Skeletal Muscle Relaxants Flashcards
Neuromuscular blocking drugs
a) Nondepolarizing
i) Isoquinoline derivatives
(1) Atracurium
(2) Cisatracurium
(3) Doxacurium
(4) Mivacurium
(5) Tubocurarine
ii) Steroid derivatives
(1) Pancuronium (
2) Pipercuronium
(3) Rocuronium
(4) Vecuronium
b) Depolarizing
i) Succinylcholine
Acetylcholinesterase inhibitors
a) Ambenonium
b) Donepezil
c) Echothiophate
d) Edrophonium
e) Galantamine
f) Neostigmine
g) Physostigmine
h) Pyridostigmine
i) Rivastigmine
j) Tacrine
Antimuscarinic compounds
a) Atropine, glycopyrrolate
4) Cholinesterase reactivators
a) Pralidoxime
Muscle relaxants (Spasmolytics)
a) Centrally acting spasmolytics
i) Baclofen
ii) Carisprodol (Soma)
iii) Chlorzoxazone
iv) Cyclobenzaprine (Flexeril)
v) Diazepam (Valium)
vi) Metaxalone
vii) Methocarbamol
viii) Orphenadrine
ix) Tizanidine
b) Non-centrally acting spasmolytics
i) Dantrolene
ii) Botulinum toxin
Immunologic Drugs for Multiple Sclerosis
a) Azathioprine
b) Dalfampridine
c) Glucocorticoids
d) Cyclophosphamide
e) Glatiramer acetate
f) Interferons
- i) Interferon-beta-1a
- ii) Interferon-beta-1b
g) Mitoxantrone
h) Natalizumab
Neuromuscular blockers (may also be called antinicotinic drugs)
i) Interfere with transmission at the neuromuscular end plate and lack CNS activity
ii) Used primarily as adjuncts during general anesthesia to achieve adequate muscle relaxation without the cardiorespiratory depressant effects produced by deep anesthesia
iii) No known effect on consciousness or pain threshold
Spasmolytics
i) Used to reduce spasticity in a variety of neurologic conditions (e.g., chronic back pain, fibromyalgia, and muscle spasms)
ii) Traditionally have been called “centrally acting” muscle relaxants
iii) Due to their actions within the CNS, most spasmolytic agents will be covered in the Neuroscience System II course
NEUROMUSCULAR BLOCKING DRUGS
Blockade of end plate function is accomplished by two basic mechanisms
i) Nondepolarizing neuromuscular blocking agents
(1) Act as antagonists of the nicotinic acetylcholine receptor (nAChR)
(2) Prototype: d-tubocurarine
ii) Depolarizing neuromuscular blocking agents
(1) Blockade can be produced by the excess of a depolarizing agonist (e.g., excess acetylcholine (ACh), see below)
(2) Prototype: succinylcholine
NONDEPOLARIZING NEUROMUSCULAR BLOCKING AGENTS
Highly polar; must be administered parenterally
MOA: competitive antagonists at the nAChR ii) As a general rule, larger muscles (abdominal, trunk, paraspinous, diaphragm) are more resistant to blockade and recover more rapidly (the diaphragm is usually the last muscle to be paralyzed and the quickest to recover)
Reversal of neuromuscular blockade-reversed upon the addition of acetylcholine using an acetylcholine esterase (AChE) inhibitor
Anticholinergic agents (e.g., atropine, glycopyrrolate) are coadministered with AChE inhibitors to minimize adverse cholinergic effects (bradycardia, bronchoconstriction, salivation, nausea, vomiting) at muscarinic AChRs
Adverse effects of nondepolarizing agents-histamine release, which can cause histamine-like wheals to appear, bronchospasm, hypotension, and bronchial and salivary secretion
At large doses, tubocurarine can produce acetylcholine receptor blockade at autonomic ganglia and at the adrenal medulla, which can result in a fall in blood pressure and tachycardia
d-tubocurarine causes significant histamine release and has a very long duration of action, its clinical use has declined in favor of more specific, shorter-acting neuromuscular blockers
Atracurium (isoquinoline derivative, intermediate acting)
(1) Inactivated by a form of spontaneous breakdown known as Hofmann elimination (2) Less histamine release than other nondepolarizing agents
Cisatracurium (isoquinoline derivative, intermediate acting)
(1) Stereoisomer of atracurium with fewer side effects (less laudanosine, histamine release)
(2) Can be used even with significant renal and hepatic impairment; devoid of CV effects
Doxacurium
(1) Not often used because of the long-lasting effects as well as high degree of elimination by the kidney (not used in patients with renal failure); devoid of CV effects
Rocuronium
(a) Rocuronium has the most rapid time of onset (60-120 seconds)
(b) Alternative to succinylcholine
Mivacurium (isoquinoline derivative, short acting)
(1) Large doses can be associated with histamine release and subsequent CV effects
(2) Metabolism by plasma cholinesterase
Steroid derivatives
