Muscle Relaxants: Mechanisms and Applications
undefined
Centrally active
Centrally active
•
Baclofen
Baclofen
•
Benzodiazepines:
Benzodiazepines:
•
Tetrazepam
Tetrazepam
•
Diazepam
Diazepam
•
Clonazepam
Clonazepam
•
Thiocolchicoside
Thiocolchicoside
•
Mephenoxalone
Mephenoxalone
•
Tizanidine
Tizanidine
•
Guaifenesin
Guaifenesin
•
Orphenadrine
Orphenadrine
Peripherally active
Peripherally active
•
Presynaptically active:
Presynaptically active:
botulinum toxin
botulinum toxin
•
Postsynaptically active:
Postsynaptically active:
•
Depolarizing blocking
Depolarizing blocking
agents
agents
(suxamethonium)
(suxamethonium)
•
Non-depolarizing
Non-depolarizing
blocking agents
blocking agents
(atracurium, vecuronium,
(atracurium, vecuronium,
pancuronium etc.)
pancuronium etc.)
Mechanism of action
Mechanism of action
•
A
A
t
t
t
t
e
e
n
n
u
u
a
a
t
t
e
e
t
t
r
r
a
a
n
n
s
s
m
m
i
i
s
s
s
s
i
i
o
o
n
n
o
o
f
f
m
m
o
o
t
t
o
o
r
r
i
i
c
c
i
i
m
m
p
p
u
u
l
l
s
s
e
e
s
s
i
i
n
n
s
s
p
p
i
i
n
n
a
a
l
l
c
c
o
o
r
r
d
d
a
a
n
n
d
d
C
C
N
N
S
S
•
Decrease muscle tone
Decrease muscle tone
, do not influence
, do not influence
intentional
intentional
contractions
contractions
→ weaker muscle relaxant activity
→ weaker muscle relaxant activity
•
A
A
E
E
:
:
d
d
e
e
p
p
r
r
e
e
s
s
s
s
i
i
o
o
n
n
o
o
f
f
C
C
N
N
S
S
→
→
s
s
e
e
d
d
a
a
t
t
i
i
o
o
n
n
,
,
s
s
o
o
m
m
n
n
o
o
l
l
e
e
n
n
c
c
e
e
,
,
c
c
o
o
n
n
f
f
u
u
s
s
i
i
o
o
n
n
…
…
•
A
A
c
c
u
u
t
t
e
e
a
a
n
n
d
d
c
c
h
h
r
r
o
o
n
n
i
i
c
c
p
p
a
a
i
i
n
n
f
f
u
u
l
l
s
s
p
p
a
a
s
s
m
m
s
s
–
–
p
p
.
.
o
o
.
.
,
,
p
p
a
a
r
r
e
e
n
n
t
t
e
e
r
r
a
a
l
l
l
l
y
y
•
Spastic
Spastic
rheumatism
rheumatism
•
Damage of
Damage of
n. ischiadicus
n. ischiadicus
(spasms of deep
(spasms of deep
paravertebral muscles, compressions in intervertebral
paravertebral muscles, compressions in intervertebral
space etc.)
space etc.)
