Skeletal Muscle Relaxants Flashcards
Identify appropriate therapy for reversing neuromuscular blockade induced by skeletal muscle relaxants (i.e., d-tubocurarine)
Acetylcholinesterase (AChE) inhibitor
[note that larger doses of nondepolarizing agents diminish the antagonizing effects of cholinesterase inhibitors due to blockade of channel pore, which occurs at higher doses]
AChE inhibitors may be used for reversing neuromuscular blockade induced by skeletal muscle relaxants (i.e., d-tubocurarine). List anticipated adverse effects of this reversal
Bradycardia Bronchoconstriction Salivation Nausea Vomiting
AChE inhibitors may be used for reversing neuromuscular blockade induced by skeletal muscle relaxants (i.e., d-tubocurarine). This reversal may produce adverse cholinergic effects such as bradycardia, bronchoconstriction, salivation, nausea, and vomiting. What drugs may be co-administered to minimize these adverse effects at muscarinic AChRs?
Anticholinergic agents (e.g., atropine, glycopyrrolate)
MOA of nondepolarizing neuromuscular blocking agents such as d-tubocurarine
Competitive antagonism at the nAChR
Some nondepolarizing agents produce ______ release, which can cause wheals on the skin, bronchospasm, hypotension, and bronchial and salivary secretion. Premedication with an __________ can attenuate these effects
Histamine; anti-histamine
At large doses, ______ can produce ACh receptor blockade at autonomic ganglia and at the adrenal medulla, which can result in a fall in BP and tachycardia
Tubocurarine
________ is a nondepolarizing agent that causes significant histamine release, and has a very long duration of action, so its clinical use has declined in favor of more specific and shorter-acting neuromuscular blockers
d-tubocurarine
Anesthetics exhibit drug-drug interactions with nondepolarizing neuromuscular blocking agents — Specifically, inhaled anesthetics potentiate the neuromuscular blockade produced by nondepolarizing muscle relaxants in a dose-dependent manner. What inhaled anesthetic has the strongest potentiating effect?
Isoflurane
[followed by sevoflurane = desflurane = enflurane = halothane > nitrous oxide]
What effect do antibiotics have on nondepolarizing neuromuscular blocking agents?
Aminoglycosides (gentamicin, tobramycin, amikacin, streptomycin, neomycin, paramomycin, netilimicin, spectinomycin) have been shown to enhance neuromuscular blockade
Some abx reduce the release of ACh in the prejunctional neuron, likely due to blockade of specific P-type calcium channels
Other agents that block signaling at the NMJ (e.g., tetrodotoxin, local anesthetics, botulinum toxin), ________ the actions of nondepolarizing agents
Enhance
Effect of aging on neuromuscular response to nondepolarizing agents
Prolonged duration of action from nondepolarizing relaxants occurs in elderly pts with reduced hepatic and renal function
Neuromuscular blockade by nondepolarizing muscle relaxants is _____ in pts with myasthenia gravis
Enhanced
Pts with _____________ and those with ______________ disease are resistant to nondepolarizing muscle relaxants (likely due to the increased expression of _______, which requires an increase in dose)
Severe burns; upper motor neuron; nAChRs
List 4 isoquinoline derived nondepolarizing muscle relaxants
Atracurium (intermediate acting)
Cisatracurium (intermediate acting)
Doxacurium (long acting)
Mivacurium (short acting)
List 4 steroid derived nondepolarizing muscle relaxants
Intermediate acting: vecuronium, rocuronium
Long-acting: pancuronium, pipecuronium
______ and _____ are steroid muscle relaxants that 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
Vecuronium
Rocuronium
Which type of neuromuscular blocking agents have the least tendency to cause histamine release — isoquinoline-derived or steroid-derived?
Steroid-derived
Which steroid-derived nondepolarizing muscle relaxant has the most rapid time of onset (60-120 seconds) and can be used as an alternative to succinylcholine?
Rocuronium
_______ is the only depolarizing drug that is used clinically; it has an ultra-short duration of action due to rapid hydrolysis and inactivation in the liver and plasma. Prolonged neuromuscular blockade can occur in pts with a genetically abnormal variant of plasma _______. It is not effectively metabolized at the synapse by ________.
