Pharm Muscle Relaxants Flashcards
Skeletal muscle relaxants
Manage spasticity (upper motor neuron) and spasms (lower acute neuron) in pts w/ LMN and UMN lesions
Spasticity
Stiff or rigid muscles (tightness)
Abnormally elevated muscle tone
Increase in muscle tone or contractions cause movements to be stiff and awkward
Considered a permanent condition and may progress to disabling condition if therapy is not instituted
Two classes of muscle relaxants
Neuromuscular blocking drugs
-depolarizing (succinylcholine)
-nondepolarizing - long duration (tubocurarine), short duration (mivacurium)
Skeletal muscle spasmolytic drugs
-For chronic conditions: CNS action (Baclofen, diazepam, tizanidine); muscle action (dantrolene)
-For acute conditions: cyclobenzaprine
Nondepolarizing neuromuscular blocking drugs
Can be used in conjunction with procedures requiring anesthetics e.g. Tracheotomy
Succinylcholine
nACh agonist/Tx short term muscle relaxant in endotrach intubation/Mentioned: contraindicated with pseudocholinesterases (butyrylcholinesterase) as it breaks succinylcholine very quickly
MOA of succinylcholine
Depolarizing skeletal muscle relaxant
It combines with cholinergic receptors of the motor end plate to produce depolarization (observed as fascinations or spasms)
***** “persistent” depolarization of the neuromuscular junction leading to desensitization and eventually muscle relax
Therapeutic use of nonpolarizing neuromuscular blocking drugs
High dose will be administered to paralyze person prior to giving potassium bromide to kill them
Used as an adjunctive therapy for general anesthetics ; used to produce muscle paralysis in order to facilitate surgery or artificial ventilation
CNS action spasmolytic drugs
Treat muscle spasms or muscle cramps
Muscle action of spasmolytic drugs
Treat Spasticity
Therapeutics of spasmolytics
Drug that reduces abnormally elevated muscle tone (spasticity) without paralysis
What are Spasms or cramps
Spasms are sudden, violent, painful, involuntary contractions of a muscle or group of muscles
Tend to occur in acute setting and are temporary (whereas spasticity appears in a chronic setting and are persistent)
What neurons are involved in spasms?
Motor neurons
Balance between musculoskeletal movement and body posture
Cell bodies resides in the ventral ganglia
LMN
Acetylcholine is chief neurotransmitter
Action potentials and NMJ
Action potentials by motor neurons are conducted directly to nerve terminals in muscle fibers that form synapses called neuromuscular junctions
Acetylcholine is released from the nerve terminal to what receptors on the muscle for contraction ?
Nicotinic receptors
What type of injury involves Spasticity ?
Upper motor neuron
Spasticity is an increase in the passive stretch resistance (which is the force of gravity on the limb or on the body weighing down on it) of a muscle or muscle group
What are the etiologies of spasticity (more permanent)?
Head injuries, cerebral palsy, Ms, stroke
Cerebrovascular accident
Closed head injury
Hemiplegia- paralysis of the arm, leg, trunk on the same side of the body
Paraplegia- spinal injury results in an impairment in motor or sensory function of the lower half of person’s body
Quadriplegia- paralysis or partial paralysis of all limbs of the body
MS -demyelination of neurons
Poliomyelitis
Spinal cord trauma
Compare spasm and spasticity
Spasm - sudden, violent, painful involuntary contractions of a muscle or group of muscles
Mediator is lower motor neurons
Spasticity- increased muscle tone, or muscle contractions that cause stiff, awkward movement
Mediator is upper motor neurons
What are etiologies for spasm?
Acute/treatable
Bursitis Dislocation Fracture Epilepsy Herniated disc Hypocalcemia Myositis, neuritis Strains Whiplash injuries
Atracurium
Pancuronium
Gallamine
Neuromuscular blockers
Muscle relaxants
Indirect acting bc they interfere with transmission at the neuromuscular end plate and are not centrally acting drugs
Baclofen, diazepam, tizanidine
Spasmolytics that have traditionally been called “centrally acting” muscle relaxants
However, dantrolene is a peripherally acting and has no significant central effects
Major uses of spasmolytic drugs
Skeletal muscle relaxants
For muscle strains and back pain
Muscle strains-accompanied by pain
Back pains-poor posture, abnormal gait
Stretch reflex arc
UMN (Ia afferents carried from spindle fiber) acts at all times on interneurons to cause inhibition if muscle contraction ?
A lesion at UMN prevents this inhibition and results in spasticity
What lesion leads to spasticity?
