Pharmacology of Anxiolytic Sedative Hypnotics Philip G Janicak MD Professor of Psychiatry Rush University 01 13 19 1 pharmacology of anxiolytic sedative hypnotics Objectives 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 disorders 01 13 19 2 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 13 19 3 ANTIANXIETY AGENTS Generic Name Trade Name BENZODIAZEPINES Chlordiazepoxide Librium others Diazepam Valium others Oxazepam Serax others Chlorazepate Tranxene others Lorazepam Ativan Prazepam Centrax Halazepam Paxipam Alprazolam Xanax AZAPIRONES Buspirone Buspar SEROTONERGIC AGENTS SSRI Sertraline others NORADRENERGIC AGENTS Clonidine Blockers SEROTONERGIC NORADRENERGIC AGENTS Venlafaxine Effexor ANTIHISTAMINES Diphenhydramine Benadryl 01 13 19 Daily Dosage mg day 10 100 2 40 30 120 15 60 1 10 20 60 60 160 0 75 4 15 60 25 250 75 375 25 50 4 SEDATIVE HYPNOTICS Generic Name 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 NONBENZODIAZEPINES Zolpidem Zaleplon Ambien Sonata 5 20 5 20 SEDATING ANTIDEPRESSANTS Trazodone Dyserel 25 100 BARBITURATE LIKE Chloral Hydrate Notec 500 1500 OTHER Melatonin 01 13 19 Trade Name 0 3 2 5 pharmacology of anxiolytic sedative hypnotics Pharmacodynamics Benzodiazepines Specific binding site associated with GABAA receptorchloride 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 synaptic 01 13 19 6 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 13 19 7 pharmacology of anxiolytic sedative hypnotics BZD Receptor Activity Full Agonist Anxiolytic Sed Hypnotic Myorelaxant Anticonvulsant Amnestic Dependency 01 13 19 Partial Agonist Anxiolytic Partial Inverse Antagonist Agonist No clinical Promnestic effect Anxiogenic Pro convulsant Full Inverse Agonist Promnestic Anxiogenic Pro convulsant 8 GABAA BZD Supramolecular Complex 01 13 19 9 GABAA Receptor Structure Cl Benzodiazepines Agonists AntagonistsInverse Agonists GABA Agonists Muscimol GABA Antagonists Bicuculline DBI Peptides Barbiturates Neuroactive Steroids Convulsants Picrotoxin TBPS 01 13 19 S M Paul 1995 Alcohols Anesthetics 10 pharmacology of anxiolytic sedative hypnotics Benzodiazepinebinding domain Cytoplasm 01 13 19 GABAA receptor 11 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 13 19 12 pharmacology of anxiolytic sedative hypnotics Serotonin Receptors Anxiety 01 13 19 5 HT1A 5 HT1C 5 HT2 5 HT4 Sexual Function 5 HT1A 5 HT2 Schizophrenia 5 HT2 5 HT4 13 pharmacology of anxiolytic sedative hypnotics Noradrenergic Model Pathways primarily originate in locus coeruleus LC Stimuli norepinephrine release stimulation of the sympathetic nervous system Hypersensitivity to autonomic nervous system 01 13 19 14 pharmacology of anxiolytic sedative hypnotics Norepinephrine 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 anxiety 01 13 19 15 pharmacology of anxiolytic sedative hypnotics Pharmacokinetics 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 action Chronic use in equilibrium with fat tissues Half life In part determines duration of action Metabolism lorazepam oxazepam temazepam not metabolized by liver 01 13 19 16 pharmacology of anxiolytic sedative hypnotics Drug 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 phenytoin 01 13 19 17 pharmacology of anxiolytic sedative hypnotics Adverse Effects Benzodiazepines Sedation and impairment of performance Psychomotor skills driving engaging in dangerous physical activities using hazardous machinery especially during initial phase of treatment Memory impairment Anterograde amnesia desired before surgery other procedures Dose related and tolerance may not develop Most likely with triazolam Disinhibition Possible risk factors history of aggression impulsivity borderline or antisocial personality 01 13 19 18 pharmacology of anxiolytic sedative hypnotics Abuse Dependence Withdrawal and Rebound Anxiety Benzodiazepines Abuse potential decreased when properly prescribed and supervised Dependence may occur at usual doses taken beyond several weeks Withdrawal may occur even when discontinuation is not abrupt e g by 10 every 3 days Symptoms include tachycardia increased blood pressure muscle cramps anxiety insomnia panic attacks impairment of memory and concentration perceptual disturbances derealization hallucinations hyperpyrexia seizures May continue for months Rebound anxiety return of target symptoms with increase intensity 01 13 19 19 pharmacology of anxiolytic sedative hypnotics Pharmacokinetics Pharmacodynamics Buspirone Onset of action i e weeks versus days 01 13 19 No sedation or impairment of performance No cross tolerance with BZDs No tolerance or withdrawal No abuse potential 20
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