Skeletal Muscle Relaxants
Dr. Kaukab Azim
Drug List
Neuromuscular Blockers
Non-depolarizing
Blockers
Tubocurarine
Depolarizing
Blockers
Spasmolytic Drugs
Central
Peripheral
Baclofen
Dantrolene
Mivacurium
Tizanidine
Botulinum Toxin
Cisatracurium
Gabapentin
Succinylcholine
Benzodiazepines
* More drugs are mentioned in other slides
Muscle
Nerve
Nerve
1.
2.
3.
4.
5.
Presynaptic terminal
Sarcolemma
Synaptic vesicles
Acetylcholine receptors
Mitchondrion
Na+
Neuromuscular
Blocking Drugs
Competitive
Tubocurarine
Gallamine
Pancuronium
Vecuronium
Atracurium
Rocuronium
Depolarizing
Suxamethonium
ACh
Na+
α
ACh
δ
γ
α
β
Posterior Roots
Anterior Roots
Posterior Roots
Anterior Roots
Muscle Relaxants
What are they used for?
• Facilitate intubation of the trachea
• Facilitate mechanical ventilation
• Optimized surgical working conditions
• Treatment of Convulsions / seizures
Also used for
• Muscle spasticity
• Muscle Spasms
What are spasticity and spasms?
Spasticity can be described as involuntary muscle stiffness and spasms as
involuntary muscle contractions. Any muscle can be affected but spasticity and
spasms tend to predominantly affect a person's limbs or trunk.
Definition of muscle spasm
1. Increased muscle tone
2. together with muscle weakness
It is often associated with cerebral palsy,
multiple sclerosis, and stroke.
Causes of Muscle Spasms
• Seen after musculoskeletal injury and
inflammation
• Involve afferent nociceptive input from
damaged area
• Excitation of alpha motor outflow
• Tonic contraction of affected muscle
• Build up of pain-mediating metabolites
Levels of Muscle Relaxant Intervention
• Spinal Cord
• NEUROMUSCULAR Junction
• Muscle Cells
Muscle Relaxants
Definition:
Drugs which relax skeletal muscles by acting at
the neuromuscular junction
• Depolarizing muscle relaxant
Succinylcholine
• Nondepolarizing muscle relaxants
Short acting
Intermediate acting
Long acting
They can also be called
1) Antagonist (nondepolarizing) neuromuscular
blocking drugs prevent access of acetylcholine
to its NM receptor and prevent depolarization of
the motor end plate (d-tubocurarine)
2) Agonist (depolarizing) neuromuscular blocking
drugs produce excessive depolarization of the
motor end plate by causing excessive
stimulation of the NM receptor (Succinylcholine)
Succinylcholine
What is the mechanism of action?
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Physically resemble Ach
Act as acetylcholine receptor agonist
Not metabolized locally at NMJ
Metabolized by pseudocholinesterase in plasma
Depolarizing action persists > Ach
Continuous end-plate depolarization causes muscle
relaxation
Succinylcholine
• What is the clinical use of succinylcholine?
– Most often used to facilitate intubation
– Onset 30-60 seconds, duration 5-10 minutes
Succinylcholine
What is phase I neuromuscular blockade?
Repetitive firing and release of neurotransmitter.
Acetylcholine receptors remain open. Preceded by
fasciculations.
What is phase II neuromuscular blockade?
Postjunctional membrane does not respond to ACh even
when resting membrane potential is restored
i.e. Desensitisation blockade or Phase II block.
Succinylcholine
Does it have side effects?
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Cardiovascular
Fasciculation
Muscle pain
Increase intraocular pressure
Increase intragastric pressure
Increase intracranial pressure
Hyperkalemia
Malignant hyperthermia
Nondepolarizing Muscle Relaxants
Long acting
Pancuronium
Intermediate acting
Atracurium
Vecuronium
Rocuronium
Cisatracurium
Short acting
Mivacurium
Mechanism of Action
All bind nicotinic Ach receptors
and competitively block
Acetylcholine, thereby
preventing muscle contraction
i.e.
They are competitive
antagonists
Tubocurarine
• This was the first muscle relaxant used clinically
• Therapeutic Use: Adjuvant drugs in surgical anesthesia
• Pharmacology: Must be given by injection because they
are poorly absorbed orally. Do not cross the BBB.
• Elimination: Generally excreted unchanged (i.e. not
metabolized).
• Adverse Effects: Tubocurarine causes release of
histamine from mast cells – decrease in blood pressure,
bronchospasms, skin wheals.
• Drug interaction: Competes with succinylcholine for it’s
the end plate depolarizing effect.
Pancuronium
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It is an Aminosteroid compound
Onset 3-5 minutes, duration 60-90 minutes
Elimination mainly by kidney (85%), liver (15%)
Side effects : hypertension, tachycrdia,
dysrhythmia,
Vecuronium
• Analogue of pancuronium
• Much less vagolytic effect and shorter duration
than pancuronium
• Onset 3-5 minutes duration 20-35 minutes
• Elimination 40% by kidney, 60% by liver
Rocuronium
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Analogue of vecuronium
Rapid onset 1-2 minutes, duration 20-35 minutes
Onset of action similar to that of succinylcholine
Intubating dose 0.6 mg/kg
Elimination primarily by liver, slightly by kidney
Atracurium
Metabolized by
• Ester hydrolysis
• Hofmann elimination (spontaneous degradation in plasma and
tissue at normal body pH and temperature)
Onset 3-5 minutes, duration 25-35 minutes
Side effects:
• histamine release causing hypotension, tachycardia,
bronchospasm
• Laudanosine toxicity
(Laudanosine is a metabolite of atracurium and
cisatracurium. It decreases seizure threshold and this it can
induce seizures, however, such concentrations are unlikely to
be produced at therapeutic doses)
Cisatracurium
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Isomer of atracurium
Metabolized by Hofmann elimination
Onset 3-5 minutes, duration 20-35 minutes
Minimal cardiovascular side effects
Much less laudanosine produced
Mivacurium
• Has the shortest duration of action of all
nondepolarizing muscle relaxants
• Onset of action is significantly slower
• Use of a larger dose to speed the onset can be
associated with profound histamine release leading
to hypotension, flushing, and bronchospasm.