Succinylcholine
Cholinesterase
Acetylcholinesterase
Effects of succinylcholine are similar to ACh (i.e., succinylcholine is a ______ agonist), but with a _______ duration of action compared to ACh
nAChR; longer
Phase I block vs. phase II block caused by succinylcholine
Phase I block caused by succinylcholine = depolarizing; augmented by cholinesterase inhibitors
Phase II block caused by succinylcholine = desensitizing; reversed by cholinesterase inhibitors (increase in ACh at NMJ)
Describe initial response to a standard pharmacological dose of IV succinylcholine
Transient muscle fasciculations over the chest and abdomen within 30 seconds
Paralysis develops rapidly (<90 seconds) in arm, neck, and leg muscles initially, followed by respiratory muscles
_______ is often used for rapid sequence induction (e.g., during emergency surgery when objective is to secure airway rapidly and prevent soiling of lungs with gastric contents) and for quick surgical procedures in which an ultrashort acting neuromuscular blocker is practical
Succinylcholine
Administering succinylcholine during halothane anesthesia may lead to __________ as an adverse effect
Cardiac arrhythmias
Stimulation of nAChRs and mAChRs by succinylcholine produces negative inotropic (cardiac muscle contraction strength) and chronotropic (heart rate) effects, which may be attenuated by administration of __________. Large doses can cause _______ inotropic and chronotropic effects
An anticholinergic (atropine); positive
Pts with burns, nerve damage or neuromuscular disease, closed head injury, and other trauma can respond to succinylcholine by releasing ______ into the blood, which on rare occasions can cause ________
Potassium; cardiac arrest
Other AEs of succinylcholine include increased _______ pressure, increased _______pressure, and ______ pain
Intraocular; intragastric; muscle
Contraindications to succinylcholine
Personal or family hx of malignant hyperthermia
Myopathies associated with elevated serum CPK values
Acute phase of injury following major burns, multiple trauma, extensive denervation of skeletal muscle, or upper motor neuron injury
Black box warning associated with succinylcholine
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)
The combination of succinylcholine and volatile anesthetics can result in malignant hyperthermia. Malignant hyperthermia is caused by abnormal release of calcium from stores in skeletal msucle and is treated with _________
Aside from volatile and local anesthetics, succinylcholine also has interactions with ________ and _______ drugs
Dantrolene
Antibiotics; antiarrhythmic
Uses of neurmuscular blocking drugs
Surgical relaxation
Tracheal intubation
Control of ventilation — provides adequate gas exchange and prevents atelectasis in pts who have ventilatory failure; reduce chest wall resistance and improve thoracic compliance
Treatment of convulsions — attenuates peripheral motor manifestations associated with status epilepticus or local anesthetic toxicity; no effect on CNS because they do not cross BBB
3 subgroups of AChE inhibitors
Alcohols — positively charged, reversible, short duration (ex: edrophonium)
Carbamic acid esters — can be positively charged or neutral, reversible, longer duration (ex: neostigmine, pyridostigmine, physostigmine)
Organophosphates — neutral, highly lipid soluble; irreversible (ex: echothiophate, parathion, malathion, sarin, soman)
Solubility and CNS distribution of quaternary and charged AChE inhibitors (neostigmine, pyridostigmine, edrophonium, echothiophate)
Relatively insoluble (parenteral admin)
No CNS distribution
Solubility and CNS distribution of tertiary and uncharged AChE inhibitors (physostigmine, donepezil, tacrine, rivastigmine, galantamine)
Well absorbed from all sites
CNS distribution
Organophosphates are lipid-soluble and readily absorbed from the skin, lung, gut, and conjunctiva. CNS distribution occurs (except for ______, which is charged).
