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

b e e n h a k k e r l a b . o r g

Sedative-Hypnotics & the Treatment of Hypersomnia 100 ms 20 pA

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

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

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

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

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

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

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

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

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

GABAA Receptor outside of neuron inside of neuron

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

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

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

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

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

Allosteric Modulation 5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 a b g GABA BDZ 7 types: positive (agonism) GABA Relative GABA- induced current 2.0 0.5 1.0 benzodiazapines negative (inverse agonism) bCCE 6 antagonist (blocker) - Rudolph & Knoflach, 2011 Flumazenil

Allosteric Modulation 5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 a b g GABA BDZ 7 types: positive (agonism) GABA + pos mod GABA Relative GABA- induced current benzodiazapines 0.5 negative (inverse agonism) 1.0 bCCE 6 2.0 antagonist (blocker) - Rudolph & Knoflach, 2011 Flumazenil

Allosteric Modulation 5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 a b g GABA BDZ 7 types: positive (agonism) GABA + pos mod GABA + neg mod GABA Relative GABA- induced current benzodiazapines 0.5 negative (inverse agonism) 1.0 bCCE 6 2.0 antagonist (blocker) - Rudolph & Knoflach, 2011 Flumazenil

Allosteric Modulation 5 Allosteric Modulation definition: modulation achieved by binding of a drug to a site distinct from the site required for activation. - Rudolph & Knoflach, 2011 a b g GABA BDZ 7 types: positive (agonism) GABA + pos mod GABA + neg mod GABA + antag GABA Relative GABA- induced current benzodiazapines 0.5 negative (inverse agonism) 1.0 bCCE 6 2.0 antagonist (blocker) - Rudolph & Knoflach, 2011 Flumazenil

they lower the lethal dose of other CNS depressants 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) a b g GABA binding site BAR actions are dose-dependent: most sedative hypnotics (e.g. barbiturates) anxiolysis sedation hypnosis CNS effects death anesthesia 8 Benzodiazepines benzos by themselves do not: cause fatalities produce anesthesia BUT they lower the lethal dose of other CNS depressants (e.g. alcohol) dose 9 from Patrice Guyenet, UVA Pharm Dept.

they lower the lethal dose of other CNS depressants 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) a b g GABA binding site BAR actions are dose-dependent: anxiolysis sedation hypnosis CNS effects most sedative hypnotics (e.g. barbiturates) death anesthesia 8 benzos by themselves do not: cause fatalities produce anesthesia Benzodiazepines + alcohol BUT they lower the lethal dose of other CNS depressants (e.g. alcohol) dose 9 from Patrice Guyenet, UVA Pharm Dept.

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: anxiolysis sedation hypnosis CNS effects anesthesia death Problems pharmacokinetics redistribution metabolism side effects flurazepam ideal hypnotic Benzodiazepines ideal anxiolytic 8 16 24 time (hours) dose from Patrice Guyenet, UVA Pharm Dept.

Benzodiazepine Metabolism metabolized by the liver (CYPs) pharmacokinetics highly variable 25 50 75 100 alprazolam chlordiazepoxide clonazepam clorazepate diazepam estazolam flurazepam lorazepam midazolam oxazepam quazepam temazepam triazolam T1/2 (hours) Goodman & Gilman, 2011 10

Benzodiazepine Metabolism metabolized by the liver (CYPs) pharmacokinetics highly variable 25 50 75 100 T1/2 (hours) Goodman & Gilman, 2011 short-acting (t1/2<6hrs) 10 intermediate- acting (t1/2: 6-24hrs) long-acting (t1/2>24hrs) alprazolam clonazepam clorazepate diazepam estazolam flurazepam lorazepam midazolam oxazepam quazepam temazepam triazolam chlordiazepoxide age-dependent 40 80 25 50 75 100 Age (years) T1/2 (hours) from Patrice Guyenet, UVA Pharm Dept. 11 over-sedation can occur with ‘standard doses’ can be sex-dependent Greenblatt et al., 2000

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

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

GABAA Receptor (from above) g a b b a a1-6 b1-3 g1-3 d subunits chloride pore (i.e. pentameric) g GABA binding site benzo binding site a b b a a1-6 b1-3 g1-3 d subunits Inhibitory Current + benzodiazapene 20 pA 100 ms

GABAA Receptor (from above) g a b b a a1-6 b1-3 g1-3 d subunits a1 a2 chloride pore (i.e. pentameric) g GABA binding site benzo binding site a b b a a1-6 b1-3 g1-3 d subunits a1 a2 a3 a5 other Inhibitory Current + benzodiazapene 20 pA 100 ms

