Pharm: Skeletal Muscle Relaxants Flashcards
In which 2 conditions are patients resistant to non-depolarizing muscle relaxants (due to ↑ expression of nAChRs)?
Severe burns and upper motor neuron dz
What occurs in the Phase I block after dose of Succinylcholine?
- Activates nAChR –> depolarization of motor end plate: muscle contraction
- Membranes remain depolarized and unresponsive to subsequent impusles; flaccid paralysis results
Which drugs potentiate the neuromuscular blockage produced by nondepolarizing muscle relaxants in a dose-dependent fashion; list 6 drugs in this class in order of greatest to least effect?
Inhaled anesthetics: isoflurane >> sevoflurane = desflurane = enflurane = halothane > nitrous oxide
The combination of Succinylcholine and volatile anesthetics can result in what; how is this treated?
Malignant hyperthermia (rare); tx with Dantrolene
What is the MOA of Dantrolene?
- Inhibits the ryanodine receptor (RyR) –> prevents release of Ca2+ from sarcoplasmic reticulum
- Impaired skeletal muscle contraction; cardiac and smooth m. unaffected
What are 4 major uses of neuromuscular blocking drugs?
- Surgical relaxation
- Tracheal intubation
- Control of ventilation: for adequate gas exchange and prevents atelectasis in pt’s who have ventilatory failure; reduce chest wall resistance and improve thoracic compliance
- Tx of convulsions: of status epileptics or local anesthetic toxicity
Which 3 AChE inhibitors are used to tx Alzheimers and Dementia associated with Parkinsons?
Donepezil, Rivastigmine, and Galantamine
The centrally-acting spasmolytic, Carisprodol, is metabolized to what; why is this useful?
Meprobamate, which has anxiolytic and sedative effects (used to manage anxiety disorders)
Which 2 intermediate-acting steroid muscle relaxants undergo biliary excretion or hepatic metabolism for elimination and are more likely to be used clinically?
Vecuronium and Rocuronium
Which 5 AChE inhibitors are tertiary/uncharged; well absorbed from all sites and have CNS distribution?
Physostigmine + Donepezil + Tacrine + Rivastigmine + Galantamine
Which steroid muscle relaxant has the most rapid time of onset (60-120 sec.) and is an alternative to succinylcholine?
Rocuronium
What occurs if cholinesterase inhibitors are given during the phase I depolarizing block of Succinylcholine?
Potentiate the block; not reversal
Which agents are co-administered with AChE inhibitors during reversal of the effects of neuromuscular blocking agents to minimize adverse cholinergic effects?
Anticholinergic agents i.e., Atropine, Glycopyrrolate –> minimize DUMBBELSS
Succinylcholine is often used in what 2 scenarios?
- For rapid sequence induction i.e., emergency surgery when the objective is to secure the airway rapidly and prevent soiling of the lungs with gastric contents
- For quick surgical procedures where an ultrashort acting neuromuscular blocker is practical
What is the MOA of the centrally-acting spasmolytic, Baclofen?
GABAB receptor agonist; results in hyperpolarization (due to ↑ K+ conductance) and inhibition of excitatory NT release in brain and spinal cord
What is Glatiramer Acetate and it’s MOA?
- Mix of polymers of 4 AA’s (L-alanine, L-glutamic acid, L-lysine, and L-tyrosine) antigenically similar to myelin basic protein
- Induces and activates T-lymphocyte suppressor cells specific for myelin antigen
- Also interference w/ antigen-presenting function of certain immune cells opposing pathogenic T-cell function
What is the MOA of interferon-beta-1a and beta-1b used for MS?
Interferes w/ T-cell adhesion to the endothelium at BBB by binding VLA-4 on T cells or by inhibiting T-cell expression of MMP
What are 3 AE’s of the the centrally-acting spasmolytic, Cyclobenzaprine?
Drowsiness + dizziness + xerostomia
Which AE of Succinylcholine may be seen when administered during halothane anesthesia?
Cardiac arrhythmias
Succinylcholine may cause increased pressure in which 2 locations as an AE?
↑ intraocular pressure and ↑ intragastric pressure
What is the action of the centrally-acting spasmolytic, Cyclobenzaprine?
Reduces tonic somatic motor activity by influencing both alpha and gamma motor neurons
Which AChE inhibitor is preferred as an antidote for anticholinergic intoxication?
