Drugs used in schizophreniaObjectives:

Ø Listtheclassificationofantipsychoticdrugsusedinschizophrenia.Ø Describebrieflythemechanismofantipsychoticactionofthese

drugs.Ø Describethepharmacologicalactionsofantipsychoticdrugs.Ø Relatebetweenpharmacologicalactions&adverseeffectsof

antipsychoticdrugs.Ø Enumeratetheclinicalusesofantipsychoticdrugs.Ø Describetheadvantagesofatypicalantipsychoticdrugsovertypical

drugs.

extrainformationandfurtherexplanation

important

doctorsnotes

Drugsnames

Mnemonics

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Psycho

ses: Schizophreniaaffect

thoughts

AffectivePsychosesaffectsmood

Mania.

Depression

Manic-depressiveillness(bipolaraffective

disorder).

Schizophrenia

Itisathoughtdisordercharacterizedbydivorcementfromrealityinmindofpatient.itmayinvolvehallucinations,delusions,intensesuspicion, paranoia (fellingofpersecutionorcontrolby

externalforces).

Positive Symptoms Negative Symptoms(FAMILYMEMBERS noticethesechangesnotthepatient)

1. Hallucinations.2. Delusions.3. Paranoia.

1. Socialwithdrawal.2. Anhedonia(absenceofpleasure).3. Emotionalblunting.

Dopaminergic pathways in the brain :Schizophreniadrugsaffectallthepathways

1- Mesolimbic-mesocorticalpathwayschizophreniadrugshave

therapeutic effectonthesepathways

2- Nigrostriatalpathway

3- Tuberoinfundibular pathway

4- Medullary-periventricularpathway

behavior

co-ordinationofvoluntarymovements

endocrineeffects

(metaboliceffects)

DOPAMINERECEPTORS:Thereareatleastfivesubtypesofreceptors:

D1,D2,D3,D4,D5D2istheclassicaldopaminereceptor

MostofschizophreniadrugssideeffectscomesfromblockingD2receptorsinpathwaysotherthanMesolimbic-mesocortical .IfweavoidblockingD2so,weavoidthesesideeffects

aregroupofdrugsusedinthetreatmentofschizophrenia.-Oldname(neurolepticdrugs)

What are they ?

Classification:

Drugsusedinschizophreniaareclassifiedaccordingtochemicalstructures Into

Typical Atypical

discoveredfirst,nonselective,manysideeffects,rarelyusednowadays.

moreselective,lesssideeffects,1stlinetreatmentforschizophrenia.

Classification of antipsychotic drugs

TypicalAntipsychoticDrugs→ affect D2mainly ExceptCariprazine onD3 → treat the+vesymptoms.

Phenothiazine derivativesItschemicalstructuresimilartoTCAs→similarADRs

Suchas:Chlorpromazine(Protype veryold),Thioridazine

Butyrophenones Suchas:Haloperidol

Thioxanthene Suchas:Thiothixene

AtypicalAntipsychoticDrugs betterthantypical → AffectbothDA&5-HTreceptors→treat+ve &-ve symptmos.

Dibenzodiazepines Suchas:Clozapine

Benzisoxazoles Suchas:Risperidone

Thienobenzodiazepines Suchas:Olanzapine

Dibenzothiazepines Suchas:Quetiapine

Benzisothiazoles Suchas:Ziprasidone

piperazine/piperidine derivatives Suchas:Cariprazine (approvedin2015bytheFDA)

The pharmacological action of antipsychotic drugs result from

Blockingdopamine receptorsatdifferentareasinthebrain.

Blockingmuscarinic receptors

Blockingα-adrenergicreceptors

BlockingH1receptors

Better!

AdvantagesofAtypicaldrugsAdverseeffectsonCNS

Theyblockbothdopaminergic&serotonergic receptors.Theyareeffectiveinrefractorycasesofschizophrenia.Theyproducefewextrapyramidaleffects.

Theyareduetoblockingdopaminereceptorsatareasotherthanmesolimbicarea(extrapyramidaleffects).

Beforestartingthepharmacologicalactionsweneedtobefamiliarwiththeseconcepts:- Psychomotorslowing:involvesaslowing-downofthoughtandareductionof- physicalmovementsinanindividual.- Psychoticdisorder:abnormalthinkingandperceptions.- Agitation:astateofanxietyornervousexcitement.- Tardive dyskinesia:aneurologicaldisordercharacterizedbyinvoluntarymovementsofthe

faceandjaw.- Galactorrhea:excessiveorinappropriateproductionofmilk.- Amenorrhea:anabnormalabsenceofmenstruation.- Gynecomastia:enlargementofaman'sbreasts,usuallyduetohormoneimbalanceor

hormonetherapy.- Impotence:inabilitytodevelopormaintainanerectionofthepenisduringsexualactivityin

humans.- Pruritus:severeitchingofthe skin.

