NMS Paroxetine - neutropenia

C DOSE


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C-DOSE

Available 25,100mg Initial dose -12.5mg twice daily

once 2-3 days max. 300mg Maintenance150- 450 mg/day Titration

2ndday -50mg Daily 25-50mg till 300-450mg Then twice weekly

Max. dose 900 mg/day OLANZAPINE


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OLANZAPINE

Thienobenzodiazepine Thieno ring substituted for clozapine,

carbonyl ring Peak level 6hrs t -31 hrs

I.M. onset within 45 mins. 5HT2A/2C antagonist 5HT6,5HT3,D1-

D4 ,1, H1,M1

64-84% D2 occupancy


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OLANZAPINE


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OLANZAPINE

MetabolieCYP 1A2 Olanz.

Fluvoxamine

Ciprofloxacin

Ethanaol

Olanz. Nicotine

CBZ

Modafinil

Omeprazole

Bld. Conc. >23ng/ml -favourable

O INDICATIONS


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O-INDICATIONS

Acute Schz.- calming effect Maintenance treatment in Schz.

MonotherapyMania & mixedAgitation in Bipolar Mania & Schz.Adju.SSRI for PTSD Tourettessyndrome Dementia & Psychosis

Anorexia Nervosa, Autism

O DOSAGE


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O-DOSAGE

Available2.5,5,7.5,10,15,20 mg tablets 5,10,15 mg orally disintegrating tablets Starting dose5-10mg/day

Maintenance -10-20 mg/day Titration

5mg once a day

At intervals of once in 5 days Max. dose30mg/day I.M. 2.5 - 10 mgrepeat every 2 hrs till

agitation settle down


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O-SIDE EFFECTS

Wt. gain - > 7%

TGL > 500mg/dl Hyperglycemia,DM,Insulin resistancewithin 6 months

SGOT > 3 times Dry mouth,dizziness,somnolence,constipation EPS & dose related


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O-HIGH RISK Pregnancy

Cat. C drug

LBW Gestational DM

Lactation1% maternal dose


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QUETIAPINE

Dibenzothiazepine

Peak 1-2 hrs t - 6hrs ,steady state level48hrs Potent 5-HT2 blocker(72%), H1,1, 2 Low affinity for D1,D2(44%),D4,M1 Fast dissociation


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Q INDICATIONS


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Q-INDICATIONS

Schz.acute and maintenance Bipolar I &IIDepressive episode

(acute & continued treatment) Bipolar lManic- acute treatment Psychosis in Parkinsons disease InsomniaSleep inductionH1 blockade

Sleep maintenance5HT2A antagonist

Q-ADVERSE EFFECTS


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Q ADVERSE EFFECTS

Orthostatic hypertension

Cataract Fluctuation in T4 level -20% SGOT

Sedation,Somnolence,Suicidal ideation Wt. gain, Hypertriglyceridemia Less EPS


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Q-HIGH RISK GROUPS

PregnancyCat. C drug LBW Safe to use in pregnancy Lactation0.09% of maternal dose

Q DOSAGE


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Q-DOSAGE

Starting dose 25mg twice a day Maintenance200-800mg/day

Max.800mg/day Titration25 mg b.dD1

100 mgD2

400 mgD4

Further increase of 50mg b.d. every 2 days

Q-DOSAGE


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Q DOSAGE

ManiaD1-100

D8- 800 mg/day

DepressionD1- 50mg

D2- 100mg

D3- 200mg

D4- 300mg

Quetiapine extended release Once daily at bed time

initial 300mg

Q-INTERACTION


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Q INTERACTION

CYP 3A4 Quetiapine

Nefazodone Erythromycin Ketoconazole Protease inhibitor

Quetiapine CBZ Phenytoin modafenil


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Q-INTERACTION

No dose adjustment Lithium Lorazepam Fluoxetine Risperidone

Haloperidol Imipramine


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ZIPRASIDONE

Benzisothiazolyl piperazine

Peak plasma level 6-8hrs t - 5-10 hrsAfter I.M. inj.