Physostigmine - can cross the BBB
Prolonged neuromuscular blockade after a dose of succinylcholine can occur in pt’s with genetically abnormal what?
Variant of plasma cholinesterase
What are 3 AE’s associated with Dantrolene?
- Generalized muscle weakness
- Sedation
- Occasionally hepatitis
Why has the clinical use of the neuromuscular blocking agent, d-tubocurarine, declined in favor of other agents?
Causes significant histamine release and has very long duration of action
What is the tx for AChE inhibitor intoxication?
- Atropine in combo w/ maintenance of vital signs (respiration) and decontamination; will only be effective at mAChRs
- To regenerate AChE at NMJ, give pralidoxime
- Atopine + pralidoxime + benzodiazepine are typically combined
What is the effect on arteries/veins with normal dose of AChE inhibitor vs. high-dose?
- Normal: dilation (via EDRF)
- High-dose: constriction
How are glucocorticoids used for tx of MS?
Monthly bolus IV glucocorticoids (typically methylprednisolone) used for tx of 1’ or 2’ progressive MS alone or in combo w/ other immunomodulatory/immunosuppressive meds
Prolonged duration of action from nondepolarizing muscle relaxants occurs in which patient population?
Elderly patients with ↓ hepatic and renal function
Which AChE inhibitor of the organophosphate type is charged and does not have CNS distribution?
Echothiophate
The precise MOA for the centrally-acting spasmolytic, Carisprodol, is unknown but it acts as what?
CNS depressant
List 3 contraindications for using Succinylcholine?
- Personal or family hx of malignant hyperthermia
- Myopathies associated w/ ↑ CPK values
- Acute phase of injury following: major burns, multiple trauma, extensive denervation of skeletal m. or upper motor neuron injury
What are the benefits of using interferon-beta-1a and beta-1b to tx MS?
- Reduction of relapses by 1/3
- Reduction of new MRI T2 lesions and the volume of enlarging T2 lesions
- Reduction in the number and volume of Gd-enhancing lesions
- Slowing of brain atrophy
How can the potential negative inotropic (contraction strength) and chronotropic (heart rate) effects of Succinylcholine be attenuated?
Administration of an anticholinergic i.e., Atopine
Which non-depolarizing muscle relaxant is not often used because of long-lasting effects as well as high degree of elimination by the kidney?
Doxacurium
Patients with what underlying conditions may respond to Succinylcholine by releasing K+ into the blood, which on rare occasions can lead to cardiac arrest?
Pt’s with burns, nerve damage, or neuromuscular disease, closed head injury or other trauma
Which non-depolarizing muscle relaxant is inactivated by a form of spontaneous breakdown known as Hofmann elimination and causes less histamine release than others in this class?
Atracurium
What are the effects of the α2-adrenergic agonist, Tizanidine?
Drowsiness + hypotension + dry mouth + asthenia/muscle weakness
The effects of nondepolarizing neuromuscular blocking agents are reversed how?
Addition of an acetylcholine esterase (AChE) inhibitors
AChE inhibitors may enhance which effect of beta-blockers?
Bradycardia
Which non-depolarizing muscle relaxant, in large doses, is associated with histamine release and is the only one associated with CV effects?
Mivacurium
What are some of the AE’s associated with Baclofen?
- Drowsiness
- ↑ seizure activity in epileptic pt’s (withdrawl must be done slowly)
- Vertigo + dizziness
- Psychiatric disturbances + insomnia + slurred speech + ataxia
- Hypotonia + muscle weakness
What is the MOA of Diazepam?
Promotes binding of GABA to GABAA receptor = ↑ frequency of channel openings –> ↑ inhibitory transmission and ↓ spasticity
What is Dantrolene used for?
- Tx spasticity assoc. w/ UMN disorders (i.e., spinal cord injury, stroke, cerebral palsy, or MS)
- Malignant hyperthermia
- Neuroleptic malignant syndrome i.e., toxicity of antipsychotic drugs
What are the 3 standard AChE inhibitors used in the symptomatic tx of myasthenia gravis; why?
- Pyridostigmine, neostigmine, and ambenonium
- Do not cross BBB
Which non-depolarizing muscle relaxant can be used in pt’s with significant renal and hepatic impairment?