Since the interaction between organophosphates and AChE is covalent and irreversible, there is virtually little metabolism and excretion via common biotransformation pathways. Regeneration of AChE by rapid administration of ________ is required in order to reestablish the termination of ACh signaling at the NMJ
Echothiophate
Pralidoxime
Organ system effects of AChE inhibitors
Depending on site of action, AChE inhibitors have the ability to stimulate mAChRs at autonomic effector organs AND stimulate (followed by depression or paralysis) all autonomic ganglia and skeletal muscle via nAChRs
Effects of AChE inhibitors on CNS in low vs. high concentrations
Low: diffuse activation on EEG and a subjective altering response
High: generalized convulsions d/t neuronla hyperstimulation (may be followed by coma and respiratory arrest)
Effects of AChE inhibitors on NMJ
Therapeutic concentrations prolong and intensify actions of ACh, which increases strength of contraction
High concentrations lead to fibrillation and fasciculations of muscle fibers
Continued inhibition of AChE results in progression of depolarizing neuromuscular blockade to nondepolarizing blockade (as seen with succinylcholine); some quaternary carbamate AChE inhibitors have additional direct nicotinic agonist effects at NMJ (e.g., neostigmine)
Major therapeutic uses of AChE inhibitors
Eye: Glaucoma, accommodative esotropia
GI and urinary tracts: postoperative atony, neurogenic bladder
NMJ: myasthenia gravis, curare-induced neuromuscular paralysis
Heart: rarely for certain atrial arrhythmias
Alzheimer disease
_______, ________, and _______ are the standard AChE inhibitors used in symptomatic treatment of myasthenia gravis (do not cross the BBB); due to relatively short duration of action of these agents, repeated dosing is required every 2-8 hours depending upon agent, dose, and clinical response
Pyridostigmine
Neostigmine
Ambenonium
The short-acting agent _______ had been used as a diagnostic agent for MG; now replaced by ice pack test and immunologic and/or electrophysiologic testing
Edrophonium
Define myasthenic crisis vs cholinergic crisis
Myasthenic crisis — life-threatening condition defined as weakness from acquired myasthenia gravis that is severe enought to necessitate intubation
Cholinergic crisis — potential major side effect of excessive AChE inhibitors; the main symptom is muscle weakness, similar to myasthenic crisis
How is myasthenic crisis differentiated from cholinergic crisis clinically?
Give AChE inhibitor (edrophonium)
If pt is in myasthenic crisis, the symptoms will improve
If pt is in cholinergic crisis, symptoms will remain unchanged or worsen
________ is commonly used to reverse neuromuscular blocking drug-induced paralysis
Neostigmine
[AChE inhibitors may also be used to tx paralytic ileus, atony of urinary bladder, and congenital megacolon]
Identify and explain symptoms of muscarinic receptor antagonism
Cutaneous vasodilation Anhidrosis Anhydrotic hyperthermia Nonreactive mydriasis Delirium Hallucinations Reduced desire to urinate
Appropriate pharmacologic therapy for symptoms such as cutaneous vasodilation, anhidrosis, anhydrotic hyperthermia, nonreactive mydriasis, delirium, hallucinations, and reduced desire to urinate due to reduced or blocked mAChR stimulation
Physostigmine is preferred because it crosses the BBB
AChE intoxication/excess may manifest as miosis, salivation, sweating, bronchial constriction, vomiting, diarrhea, confusion, ataxia, generalized convulsions, coma, and/or respiratory paralysis. Identify appropriate drug therapy to minimize effects at both mAChRs and nAChRs
Atropine (effective at mAChRs)
Pralidoxime (cholinesterase regenerator at nAChRs)
Benzodiazepine (anticonvulsant)
List 5 centrally acting spasmolytics (muscle relaxants)
Baclofen Carisprodol Cyclobenzaprine Diazepam Tizanidine
2 non-centrally acting spasmolytics
Dantrolene
Botulinum toxin
Centrally acting spasmolytic that is as effective as diazepam in reducing spasticity and causes less sedation; does not reduce overally muscle strength as much as dantrolene
Baclofen
MOA of baclofen
Agonist at GABA(B) receptors