UMN
Interneurons
2 small interneurons that act as inhibitory by release of GABA and glycine
Where are the cell bodies for LMN?
Ventral root ganglion
Centrally acting skeletal muscle relaxants
Drugs used to treat spasticity or UMN lesions
Baclofen
Botox
Diazepam -acts on alpha-2 (centrally active)
Tizanidine
Peripherally acting drug for spasticity
Dantrolene which acts on the muscle itself
Baclofen
GABA mimetic - drug may act by mimicking the actions of GABA on spinal neurons
Acts within the spinal cord to suppress hyperactive reflexes
Involved in regulation of muscle movement
Structurally analog of GABA selective to GABAb
Longer half life than GABA
Baclofen and diazepam
Assists in GABA-mediated signal transduction
Diazepam
Facilitates GABA-mediated presynaptic inhibition
Anti-anxiety agent
Member of Benzodiazepine
Tx. Spasticity and spasms (LMNs and UMNs)
Can be used in pts with muscle spasm of almost any origin, including local muscle trauma
Tizanidine
Acts on UMNs and inhibits their firing
Stimulates relaxation
Acts on alpha2 adrenergic agonist (central)
Can be used for neuropathic pain but it interferes with alpha 2
Tx hypotension, drowsiness, dry mouth ? Or causes these?
MOA of Baclofen
The drug interferes with the release of excitatory transmitters
Stabilizes the neuron and prevents it from firing ; allows rigid
Dorsal horn of the spinal cord
Sensory going in
Ventral horn of the spinal cord
Motor going out
Baclofen action
Acts on the level of spinal cord to restore inhibiting tone
Therapeutic use of Baclofen
Can reduce spasticity associated with MS, spinal cord, injury, and cerebral palsy
Not effective in stroke!!!!
Decreases flexor and extensor spasms
Suppresses resistance to passive movement
Reduce the discomfort of spasticity and allowing increased performance
Passive resistance of muscle
Muscle tone is continuous and its passive contraction
In other words, it is the muscle’s resistance to passive stretch during resting state
Baclofen is preferred over what drug in patients whose spasticity is associated with significant muscle weakness?
Dantrolene
Baclofen is effective (does not relieve spasticity) of what disease ?
Parkinson’s
Baclofen’s pharmacokinetics
Good absorption Time to peak concentration is 2-3 hrs Variable onset of action (hours to days) Half life - 2.5-4 hours Metabolized in the liver Excreted in the kidneys
Baclofen accumulation
Since GABA recpts are everywhere …
If it accumulates in the body, it can act on other GABA receptors, causing sedation, drowsiness, and dizziness bc it depresses the CNS (therefore pts shouldn’t drink alcohol while taking it
Adverse effects of Baclofen
The most common side effects involve the CNS and GI tract
CNS effects: depressant, drowsiness, dizziness, weakness, and fatigue
-most intense during the early phase of therapy and diminish with continued drug use (tolerance?)
Contraindications of Baclofen
Pts should be cautioned against the use of alcohol and other CNS depressants Since Baclofen potentiates the depressant action of the drugs
Skeletal muscle spasms caused by rheumatoid arthritis
Dantrolene
Ryanadine receptor antagonist - prevents calcium release
Ryandine rcpt mediates ca2+ associated ca2+ release
Acts directly on skeletal muscle to relieve spasticity from UMN injury
(Unlike Baclofen and diazepam)
Relieves Sx of malignant hyperthermia by acting on the SR to block calcium release
What receptor does diazepam bind to?
Act within. The CNS by facilitating GABA mediated presynaptic inhibition (mimics the actions of GABAa at rcpts in the spinal cord and brain)
Binds to specific subunit of GABA rcpt
Tx, SfX, and dosage of diazepam
SfX: Produces sedation in last pts at doses required to significantly reduce muscle tone
Causes dizziness
Minimize sedation by administering low doses
Dosage begins at 4 mg/d gradually increased to 60 mg/d
Drug preferred over dantrolene in pts with marginal strength -wont cause more muscle weakness unlike other drugs
High affinity of drug to plasma proteins
Drug interactions
Long half life
Baclofen drug interactions
Alcohol
Antihistamine-
CNS Depressants -potentiates each other by causing excessive CNS depression
MAO inhibitors
What effects are associated with the drug interactions for Baclofen ?