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

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

a Subunits and Selectivity a2-selective agents a1-selective agents 20-fold higher affinity for receptors containing a1 subunits a1 a2 non-sedating anxiolytics hopefully soon… ‘Z compounds’ technically non-benzos good for insonmia a3 a5 benzodiazepine Cl CH3 O diazepam O2N H clonazepam imidazopyridine 14 13 (zolpidem) Rudolph & Knoflach, 2011

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

Benzodiazepines: Therapeutic Uses 15 Benzodiazepines: Therapeutic Uses maximize therapy, minimize side-effects sedation-hypnosis true benzodiazepines Triazolam (closest to ‘ideal hypnotic’) anesthesia death anxiolysis sedation hypnosis 8 16 24 time (hours) ideal hypnotic Flurazepam (less ‘early morning insomnia’) Z compounds Zolpidem (Ambien) ideal anxiolytic Zaleplon (Sonata) Eszopiclone (Lunesta) 16 anxiolysis most benzos with medium- to long-T1/2 work low doses often used a2-selective benzos are actively being developed severe anxiety: associated with prominent autonomic signs (e.g. panic disorders) high-potency benzos used Lorazepam (Ativin) Alprazolam (Xanax) Clonazepam (Klonopin) anticonvulsant only a few used (e.g. lorazepam, clonazepam, clorozepate)

Benzodiazepines: Last Couple of Things Tolerance primarily observed with anticonvulsant actions 17 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 (300,000-600,000 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) 18 benzodiazepine stupor potential risk of seizures

Sedative-Hypnotics & the Treatment of Hypersomnia

Barbiturates Directly bind to GABA binding site (at high doses) activates channel and causes chloride conductance a b g GABA binding site BAR 19 High doses are fatal anesthesia death anxiolysis sedation hypnosis CNS effects dose Benzodiazepines most sedative hypnotics (e.g. barbituates) alcohol 20 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 norepinephrine amphetamine NH2 amphetamine and related drugs stimulate release of: dopamine stimulates reward mechanisms, causes psychosis/addiction CNS norepinephrine increased vigilance, anorexia serotonin increased vigilance, anorexia norepinephrine hypertension, strokes, arrhythmias sympathetic nerve terminals 21

Amphetamine: Mechanism cell body synapse GABA receptor axon GABA

Amphetamine: Mechanism cell body synapse axon 22 norepinephrine

Amphetamine: Mechanism 22 axon terminal

Amphetamine: Mechanism 22 axon terminal

Amphetamine: Mechanism 22 norepinephrine NET (NE Transporter) axon terminal vesicle transporter 2) VMAT2 (vesicular monoamine Catecholamine uptake via plasmalemmal transporter Packaged in vesicles for subsequent release

Amphetamine: Mechanism 22 norepinephrine amphetamine amphetamine is a weak lipophilic base (pKa = 9.9) NET (NE Transporter) reverse transport axon terminal vesicle Catecholamine uptake via plasmalemmal transporter plus amphetamine Reverse transport leads to catecholamine release Packaged in vesicles for subsequent release Alkalinization shuts down vesicular catecholamine sequestration

Amphetamine d-isomer 3-4 times more potent than l-isomer 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: 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 23 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 mechanism(s) not well-understood (but activates wake-promoting neurons) 24 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 a b g GABA BDZ 20 pA 100 ms Benzodiazepines: dose- dependent effects Benzodiazepines: T1/2’s highly variable Benzodiazepines: ideal hypnotic VS anxiolytic Benzodiazepines: a subunits

Sedative-Hypnotics & the Treatment of Hypersomnia Inhibition in the Brain Barbiturates: directly activate GABAA R’s a b g BDZ 20 pA 100 ms BAR Benzodiazepines: positive allosteric modulators of GABAA R’s a b g GABA BDZ 20 pA 100 ms Benzodiazepines: dose- dependent effects Benzodiazepines: T1/2’s highly 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 a b g BDZ 20 pA 100 ms BAR Benzodiazepines: dose- dependent effects Benzodiazepines: T1/2’s highly 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 a b g BDZ 20 pA 100 ms BAR 100 ms 20 pA Benzodiazepines: dose- dependent effects Benzodiazepines: T1/2’s highly variable Amphetamine: catecholamine release Benzodiazepines: ideal hypnotic VS anxiolytic Benzodiazepines: a subunits suggested reading Basic & Clinical Pharmacology, 12th ed. (chapter 22) Bertram G. Katzung, Susan B. Masters, Anthony J. Trevor Pharmacological Basis of Therapeutics, 12th ed. (Chapter 17) Goodman & Gilman questions: markbeen@virginia.edu