•
Spastic disorders
Spastic disorders
associated with
associated with
cerebral palsy
cerebral palsy
,
,
multiple sclerosis
multiple sclerosis
,
,
injuries
injuries
of brain or spine…
of brain or spine…
Mechanism of action:
Mechanism of action:
•
I
I
n
n
c
c
r
r
e
e
a
a
s
s
e
e
e
e
f
f
f
f
e
e
c
c
t
t
s
s
o
o
f
f
i
i
n
n
h
h
i
i
b
b
i
i
t
t
o
o
r
r
y
y
n
n
e
e
u
u
r
r
o
o
t
t
r
r
a
a
n
n
s
s
m
m
i
i
t
t
t
t
e
e
r
r
γ
γ
-
-
a
a
m
m
i
i
n
n
o
o
b
b
u
u
t
t
y
y
r
r
i
i
c
c
a
a
c
c
i
i
d
d
(
(
G
G
A
A
B
B
A
A
)
)
i
i
n
n
C
C
N
N
S
S
a
a
n
n
d
d
s
s
p
p
i
i
n
n
e
e
c
c
o
o
r
r
d
d
B
B
a
a
c
c
l
l
o
o
f
f
e
e
n
n
•
Attenuates the activation of motor neurons in the
Attenuates the activation of motor neurons in the
spine cord
spine cord
•
GABA
GABA
B
B
receptor agonist
receptor agonist
•
Multiple sclerosis, cerebral palsy, injuries of brain and
Multiple sclerosis, cerebral palsy, injuries of brain and
spinal cord…
spinal cord…
•
Baclofen
Baclofen
•
Benzodiazepines:
Benzodiazepines:
•
Tetrazepam
Tetrazepam
•
Diazepam
Diazepam
•
Clonazepam
Clonazepam
•
Thiocolchicoside
Thiocolchicoside
•
Mephenoxalone
Mephenoxalone
•
Tizanidine
Tizanidine
•
Guaifenesin
Guaifenesin
•
Orphenadrine
Orphenadrine
Psychiatric medication
Psychiatric medication
with 5 effects:
with 5 effects:
Anxiolytic
Anxiolytic
Hypnotic
Hypnotic
M
M
u
u
s
s
c
c
l
l
e
e
r
r
e
e
l
l
a
a
x
x
a
a
n
n
t
t
Anticonvulsant
Anticonvulsant
Amnestic
Amnestic
Low doses have
Low doses have
expectorant
expectorant
effect,
effect,
Higher doses have
Higher doses have
muscle relaxant
muscle relaxant
and
and
anxiolytic
anxiolytic
effect
effect
M
M
o
o
A
A
:
:
E
E
n
n
h
h
a
a
n
n
c
c
e
e
o
o
f
f
G
G
A
A
B
B
A
A
e
e
r
r
g
g
i
i
c
c
transmission – GABA
transmission – GABA
A
A
receptors
receptors
Centrally active
Centrally active
•
Baclofen
Baclofen
•
Benzodiazepines:
Benzodiazepines:
•
Tetrazepam
Tetrazepam
•
Diazepam
Diazepam
•
Clonazepam
Clonazepam
•
Thiocolchicoside
Thiocolchicoside
•
Mephenoxalone
Mephenoxalone
•
Tizanidine
Tizanidine
•
Guaifenesin
Guaifenesin
•
Orphenadrine
Orphenadrine
Peripherally active
Peripherally active
•
Presynaptically active:
Presynaptically active:
botulinum toxin
botulinum toxin
•
Postsynaptically active:
Postsynaptically active:
•
Depolarizing blocking
Depolarizing blocking
agents
agents
(suxamethonium)
(suxamethonium)
•
Non-depolarizing
Non-depolarizing
blocking agents
blocking agents
(atracurium, vecuronium,
(atracurium, vecuronium,
pancuronium etc.)
pancuronium etc.)
