SP.236 / ESG.SP236 Exploring Pharmacology Spring 2009
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1 MIT OpenCourseWare SP.236 / ESG.SP236 Exploring Pharmacology Spring 2009 For information about citing these materials or our Terms of Use, visit:
2 Atypical (2 nd Generation) Antipsychotics
3 What do antipsychotics treat? Psychotic Disorders (Psychosis) Abnormal Thinking and Perceptions Loss of Contact with Reality Delusions (false beliefs) Hallucinations Schizophreniform Brief Psychotic Disorder Schizophrenia Schizoaffective Disorder Delusional Disorder Shared Psychotic Disorder (rare) Korsakoff Psychosis (rare)
4 1 st Generation vs. 2 nd Generation 1 st Generation - Typical Dopamine Antagonists Unpleasant Side Effects Muscle stiffness Tremor Abnormal movements Tardive Dyskinesia Decreased sexual interest Amenorrhea Anorgasmia Oligomenorrhea Galactorrhea Impaired Cognition 2 nd Generation - Atypical Dopamine and other Neurotransmitter Antagonists Mild, Temporary, Unpleasant Side Effects Drowsiness Rapid heartbeat Dizziness when changing position Weight gain Decreased sexual interest Possible amenorrhea Agranulocytosis (Clozapine ~1% of patients)
5 Atypical Antipsychotic Medications Clozapine (Clozaril) Risperidone (Risperdal) Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Sertindole Aripiprazole All vary in specific side-effect profiles
6 Receptor Profiles Haloperidol 1 Clozapine Risperidone Olanzapine D1 Quetiapine 1 5-HT2 D1 5-HT2 1 H1 M1 D1 5-HT2 1 Ziprasidone 2 1 D1 5-HT D1 Μ 5-HT2 Amisulpride 3 /D3 5-HT2 Η1 D1 1 Haloperidol, conventional antipay choice, is included here for comparison purpose only. 2 Ziprasidone is normally under FDA review, and its receptor actually profile has been definitely established 3 Amisulpride is also currently under FDA review; Its receptor activity profile has not been definitively established but is expected to involve and D3 activity only. D1, = Dopaminergic; 5-HT2 = Serotonergic; 1, 2 = Adrenergic; H1 = Histaminergic; M, M1 = Muscarinic. 1 Figure by MIT OpenCourseWare.
7 Fast-Off- Theory New atypical antipsychotic e.g Quetiapine Older medicine e.g. Haloperidol Fast Off Slow Off Loosely Bound Medicine Dopamine receptor in cell membrane Tightly Bound Medicine Antipsychotic activity without adverse EPS Antipsychotic activity but risk of adverse EPS Antagonism EPS = Extrapyramidal Symptoms Seeman, 2004 Figure by MIT OpenCourseWare.
8 Partial Dopamine Agonism Aripiprazole (OPC-14597) High Affinity for and D3 receptors Works on: Postsynaptic receptors Presynaptic autoreceptors 5-HT1A partial agonism 5-HT2A antagonism Modest affinity for alpha1-adrenergic, H1, 5-HT7 receptors
9 Serotonin-Dopamine Antagonism 5HT2A receptor SDA receptor 5HT2A Pituatary lactotroph receptor Prolactin SDA 5HT2A receptor SDA SDA Nigrostriatal Pathway Serotonin-Dopamine Antagonist Figures by MIT OpenCourseWare. Higher ratio of drug affinity for serotonin receptor relative to dopamine receptor explains enhanced efficacy and reduce EPS (Meltzer et al) 5-HT2A AND antagonist
10 5-HT1A Agonism Clozapine Increases effect of dopaminergic antagonists Counteracts induction of EPS Enhances prefrontal dopamine release Useful against negative symptoms and cognitive dysfunction
11 Glutamate Antagonism Phencyclidine (PCP) Ketamine N-methyl-D-aspartate (NMDA) receptor antagonists Induce Schizophrenia-like symptoms Clozapine and Olanzapine Inhibit PCP in brain slices Block ketamine-induced brain metabolic activation Metabotropic Receptors Modify amounts of glutamate cells release, instead of turning them on or off
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