PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS SEDATIVE HYPNOTICS Yogesh Dwivedi Ph D Assistant Professor of Psychiatry and Pharmacology Department of Psychiatry University of Illinois at Chicago Email ydwivedi psych uic edu Pharmacodynamics of Antipsychotics 1 Psychosis Symptoms Positive Symptoms Delusion Hallucination Disorganized speech Disorganized behavior Agitation Negative Symptoms Passivity Apathetic social withdrawal Stereotyped thinking Anhedonia Attentional impairment Emotional withdrawal Cognitive Symptoms Impaired verbal fluency Problems with serial learning Problems with focusing attention Concentration Dopamine Pathway Limbic cortex Anterior pituitary a nigrostriatal pathway b mesolimbic pathway Increase in dopamine causes positive symptoms of schizophrenia c mesocortical pathway Deficit in dopamine causes negative and cognitive symptoms of schizophrenia d tuberoinfundibular pathway 2 Key Dopamine Pathways Mesolimbic pathway Hyperactivity on this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia Nigrostriatal 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 dyskinesia Tuberoinfundibular pathway Increased neuronal activity of this pathway inhibits prolactin release Blockade of D2 receptor increases prolactin release and causes galactorrhea amenorrhea Neurodevelopmental Abnormalities in Schizophrenia 3 Stages of Schizophrenia Over a Life Time Age Increased excitatory glutamatergic neurotransmission Antipsychotics First generation Chlorpromazine Acetaphenazine Fluphenazine Haloperidol Trifluoperazine Triflupromazine Second generation Clozapine Risperidone Olanzapine Quetiapine Ziprasidone 4 First Generation Antipsychotics Blockade of D2 receptors in mesolimbic pathway resulting in reduced positive symptoms of schizophrenia Blockade of D2 receptors in mesocortical pathway which is already deficient in schizophrenia causes cognitive symptoms or worsen negative symptoms Blockade of D2 receptors in nigrostriatal pathway produces EPS such as motor abnormalities parkinsonism tardive dyskinesia or hyperkinetic movement disorder Blockade of D2 receptors in tuberoinfundibular pathway causes hyperprolactinemia side effects dry mouth blurred vision drowsiness weight gain dizziness low bp cholinergic properties EPS Chlorpromazine Stahl 2002 Anticholinergic M1 Drugs and EPS Acetylcholine may cause EPS 1 2 3 Dopamine and acetylchilone has reciprocal relationship Stronger anticholinergic agents cause fewer EPS 5 Second Generation Antipsychotics 5HT2A and D2 antagonists SDAs Serotonin Dopamine Interaction 1 6 3 2 Key 5HT interact with 5HT2A receptors at postsynaptic level both at DA cell bodies and at axon terminals and inhibits the release of DA or 5HT2A antagonists cause more release of DA The action of 5HT2A and D2 antagonism causes different effects in different dopamine pathways Key Dopamine Pathways Mesolimbic pathway More dopamine or hyperactivity on this pathway is associated with positive symptoms of schizophrenia Mesocortical pathway Mesocortical pathway Deficit Deficit in in dopamine dopamine in in this this pathway pathway is is associated associated with with negative negative and and cognitive cognitive symptoms symptoms of of schizophrenia schizophrenia Nigrostriatal pathway Nigrostriatal pathway Part Part of of extrapyramidal extrapyramidal system system and and controls controls motor motor movement movement Blockade Blockade of of D2 D2 receptors receptors causes causes disorder deficiency deficiency in in dopamine dopamine in in this this pathway pathway and and thus thus movement movement disord disorder such such as as Parkinson s Parkinson s disease disease hyperkinetic hyperkinetic movement movement such such as as tardive tardive dyskinesia dyskinesia T pathway uberoinfundibular pathway Tuberoinfundibular Increased Increased neuronal neuronal activity activity of of this this pathway pathway inhibits inhibits prolactin prolactin release release Blockade Blockade of of D2 D2 receptor receptor increases increases prolactin prolactin release release and and causes causes galactorrhea galactorrhea amenorrhea amenorrhea 7 Second Generation Antipsychotics In mesolimbic pathway the action of D2 receptor blockade of antipsychotics are more robust than 5HT2A antagonism This may help reducing positive symptoms Key Dopamine Pathways Mesolimbic pathway Mesolimbic pathway Hyperactivity symptoms Hyperactivity on on this this pathway pathway is is associated associated with with positive positive sympto symptoms of of schizophrenia schizophrenia Mesocortical pathway Deficit in dopamine in this pathway is associated with negative and cognitive symptoms of schizophrenia Nigrostriatal pathway Nigrostriatal pathway Part Part of of extrapyramidal extrapyramidal system system and and controls controls motor motor movement movement Blockade Blockade of of D2 D2 receptors receptors causes causes disorder deficiency deficiency in in dopamine dopamine in in this this pathway pathway and and thus thus movement movement disord disorder such such as as Parkinson s Parkinson s disease disease hyperkinetic hyperkinetic movement movement such such as as tardive tardive dyskinesia dyskinesia T pathway uberoinfundibular pathway Tuberoinfundibular Increased Increased neuronal neuronal activity activity of of this this pathway pathway inhibits inhibits prolactin prolactin release release Blockade Blockade of of D2 D2 receptor receptor increases increases prolactin prolactin release release and and causes causes galactorrhea galactorrhea amenorrhea amenorrhea 8 In mesocortical pathway dopamine deficiency causes negative and cognitive symptoms In mesocortical pathway there is more 5HT2A receptors than D2 receptors Thus 5HT antagonistic property is more profound that D2 receptor blocking property This may help improving negative symptoms Key Dopamine Pathways Mesolimbic pathway Mesolimbic pathway Hyperactivity symptoms Hyperactivity on on this this pathway pathway is is associated associated with with positive positive sympto symptoms of of schizophrenia schizophrenia Mesocortical pathway Mesocortical pathway Deficit Deficit in in dopamine dopamine in in this this pathway pathway is
View Full Document
Unlocking...