Peak1hr t - 2-5 hrs


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Z-MECH.OF ACTION

5 HT 2 A : D 2 Antagonist(11 : 1 ) D1,D3,D4 Antagonist

Agonist 5HT1A, antagonist 5HT2C, 5HT1DAffects NE, Serotonin uptake sites


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Z-INDICATIONS

Schz.

1.Acute episodes2. Preventing relapses

3.Acute agitation

Z ADVERSE REACTIONS


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Z- ADVERSE REACTIONS

QT prolongation(4.7-1.4 msec in 120 mg/day)

Dont administer in Pts. Taking CPZ Thioridazine

Gatifloxacin, Moxifloxacin Guinidine Tacrolimus

Z DRUG INTERACTION


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Z- DRUG INTERACTION

CYP 3A4 Ziprasidone

Ketoconazole Erythromycin Protease inhibitor

Ziprasidone CBZ Phenytoin Modafinil

Z-DOSAGE


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Available 20,40,60,80 mg capsules

I.M. Inj. 20 mg/ ml vial Starting dose20mg twice a day with food Maintenance20-80 mg B.D

Titrationonce in 2 days Maximum80 mg B.D. I.M. inj.

Titration 10 mg once in 2 hrs

20 mg once in 4 hrs

Max. 40 mg/day for 3 days


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ZOTEPINE

SDA antagonist 5HT2C,H1 antagonistwt. gain

1 antagonistsedation 5HT2C,NRIefficacy for mood symptoms Perospirone,sertindole - STA antagonist

- QTc prolongation

Loxapineatypical at low doses- metabolite Amoxapine (NARI) effective as antidepressant


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ASENAPINE

Antipsychotic with antidepressant action

Serotonin,Dopamine antagonist

5HT1A partial agonist

5HT2C antagonistrelease DA,NE in prefrontal

cortex

- antidepressant effect

Half life24 hrs Dose5mg S/L twice daily

Max. dose10mg twice daily


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ARIPIPRAZOLE


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ARIPIPRAZOLE

Quinoline derivative Peak plasma conc. 3-5hrs

t - 75 hrs Metabolitedehydroaripiprazole t 1/2 96 hrs Bioavailability 87% Steady state plasma conc. 14 days Metabolised by CYP 3A4, 2B6


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ARIPIPRAZOLE

Partial agonist D2 receptor

5HT1A partial agonist

5HT2A/2C ,D3,H1 antagonist

A DOSAGE


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A-DOSAGE

Starting dose10 -15 mg OD

Maintenance dose 10-30 mg/day

Titration- should not be made before 2

weeks

Max . Dose 30mg/day

A- DRUG INTERACTION


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CYP 2D6, 3A4 Arpiprazole

Quinidine

SSRI Erythromycin Protease inhibitor

Arpiprazole CBZ Phenytoin


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A-INDICATIONS

Schizophreniaacute & maintenancetreatment

Adolescents started at 2mg max.10mg Bipolar disorder

Adjunctive treatment for depression I.M. dose for agitation


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A-DOSAGE

Available - 5,10,15,20,30 mg tabs. I.M.9.75 mg effective in 45 mins.


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A-ADVERSE EFFECTS

Akathisialike-activation Insomnia

seizures


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AMISULPRIDE

Substituted Benzamide Partial agonist at D2 receptor High affinity for presynaptic D2,D3 receptor


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AMISULPRIDE -ADVANTAGES

Lacks affinity for D1negative symptomsimprovement

No affinity for 5HT2A/1A- low EPS Function as D partial agonist at low doses

D2 antagonist at high doses


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AMISULPRIDE -DISADVANTAGES

QTc prolongation Prolactin

Wt. gain


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AMISULPRIDE - DOSE

Available dose50,100,200 mg tabs. Dose range200-1000 mg/day Maintenance400mg/day


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SULPRIDE

At low dose function as atypical antipsychotic At high dose function as typical antipsychotic


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BIFEPRUNOX

DPA + SPA agonist Full agonist than Aripiprazole- nausea & vomiting

Efficacy - +ve symptoms of Schz., Mania


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Antipsychotic Agents PPT