Beruflich Dokumente
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Learning
Objectives
Understand
the
role
of
GABA
in
the
CNS
List
drugs
that
aect
the
GABA
system
and
their
physiologic
and
clinical
eects
Dierentiate
muscle
relaxants
that
work
on
the
motor
end
plate
vs.
centrally-acting
agents
Understand
the
common
side-eects
of
drugs
in
the
sedative-hypnotic
and
skeletal
muscle
relaxant
class
Dene
the
terms
tolerance,
dependence,
and
addiction
1/25/11
Sedative-hypnotics
Alcohol
Ethanol
Benzodiazepines
Alprazolam,
clonazepam,
diazepam,
lorazepam,
temazepam
Barbiturates
Phenobarbital,
secobarbital
Newer
hypnotics
Zolpidem,
zaleplon,
eszopliclone
Centrally-acting
spasmolytics
Baclofen,
cyclobenzaprine,
carisoprodol,
metaxalone,
methocarbamol,
tizanidine
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Recommended
Reading
Katzung
BG,
et
al.
(eds)
Basic
and
Clinical
Pharmacology,
11th
edition
Chapter
22:
Sedative-hypnotic
drugs
Chapter
23:
The
alcohols
Chapter
27:
Skeletal
muscle
relaxants
Sedative-Hypnotics
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Classication
Sedative-hypnotics
are
so
named
because
they
reduce
anxiety
and
cause
drowsiness
Sedatives
or
anxiolytics
exert
a
calming
eect
Hypnotics
produce
drowsiness
and
encourage
onset
and
maintenance
of
sleep
Sometimes
referred
to
as
central
nervous
system
(CNS)
depressants
Depressant
activity
is
graded
and
dose-dependent
(see
graphic
next
slide)
Most exert their pharmacologic eect via action on gamma-amino butyric acid (GABA) receptors in the CNS
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GABA
Major
inhibitory
neurotransmitter
GABA-releasing
neurons
found
throughout
the
CNS
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Alcohol
Ethyl
alcohol
(ethanol)
is
rapidly
absorbed
from
the
GI
tract
Other
forms
of
alcohol:
Methanol
Isopropryl
alcohol
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Ethanol
Two
major
pharmacologic
eects
in
the
CNS:
Enhances
the
action
of
GABA
at
GABAA
receptors
Inhibits
the
ability
of
glutamate
to
open
cation
channels
associated
with
NMDA
receptors
Other
eects:
Heart
depression
of
myocardial
contractility
Smooth
muscle
vasodilation
in
the
periphery
Clinical
uses:
Self-treatment
of
anxiety,
depression,
essential
tremor
Benzodiazepines
Group
of
chemically-similar
compounds
used
as
anxiolytics
and
hypnotics
Bind
with
GABAA
receptors
to
enhance
GABA-ergic
activity
Undergo
hepatic
metabolism
Phase
I
(oxidation)
Some
have
active
metabolites
with
long
half-lives
Phase II (conjugation)
Intermediate-acting
Clorazepam,
lorazepam
Long-acting
Diazepam,
urazepam
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Barbiturates
Older
agents,
no
longer
commonly
used
as
sedative-hypnotics
Long
half-lives
can
lead
to
accumulation
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Non-BZ
Hypnotics
A
group
of
newer
agents
introduced
in
the
past
decade
Bind
to
GABAA
receptor
at
dierent
site
than
BZs
Rapidly
absorbed,
few
metabolites,
short-half
lives
Heavily
marketed,
commonly
prescribed
sleep
aids
(Ambien,
Sonata,
Lunesta)
Flumazenil
Antagonist
of
benzodiazepines,
eszopiclone,
zaleplon,
zolpidem
Doesnt
block
actions
of
ethanol
or
barbiturates
May
be
used
in
overdose
management
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Physiologic
Eects
Sedation
Most
agents
reduce
anxiety
at
low
doses
Beyond
simply
causing
drowsiness
Hypnosis
Will
induce
sleep
at
higher
doses
Decrease
sleep
latency
Increase
stage
2
NREM
Decrease
REM
sleep
Decrease
stage
4
NREM
10
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Physiologic
Eects
Anesthesia
High
doses
of
sedative- hypnotics
can
depress
the
CNS
to
the
point
of
general
anesthesia
Barbiturates
have
favorable
