SedativeHypnotics the Treatment of Hypersomnia Mark Beenhakker Pharmacology

Sedative-Hypnotics & the Treatment of Hypersomnia Mark Beenhakker Pharmacology markbeen@virginia. edu

beenhakkerlab. org

Sedative-Hypnotics & the Treatment of Hypersomnia 20 p. A 100 ms

Sedative-Hypnotics & the Treatment of Hypersomnia + benzodiazepine 20 p. A 100 ms anxiolysis sedation-hypnosis anticonvulsant

Sedative-Hypnotics & the Treatment of Hypersomnia LO + benzodiazepine 20 p. A 100 ms anxiolysis sedation-hypnosis anticonvulsant

Inhibition in the Brain cell body axon Inhibitory Current synapse GABA 20 p. A GABA receptor 100 ms 1

Inhibition in the Brain cell body axon Inhibitory Current + benzodiazepine synapse GABA 20 p. A Today GABA Receptors Benzodiazepines Barbiturates Amphetamines GABA receptor 100 ms 1

Two Types of GABA Receptors ionotropic metabotropic GABAA GABAB outside of neuron inside of neuron 2

Two Types of GABA Receptors GABA ionotropic metabotropic GABAA GABAB outside of neuron binding site inside of neuron 2

Two Types of GABA Receptors chloride outside of neuron GABA binding site inside of neuron chloride GABAA Inhibitory Current 20 p. A 100 ms 2 GABAB

Two Types of GABA Receptors outside of neuron potassium/calcium GABA binding site inside of neuron chloride 2 nd m. GABAA Inhibitory Current 20 p. A 100 ms 2 GABAB epilepsy addiction anxiety & depression 3

Two Types of GABA Receptors outside of neuron potassium/calcium GABA binding site inside of neuron 2 nd m. chloride GABAA Inhibitory Current + benzodiazepine 20 p. A 100 ms 2 GABAB epilepsy addiction anxiety & depression 3

GABAA Receptor outside of neuron inside of neuron

GABAA Receptor (from above) 5 subunits (i. e. pentameric) chloride pore

GABAA Receptor (from above) 5 subunits (i. e. pentameric) chloride pore a b subunits g d

GABAA Receptor (from above) 5 subunits (i. e. pentameric) a g b b a chloride pore a b subunits g d

GABAA Receptor (from above) 5 subunits (i. e. pentameric) a g b GABA binding site b a GABA chloride pore Inhibitory Current 20 p. A a b subunits g d 100 ms

GABAA Receptor (from above) 4 5 subunits (i. e. pentameric) BDZ benzo binding site a g b b a GABA binding site GABA chloride pore Inhibitory Current + benzodiazepine 20 p. A a b subunits g d 100 ms

5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 BDZ g a b b a GABA 7 6 negative (inverse agonism) b. CCE antagonist (blocker) Flumazenil GABA 0 Relative GABAinduced current types: positive (agonism) benzodiazapines 0. 5 1. 0 2. 0 - Rudolph & Knoflach, 2011

5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 BDZ g a b b a GABA 7 6 negative (inverse agonism) b. CCE antagonist (blocker) Flumazenil GABA + pos mod 0 Relative GABAinduced current types: positive (agonism) benzodiazapines 0. 5 1. 0 2. 0 - Rudolph & Knoflach, 2011

5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 BDZ g a b b a GABA 7 6 negative (inverse agonism) b. CCE antagonist (blocker) Flumazenil GABA + pos mod GABA + neg mod 0 Relative GABAinduced current types: positive (agonism) benzodiazapines 0. 5 1. 0 2. 0 - Rudolph & Knoflach, 2011

5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 BDZ g a b b a GABA 7 6 negative (inverse agonism) b. CCE antagonist (blocker) Flumazenil GABA + pos mod GABA + neg mod GABA + antag 0 Relative GABAinduced current types: positive (agonism) benzodiazapines 0. 5 1. 0 2. 0 - Rudolph & Knoflach, 2011

Benzodiazepines there are many Diazepam (Valium) among the first (launched 1963). 4 benzodiazepines are among the 200 most commonly prescribed drugs in the U. S. Alprazolam (Xanax) Clonazepam (Klonopin) Diazepam (Valium) Lorazepam (Ativan) actions are dose-dependent: death most sedative hypnotics (e. g. barbiturates) g b a. BAR 8 CNS effects GABA binding site anesthesia hypnosis sedation anxiolysis Benzodiazepines benzos by themselves do not: produce anesthesia cause fatalities BUT dose from Patrice Guyenet, UVA Pharm Dept. they lower the lethal dose of other CNS depressants (e. g. alcohol) 9

Benzodiazepines there are many Diazepam (Valium) among the first (launched 1963). 4 benzodiazepines are among the 200 most commonly prescribed drugs in the U. S. Alprazolam (Xanax) Clonazepam (Klonopin) Diazepam (Valium) Lorazepam (Ativan) actions are dose-dependent: death most sedative hypnotics (e. g. barbiturates) g b a. BAR 8 CNS effects GABA binding site anesthesia hypnosis sedation anxiolysis Benzodiazepines + alcohol dose from Patrice Guyenet, UVA Pharm Dept. benzos by themselves do not: produce anesthesia cause fatalities BUT they lower the lethal dose of other CNS depressants (e. g. alcohol) 9