increase risk of hepatotoxicity with combination of chlorzoxazone and alcohol
Increase CNS depression
Chlorzoxazone
Tx spasms
MOA of dantrolene
Suppression of calcium release from sarcoplasmic reticulum (SR)
Will lead to decrease ability of skeletal muscle to contract
Also used to tx Malignant hyperthermia
Malignant hyperthermia
Autosomal dominant
Defect in the Ryanodine recpt causing more ca2+ release
Severe muscle contractions
Fast rise in body temperature
A life-threatening syndrome that can be triggered by any general anesthetic and by succinylcholine, a neuromuscular blocking agent
Tx, SfX, and therapeutic use dantrolene
Minimal effects on smooth muscle and cardiac muscle which is a therapeutic advantage - therefore, it wouldn’t increase TPR and Bp
Tx. Spasticity associated with MS, cerebral palsy, and spinal cord injury, malignant t hyperthermia ( inherited, muscle breakdown)
Can be associated with significant decrease in strength ( generalized reduction in the ability for skeletal m. To contract)
Sx of malignant hyperthermia
Muscle rigidity
Profound elevation of temperature
Heat is generated by muscle contraction occurring secondary to massive release of calcium from the SR
Adverse toxic effects of dantrolene
Hepatic - dose related liver damage - most serious
Liver damage incidence 1/1000
Death - due to extensive liver damage
CNS : drowsiness, dizziness, malaise, lightheadness, insomnia, fatigue, confusion
Urinary : increased urinary frequency
What tests should be performed prior to tx with dantrolene
Liver function test
Monitor liver damage
Dantrolene drug interactions
Increased toxicity : estrogen, CNS depressants, Clindamycin, Verapamil, Warfarin, Clofibrate, Tolbutamine
Dantrolene-estrogen
Hepatotoxicity
Post-menopausal women on estrogen regimen
Produces additive effect to liver toxicity
Dantrolene-CNS depressant
Sedation
Dantrolene-Clindamycin
Increased neuromuscular blockage
Dantrolene-verapamil
Hyperkalemia and cardiac depression
Verapamil is a calcium channel blocker - treat angina and hypertension
Warfarin, Clofibrate, Tolbutamine
Drug interaction with dantrolene
Interaction occurs at the level of enzyme mechanism
Drugs for muscle (acute local) spasms or LMN legions
Carisoprodol, Chlorophenesin, Chlorzoxazone, cyclobenzaprine, diazepam, metaxalone, methocarbamol, vigabratin
Carisoprodol
Metabolized to a different drug used to treat anxiety - has sedative or hypnotic properties
Contraindicated with pts that have known hypersensitivity to meprobamate
Meprobamate
Highly addictive
Metabolite of carisprodol
Combined with rohypnol (date rape drug)
Chlorophenesin
Anti fungal and antibiotic
Potential interaction with Baclofen
Contraindicated during pregnancy !
Chlorzoxazone
For spasms from trauma or electrolyte imbalance
Cyclobenzaprine
Injury- related spasms
May be regarded as the prototype of the group (acute local spasm drugs)
Has muscuranic effects - contraction of the detrusor muscle by bladder - urinary incontinence?)
Will not work well in pts with muscle spams due to cerebral palsy or spinal cord injury
Metaxalone
For strains, sprains
Increase absorption with food
Can cause headaches, dizziness, but less addictive than carisprodol
Methocarbamol
High risk in elderly
Skeletal muscle relaxant
Slow down heart
May cause skin rash, itching, and significant depression of the CNS (therefore can cause sedation)
Vigabratin
GABA transaminase inhibitor
GABA transaminase
uses GABA as a substrate to produce something else (transforms it; uses it up)
Inhibition of this enzyme allows GABA to linger, allowing significant relief from spasms and pain
Orphenadrine
Anti cholinergic properties Tx acute local muscle spasm ; fibromyalgia (acting on NET) Antihistamine of H1 receptor inhibits muscuranic rcpts Inhibits NMDA rcpt in CNS Inhibits NE reuptake by blocking NET
How do the drugs for acute local muscle spasm work?
Promoted for the relief of acute temporary muscle spasm caused by local trauma or strain
Most act as sedative or at the level of spinal cord or brain stem
What promotes long half life and drug interaction?
High level of protein binding
Cyclobenzaprine has 93% protein binding
Dantrolene has high protein binding but half life is in hours
And half life is 1-3 days but unlike other muscle relaxants that have half life in hours
Contraindications of cyclobenzaprine
MI, cardiac conduction disorders, hyperthyroidism
Contraindications of dantrolene
Active hepatic disease
Muscle spasms caused by rheumatoid arthritis
Botox
Binds to synaptobrevin, syntaxin, or SNAP-25
Depending on the type
Tx spasticity from cerebral palsy, cosmetic surgery
