Pharmacology of Anxiolytic Sedative Hypnotics Philip G Janicak MD Professor of Psychiatry and Pharmacology University of Illinois at Chicago 01 15 19 1 pharmacology of anxiolytic sedative hypnotics Abstract Recent anxiolytic and sedative hypnotic agents offer comparable efficacy fewer serious adverse effects and less risk of a fatal consequence due to accidental or intentional overdose in comparison to alcohol barbiturates and other nonbarbiturate agents e g meprobamate Unfortunately they have not entirely eliminated the hazards of tolerance dependency and withdrawal syndromes although they have a lower abuse potential than their predecessors For these reasons it is important to become knowledgeable about the basic pharmacology of these drugs in addition to their appropriate clinical indications dosages and duration of usage Most importantly their limitations must receive as much attention as their assets 01 15 19 2 pharmacology of anxiolytic sedative hypnotics Objectives Review different classes of antianxiety and sedative hypnotic agents in terms of their pharmacodynamics pharmacokinetics adverse effects and potential for drug interactions Review diagnostic indications for anxiolytic sedative hypnotics Review treatment strategies for anxiety and sleep disorders 01 15 19 3 pharmacology of anxiolytic sedative hypnotics Anxiety Natural human experience Subjective qualities of fear or related emotions Ensures survival and adaptation In excess can cripple and destroy Subjective physiological behavioral aspects 01 15 19 4 pharmacology of anxiolytic sedative hypnotics Anxiety Symptoms Anxiety symptoms are associated with numerous medical conditions 01 15 19 Cardiovascular disease Endocrine disease Gastrointestinal disease Neurologic disease Drug induced 5 Lifetime And 12 Month Prevalence Of Anxiety Disorders In The NCS Anxiety Disorders Lifetime 12 Month Panic Disorder 3 5 2 3 Agoraphobia without panic 5 3 2 6 Social Phobia 13 3 7 9 Simple Phobia 11 3 8 8 Generalized Anxiety Disorder 5 1 3 1 Posttraumatic Stress Disorder 7 6 3 9 Any anxiety disorder 28 7 19 3 Kessler et al Arch Gen Psychiatry 1994 51 8 01 15 19 6 ANTIANXIETY AGENTS Generic Names BENZODIAZEPINES Chlordiazepoxide Diazepam Oxazepam Chlorazepate Lorazepam Prazepam Halazepam Alprazolam AZAPIRONES Buspirone ANTIDEPRESSANTS SSRI Venlafaxine 01 15 19 Trade Names Daily Dosage mg day Librium others Valium others Serax others Tranxene others Ativan Centrax Paxipam Xanax 10 100 2 40 30 120 15 60 1 10 20 60 60 160 0 75 4 Buspar 15 60 Sertraline others Effexor 25 250 75 375 7 SEDATIVE HYPNOTICS Generic Names BENZODIAZEPINES Long acting Flurazepam Quazepam Intermediate acting Estazolam Temazepam Short acting Triazolam Daily Dosage mg day Dalmane Doral 15 45 7 5 15 Prosom Restoril 0 5 2 15 45 Halcion 0 125 0 25 NONBENZODIAZEPINE Zolpidem Zaleplon Ambien Sonata 5 20 5 20 SEDATING ANTIDEPRESSANTS Trazodone Dyserel 25 100 BARBITURATE LIKE Chloral Hydrate Notec 500 1500 OTHER Melatonin 01 15 19 Trade Names 0 3 2 8 pharmacology of anxiolytic sedative hypnotics Pharmacodynamics Benzodiazepines Specific binding site associated with GABAA receptorchloride ion channel Potentiate GABA Serotonergic effects e g clonazepam Azapirone e g buspirone 5 HT1A agonist acutely firing in dorsal raphe nuclei chronically receptor desensitization activity Beta blockers receptors central and peripheral post synaptic Clonidine Agonist at 2 receptors central pre synaptic Antidepressants 01 15 19 9 pharmacology of anxiolytic sedative hypnotics GABA Function and Distribution Inhibitory neurotransmitter Widely distributed throughout CNS Local inhibitory action therefore rapidly alters neuronal output Desensitization to inhibitory effects with chronic stimulation of GABA 01 15 19 10 GABAA BZD Supramolecular Complex 01 15 19 11 GABAA Receptor Structure Cl Benzodiazepines Agonists AntagonistsInverse Agonists GABA Agonists Muscimol GABA Antagonists Bicuculline DBI Peptides Barbiturates Neuroactive Steroids Convulsants Picrotoxin TBPS 01 15 19 S M Paul 1995 Alcohols Anesthetics 12 pharmacology of anxiolytic sedative hypnotics Benzodiazepinebinding domain Cytoplasm 01 15 19 GABAA receptor 13 pharmacology of anxiolytic sedative hypnotics BZD Receptors Type I Predominates in cerebellum Anxiolytic properties Less sedative properties Type II Located in cortex hippocampus spinal cord No anxiolytic properties Sedative properties Type III Located in peripheral tissue No anxiolytic properties other properties 01 15 19 14 pharmacology of anxiolytic sedative hypnotics BZD Receptor Activity Full Agonist Anxiolytic Sed Hypnotic Myorelaxant Anticonvulsant Amnestic Dependency 01 15 19 Partial Agonist Anxiolytic Partial Inverse Antagonist Agonist No clinical Promnestic effect Anxiogenic Pro convulsant Full Inverse Agonist Promnestic Anxiogenic Pro convulsant 15 pharmacology of anxiolytic sedative hypnotics Non Benzodiazepine Agents Imidazopyridines e g zolpidem alpidem Pyrazolopyrimidine e g zaleplon Cyclopyrralone e g zopiclone Sedating antidepressants e g trazodone 01 15 19 16 pharmacology of anxiolytic sedative hypnotics Non Benzodiazepine Agents con t Antihistamines e g diphenhydramine Natural Remedies e g melatonin valerian B carbolines e g abecarnil BZD structural derivatives e g biretazanil 01 15 19 17 pharmacology of anxiolytic sedative hypnotics Serotonin Model Majority of 5 HT pathways originate in the dorsal raphe DR DR innervates cortex hypothalamus thalamus and limbic system 5 HT mediates behavioral effects in animal models and humans 01 15 19 18 pharmacology of anxiolytic sedative hypnotics Serotonin Receptors 5 HT1A Anxiety alcoholism sexual function 5 HT1C Anxiety migraine pain 5 HT1D Migraine pain 5 HT2 Anxiety depression schizophrenia negative symptoms sexual function Migraine pain emesis schizophrenia e g ondansetron Anxiety schizophrenia 5 HT3 5 HT4 01 15 19 19 pharmacology of anxiolytic sedative hypnotics Serotonin Agents Indications for Anxiety Related Disorders SSRI Sertraline OCD PD PTSD Paroxetine OCD PD SAD GAD Fluoxetine OCD BN PMDD Fluvoxamine OCD Venlafaxine GAD Buspirone GAD 01 15 19 20 pharmacology of anxiolytic sedative hypnotics Noradrenergic Model Hypersensitivity to autonomic nervous system Locus coeruleus LC Stimuli norepinephrine release stimulation of the sympathetic nervous system 01 15 19 21 pharmacology of anxiolytic sedative hypnotics Norepinephrine Receptors Locus coeruleus Alpha 2 adrenergic receptors somatodendritic autoreceptors terminal
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