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

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

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

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

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

6. GABAA Receptor
outside of neuron
inside of neuron

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

8. GABAA Receptor (from above) g a b b a a b g d subunits 5 subunits4
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

9. Allosteric Modulation5
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

10. 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)
actions are dose-dependent:
anxiolysis
sedation
hypnosis
CNS effects
most sedative hypnotics
(e.g. barbituates)
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.

11. 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
side effects
ideal hypnotic
ideal anxiolytic 8 16 24
time (hours)
from Patrice Guyenet, UVA Pharm Dept.

12. 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
Benzodiazepines 8 16 24
time (hours)
from Patrice Guyenet, UVA Pharm Dept.

13. 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

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

15. 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

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

17. a Subunits and Selectivity
Rudolph & Knoflach, 2011

18. a Subunits and Selectivity
a1-selective agents
20-fold higher affinity for
receptors containing a1
subunits a1
‘Z compounds’
technically non-benzos
good for insonmia Cl
CH3 O
diazepam
O2N H
clonazepam
imidazopyridine 14 13
(zolpidem)
Rudolph & Knoflach, 2011

19. a Subunits and Selectivity
a2-selective agents a2
non-sedating anxiolytics
hopefully soon…
Rudolph & Knoflach, 2011

20. Benzodiazepines: Therapeutic Uses15
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)

21. 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 % of adult population abuse or are
dependent upon benzos (300, ,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

22. Sedative-Hypnotics & the
Treatment of Hypersomnia

23. Barbituates 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

24. Amphetamine
Resembles catecholamines but more lipid soluble (can cross BBB)
catecholamines: norepinephrine, dopamine, serotonin
norepinephrine
amphetamine
NH2 21

25. 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:
dopamine stimulates reward mechanisms, causes psychosis/addiction
CNS
norepinephrine increased vigilance, anorexia
serotonin increased vigilance, anorexia
norepinephrine hypertension, strokes, arrhythmias
sympathetic
nerve
terminals 21

26. Amphetamine: Mechanism
cell body
synapse
GABA
receptor
axon
GABA

27. Amphetamine: Mechanism
cell body
synapse
axon 22
norepinephrine

28. Amphetamine: Mechanism22
norepinephrine
NET (NE Transporter)
axon terminal
vesicle
transporter 2)
VMAT2 (vesicular monoamine
Catecholamine uptake via
plasmalemmal transporter
Packaged in vesicles for
subsequent release

29. Amphetamine: Mechanism22
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

30. 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 ( % 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

31. 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

32. Sedative-Hypnotics & the Treatment of Hypersomnia
Barbituates: directly
activate GABAA R’s a b g
BDZ
20 pA
100 ms
BAR
Benzodiazepines: dose-
dependent effects
Amphetamine: catecholamine
release

33. Sedative-Hypnotics & the Treatment of Hypersomnia
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: