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100 ms
20 pA
100 ms
20 pA
Sedative-Hypnotics & theTreatment of Hypersomnia
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100 ms
20 pA
+ benzodiazepine
sedation-hypnosis anticonvulsantanxiolysis
Sedative-Hypnotics & the
Treatment of Hypersomnia
LO
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Inhibition in the Brain
Inhibitory Current
100 ms
20 pA
cell body
synapse
GABAreceptor
axon
GABA
1
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Inhibition in the Brain
Inhibitory Current
100 ms
20 pA
+ benzodiazepine
cell body
synapse
GABAreceptor
axon
GABA
TodayGABA Receptors
Benzodiazepines
Barbituates
Amphetamines 1
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Two Types of GABA Receptors
GABA GABA
GABAA GABAB
chloride
binding site
potassium/calcium
20 pA
100 ms
Inhibitory Current
outside of neuron
inside of neuron
epilepsy
addiction
anxiety & depression
2nd m.
32
ionotropic metabotropic
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GABAA Receptor
outside of neuron
inside of neuron
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GABAA Receptor(from above)
5 subunits
chloride pore
(i.e. pentameric)
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a
ab
bg
20 pA
100 ms
Inhibitory CurrentInhibitory Current+ benzodiazepine
20 pA
100 ms
GABAA Receptor(from above)
benzobinding
site
GABAbinding
site
GABA
BDZ
5 subunits
chloride pore
(i.e. pentameric)
4
a b g dsubunits
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Allosteric Modulationmodulation achieved by binding of a drug to a site distinctfrom the site required for activation.
definition:
- Rudolph & Knoflach, 2011
GABAGABA
+ pos modGABA
+ neg modGABA
+ antag
Re
lati
ve
GA
BA
-in
du
ce
d c
urr
en
t2.0
0
0.5
1.0
- Rudolph & Knoflach, 2011
a
ab
b
g
GABA
BDZ
types: positive (agonism)
negative (inverse agonism)
antagonist (blocker)
benzodiazapines
bCCE
Flumazenil
5
6
7
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anesthesia
death
Benzodiazepinesthere 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
CN
S e
ffe
cts
dose
most sedative hypnotics(e.g. barbituates)
Benzodiazepines+ alcohol
from Patrice Guyenet, UVA Pharm Dept.
BUTthey lower the lethal doseof other CNS depressants
(e.g. alcohol)
benzos by themselves do not:
cause fatalitiesproduce anesthesia
9
8
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Benzodiazepinesthere 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
CN
S e
ffe
cts anesthesia
death
0 8 16 24time (hours)
ideal hypnotic
ideal anxiolytic
from Patrice Guyenet, UVA Pharm Dept.
Problemspharmacokineticsside effects
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Benzodiazepinesthere 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
CN
S e
ffe
cts anesthesia
death
0 8 16 24time (hours)
Benzodiazepines
from Patrice Guyenet, UVA Pharm Dept.
redistribution
metabolism
Problemspharmacokineticsside effects
flurazepam
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11
Benzodiazepine Metabolismmetabolized by the liver (CYPs)
pharmacokinetics highly variable
0
25
50
75
100
T1
/2 (
ho
urs
)
Goodman & Gilman, 2011
40 800
25
50
75
100
Age (years)
T1
/2 (
ho
urs
)
from Patrice Guyenet, UVA Pharm Dept.
short-acting (t1/2<6hrs)
intermediate-acting (t1/2: 6-24hrs)
long-acting (t1/2>24hrs)
age-dependent
can be sex-dependentover-sedation can occur with ‘standard doses’
Greenblatt et al., 2000
10
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Benzodiazepines: Effect Selectivity
anesthesia
death
anxiolysis
sedation
hypnosis
CN
S e
ffe
cts
0 8 16 24time (hours)
Benzodiazepines
ideal hypnotic
ideal anxiolytic
CNS effects
12
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a
ab
bg
GABAA Receptor(from above)
benzobinding
site
GABAbinding
site
a1-6 b1-3 g1-3 dsubunits
Inhibitory Current+ benzodiazapene
20 pA
100 ms
5 subunits
chloride pore
(i.e. pentameric)
a1
a2a3
a5
other
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a Subunits and Selectivity
a1 a2 a3 a5
Sedation AnxiolysisMuscle
RelaxationAnti-
Convulsant
the good
Amnesia Addiction
the bad
Tan et al., 2011
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a2
a Subunits and Selectivity
a1 a2 a3 a5
a1
a3 a5
Rudolph & Knoflach, 2011
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a1-selective agents20-fold higher affinity forreceptors containing a1subunits
a Subunits and Selectivity
a1 a2 a3 a5
a1
‘Z compounds’
technically non-benzos
good for insonmia
Rudolph & Knoflach, 2011
(zolpidem)
Cl
CH3 O
diazepam
O2N
Cl
H O
clonazepam imidazopyridine13
14
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a2
a Subunits and Selectivity
a1 a2 a3 a5
a2-selective agentsnon-sedating anxiolyticshopefully soon…
Rudolph & Knoflach, 2011
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Benzodiazepines: Therapeutic Usesmaximize therapy, minimize side-effects
anesthesia
death
anxiolysissedationhypnosis
0 8 16 24time (hours)
ideal hypnotic
sedation-hypnosistrue benzodiazepines
Triazolam (closest to ‘ideal hypnotic’)
Flurazepam (less ‘early morning insomnia’)
Z compoundsZolpidem (Ambien)
Zaleplon (Sonata)Eszopiclone (Lunesta)
