Skeletal muscle relaxants

Prepared By Staff Members of Pharmacology

Faculty of medicine
Nahda University
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2/2020
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 Intended learning outcomes

By the end of the lecture , the students will be able to:

§ Identify skeletal muscle relaxants,
Ø types,
Ø clinical uses
Ø mechanisms of action
Ø adverse effects
§ Realize drugs and diseases that interact with competitive
neuromuscular blockers
§ Discuss the anti-spasticity drugs : types , members & uses
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2018
 A normal motor unit contain:
the motor neuron + motor nerve + the muscle
fibers

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 Nm Nm Nm Nm

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 Nicotinic receptor
ACh ACh Ø initiating excitation contraction
Na+ Na+ coupling.
Ø The released acetylcholine is
Na+ quickly removed froa membrane
ion channel receptor which is
composed of 4 peptides (2 α, one ß,
one γ and one δ subunits).
Ø Acetylcholine combines with 2 α
subunits to open the channel
leading to depolarization of end
plate membrane. Contraction is
induced by Ca++ release from
sarcoplasmic reticulum m end plate
by enzymatic destruction by
acetylcholinesterase enzyme
α Helices forming gate
Skeletal Muscle Relaxation, Clinical Benefits
In conjugation with General Anesthetics:
• Facilitate intubation of the trachea
• Facilitate mechanical ventilation
• Optimized surgical working conditions
Skeletal Muscle Relaxants
 Drugs that block neuromuscular transmission
by acting presynaptically
Hemicholinium ↓
choline uptake
choline
Vesamicol
carrier
carrier active
acetate ACh
choline
CAT E Ca++ Effector
proteoglycan
Triethylcholine ATP organ
VIP
M

Excess Mg,
choline acetyl-transferase enzyme = CAT E lack of Ca,
local anaesthetics
botulinum toxins
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Classification
 Skeletal Muscle Relaxants
q Non-depolarizing blockade (competitive):
Neuromuscular paralysis that results from
pharmacologic antagonism at the acetylcholine receptor
of the motor end plate
q Depolarizing blockade (non-competitive):
Neuromuscular paralysis that results from persistent
depolarization of the motor end plate
q Anti-spasticity drugs : A drug that reduces abnormally
elevated muscle tone (spasm) without paralysis
 History of Skeletal Muscle Relaxants
ž Curare is a common name for various plant extract
alkaloid arrow
ž poisons originating from Central and South America.
ž • Source: Strychnos toxifera
ž • Tubocurarine name because of packing in “hollow bamboo
tubes ”
 Non-depolarizing
Competitive Neuromuscular Blockers
Pharmacokinetics
Ø All agents are given parenterally
Ø They are highly polar (quaternary ammonium) drugs
and do not cross the blood-brain barrier
Ø Most of them are metabolized in the liver and
excreted by the kidney
Ø Atracurium and Cisatracurium clearance involves
rapid spontaneous breakdown (Hofmann elimination)
Mechanism of action
Ø They prevent the action of acetylcholine at the
skeletal muscle end plate (Nm blockers )
Ø They act as competitive blockers (the blockade can be
overcome by increasing the amount of acetylcholine)
Ø Their effect is reversed by cholinesterase inhibitors
e.g. neostigmine
Ø Sugammadex is a novel antagonist of rocuronium
Ø Rocuronium has the most rapid onset (1- 2 minutes)
 The pharmacological effects
of Non-depolarizing Competitive NM blockers
1- Paralysis of the muscles
start in: Onset after 1-2 minutes
- face, limbs, trunk and Duration of paralysis is ½ - 1 hour.
- finally intercostals and diaphragm.

- Recovery is in the reverse order.

Over dose : Death is due to respiratory failure.