Mechanism of action
Mechanism of action
1.) Presynaptically active agents
1.) Presynaptically active agents
–
Decrease ACh release
Decrease ACh release
–
B
B
o
o
t
t
u
u
l
l
i
i
n
n
u
u
m
m
t
t
o
o
x
x
i
i
n
n
2.) Postsynaptically active agents
2.) Postsynaptically active agents
–
Act on nicotinic receptors (N
Act on nicotinic receptors (N
M
M
)
)
•
Non-depolarizing
Non-depolarizing
•
Depolarizing
Depolarizing
•
Firstly described in 15
Firstly described in 15
th
th
century
century
by european explorers in S. America
by european explorers in S. America
•
Used by natives as arrow poisons
Used by natives as arrow poisons
•
Tubocurarine
Tubocurarine
– natural alkaloid
– natural alkaloid
•
Competitive
Competitive
N
N
M
M
receptors antagonists
receptors antagonists
•
A
A
E
E
:
:
r
r
e
e
l
l
e
e
a
a
s
s
e
e
o
o
f
f
h
h
i
i
s
s
t
t
a
a
m
m
i
i
n
n
e
e
(
(
b
b
r
r
o
o
n
n
c
c
h
h
o
o
c
c
o
o
n
n
s
s
t
t
r
r
i
i
c
c
t
t
i
i
o
o
n
n
,
,
h
h
y
y
p
p
o
o
t
t
e
e
n
n
s
s
i
i
o
o
n
n
,
,
s
s
y
y
n
n
c
c
o
o
p
p
e
e
–
–
f
f
a
a
i
i
n
n
t
t
i
i
n
n
g
g
)
)
•
Progressive relaxation:
Progressive relaxation:
eye muscles
eye muscles
→
→
muscles of
muscles of
mastication
mastication
→
→
neck and limbs
neck and limbs
→
→
trunk
trunk
→ diaphragm
→ diaphragm
•
Administered parenterally
Administered parenterally
•
E
E
f
f
f
f
e
e
c
c
t
t
w
w
e
e
a
a
k
k
e
e
n
n
s
s
a
a
n
n
d
d
i
i
s
s
r
r
e
e
v
v
e
e
r
r
s
s
i
i
b
b
l
l
e
e
–
–
c
c
o
o
m
m
p
p
e
e
t
t
i
i
t
t
i
i
o
o
n
n
o
o
f
f
r
r
e
e
c
c
e
e
p
p
t
t
o
o
r
r
s
s
•
With long effect (1-2 h):
With long effect (1-2 h):
tubocurarine, pancuronium,
tubocurarine, pancuronium,
pipecuronium, vecuronium
pipecuronium, vecuronium
•
With short efect (10-30 min):
With short efect (10-30 min):
alcuronium, atracurium
alcuronium, atracurium
•
Surgery – muscle relaxation
Surgery – muscle relaxation
in the operating field
in the operating field
, or
, or
before
before
mechanical ventilation
mechanical ventilation
(tracheal intubation)
(tracheal intubation)
•
Ovedosing:
Ovedosing:
antidote
antidote
=
=
acetylcholinesterase inhibitors
acetylcholinesterase inhibitors
(neostigmine, pyridostigmine…)
(neostigmine, pyridostigmine…)
•
N
N
M
M
receptor agonists
receptor agonists
•
O
O
p
p
e
e
n
n
N
N
a
a
+
+
c
c
h
h
a
a
n
n
n
n
e
e
l
l
s
s
→
→
c
c
a
a
u
u
s
s
e
e
l
l
o
o
n
n
g
g
-
-
t
t
e
e
r
r
m
m
d
d
e
e
p
p
o
o
l
l
a
a
r
r
i
i
z
z
a
a
t
t
i
i
o
o
n
n
→
→
r
r
e
e
s
s
i
i
s
s
t
t
a
a
n
n
c
c
y
y
t
t
o
o
a
a
c
c
t
t
i
i
v
v
a
a
t
t
i
i
o
o
n
n
b
b
y
y
A
A
C
C
h
h
=
=
d
d
e
e
p
p
o
o
l
l
a
a
r
r
i
i
z
z
a
a
t
t
i
i
o
o
n
n
b
b
l
l
o
o
c
c
k
k
a
a
d
d
e
e
•
Remain on the receptor for a longer time,
Remain on the receptor for a longer time,
resistant to AChE
resistant to AChE
•
Fasciculation
Fasciculation
(muscle twitches)
(muscle twitches)
→
→
muscle relaxation
muscle relaxation
(paralysis)
(paralysis)
•
A
A
E
E
:
:
c
c
a
a
r
r
d
d
i
i
a
a
c
c
a
a
r
r
r
r
h
h
y
y
t
t
h
h
m
m
i
i
a
a
s
s
,
,
h
h
y
y
p
p
e
e
r
r
k
k
a
a
l
l
e
e
m
m
i
i
a
a
,
,
i
i
n
n
c
c
r
r
e
e
a
a
s
s
e
e
o
o
f
f
i
i
n
n
t
t
r
r
a
a
o
o
c
c
u
u
l
l
a
a
r
r
p
p
r
r
e
e
s
s
s
s
u
u
r
r
e
e
(
(
I
I
O
O
P
P
)
)
+
+
m
m
a
a
l
l
i
i
g
g
n
n
a
a
n
n
t
t
h
h
y
y
p
p
e
e
r
r
t
t
h
h
e
e
r
r
m
m
i
i
a
a
!