characteristics
BZs
are
used
IV
in
combo
with
other
agents
Anticonvulsant
Both
BZs
and
barbiturates
inhibit
the
spread
of
epileptiform
electrical
activity
Agents
used:
Phenobarbital
Clonazepam
Diazepam
Lorazepam
Physiologic
Eects
Muscle
Relaxation
BZs
and
meprobamate
have
inhibitory
eects
on
polysynaptic
reexes
May
also
depress
transmission
at
skeletal
neuromuscular
junctions
Agents:
Clonazepam
Diazepam
At
hypnotic
doses,
these
agents
produce
eects
on
respiration
similar
to
natural
sleep
At
higher
doses
or
in
respiratory/cardiac
compromised
patients
may
induce:
Respiratory
depression
Circulatory
collapse
Respiratory/Cardiac Eects
11
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Abuse
Potential
Most
sedative-hypnotics
can
be
misused
and
may
be
compulsively
abused
Important
denitions:
Tolerance:
the
need
for
higher
doses
to
produce
response
Physical
dependence:
withdrawal
symptoms
elicited
upon
discontinuation
Addiction:
use
despite
harm;
psychological
craving
and
display
of
addictive
behaviors
The BZs, barbiturates, and non-BZ agents (i.e. zolpidem) are Schedule IV Controlled Substances in the US
12
1/25/11
Other
Agents
Ramelteon
(Rozerem)
Agonist
at
MT1
and
MT2
(melatonin
receptors)
No
direct
eects
on
GABA
Reduces
sleep
latency,
but
does
not
appear
to
aect
other
aspects
of
sleep
architecture
May
decrease
testosterone
and
increase
prolactin
levels
Not
a
controlled
substance
Buspirone
(Buspar)
Reduces
anxiety
without
causing
marked
sedation
or
euphoria
Acts
via
serotonin
and
dopamine
receptors;
no
direct
GABA
activity
Not
appropriate
for
acute
anxiety
states
Does
not
potentiate
impairment
caused
by
other
sedative-hypnotics
Antidepressants
Tricyclic
antidepressants:
amitriptyline
(Elavil)
Trazodone
(Desyrel)
SSRIs:
uoxetine
(Prozac),
sertraline
(Zoloft)
Antipsychotics
Quetiapine
13
1/25/11
Centrally-acting
relaxants
Benzodiazepines
Baclofen,
Cyclobenzaprine,
Carisoprodol,
Methocarbamol
14
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History
Curare
is
a
poison
derived
from
South
American
plants
Natives
used
it
as
arrow
poison
in
hunting
Produces
skeletal
and
respiratory
muscle
paralysis
Active
compound
is
d- tubocurarine
Helped
in
our
understanding
of
neuromuscular
function
15
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Neuromuscular Function
Example: succinylcholine
16
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Botulinum
Toxin
Blockade
of
ACh
activity
at
the
motor
end
plate
may
also
occur
if
ACh
is
not
released
pre- synaptically
Result
is
paralysis
Botulism
BoTox
Cosmetic
Other
uses
Tracheal
intubation
Via
relaxation
of
pharyngeal
and
laryngeal
muscles
allows
for
placement
of
tracheal
tubes
Control
of
ventilation
Administered
in
ICU
to
patients
with
ventilatory
failure
Allows
for
adequate
gas
exchange
Treatment
of
convulsions
Occasionally
used
for
attenuate
peripheral
manifestations
of
seizure
activity
17
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Spasmolytic
Drugs
Two
major
clinical
classications:
Drugs
for
the
treatment
of
spasticity
Drugs
for
the
treatment
of
muscle
spasms
Spasticity
Characterized
by
exaggerated
muscle
stretch
reex
Abnormal
reex
activity
is
velocity
dependent,
with
rapid
lengthening
of
the
muscle
causing
a
strong
contraction
in
the
stretched
muscle
Occurs
when
supra-spinal
control
is
lost
because
of
damage
to
or
a
lesion
on
the
spinal
cord/brain
Causes
include:
Cerebrovascular
accident
(CVA),
cerebral
palsy
(CP),
multiple
sclerosis
(MS),
or
spinal/head
trauma
18
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Spasticity
Often
composed
of
the
following
triad:
Painful
mass
muscle
spasms
Rigid
posturing
of
limbs
Increased
reexes
http://www.comawakening.com/spasticity.html
Muscle