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 Drug Elimination Duration Histamine Ganglion M2 block
release blockade

Isoquinoline derivatives
J kidney > ½ hour ++ + ---
Tubocurarine Long acting
= curare
J kidney + + ---
Metocurine
J JJ 1/3-1/2 hour + --- ---
Atracurium Spontaneou Intermediate
s
Hofmann
elimination
10-20 minute ++ ---- -----
Mivacurium JJJJ
Plasma Shortest
cholinestera
se Short acting

Steroid derivatives
J kidney ؽ hour Moderate Block cardiac
Pancuronium muscurinic receptor (M2)
ØLong acting

JJ 1/3-1/2 hour Less cardiovascular

Vecuronium effects than
Liver, Intermediate
Rocuronium acting Pancuronium.

Others
Gallamine [Flaxedil] J kidney > ½ hour Strong Block cardiac
muscurinic receptor
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Toxicity of Competitive NM blockers:
1. Respiratory failure
2. Hypotension due to muscle paralysis and histamine release
3. Bronchospasm due to histamine release
4. Tachycardia
TTT of Respiratory failure :
1. Artificial respiration.
2. Antidode by neostigmine
- Ach action: - é M è GIT, Urinary
- é N è muscle twitches]
- direct action on skeletal ms ðð powerful muscle stimulation - CNS è no action
or edrophonium [shorter duration of action than neostigmine]
- Preceded by Atropine IV è to block the unwanted muscurinic actions
[tachycardia].
3. Anti-histaminics
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 Antagonism of Competitive NM blockers

Use ChE inhibitors such as

Because they are neostigmine,
competitive blockers, their physostigmine,
action can be reversed by edrophonium together with
increasing the atropine to protect
concentration of muscarinic receptors
endogenous ACh at the against excessive
NMJ. stimulation by increased
levels of ACh.

Sugammadex forms complex with rocuronium >

vecuronium > pancuronium which diffuse away
from the NM junction back into the circulation and
then excreted in urine.
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Drug interactions:
neuromuscular blockade is potentiated and prolonged by
Ø inhaled anesthetics,
Ø aminoglycoside antibiotics
Ø antiarrhythmic drugs
Ø Myasthenia gravis
Ø Advanced age
Ø Liver disease
 Depolarizing Neuromuscular Blockers
Pharmacokinetics
q Succinylcholine is given parenterally,
ž a quaternary amine.

q Succinylcholine is metabolized by a cholinesterase

(butyrylcholinesterase or pseudocholinesterase) in the liver and
plasma
Succinylcholine -----succinyl-monocholine---- succinic acid + choline

q If given intravenously, Succinylcholine onset is 30-60 seconds

and duration is 4-6 minutes

q Duration may be prolonged in patients with genetic variants of

plasma cholinesterase that metabolize succinylcholine very slowly
Mechanism of action
q Succinylcholineacts like a nicotinic agonist and
depolarizes the neuromuscular end plate

q Because tension cannot be maintained in skeletal

muscle without periodic repolarization and
depolarization of the end plate, continuous
depolarization results in muscle relaxation and
paralysis
 Action:

Ø It produces depolarization, which is not followed by

repolarization (phase I block)
Ø so produces initial muscle fasciculation
Ø followed by paralysis.
This is followed by phase II block (desensitization block) which is
similar to non-depolarizing block.
phase I Phase II
u -Mechanism Depolarization Desensitization
v -Anti-ch.E. Potentiation Antagonism
Uses: for endotracheal intubation
Toxicity of succinylcholine
ž Respiratory Failure
Treated with
1- Artificial respiration
2- Fresh blood transfusion
q Bradycardia caused by succinylcholine (Activates cardiac
muscarinic receptors)
q Hyperkalemia caused by succinylcholine (especially in
patients with burns)
q Muscle pain: caused by succinylcholine (it is a common
postoperative complaint)
q Increase intraocular pressure & Intragastric pressure
 Malignant hyperthermia in susceptible person.
Ø A hereditary disease,
Ø which may occur in response to general anesthesia or
succinylcholine.
Ø There is inability of sarcoplasmic reticulum to
sequester calcium ( defect in Ryanodine receptors)
Ø resulting in muscle contraction, lactic acid
production and increased body temperature due to
uncoupling of oxidative phosphorylation.
Ø Treatment : I.V. dantroline, cooling and correct
acidosis
In case of Malignant hyperthermia in susceptible
person.