Antip

sychoticeffe

ct Itseffe

ct:

(it’sthemainuse). It takesfrom10daysto3weekstostartitsaction- Produceemotionalquieting

andpsychomotorslowing.- Decreasinghallucinations,delusions

andagitation.

Mecha

nism

:

blockageofdopamine receptorsinthemesolimbicsystem.→treat+ve symptoms.

*Atypicaldrugsexerttheirantipsychoticactionthroughblockingserotonergic(5HT2)anddopaminergicreceptors→.treat–ve symptomsalso.

Extrap

yram

idalsy

mptom

s

Itseffe

ct: EXTRAPYRAMDAL= PARKINSOMISMLIKEEFFECT.

- Abnormalinvoluntarymovementssuchastremors,parkinsonism,andtardivedyskinesia.

Mecha

nism

:

blockageofdopaminereceptorsinthenigrostriatum.

Endo

crineeffects

Itseffe

ct: - Galactorrhea

- Amenorrhea cause false +ve pregnancy test- Gynecomastia & impotence.

Mecha

nism

:

prevent dopamine from inhibiting prolactinrelease from pituitary gland and that will leadto hyperprolactinemia.

female

Formale

Metab

oliceffect: Itseffe

ct: changesineatingbehavior

andweight gain.Mecha

nism

: blockageofdopaminereceptorsinthemedullary-periventricular pathway.

Antie

meticeffect:

Itseffe

ct: Effectiveagainstdrugand

disease- inducedvomiting.(not-motionsickness)

Mecha

nism

:

blockageof dopaminereceptorsintheCTZofthemedulla.Thechemoreceptortriggerzone(CTZ)isanareaofthemedullaoblongatathatreceivesinputsfromblood-bornedrugsorhormones,andcommunicateswithotherstructuresinthevomitingcentertoinitiate vomiting.

CNS

Other

Temperature regulation:

Maycauseloweringofbodytemp.Mechanism:heatlossasaresultofvasodilationduetoalpha1-blocking orcentral effect.

ECGchanges:

prolongationofQTinterval,abnormalconfigurationSTsegmentandT wave.

c.I :incardiacpatientsAntihistaminiceffect:

sedationduetoH1receptor blockage.

Quinidine-like action:

Increasingactionpotential durationaswellasprolongedQT interval.Itcausesarrhythmia

*veryimportant

*veryimportant

*veryimportant

*veryimportant

*veryimportant

ANS

Anticho

linergice

ffects

Itseffe

ct: -Blurredvision

-Drymouth-Urinaryretention-Constipation

Mecha

nism

:

blockageofmuscarinicreceptors.

Antia

dren

ergice

ffects

Itseffe

ct:

- Posturalhypotension- Impotence- failureofejaculation.

Mecha

nism

: blockageofalpha1-adrenergicreceptors.

NOTE:Nonof theatypicalgroupcausesantiadrenergiceffect.

Beneficialeffect

Anti-arrhythmicdrug

CNS1- Sedation,drowsiness,fatigue→haloperidol (typical),Risperidone (atypical)

2- Extrapyramidalsymptoms:→Some occurringearly(Parkinson’ssyndrome),otherlateoccurring

B)NeurolepticMalignantSyndromeA)TardiveDyskinesia(IRREVERSIBLE MANIFSTATIONifwedon’tstopthedrug)

• Rarebutlifethreatening→Symptomsaremusclerigidityandhighfever(clinicallysimilartoanaesthetic malignanthyperthermia).

• Thestressleukocytosisandhighfeverassociatedwiththissyndromemaywronglysuggestaninfection.).

• (fromLatintardus,sloworlatecoming)Itisadisorderofinvoluntarymovements(choreoathetoidmovementsoflips,tongue,face,jaws,andlimbs)

• Choreoathetosis:combinationofchorea(irregularmigratingcontractions)andathetosis (twisting)

ANS2- AntiadrenergicEffects:1- AnticholinergicEffects:

• Posturalhypotension.• Impotence• Failureofejaculation.

Chlopromazine (typical)Thioridazine (typical)

• Blurredvision.• Drymouth.• Urinaryretention.• Constipation→

Suchaswith:Chlorpromazine (typical), Clozapine(atypical)

Misc

ellane

ousE

ffects:

Obstrucivejaundice

Granulardepositsincornea

Retinaldeposits(Onlythioridazine)

Weightgain

En

docrineEffects: Gynecomastia

Gynecomastia

Amenorrhoea

ClozapineAgranulocytosis(lifethreating)- About1-2%- Usuallyhappenafter6-18weeks- WeeklyWBCismandatory- Seizures

*Agranulocytosis,alsoknownasagranulosis orgranulopenia,isanacuteconditioninvolvingasevereanddangerousleukopenia(loweredwhitebloodcellcount)

*veryimportant

Duetoprolonguse Hasageneticelement

یجمع كل االعراض الجانبیة المعروفة

MostlyAtypical

Unwantedpharmacologicaleffects

NON-PSYCHIATRICPSYCHIATRICØ Nauseaandvomiting (prochlorperazine

andbenzquinamide) Onlyusedasantiemetics

Ø Pruritis (Itchingbecauseofanti-histamineeffect)

Ø Preoperativesedation(rareuse)

Ø Schizophrenia (primaryindication)Ø AcutemaniaØ Manic-depressiveillness(bipolar

affectivedisorder)duringthemanicphaseAtypical

Bipolaraffectivedisorderischaracterizedbyperiodsofdeep,prolonged,andprofounddepressionthatalternatewithperiodsofanexcessivelyelevatedorirritablemoodknownasmania.

