Sedative-Hypnotic Drugs and Anxiety Disorders.AnxietySlide 3Anxiety Disorders (DSM-IV)Anxiety Disorders: PrevalenceSpectrum of Depression and Anxiety DisordersNeurobiology of Anxiety DisordersSlide 8Slide 9Drugs useful in the treatment of anxiety disorders.Statement from the British Committee for the Review of Medicines.Benzodiazepines - PropertiesSlide 13Slide 14Benzodiazepines - IndicationsBenzodiazepines – Mechanism of ActionAutoradiography of GABA-A Receptors.Pharmacological Effects of Benzodiazepines are Concentration-Dependent.Practical Points regarding Benzodiazepines.Newer sedative/hypnotic drugs.Buspirone (BuSpar®)Serotonin Pathways in the CNSSerotonin and AnxietyZolpidem (Ambien®)Sedative-Hypnotic Drugs and Anxiety Disorders.Patrick T. Ronaldson, PhDDepartment of Medical PharmacologyUniversity of ArizonaAnxietyTerm used to describe both symptoms and disordersOccurs normally as signal of impending danger or threatVery common, occurs in many disorders in addition to the anxiety disordersDifferentiated from fear on basis of whether there is a clear source of danger i.e. “fight or flight” response Adaptive value : helps to plan and prepare for threatmoderate levels enhance learning and performance Maladaptive when chronic / severeAnxietySymptoms include : physiological symptoms of activated sympathetic nervous system (increased heart rate, increased respiration, sweating etc.)cognitive component (awareness of being frightened)behavioral components (urge to escape)Anxiety Disorders (DSM-IV)Panic disorder with or without agoraphobiaAgoraphobia without panic disorderSpecific phobiasSocial phobiaObsessive compulsive disorderPosttraumatic stress disorderAcute stress disorderGeneralized anxiety disorderAnxiety disorder due to a general medical conditionSubstance-induced anxiety disorderAnxiety disorder not otherwise specifiedAnxiety Disorders: PrevalenceDepressionDepressionSocial Social anxiety disorderanxiety disorderPosttraumatic Posttraumatic stress disorderstress disorderGeneralized Generalized anxiety disorderanxiety disorderPanic disorderPanic disorderObsessive-Obsessive-compulsive disordercompulsive disorder17%17%13%13%7.8%7.8%5%5%3.5%3.5%2.5%2.5%Kessler RC, et al. Arch Gen Psychiatry 1994;51:8-19Stein MB, et al. JAMA 1998;280:708-713 Kessler RC, et al. Arch Gen Psychiatry 1995;52:1048-1060Lifetime Prevalence of Anxiety Lifetime Prevalence of Anxiety Disorders: 25%Disorders: 25%Spectrum of Depression and Anxiety DisordersGeneralized anxiety disorderGeneralized anxiety disorderDepressionDepressionSocial Social anxiety anxiety disorderdisorderPanic disorderPanic disorderObsessive-compulsive disorderObsessive-compulsive disorderPosttraumatic Posttraumatic stress disorderstress disorderNeurobiology of Anxiety DisordersCNS equilibrium is determined by a balance between excitatory and inhibitory neurotransmissionExcitation -> Glutamate is prototypical NT.Inhibition -> GABA is prototypical NT.Inhibition via GABA is primarily mediated by the ionotropic GABA-A receptor.GABA binding to GABA-A results in an increase in neuronal Cl- conductance and subsequent neuronal hyperpolarization.Neurobiology of Anxiety DisordersCl- - equilibrium potential is approximately -80 mVAn increase in Cl- influx will decrease the resting potential of a neuron.Therefore, the post-synaptic neuron will require a greater excitatory stimulus to fire an action potential.Neurobiology of Anxiety DisordersBenzodiazepines – major class of anxiolytic drugs.Act primarily via a selective binding sites on the GABA-A receptor.- high-affinity site.- low-affinity site.POTENTIATE the effects of GABA at the GABA-A receptor.GABA ReceptorDrugs useful in the treatment of anxiety disorders.Generic name Trade name Half-life (hrs) Dosage (mg/day)Long-acting benzodiazepinesDiazepam Valium 20-80 2-60Chlordiazepoxide Librium 24-48 15-100Clorazepate Tranxene 100 7.5-60Estazolam ProSom 10-24 0.5-2.0Prazepam Centrax 100 20-60Quazepam Doral 30-100 7.5-15Halazepam Paxipam 15-100 20-160Clonazepam* Klonopin 34 1.5-20Flurazepam+ Dalmane 100 15-30Short-acting benzodiazepinesOxazepam Serax 8 30-120Lorazepam Ativan 15 2-6Alprazolam Xanax 12 0.5-6Temazepam+ Restoril 11 15-30Triazolam+ Halcion 2 0.125-0.5Midazolam# Versed 2 2-4Non-benzodiazepine sedative/hypnoticsBuspirone (BuSpar) Serotonin 1a agonistZolpidem (Ambien) binds to benzodiazepine receptorMeprobamate (Miltown)Chloral hydrate (Noctec)* marketed as an anti-convulsant+marketed as a hypnotic#parenteral onlyStatement from the British Committee for the Review of Medicines.“All benzodiazepines are efficacious in the short-term treatment of anxiety and insomnia. There is no evidence which can justify the particular use of any particular benzodiazepine in either anxiety or insomnia. The usual division of benzodiazepines into rigid treatment categories of antianxiety agents and hypnotics does not appear to be based on the known pharmacological or clinical properties of this group of compounds.”Caveat – different benzodiazepines have additional actions (i.e., muscle relaxants, anticonvulsants, anesthetics) and different half-lives.Benzodiazepines - PropertiesPrototypical Benzodiazepine = Diazepam (Valium).Highly lipophilic – well-absorbed orally and easily crosses the blood-brain and blood-placental barriers.Hepatic metabolism – converted to hydrophilic metabolites for renal elimination.Metabolite = desmethyldiazepamSame metabolite for diazepam, chlordiazepam, prazepam, and clorazepate.Desmethyldiazepam itself is pharmacologically active as an anxiolytic.Desmethyldiazepam is converted to oxazepam in the liver.Short-acting metabolite.Directly glucuronidated (as is lorazepam and flurazepam) and excreted by the kidney.Benzodiazepines - PropertiesPharmacological Effects:Reduction of anxiety.Induction of sleep.Anesthesia – some benzodiazepines.Respiratory depression not as great as observed with barbiturates.Adverse Effects – primarily observed at plasma concentrations exceeding anxiolytic range.Expected side effects: sedation, ataxia, dependence.Impaired cognition and motor function.Confusion.Amnesia.Fatal overdose is uncommon, except when taken with alcohol.Benzodiazepines - PropertiesBenzodiazepines may induce tolerance in some individuals.Discontinuation of benzodiazepine therapy in tolerant patients MUST be