• Clearance of mivacurium by plasma cholinesterase
is rapid and independent of the liver or kidney.
• Mivacurium is no longer in widespread clinical use.
It is an investigational ultra-short-acting
Drug Interactions
• Cholinesterase Inhibitors decrease the effectiveness of
nondepolarizing agents
•
• Aminoglycoside antibiotics increase action of
nondepolarizing drugs
• Calcium channel blockers increase the actions of
nondepolarizing drugs
• Inhalational anesthetics enhance neuromuscular blockade
by nondepolarizing drugs
Reversal of Neuromuscular
Blockade
Why do we need to reverse the effect of neuromuscular
blockers?
Because they paralyze the muscles. Once the surgery is
over, the muscles need to work again.
Goal: re-establishment of spontaneous respiration and the ability
to protect airway from aspiration
Reversal of Neuromuscular Blockade
by Anticholinesterases
Effectiveness of anticholinesterases depends on the
degree of recovery present when they are administered
Anticholinesterases
Neostigmine
• Onset 3-5 minutes, elimination halflife 77 minutes
Pyridostigmine
Edrophonium
What is the mechanism of action?
• Inhibiting activity of acetylcholineesterase
• More Ach available at NMJ, compete for sites on
nicotinic cholinergic receptors
• Action at muscarinic cholinergic receptor
• Bradycardia
• Hypersecretion
• Increased intestinal tone
What do we do about side effects?
• Muscarinic side effects are minimized by
anticholinergic agents
• Atropine
• Dose 0.01-0.02 mg/kg
• Scopolamine
• glycopyrrolate
Drug List
Neuromuscular Blockers
Non-depolarizing
Blockers
Tubocurarine
Depolarizing
Blockers
Spasmolytic Drugs
Central
Peripheral
Baclofen
Dantrolene
Mivacurium
Tizanidine
Botulinum Toxin
Cisatracurium
Gabapentin
Succinylcholine
Benzodiazepines
* More drugs are mentioned in other slides
Centrally acting spasmolytic drugs
Drug
Mechanism
Baclophen
GABAB receptors causing
hyperpolarization by increasing potassium
conductance
Averse effects: drowsiness and increased
seizure activity
Tizanidine
α2 adrenoreceptor agonist
Gabapentin
Unknown but may enhance GABA
synthesis
Diazepam
GABAA receptor
Baclofen
• Mechanism of action: GABAB agonist
• Clinical effects: decreased resistance to
passive ROM, decreased hyperreflexia;
reduced painful spasms; reduced anxiety
Baclofen
• Adverse effects: weakness, sedation,
hypotonia, ataxia, confusion, fatigue,
nausea, liver toxicity
• Chronic effects: rapid withdrawal may cause
seizures, confusion, increased spasticity
• Route of administration: oral, intrathecal
Tizanidine and Clonidine
• Mechanism of action: alpha-2 receptor
agonist
• Clinical effects: reduced tone, spasm
frequency, and hyperreflexia
Tizanidine and Clonidine
• Adverse effects: drowsiness, dizziness, dry
mouth, orthostatic hypotension
• Chronic effects: rebound hypertension with
rapid withdrawal
• Route of administration: oral, transdermal
patch (Clonidine)
Benzodiazepines
• Diazepam
• Lorazepam (Ativan)
• Clonazepam
• Clorazepate
• Ketazolam
• Tetrazepam
Diazepam (Valium)
• Mechanism of action: enhance GABAA
activity (chloride channels)
• Clinical effects: decreased resistance to
passive joint range of motion (ROM);
decreased hyperreflexia; reduced painful
spasms; sedation; reduced anxiety
Diazepam (Valium)
• Adverse effects: sedation, weakness,
hypotension, memory impairment, ataxia,
confusion, depression
• Chronic effects: dependency, withdrawal,
and tolerance possible
• Routes of administration: oral, intravenous,
rectal
Peripheraly acting spasmolytic drugs
Dantrolene
Mechanism of action:
Dantrolene reduces skeletal muscle strength by interfering
with excitation-contraction coupling in the muscle fibers
Normal contraction involves release of calcium from its stores
in the sarcoplasmic reticulum through a calcium channel
Dantrolene interferes with the release of calcium through this
sarcoplasmic reticulum calcium channel.
Dantrolene:
Indications:
1- Muscle spasticity
2- Malignant hyperthermia:
Botulinum Toxin (Botox)
• Enters the pre-synaptic terminal and binds to
acetylcholine
• Inhibits acetlycholine from entering the synaptic cleft
• Toxin serves as a block at the neuromuscular unction
• Can be administered to a specific muscle or group via
local injection
Botox
• Used in treatment of patients with focal
dystonia as found in stroke and spinal cord
lesions
• Used to restore volitional motor control thus
increasing use of extremities and improving
function, mobility and opportunities to
participate in meaningful occupations
• Prevention of joint contraction and fixation