Benzodiazepines there are many Diazepam (Valium) among the first (launched 1963). 4 benzodiazepines are among the 200 most commonly prescribed drugs in the U. S. Alprazolam (Xanax) Clonazepam (Klonopin) Diazepam (Valium) Lorazepam (Ativan) actions are dose-dependent: CNS effects death anesthesia Problems pharmacokinetics side effects redistribution ideal hypnotic hypnosis sedation anxiolysis Benzodiazepines flurazepam metabolism ideal anxiolytic 0 8 16 dose time (hours) 24 from Patrice Guyenet, UVA Pharm Dept.

Benzodiazepine Metabolism 10 T 1/2 (hours) metabolized by the liver (CYPs) pharmacokinetics highly variable 100 75 50 Goodman & Gilman, 2011 25 0 lam ide zepamzepate zepamazolamzepam zolam azo pox tria dia est flura lora mid oxa qua tema alpr rdiaze clona clora o l h c

Benzodiazepine Metabolism 100 75 50 Goodman & Gilman, 2011 25 0 short-acting (t 1/2<6 hrs) intermediateacting (t 1/2: 6 -24 hrs) long-acting (t 1/2>24 hrs) lam ide zepamzepate zepamazolamzepam zolam azo pox tria dia est flura lora mid oxa qua tema alpr rdiaze clona clora o l h c age-dependent T 1/2 (hours) 10 T 1/2 (hours) metabolized by the liver (CYPs) pharmacokinetics highly variable 100 75 50 25 0 11 40 80 Age (years) from Patrice Guyenet, UVA Pharm Dept. over-sedation can occur with ‘standard doses’ can be sex-dependent Greenblatt et al. , 2000

Benzodiazepines: Effect Selectivity CNS effects death anesthesia ideal hypnotic hypnosis sedation anxiolysis Benzodiazepines ideal anxiolytic 0 8 16 time (hours) 24 12 CNS effects

GABAA Receptor (from above) 5 subunits (i. e. pentameric) benzo binding site a g b GABA binding site b a chloride pore Inhibitory Current + benzodiazapene 20 p. A a b subunits g d 100 ms

GABAA Receptor (from above) 5 subunits (i. e. pentameric) benzo binding site g a b GABA binding site b a chloride pore Inhibitory Current + benzodiazapene 20 p. A a 1 -6 b 1 -3 subunits g 1 -3 d 100 ms

GABAA Receptor (from above) 5 subunits (i. e. pentameric) benzo binding site g a b GABA binding site b a chloride pore a 5 a 3 other Inhibitory Current + benzodiazapene a 1 a 2 20 p. A a 1 -6 b 1 -3 subunits g 1 -3 d 100 ms

a Subunits and Selectivity a 1 a 2 a 3 a 5 the good Sedation Anxiolysis Muscle Relaxation the bad Anti. Convulsant Amnesia Addiction Tan et al. , 2011

a Subunits and Selectivity a 1 a 2 a 3 a 5 the good Sedation Anxiolysis Muscle Relaxation the bad Anti. Convulsant Amnesia Addiction Tan et al. , 2011

a Subunits and Selectivity a 1 a 2 -selective agents a 3 a 5 a 1 -selective agents a 2 20 -fold higher affinity for non-sedating anxiolytics hopefully soon… receptors containing a 1 subunits ‘Z compounds’ technically non-benzos a 3 CH 3 Cl H O O a 5 good for insonmia O 2 N 14 Cl diazepam Rudolph & Knoflach, 2011 13 clonazepam benzodiazepine imidazopyridine (zolpidem)

Benzodiazepines: Therapeutic Uses 15 maximize therapy, minimize side-effects sedation-hypnosis true benzodiazepines Triazolam (closest to ‘ideal hypnotic’) Flurazepam (less ‘early morning insomnia’) Z compounds Zolpidem (Ambien) Zaleplon (Sonata) Eszopiclone (Lunesta) death anesthesia ideal hypnotic hypnosis sedation anxiolysis 0 8 16 time (hours) 24 16

15 Benzodiazepines: Therapeutic Uses maximize therapy, minimize side-effects sedation-hypnosis true benzodiazepines Triazolam (closest to ‘ideal hypnotic’) Flurazepam (less ‘early morning insomnia’) Z compounds Zolpidem (Ambien) Zaleplon (Sonata) Eszopiclone (Lunesta) death anesthesia ideal hypnotic hypnosis sedation anxiolysis ideal anxiolytic 0 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) 8 16 time (hours) 24 16

Benzodiazepines: Last Couple of Things Tolerance primarily observed with anticonvulsant actions limited tolerance observed with sedative-hypnotic & anxiolytic effects 17 Dependence/Addiction physical dependence is usually mild follows general rule of drug dependence: higher dosage = more severe withdrawal longer t 1/2 = less severe withdrawal estimated that 0. 1 -0. 2% of adult population abuse or are dependent upon benzos (300, 000 -600, 000 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) benzodiazepine stupor potential risk of seizures 18