(1) Intermediate-acting steroid muscle relaxants (vecuronium, rocuronium) tend to be more dependent on biliary excretion or hepatic metabolism for their elimination and are more likely to be used clinically than long-acting steroid relaxants (pancuronium, pipecuronium)
The steroidal neuromuscular blocking agents have the least tendency to cause histamine release
Succinylcholine is the only depolarizing blocking drug used clinically
Ultra-short duration of action
Prolonged neuromuscular blockade can occur in patients with a genetically abnormal variant of plasma cholinesterase after a dose of succinylcholine
Not effectively metabolized at the synapse by acetylcholinesterase
Effects of succinylcholine are similar to ACh (i.e., succinylcholine is a nAChR agonist), but with longer duration of action compared to ACh
Phase I block (depolarizing): after activating the nAChR, depolarization of the motor end plate spreads to adjacent membranes causing muscle contraction; the depolarized membranes remain depolarized and unresponsive to subsequent impulses (i.e., a state of depolarizing blockade); because excitation-contraction coupling requires end plate repolarization and repetitive firing to maintain muscle tension, flaccid paralysis results; phase I depolarizing block is augmented, not reversed, by cholinesterase inhibitors
Phase II block (desensitizing): continued exposure to succinylcholine causes the initial end plate depolarization to decrease and the membrane becomes repolarized; the membrane is unable to be depolarized because the receptor is desensitized; although this mechanism is unclear, the channels behave as if they are in a prolonged closed state similar to nondepolarizing block; phase II desensitizing block is reversed by acetylcholinesterase inhibitors (increase in ACh at the NMJ)
Succinylcholine is often used for rapid sequence induction (e.g., during emergency surgery when the objective is to secure the airway rapidly and prevent soiling of the lungs with gastric contents) and for quick surgical procedures where an ultrashort acting neuromuscular blocker is practical
Reversal of neuromuscular blockade: Time (due to cholinesterase degradation)
BLACK BOX WARNING (cardiac arrest risk): rarely, acute rhabdomyolysis with hyperkalemia followed by ventricular dysrhythmias, cardiac arrest, and death can occur after administration to apparently healthy children with an undiagnosed skeletal muscle myopathy (usually males <8 y/o but also reported in adolescents)
In order to treat symptoms associated with myasthenia gravis, you should be able to recognize symptoms of decreased acetylcholine signaling at the neuromuscular junction, select a drug mechanism for appropriate treatment, and explain anticipated adverse effects.
AChE INHIBITORS
Mechanism of action: Inhibition of AChE (BuChE is also inhibited)
Myasthenia gravis: pyridostigmine, neostigmine, and ambenonium are the standard AChE inhibitors used in the symptomatic treatment of myasthenia gravis (do not cross the bloodbrain barrier); due to the relatively short duration of action of these agents, repeated dosing is required every 2-8 hours depending upon agent, dose, and clinical response
Myasthenic vs. cholinergic crisis
(1) Myasthenic crisis is a life-threatening condition defined as weakness from acquired myasthenia gravis that is severe enough to necessitate intubation
(2) Cholinergic crisis is a potential major side effect of excessive AChE inhibitors; the main symptom is muscle weakness, similar to myasthenic crisis
(3) To distinguish, an AChE inhibitor (edrophonium) may delineate the cause of symptoms
(a) If the patient is in myasthenic crisis the symptoms will improve
(b) If the condition is cholinergic crisis, the symptoms will remain unchanged or worsen
c) Reversal of pharmacologic paralysis: neostigmine is commonly used to reverse
Acute intoxication
i) The dominant initial signs of AChE intoxication are those of mAChR stimulation: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
ii) The route of administration dictate which symptoms are noted initially
(1) After ingestion, GI symptoms occur earliest
(2) Percutaneous absorption results in early symptoms of localized sweating and muscle fasciculations in the immediate vicinity
iii) With poisoning from lipid-soluble agents, CNS involvement follows rapidly (confusion, ataxia, generalized convulsions, coma, and respiratory paralysis)
iv) Time of death after a single acute exposure may range 5 minutes to 24 hours and is caused primarily by respiratory failure.
