4/9/2018 Sedative-Hypnotics & the Sedative-Hypnotics & the Treatment of Hypersomnia Treatment of Hypersomnia LO + benzodiazepine 20 pA 20 pA 20 pA 100 ms 100 ms 100 ms anxiolysis sedation-hypnosis anticonvulsant Inhibition in the Brain Inhibition in the Brain cell body cell body axon axon Inhibitory Current Inhibitory Current synapse synapse + benzodiazepine GABA GABA 20 pA 20 pA GABA GABA 100 ms 100 ms receptor Today receptor GABA Receptors Benzodiazepines Barbituates Amphetamines 1 1 1
4/9/2018 Two Types of GABA Receptors GABA A Receptor ionotropic metabotropic chloride potassium/calcium outside of neuron outside of neuron GABA GABA binding site inside of neuron inside of neuron 2 nd m. GABA A GABA B Inhibitory Current epilepsy addiction 20 pA 100 ms anxiety & depression 2 3 GABA A Receptor GABA A Receptor 4 (from above) (from above) 5 subunits 5 subunits (i.e. pentameric) (i.e. pentameric) g BDZ GABA binding benzo a b site binding site a b GABA chloride pore chloride pore Inhibitory Current Inhibitory Current + benzodiazepine 20 pA 20 pA a g b 100 ms 100 ms d subunits 2
4/9/2018 5 Allosteric Modulation Benzodiazepines definition: modulation achieved by binding of a drug to a site distinct there are many from the site required for activation. Diazepam ( Valium ) among the first (launched 1963). - Rudolph & Knoflach, 2011 4 benzodiazepines are among the 200 most commonly prescribed drugs in the U.S. Alprazolam ( Xanax ) g BDZ Clonazepam ( Klonopin ) a b Diazepam ( Valium ) b a GABA Lorazepam ( Ativan ) 7 actions are dose-dependent: most sedative hypnotics GABA GABA GABA (e.g. barbituates) types: GABA + pos mod + neg mod + antag death positive ( agonism ) 0 Relative GABA- induced current benzodiazapines CNS effects anesthesia 0.5 negative ( inverse agonism ) 1.0 8 benzos by themselves do not: b CCE produce anesthesia hypnosis 6 Benzodiazepines cause fatalities 2.0 sedation + alcohol antagonist ( blocker ) - Rudolph & Knoflach, 2011 BUT anxiolysis Flumazenil they lower the lethal dose of other CNS depressants dose (e.g. alcohol) 9 from Patrice Guyenet, UVA Pharm Dept. Benzodiazepines Benzodiazepines there are many there are many Diazepam ( Valium ) among the first (launched 1963). Diazepam ( Valium ) among the first (launched 1963). 4 benzodiazepines are among the 200 most commonly 4 benzodiazepines are among the 200 most commonly prescribed drugs in the U.S. prescribed drugs in the U.S. Alprazolam ( Xanax ) Alprazolam ( Xanax ) Clonazepam ( Klonopin ) Clonazepam ( Klonopin ) Diazepam ( Valium ) Diazepam ( Valium ) Lorazepam ( Ativan ) Lorazepam ( Ativan ) actions are dose-dependent: actions are dose-dependent: death death Problems Problems CNS effects pharmacokinetics CNS effects pharmacokinetics anesthesia anesthesia redistribution side effects side effects ideal hypnotic hypnosis hypnosis Benzodiazepines sedation sedation flurazepam anxiolysis anxiolysis ideal anxiolytic metabolism 0 8 16 24 0 8 16 24 time (hours) time (hours) from Patrice Guyenet, UVA Pharm Dept. from Patrice Guyenet, UVA Pharm Dept. 3
4/9/2018 Benzodiazepine Metabolism Benzodiazepines: Effect Selectivity metabolized by the liver (CYPs) pharmacokinetics highly variable 100 death T1/2 (hours) short-acting (t1/2<6hrs) 10 Goodman & Gilman, 2011 75 intermediate- CNS effects 50 anesthesia acting (t1/2: 6-24hrs) 25 long-acting (t1/2>24hrs) ideal hypnotic 0 hypnosis Benzodiazepines sedation age-dependent anxiolysis 100 11 T1/2 (hours) ideal anxiolytic 75 50 0 8 16 24 25 time (hours) 0 40 80 from Patrice Guyenet, UVA Pharm Dept. Age (years) over-sedation can occur with ‘standard doses’ can be sex-dependent 12 CNS effects Greenblatt et al., 2000 a Subunits and Selectivity GABA A Receptor (from above) a 1 a 2 a 3 a 5 5 subunits (i.e. pentameric) g GABA binding benzo a b site binding the good the bad site a b Muscle Anti- Sedation Anxiolysis Relaxation Convulsant Amnesia Addiction chloride pore Inhibitory Current a 5 a 1 + benzodiazapene a 3 a 2 20 pA a 1-6 g 1-3 other b 1-3 100 ms Tan et al., 2011 d subunits 4