Pharmacokinetics: • Incompletelyabsorbed.•Highlylipidsoluble.(SoitcancrossBBB)•Highlyboundtoplasmaproteins.•Undergoextensivefirst-passhepaticmetabolism.•Excretionbythekidney

- 2nd Generationantipsychotics- NowconsideredasFirstlinetreatmentsforschizophrenia- Little orno extrapyramidalsideeffects- Effectiveintreatmentofresistantschizophrenia.- Areeffectiveonboth positive&negativesymptoms.- Blockbothdopaminergic &serotonergic receptors.

- Refractorycasesofschizophrenia.- Toreducetheriskofrecurrentsuicidalbehaviorinpatientswithschizophrenia.

What are they ?

Clinical uses :

Drug Risperido

ne Ziprasidone Clozapine Olanzapine Quetiapine Cariprazine

Mech.

of

actio

n

BlocksD2&5HT2receptors.

BlocksD2&5HT2receptors

BlocksbothD4&5HT2receptors.

BlocksD1- D4&5HT2receptors.

BlocksD1-D2&5HT2receptors

approvedin2015bytheFDA- hashigheraffinityatD3receptor

Indicatio

ns

Druginteractions:- Shouldnotbeusedwithany

drugthatprolongstheQTinterval.

- Activitydecreasedbycarbamazepine(inducerofCYP3A4)

- Activityincreasedbyketoconazole(antifungal)(inhibitorofCYP3A4)

hasapositiveimpactonthecognitivesymptomsofschizophrenia

ADRs

- Posturalhypotension- QTprolongation- Weightgain

- Drowsiness,Akathisia(cantkeepstill),Headache,Dizziness,Weightgain.

Agranulocytosis- Seizures-Myocarditis-Excessivesalivation(duringsleep)

- Weightgain--SedationFlatulence,increasedsalivation&thirst.-Posturalhypotension.

- SedationHypotensionSluggishness

- Drymouth-Increasedappetite(weightgain)-Abdominalpain-Constipation

Contra-

indicatio

ns PatientswithlongQTinterval.

Itincreasesmortalityinelderlypatientswithdementia-relatedpsychosis.

itcontraindicatedinpatient withepilepsy

*veryimportant

Rememberit’sAtypical

Ø Drugsusedinschizophreniaareclassifiedaccordingtochemicalstructures.

Ø Theadvantagesofatypicaldrugsinclude:• Theyblockbothdopaminergic&serotonergicdrugs.• Theyareeffectiveinrefractorycasesofschizophrenia• TheyproducefewextrapyramidaleffectsØ Thepharmacologicalactionsofantipsychoticdrugsresultfrom:• Blockingdopaminereceptorsatdifferentareasinthebrain.• Blockingmuscarinicreceptors• Blockingα-adrenergicreceptors• BlockingH1receptors• AdverseeffectsonCNSareduetoblockingdopaminereceptors

atareasotherthanmesolimbicarea• BlockadeofH1,muscarinic&α- adrenergicreceptors.Ø Themainclinicaluseisinschizophrenia• Examplesofatypicaldrugsincludes:ClozapineRisperidone

OlanzapineQuetiapineZiprasidone

ThesynapseandsynapticneurotransmissionDescribethesynapseandtheprocessofchemicalneurotransmission.Indicatehowvesiclescontaininganeurotransmitter,suchasdopamine(thestars),movetowardthepresynapticmembraneasanelectricalimpulsearrivesattheterminal.Describetheprocessofdopaminerelease(showhowthevesiclesfusewiththepresynapticmembrane).Onceinsidethesynapticcleft,thedopaminecanbindtospecificproteinscalleddopaminereceptors(inblue)onthemembraneofaneighboringneuron.Introducetheideathatoccupationofreceptorsbyneurotransmitterscausesvariousactionsinthecell;activationorinhibitionofenzymes,entryorexitofcertainions.Statethatyouwilldescribehowthishappensinafewmoments

DopaminebindingtoreceptorsanduptakepumpsinthenucleusaccumbensExplainthatcocaineconcentratesinareasofthebrainthatarerichindopaminesynapses.Reviewdopaminetransmissioninthenucleusaccumbens.Pointtodopamineinthesynapseandtodopamineboundtodopaminereceptorsandtouptakepumpsontheterminal.

:قادة فريق علم األدوية

عبدالرحمن ذكري &لي التميمي : الشكر موصول ألعضاء الفريق املتميزين

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