Cisatracurium
What is the MOA of Mitoxantrone used for MS?
Antineoplastic agent; works by intercalating into DNA –> cross-links and strand breaks (related to anthracycline antibiotics)
Why must the centrally-acting spasmolytic, Carisprodol, be used only for short term; what are some AE’s?
- Schedule IV controlled due to addictive potential
- AE’s: dizziness and drowsiness
The centrally-acting spasmolytic, Carisprodol, is metabolized how; must be careful using in whom?
Metabolized by CYP2C19; use in caution with pt on CYP inhibitors
AChE inhibitors typically diminish the blockade of non-depolarizing neuromuscular blocking agents, which drug is an exception to this?
Mivacurium (metabolized by plasma AChE) –> AChE inhibitors will prolong the blockade of this agent
Which centrally-acting spasmolytic is as effective as diazepam in reducing spasticity and causes less sedation?
Baclofen
The centrally-acting spasmolytic, Cyclobenzaprine, is structurally related to which other class of drugs; how does this influence its AE’s?
- TCA antidepressants and produces antimuscarinic AE’s:
- Significant sedation + confusion + transient visual hallucinations
How can an AChE inhibitor (edrophonium) delineate between myasthenic crisis and cholinergic crisis?
- If pt is in myasthenic crisis the sx’s will improve
- If pt is in cholinergic crisis, the sx’s will remain unchanged or worsen
What are the dominant initial signs of AChE intoxication?
Those of mAChR stimulation: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
What 4 effects does Diazepam have?
- Sedation
- Muscle relaxation
- Anxiolytic
- Anticonvulsant
How do the cardiac effects of Succinylcholine differ from regular doses to high doses?
- Regular: stimulates nAChRs and mAChRs to produce negative inotropic (contraction strength) and chronotropic (heart rate) effects
- Large: can cause positive inotropic and chronotropic effects
Neuromuscular blocking agents with which chemical structure (steroid/isoquinoline) have the least tendency to cause histamine release?
Steroidal: Pancuronium, Pipercuronium, Rocuronium, and Vecuronium
As a general rule which muscles are more resistant to blockade from neuromuscular blocking agents and which recover more rapidly?
- Larger muscles (abdominal, trunk, paraspinous, diaphragm) = more resistant and recover quicker
*Diaphragm = last to be paralyzed and quickest to recover
Which AChE inhibitor is commonly used to reverse neuromuscular blocking drug-induced paralysis?
Neostigmine
Which AE’s may be seen with large doses of the neuromuscular blocking agent, Tubocurarine?
AChR blockade at autononic ganglia (adrenal medulla) –> HYPOtension + tachycardia
How is the Phase II desensitizing block by Succinylcholine reversed?
Acetylcholinesterase inhibitors
What occurs during the Phase II block after dose of Succinylcholine?
- Initial end plate depolarization ↓ and membrane is repolarized; BUT:
- Unable to depolarize because the receptor is desensitized; ACh receptors are available but don’t work.
Non-depolarizing neuromuscular blocking agents must be administered how?
Parenterally; they are highly polar
How does the pharmacokinetics of quaternary (charged) AChE inhibitors differ from the tertiary (uncharged) type?
- Quaternary: relatively insoluble (parenteral administration), no CNS distribution i.e., neostigmine, pyridostigmine, edrophonium, echothiophate
- Tertiary: well absorbed from all sites, CNS distribution i.e., physostigmine donpezil tacrine, rivastigmine, galantamine
List 3 agents that block signaling at the NMJ which can enhance the actions of nondepolarizing agents?
Tetrodotoxin, local anesthetics, and botulinum toxin
What is the black box warning associated with Succinylcholine?
- Acute rhabdomyolysis w/ hyperkalemia –> ventricular dysrhythmia, cardiac arrest, and death can occur after administration to apparently healthy children
- Usually males <8 y/o but also reported in adolescents
Which class of antibiotics have been shown to enhance neuromuscular blockade?
Aminoglycosides: gentamicin, tobramycin, streptomycin, neomycin, kanaymycin, paromycin, ntilmicin, spectinomycin
What is significant about the metabolism of the centrally-acting spasmolytic, Cyclobenzaprine?
Metabolized by CYP450; use with caution with CYP inhibitors