4/9/2018 a Subunits and Selectivity a Subunits and Selectivity a 1 a 2 a 3 a 5 a 1 a 2 a 3 a 5 a 1 -selective agents a 1 a 2 a 1 20-fold higher affinity for receptors containing a 1 subunits ‘Z compounds’ technically non-benzos good for insonmia a 3 a 5 CH 3 O H O Cl O 2 N 14 Cl diazepam 13 clonazepam imidazopyridine (zolpidem) Rudolph & Knoflach, 2011 Rudolph & Knoflach, 2011 15 a Subunits and Selectivity Benzodiazepines: Therapeutic Uses maximize therapy, minimize side-effects a 1 a 2 a 3 a 5 sedation-hypnosis true benzodiazepines Triazolam (closest to ‘ideal hypnotic’) death Flurazepam (less ‘early morning insomnia’) anesthesia Z compounds ideal hypnotic a 2 -selective agents a 2 Zolpidem ( Ambien ) hypnosis sedation ideal anxiolytic Zaleplon ( Sonata ) non-sedating anxiolytics anxiolysis Eszopiclone ( Lunesta ) hopefully soon… 0 8 16 24 16 time (hours) anxiolysis most benzos with medium- to long-T 1/2 work low doses often used a 2 -selective benzos are actively being developed severe anxiety: associated with prominent autonomic signs (e.g. panic disorders) high-potency benzos used Alprazolam ( Xanax ) Clonazepam ( Klonopin ) Lorazepam ( Ativin ) anticonvulsant only a few used (e.g. lorazepam, clonazepam, clorozepate) Rudolph & Knoflach, 2011 5
4/9/2018 Benzodiazepines: Last Couple of Things Sedative-Hypnotics & the Tolerance 17 primarily observed with anticonvulsant actions Treatment of Hypersomnia limited tolerance observed with sedative-hypnotic & anxiolytic effects Dependence/Addiction physical dependence is usually mild follows general rule of drug dependence: higher dosage = more severe withdrawal longer t1/2 = less severe withdrawal estimated that 0.1-0.2% of adult population abuse or are dependent upon benzos (300,000-600,00 people in the U.S.) GABA receptors live in the VTA (ventral tegmental area) modulating GABA receptor activity in the VTA hypothesized to increase dopamine release Benzodiazepine blocker Flumazenil ( Romazicon ) 18 benzodiazepine stupor potential risk of seizures Barbituates Amphetamine Directly bind to GABA binding site (at high doses) activates channel and causes chloride conductance g a b 19 b a BAR GABA binding site High doses are fatal most sedative hypnotics CNS effects (e.g. barbituates) alcohol death Resembles catecholamines but more lipid soluble (can cross BBB) anesthesia 20 catecholamines: norepinephrine, dopamine, serotonin hypnosis Benzodiazepines sedation anxiolysis dose NH 2 Once extensively used as sedative-hypnotics. Now largely replaced by the much safer benzos. noteworthy exceptions: norepinephrine amphetamine Pentobarbital (insomnia, pre-op sedation, seizures) 21 Phenobarbital (seizures) Thiopental (induction/maintenance of anesthesia)….short-lasting 6
4/9/2018 Amphetamine Amphetamine: Mechanism cell body axon Ma huang ‘looking for trouble’ synapse Resembles catecholamines but more lipid soluble (can cross BBB) GABA catecholamines: norepinephrine, dopamine, serotonin indirectly-acting sympathomimetic amine GABA receptor amphetamine and related drugs stimulate release of: dopamine stimulates reward mechanisms, causes psychosis/addiction CNS norepinephrine increased vigilance, anorexia serotonin increased vigilance, anorexia sympathetic norepinephrine hypertension, strokes, arrhythmias 21 nerve terminals Amphetamine: Mechanism Amphetamine: Mechanism 22 norepinephrine cell body axon NET (NE Transporter) 22 axon terminal synapse norepinephrine vesicle VMAT2 (vesicular monoamine transporter 2) Catecholamine uptake via plasmalemmal transporter Packaged in vesicles for subsequent release 7
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