Spasms
Increased
tension
in
skeletal
muscle
following
certain
musculoskeletal
injuries
and/or
inammation,
such
as
with
muscle
strains
Muscle
tension
is
involuntary,
so
the
patient
is
unable
to
relax
the
muscle
A
loop
is
created
between
nociceptive
input
from
damaged
tissue
and
motor
neurons
controlling
the
muscle
Results
in
painful,
tonic
contraction
of
the
muscle
Upper
motor
neurons
are
NOT
involved
May
occur
in
patients
with
chronic
low
back
pain
19
1/25/11
Most recommendations support the short-term (< 3 weeks) use of SMRs in combination with NSAIDs or APAP (not opioids) for musculoskeletal conditions
MOA:
decrease
polysynaptic
reex
activity
in
the
spinal
cord
and
inhibit
alpha
motor
neuron
excitability
Baclofen
blocks
pre-
and
post-synaptic
GABAB
receptors
Dantrolene
directly
inhibits
skeletal
muscle
contraction
Tizanidine
agonist
at
central
alpha-2
receptors
20
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Baclofen
Brand
name:
Lioresal
(generic
available)
Structural
analog
of
gamma-amino
butyric
acid
(GABA)
Acts
via
GABAB
receptors
Results
in
hyperpolarization
and
reduced
calcium
inux
Chemical
structure
of
baclofen
Intrathecal
Baclofen
Most
often
dosed
orally,
but
may
be
delivered
directly
into
the
subarachnoid
space
at
dierent
levels
of
the
spinal
cord
Patients
with
severe,
intractable
spasticity
Catheter
is
usually
implanted
surgically
and
attached
to
a
programmable
pump
Pump
may
also
be
implanted
SQ
http://cuidatucorazon.com
21
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Tizanidine
Brand
name:
Zanaex
Classied
as
an
alpha-2
adrenergic
agonist
Pharmacologic
studies
indicate
1/10
to
1/50
the
potency
of
clonidine
in
blood
pressure
lowering
ability
Use
for
spasticity
from:
Multiple
sclerosis
Spinal
cord
lesions
Post
CVA
Dantrolene
Sodium
Brand
name:
Dantrium
The
only
SMR
that
exerts
its
eects
directly
on
the
skeletal
muscle
cell
Impairs
the
release
of
calcium
from
the
sarcoplasmic
reticulum
during
excitation
Attenuates
muscle
contraction
and
enhances
relaxation
22
1/25/11
Dantrolene
Used
for
severe
spasticity
resulting
from:
Traumatic
spinal
cord
injury
Advanced
MS
Cerebral
palsy
Stroke
23
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Carisoprodol
Toxicity
After
oral
administration,
carisoprodol
is
metabolized
in
the
liver
to
several
biologically
active
metabolites,
including
meprobamate
Meprobamate
alone
is
a
sedative-hypnotic
formerly
available
under
the
trade
names
Miltown
or
Equanil
In
the
1960s,
meprobamate
had
a
street
value
and
was
sold
as
Uncle
Milties
or
Bams
Pharmacologically,
meprobamate
is
related
to
the
barbiturates
and
is
a
schedule
IV
controlled
substance
Abusers of carisoprodol demonstrate signs of tolerance and reportedly suer withdrawal symptoms of anxiety, tremors, and in some cases, hallucinations or seizures Acute overdose may result in CNS depression, respiratory depression, coma and death
Cyclobenzaprine
Brand
name:
Flexeril
(generic
available)
Most
commonly
prescribed
SMR
with
similar
indications
and
mechanism
of
action
as
other
members
of
its
class
Structurally
related
to
tricyclic
antidepressants
(TCAs)
Cyclobenzaprine
Amitriptyline
24
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Summary
Sedative-hypnotics
include
medications
such
as
benzodiazepines,
barbiturates,
and
non-BZ
GABAergic
agents
Used
for
anxiety,
sleep,
convulsions,
or
muscle
relaxants
BZs
dier
in
half-life
&
active
metabolites
Non-BZs
used
for
sleep
(zolpidem,
zaleplon)
Skeletal
muscle
relaxants
are
a
group
of
drugs
that
include
neuromuscular
blockers
(act
at
motor
end
plate),
centrally
acting
agents
(work
at
spinal
cord
or
brain
stem),
and
dantrolene
(directly
on
skeletal
muscle)
Used
for
spasticity
or
muscle
spasms
25