10.30.08(b): antipsychotic drugs

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Slideshow is from the University of Michigan Medical School's M2 Psychiatry sequence View additional course materials on Open.Michigan: openmi.ch/med-M2Psych

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  • 1. Author(s): Margaret Gnegy, Ph.D., 2009License: Unless otherwise noted, this material is made available under the terms ofthe Creative Commons AttributionShare Alike 3.0 License:http://creativecommons.org/licenses/by-sa/3.0/We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use,share, and adapt it. The citation key on the following slide provides information about how you may share and adapt thismaterial.Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions,corrections, or clarification regarding the use of content.For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use.Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or areplacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to yourphysician if you have questions about your medical condition.Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.

2. Citation Keyfor more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt{ Content the copyright holder, author, or law permits you to use, share and adapt. }Public Domain Government: Works that are produced by the U.S. Government. (17 USC 105)Public Domain Expired: Works that are no longer protected due to an expired copyright term.Public Domain Self Dedicated: Works that a copyright holder has dedicated to the public domain.Creative Commons Zero WaiverCreative Commons Attribution LicenseCreative Commons Attribution Share Alike LicenseCreative Commons Attribution Noncommercial LicenseCreative Commons Attribution Noncommercial Share Alike LicenseGNU Free Documentation LicenseMake Your Own Assessment{ Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. }Public Domain Ineligible: Works that are ineligible for copyright protection in the U.S. (17 USC 102(b)) *laws in yourjurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. }Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (17 USC 107) *laws in yourjurisdiction may differOur determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee thatyour use of the content is Fair.To use this content you should do your own independent analysis to determine whether or not your use will be Fair. 3. Margaret GnegyProfessorDepartment PharmacologyAntipsychotic DrugsFall 2008 3 4. The Bottom line All active antipsychotic drugs block dopaminergic activity Drugs that more potently and specifically block dopamine (DA) D2Rs & FGAs have more extrapyramidal side effects Drugs that block many receptors have more autonomic and metabolic side effects Clozapine and olanzapine have the most metabolic side effects but may be the most efficacious DA and glutamate systems strongly interact: schizophrenia may involve low glutamate receptor (NMDA) activity and high dopamine receptor activity4 5. Synthesis:TH tyrosinehydroxylaseAADC aromatic aciddecarboxylaseMetabolism:MAO monoamineoxidaseCOMT catechol-O-methyltransferaseMetabolites:DOPAC dihydroxyphenylaceticacidHVA: homovanillic acid5Feldman et al., Principles of Neuropsychopharmacology, 1997 6. Anatomy of dopamine neurons6 Brody, Larner & Minneman, Human Pharmacology, Mosby, c1998, p. 343 7. Functional neuroanatomy of DA in the CNS Nigrostriatal pathway: motor planning and execution, habit formation, learning, habituation, memory Mesolimbic: complex target-oriented behavior, integrating emotional responses, motor and sensory processing Mesocortical: cognition; orchestration of thoughts and actions in accordance with internal goals Tuberoinfundibular: tonic inhibition of prolactin release, increase growth hormone release Chemoreceptor trigger zone: emesis & nausea 7 8. Early treatments of psychosisNational Library of MedicineJerrold & Quenzer, Psychopharmacology,Bethlehem Asylum Bedlam, one of Sinauer, c2005, p. 445the first asylums (1403)18th century asylum 8 9. Early treatment of psychosis Consequence of antipsychotic drug discovery Reserpine Insulin shock ECT Ice or fever therapyChlorpromazineHaloperidol9Jerrold & Quenzer, Psychopharmacology, Sinauer, c2005, p. 445 10. Pharmacological evidence supporting a role of DA in the positive aspects of schizophrenia Increasing dopamine worsens psychosis High doses of amphetamine or cocaine can lead to a paranoidpsychosis Amphetamine will exacerbate an existing schizophrenic state Decreasing dopamine ameliorates psychosis Blockade of DA receptors treats psychosis Inhibition of DA synthesis ameliorates symptoms ofschizophrenia There is enhanced amphetamine-induced DA release in schizophrenia10 11. Schema of neurodevelopmental model of schizophrenia11Jerrold & Quenzer, Psychopharmacology, Sinauer, c2005, p. 