Results in hyperpolarization (due to increased K+ conductance) and inhibition of excitatory neurotransmitter release in the brain and spinal cord
AEs of Baclofen
Drowsiness and increased seizure activity in epileptic pts (withdrawal must be done slowly); vertigo, dizziness, psychiatric disturbances, insomnia, slurred speech, ataxia, hypotonia, and muscle weakness
Centrally acting spasmolytic with unclear MOA; acts as a CNS depressant and is a schedule IV controlled substance with adverse effects of dizziness and drowsiness. Metabolized by CYP2C19 so should be used with caution when coadministered with CYP inhibitors
Carisprodol
Centrally acting spasmolytic that reduces tonic somatic motor activity by influencing both alpha and gamma motor neurons; structurally related to TCAs and produces antimuscarinic side effects + sedation, confusion, and transient visual hallucinations; metabolized by CYP450s so use with caution when coadministered with CYP inhibitors
Cyclobenzaprine
MOA of diazepam
Promotes binding of GABA to GABA(A) receptor, enhancing GABA-induced ion currents
Leads to increased inhibitory transmission and a reduction in spasticity
[note: causes sedation, muscle relaxation, anxiolytic, and anticonvulsant effects; schedule IV controlled substance]
Centrally acting spasmolytic that is an alpha2-adrenergic agonist similar to clonidine, decreases excitatory input to alpha motor neurons
Tizanidine
AEs of tizanidine
Drowsiness
Hypotension
Dry mouth
Asthenia/muscle weakness
MOA of dantrolene
Inhibition of ryanodine receptor (RyR); blocks release of calcium through SR and muscle contraction is impaired
Note that cardiac and smooth muscle are unaffected due to a different RyR channel subtype
[in contrast to centrally acting spasmolytics, dantrolene reduces skeletal muscle strength by interfering with excitation-contraction coupling in muscle fibers]
AEs of dantrolene
Generalized muscle weakness
Sedation
Hepatitis
Uses for dantrolene
Spasticity associated with upper motor neuron disorders (e.g., spinal cord injury, stroke, CP, or MS) and malignant hyperthermia
MOA of botulinum toxin
Cleaves components of core SNARE complex involved in exocytosis, preventing release of ACh
Clinical uses for botulinum toxin
Strabismus and blepharospasm associated with dystonia
Cervical dystonia
Temporary improvement in appearance of lines/wrinkles of the face
Severe primary axillary hyperhidrosis
Focal spasticity
Prophylaxis of chronic migraine
AEs of botulinum toxin
Focal muscle weakness in area of injection, which may last several months
AEs of carisoprodol
Dizziness
Drowsiness
Addictive potential
AEs of cyclobenzaprine
Drowsiness/sedation Dizziness Xerostomia Confusion Transient visual hallucinations
List immunologic drugs used for multiple sclerosis
Glucocorticoids
Glatiramer acetate
Interferons
Mitoxantrone
Monthly bolus IV ________ are used for tx of primary or secondary progressive MS alone or in combo with other immunomodulatory or immunosuppressive meds
Glucocorticoids (typically 1000 mg of methylprednisolone)
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. Thought to induce and activate T cell suppressor cells specific for a myelin antigen; also proposed to interfere with APC function of certain immune cells opposing pathogenic T cell function
Glatiramer acetate
Immunologic agents used to tx MS that act on BBB by interfering with T cell adhesion to the endothelium by binding VLA-4 on T cells or by inhibiting the T cell expression of MMP
Interferons (IFN-beta-1a, IFN-beta-1b)
Antineoplastic agent used to tx MS, AML, and advanced, hormone-refractory prostate cancer by intercalating into DNA resulting in cross-links and strand breaks (related to anthracycline abx)
Mitoxantrone
Tx option for MS that results in reduction of relapses by 1/3, a reduction of new MRI T2 lesions and the volume of enlarging T2 lesions, a reduction in number and volume of Gd-enhancing lesions, and a slowing of brain atrophy
Interferons
List 10 AChE inhibitors
Ambenonium Donepezil Echothiophate Edrophonium Galantamine Neostigmine Physostigmine Pyridostigmine Rivastigmine Tacrine
2 antimuscarinic compounds
Atropine
Glycopyrrolate
Cholinesterase reactivator
Pralidoxime
