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UIC PCOL 425 - PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS SEDATIVE-HYPNOTICS

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1PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICSSEDATIVE-HYPNOTICSYogesh Dwivedi, Ph.D.Assistant Professor of Psychiatry and PharmacologyDepartment of PsychiatryUniversity of Illinois at ChicagoEmail: [email protected] of Antipsychotics2Positive Symptoms•Delusion•Hallucination•Disorganized speech•Disorganized behavior•AgitationNegative Symptoms•Passivity•Apathetic social withdrawal•Stereotyped thinking•Anhedonia•Attentional impairment•Emotional withdrawalCognitive Symptoms•Impaired verbal fluency•Problems with serial learning•Problems with focusing attention•ConcentrationPsychosis Symptomsa = nigrostriatal pathwayb = mesolimbic pathway: Increase in dopamine causes positive symptoms Increase in dopamine causes positive symptoms of schizophreniaof schizophreniac = mesocortical pathway: Deficit in dopamine causes negative and cognitive Deficit in dopamine causes negative and cognitive symptoms of schizophreniasymptoms of schizophreniad = tuberoinfundibular pathwayDopamine PathwayLimbic cortexAnterior pituitary3Mesolimbic pathway•Hyperactivity on this pathway is associated with positive symptoms of schizophreniaMesocortical pathway•Deficit in dopamine in this pathway is associated with negative and cognitive symptomsof schizophreniaNigrostriatal pathway•Part of extrapyramidal system and controls motor movement•Blockade of D2 receptors causes: -- deficiency in dopamine in this pathway and thus movement disorder such as Parkinson’s disease-- hyperkinetic movement such as tardive dyskinesiaTuberoinfundibular pathway•Increased neuronal activity of this pathway inhibits prolactin release•Blockade of D2 receptor increases prolactin release and causes:-- galactorrhea-- amenorrheaKey Dopamine PathwaysNeurodevelopmental Abnormalities in Schizophrenia4AgeStages of Schizophrenia Over a Life TimeIncreased excitatory glutamatergic neurotransmission First generationChlorpromazineAcetaphenazineFluphenazineHaloperidolTrifluoperazineTriflupromazineSecond generation•Clozapine•Risperidone•Olanzapine•Quetiapine•ZiprasidoneAntipsychotics5First Generation Antipsychotics•Blockade of D2receptors in mesolimbic pathway, resulting in reduced positive symptoms of schizophrenia•Blockade of D2receptors in mesocortical pathway, which is already deficient in schizophrenia, causes cognitive symptoms or worsennegative symptoms•Blockade of D2receptors in nigrostriatal pathway, produces EPS such as motor abnormalities (parkinsonism), tardive dyskinesiaor hyperkinetic movement disorder•Blockade of D2receptors in tuberoinfundibular pathway causes hyperprolactinemiaChlorpromazineside effects:dry mouth, blurred vision,drowsiness, weight gain, dizziness, low bpcholinergic properties: EPSStahl, 2002Anticholinergic (M1) Drugs and EPS(Acetylcholine may cause EPS)312Dopamine and acetylchilone has reciprocal relationshipStronger anticholinergic agents cause fewer EPS6Second Generation Antipsychotics5HT2Aand D2antagonists (SDAs)Serotonin-Dopamine Interaction17•Key: 5HT interact with 5HT2Areceptors at postsynaptic levelboth at DA cell bodies and at axon terminals and inhibits the release of DAor•5HT2Aantagonists cause more release of DA•The action of 5HT2Aand D2antagonism causes different effects in different dopamine pathways23Mesolimbic pathway•More dopamine or hyperactivity on this pathway is associated with positive symptoms of schizophreniaMesocorticalMesocorticalMesocorticalpathwaypathwaypathway•••Deficit in dopamine in this pathway is associated with negative Deficit in dopamine in this pathway is associated with negative Deficit in dopamine in this pathway is associated with negative and cognitive symptomsand cognitive symptomsand cognitive symptomsof schizophreniaof schizophreniaof schizophreniaNigrostriatalNigrostriatalNigrostriatalpathwaypathwaypathway•••Part of Part of Part of extrapyramidal extrapyramidal extrapyramidal system and controls motor movementsystem and controls motor movementsystem and controls motor movement•••Blockade of D2 receptors causes: Blockade of D2 receptors causes: Blockade of D2 receptors causes: ------deficiency in dopamine in this pathway and thus movement disorddeficiency in dopamine in this pathway and thus movement disorddeficiency in dopamine in this pathway and thus movement disorder such er such er such as Parkinson’s diseaseas Parkinson’s diseaseas Parkinson’s disease------hyperkinetichyperkinetichyperkineticmovement such as movement such as movement such as tardive dyskinesiatardive dyskinesiatardive dyskinesiaTTTuberoinfundibularuberoinfundibularuberoinfundibularpathwaypathwaypathway•••Increased neuronal activity of this pathway inhibitsIncreased neuronal activity of this pathway inhibitsIncreased neuronal activity of this pathway inhibitsprolactinprolactinprolactinreleasereleaserelease•••Blockade of D2 receptor increasesBlockade of D2 receptor increasesBlockade of D2 receptor increasesprolactinprolactinprolactinrelease and causes:release and causes:release and causes:------galactorrheagalactorrheagalactorrhea------amenorrheaamenorrheaamenorrheaKey Dopamine Pathways8Second Generation Antipsychotics•In mesolimbic pathway the action of D2receptor blockade ofantipsychotics are more robust than 5HT2Aantagonism. This may help reducing positive symptomsMesolimbicMesolimbicMesolimbicpathwaypathwaypathway•••Hyperactivity on this pathway is associated with positive symptoHyperactivity on this pathway is associated with positive symptoHyperactivity on this pathway is associated with positive symptoms of schizophreniams of schizophreniams of schizophreniaMesocortical pathway•Deficit in dopamine in this pathway is associated with negative and cognitive symptomsof schizophreniaNigrostriatalNigrostriatalNigrostriatalpathwaypathwaypathway•••Part of Part of Part of extrapyramidal extrapyramidal extrapyramidal system and controls motor movementsystem and controls motor movementsystem and controls motor movement•••Blockade of D2 receptors causes: Blockade of D2 receptors causes: Blockade of D2 receptors causes: ------deficiency in dopamine in this pathway and thus movement disorddeficiency in dopamine in this pathway and thus movement disorddeficiency in dopamine in this pathway and thus movement disorder such er such er such as Parkinson’s diseaseas Parkinson’s diseaseas Parkinson’s disease------hyperkinetichyperkinetichyperkineticmovement


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UIC PCOL 425 - PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS SEDATIVE-HYPNOTICS

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