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PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS AND SEDATIVE-HYPNOTICS Yogesh Dwivedi, Ph.D. Associate Professor Department of Psychiatry University of.

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Presentation on theme: "PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS AND SEDATIVE-HYPNOTICS Yogesh Dwivedi, Ph.D. Associate Professor Department of Psychiatry University of."— Presentation transcript:

1 PHARMACODYNAMICS OF ANTIPSYCHOTICS ANXIOLYTICS AND SEDATIVE-HYPNOTICS Yogesh Dwivedi, Ph.D. Associate Professor Department of Psychiatry University of Illinois at Chicago

2 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 Psychosis Symptoms

3 Neurodevelopmental Hypothesis of Schizophrenia

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

5 NMDA type glutamate receptor is a ligand-gated Ca 2+ ion channel Binding of glutamate causes opening of the channel and thus excitatory neurotransmission

6 a = nigrostriatal pathway Increase in dopamine causes positive symptoms b = mesolimbic pathway: Increase in dopamine causes positive symptoms of schizophrenia of schizophrenia Deficit in dopamine causes negative and cognitive c = mesocortical pathway: Deficit in dopamine causes negative and cognitive symptoms of schizophrenia symptoms of schizophrenia d = tuberoinfundibular pathway Dopamine Pathway Limbic cortex Anterior pituitary

7 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 Key Dopamine Pathways

8 Pharmacodynamics of Antipsychotics

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

10 DOPAMINESYMPTOMS Positive Negative EPS Increases prolactin release

11 First Generation Antipsychotics Blockade of D 2 receptors in mesolimbic pathway, resulting in reduced positive symptoms of schizophrenia Blockade of D 2 receptors in mesocortical pathway, which is already deficient in schizophrenia, causes cognitive symptoms or worsen negative symptoms Blockade of D 2 receptors in nigrostriatal pathway, produces EPS such as motor abnormalities (parkinsonism), tardive dyskinesia or hyperkinetic movement disorder Blockade of D 2 receptors in tuberoinfundibular pathway causes hyperprolactinemia Chlorpromazine side effects: dry mouth, blurred vision, drowsiness, weight gain, dizziness, low bp cholinergic properties: EPS Stahl, 2002

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

13 Second Generation Antipsychotics 5HT 2A and D 2 antagonists (SDAs)

14 Serotonin-Dopamine Interaction 1

15 Key: 5HT interact with 5HT 2A receptors at postsynaptic level both at DA cell bodies and at axon terminals and inhibits the release of DA or 5HT 2A antagonists cause more release of DA The action of 5HT 2A and D 2 antagonism causes different effects in different dopamine pathways 2 3

16 Key Dopamine Pathways

17 In mesolimbic pathway the action of D 2 receptor blockade of antipsychotics are more robust than 5HT 2A antagonism. This may help reducing positive symptoms

18 Key Dopamine Pathways

19 In mesocortical pathway, dopamine deficiency causes negative and cognitive symptoms. In mesocortical pathway, there is more 5HT 2A receptors than D 2 receptors. Thus 5HT antagonistic property is more profound than D 2 receptor blocking property. This may help improve negative symptoms

20 Key Dopamine Pathways

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

22 Key Dopamine Pathways

23 In tuberoinfundibular pathway: D2 blockade causes release of prolactin, whereas, blocking 5HT 2A inhibits release of prolactin. Antagonistic properties of antipsychotics cancel DA and 5HT 2A action

24 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 Other Actions of Second Generation Antipsychotics Stahl, 2002

25 Pharmacodynamics of Anxiolytics/ Sedative-Hypnotics

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

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

28 The Agonist Spectrum

29 Action of Agonist A balance between open and close

30 Antagonist Acting Alone A balance between open and closeNo action

31 Antagonist Acting in Presence of Agonist

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

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 BZD Receptor Activity FullAgonistPartial Agonist Antagonist Partial Inverse Agonist Full Inverse Agonist Anxiolytic Sed-Hypnotic Myorelaxant Anticonvulsant Amnestic Dependency AnxiolyticNo clinical effect Promnestic (memory enhancing) Anxiogenic Pro-convulsant Promnestic Anxiogenic Pro-convulsant

38 Serotonergic Anxiolytics (buspirone, gepirone,* tandospirone*) Partial 5HT 1A agonist Cause upregulation of presynaptic somatodendritic 5HT 1A receptors (anxiolytic action) and postsynaptic 5HT 1A 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:   2 receptor agonist Binds to  2 presynaptic autoreceptors Decreases firing and release of NE which may reduces anxiety

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

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 (5HT 2A antagonist) mirtazapine (5HT 2A antagonist) nefazodone (5HT 2A 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: , 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


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