Pharmacology of Anxiolytic/ Sedative-HypnoticsObjectivesAnxietyANTIANXIETY AGENTSSEDATIVE-HYPNOTICSPharmacodynamicsGABA Function and DistributionBZD Receptor ActivityGABAA-BZD Supramolecular ComplexGABAA Receptor Structurepharmacology of anxiolytic/sedative-hypnoticsSerotonin ModelSerotonin ReceptorsNoradrenergic ModelNorepinephrine ReceptorsPharmacokinetics: BenzodiazepinesDrug Interactions: BenzodiazepinesAdverse Effects: BenzodiazepinesAbuse, Dependence, Withdrawal, and Rebound Anxiety: BenzodiazepinesPharmacokinetics/Pharmacodynamics: BuspironeAdverse Effects: BuspironeIndications for Antianxiety/Sedative-HypnoticsTreatment Strategy for GADSlide 24Treatment Strategy for OBSESSIVE-COMPULSIVE DISORDERSlide 26Treatment Strategy for SLEEP DISORDERSSlide 28Slide 29ReferencesAbstract01/13/19 1Pharmacology of Anxiolytic/ Sedative-HypnoticsPhilip G. Janicak, MDProfessor of PsychiatryRush University01/13/19 2pharmacology of anxiolytic/sedative-hypnoticsObjectives•Review the concept of anxiety•Review different classes of antianxiety and sedative-hypnotic agents in terms of their pharmacodynamics; pharmacokinetics; adverse effects; and potential for drug interactions•Review treatment strategies for anxiety and sleep disorders01/13/19 3pharmacology of anxiolytic/sedative-hypnoticsAnxiety•Natural human experience•Subjective qualities of fear or related emotions•Ensures survival and adaptation•In excess, can cripple and destroy–Subjective, physiological, behavioral aspects01/13/19 4Generic Name Trade Name Daily Dosage (mg/day)BENZODIAZEPINESChlordiazepoxide Librium, others 10-100Diazepam Valium, others 2-40Oxazepam Serax, others 30-120Chlorazepate Tranxene, others 15-60Lorazepam Ativan 1-10Prazepam Centrax 20-60Halazepam Paxipam 60-160Alprazolam Xanax 0.75-4AZAPIRONESBuspirone Buspar 15-60SEROTONERGIC AGENTSSSRI Sertraline, others 25-250NORADRENERGIC AGENTSClonidine-BlockersSEROTONERGIC/NORADRENERGIC AGENTSVenlafaxine Effexor 75-375ANTIHISTAMINESDiphenhydramine Benadryl 25-50ANTIANXIETY AGENTS01/13/19 5Generic Name Trade Name Daily Dosage (mg /day)BENZODIAZEPINESLong-actingFlurazepam Dalmane 15-45Quazepam Doral 7.5-15Intermediate-actingEstazolam Prosom 0.5-2Temazepam Restoril 15-45Short-actingTriazolam Halcion 0.125-0.25NONBENZODIAZEPINES Zolpidem Ambien 5-20Zaleplon Sonata 5-20SEDATING ANTIDEPRESSANTSTrazodone Dyserel 25-100BARBITURATE-LIKEChloral Hydrate Notec 500-1500OTHERMelatonin 0.3-2SEDATIVE-HYPNOTICS01/13/19 6pharmacology of anxiolytic/sedative-hypnoticsPharmacodynamics•Benzodiazepines»Specific binding site associated with GABAA receptor-chloride ion channel•Azapirones (e.g., buspirone)»5-HT1A agonist: acutely, firing, in dorsal raphe nuclei; chronically, receptor desensitization activity•Serotonin Agents–SSRIs block reuptake of serotonin•Noradrenergic Agents–Beta-blockers receptors central and peripheral, post synaptic–Clonidine•Agonist at 2 receptors, central, pre-synaptic01/13/19 7pharmacology of anxiolytic/sedative-hypnoticsGABA 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 GABA01/13/19 8BZD Receptor ActivityFull AgonistPartialAgonistAntagonistPartial InverseAgonistFull InverseAgonistAnxiolyticSed-HypnoticMyorelaxantAnticonvulsantAmnesticDependencyAnxiolytic No clinicaleffectPromnesticAnxiogenicPro-convulsantPromnesticAnxiogenicPro-convulsantpharmacology of anxiolytic/sedative-hypnotics9 01/13/19GABAA-BZD Supramolecular Complex01/13/19 10S.M. Paul, 1995GABAA Receptor StructureBenzodiazepinesAgonistsAntagonists-Inverse AgonistsDBI PeptidesConvulsantsPicrotoxinTBPSCl-GABA AgonistsMuscimolGABA AntagonistsBicucullineBarbituratesNeuroactive SteroidsAlcoholsAnesthetics01/13/19 11GABAA receptorCytoplasmBenzodiazepine-binding domainpharmacology of anxiolytic/sedative-hypnotics01/13/19 12pharmacology of anxiolytic/sedative-hypnoticsSerotonin 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 humans01/13/19 13Serotonin ReceptorsAnxiety - 5-HT1A; 5-HT1C; 5-HT2; 5-HT4Sexual Function - 5-HT1A; 5-HT2Schizophrenia - 5-HT2; 5-HT4 (?)pharmacology of anxiolytic/sedative-hypnotics01/13/19 14Noradrenergic Model•Pathways primarily originate in locus coeruleus (LC)•Stimuli norepinephrine release stimulation of the sympathetic nervous system•Hypersensitivity to autonomic nervous systempharmacology of anxiolytic/sedative-hypnotics01/13/19 15Norepinephrine Receptors•Alpha -2 adrenergic receptors–somatodendritic autoreceptors–terminal autoreceptors–negative feedback system–antagonists are anxiogenic–agonists may be anxiolytic and decrease withdrawal symptoms (e.g., clonidine)•Beta adrenergic receptors–Beta-blockers (e.g., propranolol)»Social phobia»Performance anxietypharmacology of anxiolytic/sedative-hypnotics01/13/19 16Pharmacokinetics: Benzodiazepines•Absorption: rapid absorption, except clorazepate•Onset of action: increase lipid solubility faster onset•Duration of action: single dose: increased lipid solubility faster redistribution to fat tissues shorter duration of actionChronic use: in equilibrium with fat tissues•Half life: In part, determines duration of action•Metabolism: lorazepam, oxazepam, temazepam not metabolized by liverpharmacology of anxiolytic/sedative-hypnotics01/13/19 17Drug Interactions: Benzodiazepines•Additive pharmacodynamic effects (e.g., alcohol)•BZD withdrawal when other drugs that increase seizure risk are also taken•Inhibit BZD metabolism (e.g., nefazodone via P450 3A 3/4 inhibits metabolism of triazolam)•Diazepam may increase levels of digoxin and phenytoinpharmacology of anxiolytic/sedative-hypnotics01/13/19 18Adverse Effects: Benzodiazepines•Sedation and impairment of performancePsychomotor skills: driving; engaging in dangerous physical activities; using hazardous machinery, especially during initial phase of treatment•Memory impairmentAnterograde amnesia (desired before surgery, other procedures).Dose-related, and tolerance may not develop.Most likely with triazolam•DisinhibitionPossible risk factors: history of aggression, impulsivity, borderline or antisocial personalitypharmacology
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