Sedative-Hypnotics & the Treatment of Hypersomnia

Barbiturates Directly bind to GABA binding site (at high doses) activates channel and causes chloride conductance g b a BAR a b 19 GABA binding site CNS effects High doses are fatal most sedative hypnotics (e. g. barbituates) death alcohol anesthesia hypnosis sedation anxiolysis 20 Benzodiazepines dose Once extensively used as sedative-hypnotics. Now largely replaced by the much safer benzos. noteworthy exceptions: Pentobarbital (insomnia, pre-op sedation, seizures) Phenobarbital (seizures) Thiopental (induction/maintenance of anesthesia)…. short-lasting

Amphetamine Ma huang ‘looking for trouble’ Resembles catecholamines but more lipid soluble (can cross BBB) catecholamines: norepinephrine, dopamine, serotonin indirectly-acting sympathomimetic amine amphetamine and related drugs stimulate release of: CNS dopamine stimulates reward mechanisms, causes psychosis/addiction norepinephrine increased vigilance, anorexia serotonin increased vigilance, anorexia norepinephrine sympathetic nerve terminals NH 2 norepinephrine amphetamine hypertension, strokes, arrhythmias 21

Amphetamine: Mechanism cell body axon synapse GABA receptor

Amphetamine: Mechanism cell body axon 22 synapse norepinephrine

Amphetamine: Mechanism 22 axon terminal

Amphetamine: Mechanism 22 axon terminal

Amphetamine: Mechanism 22 norepinephrine NET (NE Transporter) axon terminal vesicle Catecholamine uptake via plasmalemmal transporter Packaged in vesicles for subsequent release VMAT 2 (vesicular monoamine transporter 2)

Amphetamine: Mechanism 22 amphetamine is a weak lipophilic base (p. Ka = 9. 9) norepinephrine amphetamine NET (NE Transporter) reverse transport axon terminal vesicle Catecholamine uptake via plasmalemmal transporter plus amphetamine Packaged in vesicles for subsequent release Reverse transport leads to catecholamine release Alkalinization shuts down vesicular catecholamine sequestration

Amphetamine Powerful CNS stimulant d-isomer 3 -4 times more potent than l-isomer d-amphetamine: Dextroamphetamine (Dexedrine, Dextrostat) Lisdexamfetamine (Vyvanse): inactive, prodrug of d-amphetamine Clinical uses: 23 Hypersomnia (Excessive Daytime Sleepiness [EDS]) narcolepsy (0. 03 -0. 06% of the US population) obstructive sleep apnea shift-worker disorder (EDS affects >30% of night-shift workers) Attention Deficit Hyperactivity Disorder Adverse/toxic effects Usually result from overdosage Acute toxic effects usually an extension of therapeutic effects. restlessness, dizziness, tenseness, insomnia Cardiovascular/GI side effects Alternatives Modafinil (Provigil): promotes wakefulness, reduces EDS in narcoleptics 24 mechanism(s) not well-understood (but activates wake-promoting neurons) little/no cardiovascular/cognitive side effects (main side effect = headaches) may be used to reduce cocaine dependence

Sedative-Hypnotics & the Treatment of Hypersomnia Inhibition in the Brain

Sedative-Hypnotics & the Treatment of Hypersomnia Inhibition in the Brain Benzodiazepines: positive allosteric modulators of GABAA R’s Benzodiazepines: dosedependent effects BDZ a b 20 p. A g b a GABA Benzodiazepines: T 1/2’s highly 100 ms variable Benzodiazepines: ideal hypnotic VS anxiolytic Benzodiazepines: a subunits

Sedative-Hypnotics & the Treatment of Hypersomnia Inhibition in the Brain Barbiturates: directly Benzodiazepines: positive GABA R’s allostericactivate modulators of. A GABA Benzodiazepines: dosedependent effects BDZ a b g 20 p. A b GABA a BAR Benzodiazepines: T 1/2’s highly 100 ms variable Benzodiazepines: ideal hypnotic VS anxiolytic Benzodiazepines: a subunits

Sedative-Hypnotics & the Treatment of Hypersomnia Inhibition in the Brain Barbituates: directly activate GABAA R’s Benzodiazepines: dosedependent effects BDZ a b g 20 p. A b a BAR Benzodiazepines: T 1/2’s highly 100 ms variable Benzodiazepines: ideal hypnotic VS anxiolytic Benzodiazepines: a subunits

Sedative-Hypnotics & the Treatment of Hypersomnia Inhibition in the Brain Barbituates: directly activate GABAA R’s Benzodiazepines: dosedependent effects BDZ a b g 20 p. A Amphetamine: catecholamine Benzodiazepines: T 1/2’s 100 ms release 100 ms highly variable Benzodiazepines: ideal hypnotic VS anxiolytic Benzodiazepines: a subunits 20 p. A b a BAR suggested reading Basic & Clinical Pharmacology, 12 th ed. (chapter 22) Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Pharmacological Basis of Therapeutics, 12 th ed. (Chapter 17) Goodman & Gilman questions: markbeen@virginia. edu