PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS AND SEDATIVE-HYPNOTICS

1. PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS AND SEDATIVE-HYPNOTICS Yogesh Dwivedi, Ph.D. Associate Professor Department of Psychiatry University of Illinois at Chicago Email: ydwivedi@psych.uic.edu

2. Psychosis Symptoms • Positive Symptoms • Delusion • Hallucination • Disorganized speech • Disorganized behavior • Agitation • Negative Symptoms • Passivity • Apathetic social withdrawal • Stereotyped thinking • Anhedonia (loss of joy) • Attentional impairment • Emotional withdrawal • Cognitive Symptoms • Impaired verbal fluency • Problems with serial learning • Problems with focusing attention • Concentration

3. Neurodevelopmental Hypothesis of Schizophrenia

4. Neurodegenerative Hypothesis of Schizophrenia (progressive loss of neuronal functions during the course of disease) Stages of Schizophrenia Over a Life Time Asymptomatic Negative symptoms Positive symptoms Negative/cognitive symptoms % of Brain Functioning Age (years) Increased excitatory glutamatergic neurotransmission

5. NMDA type glutamate receptor is a ligand-gated Ca2+ ion channel • Binding of glutamate causes opening of the channel and thus excitatory neurotransmission

6. 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

7. Key Dopamine Pathways • Mesolimbic pathway • Increased dopamine in 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: • -- movement disorder such as Parkinson’s disease (rigidity, akinesia, dystonia) • -- hyperkinetic movement such as tardive dyskinesia • Tuberoinfundibular pathway • Normally neurons of this pathway are active and inhibit prolactin release • Blockade of D2 receptor increases prolactin release and causes: • -- galactorrhea • -- amenorrhea

8. Pharmacodynamics of Antipsychotics

9. Antipsychotics • First generation • Chlorpromazine • Acetaphenazine • Fluphenazine • Haloperidol • Trifluoperazine • Triflupromazine • Second generation • Clozapine • Risperidone • Olanzapine • Quetiapine • Ziprasidone

10. DOPAMINE SYMPTOMS Positive Negative EPS Increases prolactin release

11. 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

12. Anticholinergic (M1) Drugs and EPS (Acetylcholine may cause EPS) 1 2 3 Dopamine and acetylchilone has reciprocal relationship Stronger anticholinergic agents cause fewer EPS

13. Second Generation Antipsychotics 5HT2A and D2 antagonists (SDAs)

14. Serotonin-Dopamine Interaction 1

15. 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

16. Key Dopamine Pathways • Mesolimbic pathway • More dopamine or 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

17. In mesolimbic pathway the action of D2 receptor blockade of • antipsychotics are more robust than 5HT2A antagonism. This may help • reducing positive symptoms

18. 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

19. 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 than D2 receptor blocking property. This may help improve • negative symptoms

20. 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

21. In nigrostriatal pathway: 5HT2A antagonists bind to 5HT2A receptors and block the release of 5HT and thus cause more DA to be released. This may reduce EPS 1 2 3 4

22. 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

23. In tuberoinfundibular pathway: D2 blockade causes release of prolactin, • whereas, blocking 5HT2A inhibits release of prolactin. Antagonistic • properties of antipsychotics cancel DA and 5HT2A action 1 2 3 4

24. Other Actions of Second Generation Antipsychotics • Clozapine: • Very few EPS • No prolactin release • Causes agranulocytosis • Weight gain • Seizures • Sedative • Risperidone: • EPS at high dose • Low TD • Less weight gain • Ziprasidone: • Very few EPS • No prolactin release • No weight gain • SRI and NRI, thus act as AD • and anxiolytic • Quetiapine: • No EPS • No prolactin release • Weight gain • Olanzapine: • No prolactin release • Nonsedative • Weight gain • Low level of TD Stahl, 2002

25. Pharmacodynamics of Anxiolytics/ Sedative-Hypnotics

26. Ionotropic GABA Receptors Benzodiazepine GABA a subunit Channel pore Barbiturates Steroids • Pentamers • Inhibitory in action because the • associated channels are permeable to • negatively charged Cl- ions • Benzodiazepines are allosteric modulators • to GABA neurotransmission Picrotoxin

27. Benzodiazepine Anxiolytics Chlordiazepoxide Diazepam Oxazepam Chlorazepate Lorazepam Prazepam Halazepam Flumazil Alprazolam Midazolam (Agonists)