!
•
Decamethonium
Decamethonium
•
Suxamethonium (succinylcholine)
Suxamethonium (succinylcholine)
•
Short-term
Short-term
muscle relaxation (3-5 min)
muscle relaxation (3-5 min)
•
Mechanical ventilation
Mechanical ventilation
(tracheal intubation)
(tracheal intubation)
•
Orthopedic manipulations
Orthopedic manipulations
– repositiong of
– repositiong of
dislocated joint, fractures
dislocated joint, fractures
•
Rare AE of
Rare AE of
depolarizing MR
depolarizing MR
and/or volatile
and/or volatile
general
general
anesthetics
anesthetics
Mechanisms:
Mechanisms:
•
D
D
e
e
f
f
e
e
c
c
t
t
o
o
f
f
R
R
Y
Y
R
R
r
r
e
e
c
c
e
e
p
p
t
t
o
o
r
r
–
–
c
c
o
o
n
n
t
t
r
r
o
o
l
l
s
s
r
r
e
e
l
l
e
e
a
a
s
s
e
e
o
o
f
f
C
C
a
a
2
2
+
+
f
f
r
r
o
o
m
m
s
s
a
a
r
r
c
c
o
o
p
p
l
l
a
a
s
s
m
m
i
i
c
c
r
r
e
e
t
t
i
i
c
c
u
u
l
l
u
u
m
m
•
Increase of Ca
Increase of Ca
2+
2+
in myocyte →
in myocyte →
uncontrolled
uncontrolled
increase
increase
of contractions, aerobic/anaerobic metabolism
of contractions, aerobic/anaerobic metabolism
•
Symptoms:
Symptoms:
hyperthermia
hyperthermia
,
,
cramps
cramps
and
and
rigidity
rigidity
,
,
↑ heart rate
↑ heart rate
and breathing, cyanosis,
and breathing, cyanosis,
lactate acidosis
lactate acidosis
,
,
rhabdomyolysis...
rhabdomyolysis...
•
60 % of untreated cases are
60 % of untreated cases are
lethal
lethal
(5 % of treated)
(5 % of treated)
•
Therapy:
Therapy:
dantrolene, intensive cooling
dantrolene, intensive cooling
•
Peripherally active muscle relaxant
Peripherally active muscle relaxant
•
Blocks the release of Ca
Blocks the release of Ca
2+
2+
from sarcoplasmic
from sarcoplasmic
reticulum by interaction with RYR
reticulum by interaction with RYR
•
Do not affect smooth muscle and myocardium
Do not affect smooth muscle and myocardium
•
Malignant hyperthermia
Malignant hyperthermia
•
Spastic disorders
Spastic disorders
associated with
associated with
spinal cord injury,
spinal cord injury,
stroke, cerebral palsy and
stroke, cerebral palsy and
multiple sclerosis
multiple sclerosis
‒
Advantage: no CNS depression
Advantage: no CNS depression
Muscle relaxants play a crucial role in managing conditions like spasticity and painful spasms. Centrally active agents modulate motor impulses in the spinal cord and CNS, while peripherally active agents target neuromuscular junctions. Baclofen, benzodiazepines, and other specific drugs serve various purposes in different conditions. By enhancing GABAergic transmission, these medications provide relief from muscle tension and spasms in patients with conditions such as multiple sclerosis and cerebral palsy.
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Overview of Muscle Relaxants Mechanism of action Centrally active Peripherally active Baclofen Benzodiazepines: Tetrazepam Diazepam Clonazepam Thiocolchicoside Mephenoxalone Tizanidine Guaifenesin Orphenadrine Presynaptically active: botulinum toxin Postsynaptically active: Depolarizing blocking agents (suxamethonium) Non-depolarizing blocking agents (atracurium, vecuronium, pancuronium etc.)