anxiolysismost benzos with medium- to long-T1/2 work
a2-selective benzos are actively being developed
associated with prominent autonomic signs (e.g. panic disorders)severe anxiety:
high-potency benzos used
Lorazepam (Ativin)
Alprazolam (Xanax)Clonazepam (Klonopin)
ideal anxiolytic
anticonvulsantonly a few used (e.g. lorazepam, clonazepam, clorozepate)
low doses often used
15
16
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Benzodiazepines: Last Couple of ThingsTolerance
primarily observed with anticonvulsant actions
limited tolerance observed with sedative-hypnotic &anxiolytic effects
Dependence/Addiction
estimated that 0.1-0.2% of adult population abuse or aredependent 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 hypothesizedto increase dopamine release
Benzodiazepine blockerFlumazenil (Romazicon)
benzodiazepine stupor
potential risk of seizures
physical dependence is usually mild
follows general rule of drug dependence:higher dosage = more severe withdrawallonger t1/2 = less severe withdrawal
17
18
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Sedative-Hypnotics & the
Treatment of Hypersomnia
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Barbituates
aab
bg
GABA binding site
Directly bind to GABA binding site (at high doses)activates channel and causes chloride conductance
High doses are fatal
anesthesia
death
anxiolysissedationhypnosis
CN
S e
ffe
cts
dose
Benzodiazepines
most sedative hypnotics(e.g. barbituates)
Once extensively used as sedative-hypnotics. Now largelyreplaced by the much safer benzos.
noteworthy exceptions:Pentobarbital (insomnia, pre-op sedation, seizures)
Phenobarbital (seizures)
Thiopental (induction/maintenance of anesthesia)….short-lasting
BAR 19
alcohol
20
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Amphetamine
Resembles catecholamines but more lipid soluble (can cross BBB)
catecholamines: norepinephrine, dopamine, serotonin
21
norepinephrine amphetamine
NH2
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Amphetamine
Ma huang‘looking for trouble’
Resembles catecholamines but more lipid soluble (can cross BBB)
indirectly-acting sympathomimetic amine
amphetamine and related drugs stimulate release of:
dopamine stimulates reward mechanisms, causes psychosis/addiction
norepinephrine increased vigilance, anorexia
serotonin increased vigilance, anorexia
CNS
norepinephrine hypertension, strokes, arrhythmiassympatheticnerve
terminals
catecholamines: norepinephrine, dopamine, serotonin
21
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cell body
synapse
GABAreceptor
axon
GABA
Amphetamine: Mechanism
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22
cell body
synapse
axon
norepinephrine
Amphetamine: Mechanism
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22
axon terminal
NET (NE Transporter)
norepinephrine
transporter 2) VMAT2 (vesicular monoamine
vesicle
Amphetamine: Mechanism
Catecholamine uptake viaplasmalemmal transporter
Packaged in vesicles for subsequent release
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22
axon terminal
NET (NE Transporter)
norepinephrine
amphetamine
reverse transport
amphetamine is aweak lipophilic base
(pKa = 9.9)
Amphetamine: Mechanism
Catecholamine uptake viaplasmalemmal transporter
Packaged in vesicles for subsequent release
plus amphetamine
Reverse transport leads tocatecholamine release
Alkalinization shuts down vesicularcatecholamine sequestration
vesicle
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Powerful CNS stimulantd-isomer 3-4 times more potent than l-isomer
d-amphetamine: Dextroamphetamine (Dexedrine, Dextrostat)
Lisdexamfetamine (Vyvanse): inactive, prodrug of d-amphetamine
Adverse/toxic effectsUsually result from overdosage
Acute toxic effects usually an extension of therapeutic effects.restlessness, dizziness, tenseness, insomnia
Amphetamine
Clinical uses:Hypersomnia (Excessive Daytime Sleepiness [EDS])
narcolepsy (0.03-0.06% of the US population)obstructive sleep apneashift-worker disorder (EDS affects >30% of night-shift workers)
Attention Deficit Hyperactivity Disorder
Cardiovascular/GI side effects
AlternativesModafinil (Provigil): promotes wakefulness, reduces EDS in narcoleptics
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
23
24
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Inhibition in the Brain
Benzodiazepines: positiveallosteric modulators of GABAA R’s
a
ab
bg
GABA
BDZ20 pA
100 ms
Benzodiazepines: dose-dependent effects
Benzodiazepines: T1/2’s highlyvariable
Benzodiazepines: idealhypnotic VS anxiolytic
Benzodiazepines: a subunits
Sedative-Hypnotics & theTreatment of Hypersomnia
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Sedative-Hypnotics & theTreatment of Hypersomnia
Barbituates: directlyactivate GABAA R’s
a
ab
bgBDZ
20 pA
100 msBAR
Benzodiazepines: dose-dependent effects
Amphetamine: catecholaminerelease
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Sedative-Hypnotics & theTreatment of Hypersomnia
questions:[email protected]
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
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