28. The Agonist Spectrum

29. Action of Agonist A balance between open and close

30. Antagonist Acting Alone A balance between open and close No action

31. Antagonist Acting in Presence of Agonist

32. Action of Inverse Agonist Complete blockade A balance between open and close

33. Action of Antagonist in Presence of Inverse Agonist Acts like agonist

34. Action of Partial Agonist Partially opens the channel

35. Antagonist Acting in the Presence Partial Agonist

36. Action of Partial Inverse Agonist

37. Full Agonist Partial Partial Inverse Full Inverse Antagonist Agonist Agonist Agonist Anxiolytic Anxiolytic No clinical Promnestic Promnestic Sed-Hypnotic effect (memory Anxiogenic Myorelaxant enhancing) Pro-convulsant Anticonvulsant Anxiogenic Amnestic Pro- convulsant Dependency BZD Receptor Activity

38. Serotonergic Anxiolytics (buspirone, gepirone,* tandospirone*) • Partial 5HT1A agonist • Cause upregulation of presynaptic somatodendritic 5HT1A receptors • (anxiolytic action) and postsynaptic 5HT1A receptors (nausea, dizziness) • As compared with benzodiazepines, lacks interaction with alcohol, • benzodiazepines, and thus cause no drug dependence, withdrawal • symptoms • Delayed effect like antidepressants • *under development/clinical trial

39. Noradrenergic Anxiolytics-I neuronal firing, Anxiety Cerebral cortex

40. Clonidine: • a2 receptor agonist • Binds to a2 presynaptic autoreceptors • Decreases firing and release of NE which may reduces anxiety

41. Noradrenergic Anxiolytics-II Blocking the postsynaptic b receptors reduces anxiety Overactivity at postsynaptic b receptors increase anxiety • Beta-blockers : • Antagonist to postsynaptic b adrenergic receptors • Decreases postsynaptic b receptor-mediated signaling

42. Cholecystokinin (CCK)* and CRF* Antagonists as Anxiolytics • Tetra-peptide CCK causes panic attacks • CCK antagonists are anxiolytic in panic disorder • Cortotropin-releasing factor is a neuropeptide which mediates • anxiety behavior. Antagonists to CRF are anxiolytics • *under development

43. Sedative-Hypnotics-I (Treatment for insomnia) • Benzodiazepines: • Rapid onset, short acting • triazolam • Delayed onset, intermediate acting • temazepam, estazolam • Rapid onset, long acting • flurazepam • quazepam • Nonbenzodiazepines: • Rapid-onset, short acting • Zaleplon • Zolpidem • Zopiclone • Act at benzodiazepine receptors • and increase the inhibitory action • of GABA • High doses required • Develop tolerance • Binds to omega-1 benzodizepine • receptors • Less cognitive, memory and motor • side effects • Shorter half life • No dependence, tolerance or • withdrawal symptoms

44. Sedative-Hypnotics II Sedative antidepressants: tricyclics (anticholinergic/antihistaminergic) trazodone (5HT2A antagonist) mirtazapine (5HT2A antagonist) nefazodone (5HT2A antagonist) Sedative antihistamines: diphenylhydramine doxylamine hydroxyzine Other sedative: chloral hydrate Natural products: melatonin Good choice with AD properties Safe with other psychotropic drugs which disrupts sleep, such as SSRIs Short-term use Causes dependency Tolerance

45. Suggeted Readings • Stahl SM. Essential Psychopharmacology: Neuroscientific Basis and Practical Applications. • Cambridge University Press, NY • Nestler EJ, Hyman SE, Malenka RC. Molecular Neuropharmacology: • A Foundation for Clinical Neuroscience. McGraw-Hill Publications • Squire LR, Bloom FE, McConnel SK, Roberts JL, Spizer NC, Zigmond MJ. Fundamental Neuroscience. • Academic Press • Dwivedi Y. ey al. Chronic Treatment of Psychoactive Drugs Modulates • Phosphoinositide-Specific Phospholipase C (PLC) Activity and mRNA and protein Expression of Selective • PLC 1 Isozyme in Rat Brain. Neuropharmacology, 43:1269-1279, 2002 • Dwivedi Y. et al. Effect of subchronic administration of antidepressants and anxiolytics on the • levels a subunits of G-proteins in rat brain J Neural Transm, 104:747, 1997