466 12. Characteristics of Antipsychotic Drugs Active against psychosis of any origin: idiopathic, metabolic, drug-induced More active against positive symptoms Antipsychotic drugs interfere with dopamine transmission, most block dopamine receptors Drugs start to work relatively quickly, but it takes a few months to reach maximum effect12 13. The potency of antipsychotic drugs in binding to the D2family of receptors is proportional to the potency of the drugs in treating schizophrenia This is not true for the potency of the drugs in blocking histamine H1, serotonin or - adrenergic receptors13 Adapted from Nestler Hyman & Malencka, Molecular Neuropharmacol.ogy, McGraw Hill, c2001, p. 402 14. -arrestin/Akt/GSK-3 pathway 14Goodman & Gilmans The Pharmacological Basis of Therapeutics, 11th Ed. Brunton et al. Eds. McGraw-Hill, c2006, p. 531 15. Modern Course of Treatment New atypical antipsychotic drugs (second generation) Conventional old-line drugs (first generation) Clozapine15 16. First Generation Antipsychotic Drugs Seda- Hypo- MotorCompound tiontension (EP) Effects PhenothiazinesR1 R2ChlorpromazineCl +++ ++ ++ Fluphenazine CF3++++++Haloperidol++++++ Haldol16 Image Sources Undetermined 17. Second Generation Antipsychotic DrugsHypo- MotorCompound SedationeffectstensionRisperidone +/++ ++ +++ Dosedependent Risperdal Clozapine++++ - ClozarilAripiprazole0/+0/+ 0/+Abilify 17Image Sources Undetermined 18. Second Generation Antipsychotic Drugs RisperdalZyprexaAripiprazoleAbilifyZiprasidoneGeodon18Image Sources Undetermined Seroquel 19. Pharmacological effects of antipsychotic drugs: blockade ofDA action19 20. In vitro profiles of the relative ability ofantipsychotic drugs to bind to specificreceptors 20Nestler Hyman & Malencka, Molecular Neuropharmacol.ogy, McGraw Hill, c2001, p. 405 21. Pharmacological effects of antipsychotic drugs21 22. Insulin signaling intersects with DA D2R and serotonin (5-HT)receptor signaling Antipsychotic drugsDA and 5-HT Rs+-arrestin+/- Girgis et al., Mol. Psychiatry, 2008 22 23. Absorption, Distribution and Fate of Antipsychotic drugs Erratic absorption Highly lipophilic t 1/2 = 6-40 hrs, most taken once a day Metabolized by cytochrome P450 enzymes Clearance from brain may be slower than clearance from plasma 23 24. Depot forms of antipsychotic drugs Are depot forms for non-compliant patients Haloperidol, fluphenazine, risperidone, [olanzapine] Paliperidone ER (Invega, active metabolite of risperidone) uses oral osmotic pump extended release technology Can give lower doses than with oral forms, less plasma level drug fluctuation Elimination following i.m. injection is very slow, half-life of 7-10 days Lower relapse rates Poor patient acceptance and no flexibility in dosing24 25. Tolerance and dependence to antipsychotic drugs Not addicting Relapse in psychosis if discontinued abruptly Tolerance develops to sedative effects No tolerance to prolactin secretion No tolerance to antipsychotic effect25 26. 26 27. Extrapyramidal side effects27 28. The dose response curves for efficacy andextrapyramidal symptoms are separatedClozapine28Adapted from Brody, Larner & Minneman, Human Pharmacology, Mosby, c1998, p. 346 29. Source UndeterminedSource Undetermined29 30. Aripiprazole (Abilify) Source Undetermined Partial agonist at D2 receptor Intrinsic activity depends on synaptic levels of DA Affinity for muscarinic, 1-adrenergic, serotonin and histamine receptors Good oral absorption, 3-5 hr to peak plasma concentration, long elimination half life Few extrapyramidal side effects 30 31. Action of aripiprazole, a D2R partial agonist, at dopaminergic synapseTRENDS in Pharmacological Sciences31 32. 32 33. Factors that may play a role inreduced EPS of 2nd generation drugs Receptor occupancy? ~60% of D2Rs need to be occupied to get therapeutic effect 80% occupation gives EPS Aripiprazole occupies ~85% Receptor binding profile: most SGAs have high affinity for a number of serotonin receptor subtypes 33 34. Glutamate also plays a role in psychosisModel of psychosis:Increased DAergicactivity in limbicregionDecreased DAergicactivity in prefrontalcortexLimbicDecreasedglutamatergic inputinto limbic (striatal)region andmesencephalonDeficits in GABAergicneurons in frontal 34Winterer and Weinberger, Trends in Neurosciences, cortex27:686, 2004. 35. Glutamate neuron 35Jerrold & Quenzer, Psychopharmacology, Sinauer, c2005 , p. 166 36. Ligand-gated channel subtypes of the glutamate receptor36 Jerrold & Quenzer, Psychopharmacology, Sinauer, c2005 , p. 167 37. N-methyl-D-aspartate receptor ligands Agonist: both glutamate andaspartate are agonists Co-agonist: glycine or D-serine Permeability: Ca2+ and Na+ Mg2+: voltage-dependent blockof the NMDA receptor Phencyclidine (PCP) andke

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