Skeletal Muscle Relaxants
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Transcript of Skeletal Muscle Relaxants
Skeletal Muscle Relaxants
Drug List
Neuromuscular Blockers Spasmolytic Drugs
Non-depolarizingBlockers
DepolarizingBlockers Central Peripheral
Tubocurarine Succinylcholine Baclofen Dantrolene
Mivacurium Tizanidine Botulinum Toxin
Cisatracurium Gabapentin
Benzodiazepines
* More drugs are mentioned in other slides
Nerve
Nerve
Muscle
1. Presynaptic terminal2. Sarcolemma3. Synaptic vesicles4. Acetylcholine receptors5. Mitchondrion
αα
β
δγ
Na+ Na+ Neuromuscular
Blocking Drugs
CompetitiveTubocurarineGallaminePancuroniumVecuroniumAtracuriumRocuronium
DepolarizingSuxamethonium
ACh
ACh
Neuromuscular
Junction
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.
Muscle Spasticity
Muscle Spasm
Definition of muscle spasm1. Increased muscle tone2. 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 relaxantsShort actingIntermediate actingLong 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?• 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
• 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?
• Cardiovascular• Fasciculation• Muscle pain• Increase intraocular pressure• Increase intragastric pressure• Increase intracranial pressure• Hyperkalemia • Malignant hyperthermia
Succinylcholine
Nondepolarizing Muscle RelaxantsLong acting
PancuroniumIntermediate acting
AtracuriumVecuroniumRocuroniumCisatracurium
Short actingMivacurium
Mechanism of Action
All bind nicotinic Ach receptors and competitively block Acetylcholine, thereby
preventing muscle contractioni.e.
They are competitive antagonists
• 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.
Tubocurarine
Pancuronium
• It is an Aminosteroid compound• Onset 3-5 minutes, duration 60-90 minutes• Elimination mainly by kidney (85%), liver (15%)• Side effects : hypertension, tachycardia,
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
• 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
AtracuriumMetabolized 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
• 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 Blockadeby Anticholinesterases
Effectiveness of anticholinesterases depends on the degree of recovery present when they are administered
AnticholinesterasesNeostigmine• Onset 3-5 minutes, elimination halflife 77 minutes
PyridostigmineEdrophonium
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 Spasmolytic Drugs
Non-depolarizingBlockers
DepolarizingBlockers Central Peripheral
Tubocurarine Succinylcholine Baclofen Dantrolene
Mivacurium Tizanidine Botulinum Toxin
Cisatracurium Gabapentin
Benzodiazepines
* More drugs are mentioned in other slides
Centrally acting spasmolytic drugs
Drug Mechanism
Baclophen
GABAB receptors causing hyperpolarization by increasing potassium conductanceAdverse 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 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
• Mechanism of action: alpha-2 receptor agonist
• Clinical effects: reduced tone, spasm frequency, and hyperreflexia
Tizanidine and Clonidine
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
• 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)
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 drugsDantrolene
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 spasticity2- 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 junction• 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
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