Treatment
i) Atropine in combination with maintenance of vital signs (respiration) and decontamination
ii) Atropine is ineffective against the peripheral neuromuscular stimulation (nAChRs)
iii) To regenerate AChE at the NMJ, cholinesterase regenerators can be administered
Cholinesterase regenerators
i) Cholinesterase reactivators (pralidoxime) are capable of regenerating active AChE enzyme by removal of the phosphorous group from the active site of the enzyme
ii) Restores the response to stimulation of the motor nerve within minutes
iii) Must be given soon after AChE inhibitor exposure iv) Atropine, pralidoxime, and a benzodiazepine (anticonvulsant) are typically combined
MUSCLE RELAXANTS (SPASMOLYTICS)
Centrally acting spasmolytics
Baclofen
(1) MOA: agonist at GABAB receptors; results in hyperpolarization (due to increased K+ conductance) and inhibition of excitatory neurotransmitter release in the brain and spinal cord
(2) As effective as diazepam in reducing spasticity and causes less sedation; does not reduce overall muscle strength as much as dantrolene
(3) Adverse effects include drowsiness and increased seizure activity in epileptic patients (withdrawal must be done slowly); vertigo, dizziness, psychiatric disturbances, insomnia, slurred speech, ataxia, hypotonia, and muscle weakness
Carisprodol
(1) Precise mechanism of action unclear; acts as CNS depressant
(2) Schedule IV controlled substance due to addictive potential (use only short term)
(3) Adverse effects include dizziness and drowsiness
(4) Metabolized by CYP2C19; use with caution when coadministered with CYP inhibitors
(5) Metabolized to meprobamate, which has anxiolytic and sedative effects (used to manage anxiety disorders)
Cyclobenzaprine
(1) Exact mechanism of action unclear; reduces tonic somatic motor activity by influencing both alpha and gamma motor neurons
(2) Structurally related to tricyclic antidepressants and produces antimuscarinic side effects (may cause significant sedation, confusion, and transient visual hallucinations)
(3) Metabolized by CYP450s; use with caution when coadministered with CYP inhibitors
(4) Adverse effects include drowsiness, dizziness, and xerostomia
Diazepam
(1) Long-acting benzodiazepine; produces sedation at the doses for spasticity
(2) MOA: promote the binding of the major inhibitory neurotransmitter in the CNS - aminobutyric acid (GABA) to the GABAA receptor, enhancing GABA-induced ion currents (increase frequency of channel openings); leads to increased inhibitory transmission and a reduction in spasticity
(3) Causes sedation, muscle relaxation, anxiolytic and anticonvulsant effects
(4) Schedule IV controlled substance
Tizanidine
(1) MOA: alpha2-adrenergic agonist (similar to clonidine); decreases excitatory input to alpha motor neurons
(2) Causes drowsiness, hypotension, dry mouth, asthenia/muscle weakness
Non-centrally acting spasmolytics
Dantrolene
(1) In contrast to the centrally acting drugs, dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in the muscle fibers
(2) MOA: causes inhibition of the ryanodine receptor (RyR); blocks the release of calcium through the sarcoplasmic reticulum and muscle contraction is impaired
(3) Cardiac and smooth muscle are unaffected due to a different RyR channel subtype
(4) Side effects include generalized muscle weakness, sedation, and occasionally hepatitis
(5) Used to treat spasticity associated with upper motor neuron disorders (e.g., spinal cord injury, stroke, cerebral palsy, or multiple sclerosis) and malignant hyperthermia
Botulinum toxin
(1) MOA: cleaves components of the core SNARE complex involved in exocytosis, preventing the release of ACh
(2) Many clinical uses: strabismus and blepharospasm associated with dystonia; cervical dystonia; temporary improvement in the appearance of lines/wrinkles of the face; severe primary axillary hyperhidrosis; focal spasticity; prophylaxis of chronic migraine
(3) Adverse effects include focal muscle weakness in the area of injection, which may last up to several months
Azathioprine
i) Immunosuppressant agent used in the treatment of rheumatoid arthritis and renal transplantation (unlabeled use in the treatment of MS, other immunologic disorders)
ii) MOA: antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins
Dalfampridine
i) MOA: Nonspecific potassium channel blocker that improves conduction in focally demyelinated axons by delaying repolarization and prolonging the duration of action potentials; enhanced neuronal conduction is thought to strengthen skeletal muscle fiber twitch activity, thereby, improving peripheral motor neurologic function
Glucocorticoids
i) Monthly bolus IV glucocorticoids (typically 1000 mg of methylprednisolone) are used for treatment of primary or secondary progressive MS alone or in combination with other immunomodulatory or immunosuppressive medications
Cyclophosphamide
i) Antineoplastic agent (alkylating agent prototype) used off-label in the treatment of MS
Glatiramer acetate
i) MOA (1) A mixture of random polymers of four amino acids (L-alanine, L-glutamic acid, L-lysine, and L-tyrosine) that is antigenically similar to myelin basic protein, which is an important component of the myelin sheath of nerves
(2) Thought to induce and activate T-lymphocyte suppressor cells specific for a myelin antigen; also proposed to interfere with the antigen-presenting function of certain immune cells opposing pathogenic T-cell function