Anticholinesterases
will prolong its duration and increase the
toxicity.
 N.B. Succinylcholine apnea may occur as a result of a
defect in pseudocholinesterase
due to

Ø Congenital enzyme defect (idiosyncracy),

Ø Liver disease or Malnutrition: decrease synthesis
Ø Anticholinesterase administration:
Ø Organo-phosphorus poisoning
 Non-depolarizing Depolarizing

Example Curare Succinylcholine

Mechanism Compete withA.ch. Maintained depolarization
Nature Antagonist Partial agonist
Effect Paralysis without Twitches paralysis
twitches
Neostigmine: Antagonize Potentiated
 Spasticity
- Spasticity can be described as involuntary muscle
stiffness.
- Spasticity mostly occurs in disorders of the central
nervous system ,stroke , cerebralpalsy
Muscle Spasm
- sudden involuntary contraction of one or more -
muscle groups
- usually an acute condition associated with -
muscle strain (partial tear of a muscle) or sprain
(partial or complete rupture of a ligament).
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 Anti-spasticity DRUGS
q Certain chronic diseases of the CNS e.g. cerebral stroke
are associated with abnormally high reflex activity in the
neuronal pathways that control skeletal muscle the result is
painful spasm
q In other circumstances, acute injury or inflammation of
muscle leads to spasm and pain
q The goal of therapy in both chronic and acute conditions is
reduction of excessive skeletal muscle tone without
reduction of strength
q Reduced spasm results in reduction of pain and improved
mobility
Central muscle relaxants

Baclofen [lioresal]
- is an agonist at GABAB
-
orally active as a muscle relaxant and
has been
- - used in the treatment of rigidity and
Diazepam
spasticity of cerebral palsy.
Adverse effects include
- Benzodiazepines drowsiness;
facilitate the action
however, patients
of GABA become
in the CNS.tolerant
to it
- Diazepam acts Bz receptors on
- Increased seizure activity in epileptic
GABAsudden
patients due to baclofen A withdrawel.
- - -Diazepam produces
Therefore, withdrawal fromsedation at the
baclofen must
3
Issue 1/ 2018
doses required
be done to reduce
very slowly. muscle 40
ž Tizanidine (Sirdalud, Roysan)
- has significant alpha 2-adrenoceptor agonist effects.
- Adverse effects: drowsiness, hypotension and dry mouth.
ž Gabapentin (Fanatrex, Gabarone)
- Gabapentin is an antiepileptic drug used as a spasmolytic
agent in multiple sclerosis.

ž Pregabaline ( Lyrica) is useful in relieving painful disorders

that involve a muscle spasm component.

ž Progabide (Gabrene)
- Progabide is a GABAA and GABAB agonist
Glycine is an inhibitory amino.
ž Cyclobenzaprine (Flexeril) (TCA) Increase NE by decrease its
uptake
- Inhibition of muscle stretch reflex in spinal cord
- Treat acute spasm due to muscle injury or inflammation
- Hepatic metabolism, duration, ~4–6 h
- Toxicities: Strong antimuscarinic effects

ž Orphenadrine (Norflex, Norgesic), chlorzoxazone (Myolgin,

Paraflex):
Like cyclobenzaprine with varying degrees of anti-muscarinic
effect.
 Direct muscle relaxants
The ryanodine receptors (RyRs) are found on intracellular
Ca2+ storage/release organelles.
Ryanodine receptors mediate the release of calcium ions
from the sarcoplasmic reticulum, an essential step in muscle
contraction.

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 Ø Dantrolene blocks the ryanodine receptor , and
decreasing intracellular calcium concentration.

► used oral or IV
► used in ttt of malignant hyperthermia
►S.E: drowsiness- diarrhea- liver damage 1%

Dantroline
Direct relaxant
Drowsiness
Diarrhea
Damage of liver
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