Centrally Active Agents Attenuate transmission of motoric impulses in spinal cord and CNS Decrease muscle tone, do not influence intentional contractions weaker muscle relaxant activity AE: depression of CNS sedation, somnolence, confusion Acute and chronic painful spasms p.o., parenterally Spastic rheumatism Damage of n. ischiadicus (spasms of deep paravertebral muscles, compressions in intervertebral space etc.) Spastic disorders associated with cerebral palsy, multiple sclerosis, injuries of brain or spine
Centrally Active Agents Mechanism of action: Increase effects of inhibitory neurotransmitter -aminobutyric acid (GABA) in CNS and spine cord Baclofen Attenuates the activation of motor neurons in the spine cord GABABreceptor agonist Multiple sclerosis, cerebral palsy, injuries of brain and spinal cord
Centrally Active Agents MoA: Enhance of GABAergic transmission GABAAreceptors Baclofen Benzodiazepines: Tetrazepam Diazepam Clonazepam Thiocolchicoside Mephenoxalone Tizanidine Guaifenesin Orphenadrine Psychiatric medication with 5 effects: Anxiolytic Hypnotic Muscle relaxant Anticonvulsant Amnestic Low doses have expectorant effect, Higher doses have muscle relaxant and anxiolytic effect
Overview of Muscle Relaxants Mechanism of action Centrally active Peripherally active Baclofen Benzodiazepines: Tetrazepam Diazepam Clonazepam Thiocolchicoside Mephenoxalone Tizanidine Guaifenesin Orphenadrine Presynaptically active: botulinum toxin Postsynaptically active: Depolarizing blocking agents (suxamethonium) Non-depolarizing blocking agents (atracurium, vecuronium, pancuronium etc.)
Peripherally Active Agents 1.) Presynaptically active agents Decrease ACh release Botulinum toxin 2.) Postsynaptically active agents Act on nicotinic receptors (NM) Non-depolarizing Depolarizing
Non-depolarizing agents Firstly described in 15thcentury by european explorers in S. America Used by natives as arrow poisons Tubocurarine natural alkaloid Competitive NM receptors antagonists AE: release of histamine (bronchoconstriction, hypotension, syncope fainting) Progressive relaxation: eye muscles muscles of mastication neck and limbs trunk diaphragm Administered parenterally Effect weakens and is reversible competition of receptors
Non-depolarizing Agents With long effect (1-2 h): tubocurarine, pancuronium, pipecuronium, vecuronium With short efect (10-30 min): alcuronium, atracurium Surgery muscle relaxation in the operating field, or before mechanical ventilation (tracheal intubation) Ovedosing: antidote = acetylcholinesterase inhibitors (neostigmine, pyridostigmine )
Depolarizing Agents NM receptor agonists Open Na+ channels cause long-term depolarization resistancy to activation by ACh = depolarization blockade Remain on the receptor for a longer time, resistant to AChE Fasciculation (muscle twitches) muscle relaxation (paralysis) AE: cardiac arrhythmias, hyperkalemia, increase of intraocular pressure (IOP) + malignant hyperthermia !
Depolarizing Agents Decamethonium Suxamethonium (succinylcholine) Short-term muscle relaxation (3-5 min) Mechanical ventilation (tracheal intubation) Orthopedic manipulations repositiong of dislocated joint, fractures
Malignant Hyperthermia Rare AE of depolarizing MR and/or volatile general anesthetics Mechanisms: Defect of RYR receptor controls release of Ca2+ from sarcoplasmic reticulum Increase of Ca2+in myocyte uncontrolled increase of contractions, aerobic/anaerobic metabolism Symptoms: hyperthermia, cramps and rigidity, heart rate and breathing, cyanosis, lactate acidosis, rhabdomyolysis... 60 % of untreated cases are lethal (5 % of treated) Therapy: dantrolene, intensive cooling
Dantrolene Peripherally active muscle relaxant Blocks the release of Ca2+from sarcoplasmic reticulum by interaction with RYR Do not affect smooth muscle and myocardium Malignant hyperthermia Spastic disorders associated with spinal cord injury, stroke, cerebral palsy and multiple sclerosis Advantage: no CNS depression
