Pharm: Skeletal Muscle Relaxants Flashcards
Non-depolarizing neuromuscular blocking agents must be administered how?
Parenterally; they are highly polar
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
The effects of nondepolarizing neuromuscular blocking agents are reversed how?
Addition of an acetylcholine esterase (AChE) inhibitors
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
Which AE’s may be seen with large doses of the neuromuscular blocking agent, Tubocurarine?
AChR blockade at autononic ganglia (adrenal medulla) –> HYPOtension + tachycardia
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
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
Which class of antibiotics have been shown to enhance neuromuscular blockade?
Aminoglycosides: gentamicin, tobramycin, streptomycin, neomycin, kanaymycin, paromycin, ntilmicin, spectinomycin
List 3 agents that block signaling at the NMJ which can enhance the actions of nondepolarizing agents?
Tetrodotoxin, local anesthetics, and botulinum toxin
In which 2 conditions are patients resistant to non-depolarizing muscle relaxants (due to ↑ expression of nAChRs)?
Severe burns and upper motor neuron dz
Prolonged duration of action from nondepolarizing muscle relaxants occurs in which patient population?
Elderly patients with ↓ hepatic and renal function
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
Which non-depolarizing muscle relaxant can be used in pt’s with significant renal and hepatic impairment?
Cisatracurium
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
Which non-depolarizing muscle relaxant, in large doses, is associated with histamine release and is the only one associated with CV effects?
Mivacurium
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
Neuromuscular blocking agents with which chemical structure (steroid/isoquinoline) have the least tendency to cause histamine release?
Steroidal: Pancuronium, Pipercuronium, Rocuronium, and Vecuronium
Which steroid muscle relaxant has the most rapid time of onset (60-120 sec.) and is an alternative to succinylcholine?
Rocuronium
Prolonged neuromuscular blockade after a dose of succinylcholine can occur in pt’s with genetically abnormal what?
Variant of plasma cholinesterase
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
What occurs if cholinesterase inhibitors are given during the phase I depolarizing block of Succinylcholine?
Potentiate the block; not reversal
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.
How is the Phase II desensitizing block by Succinylcholine reversed?
Acetylcholinesterase inhibitors
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
Which AE of Succinylcholine may be seen when administered during halothane anesthesia?
Cardiac arrhythmias
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
How can the potential negative inotropic (contraction strength) and chronotropic (heart rate) effects of Succinylcholine be attenuated?
Administration of an anticholinergic i.e., Atopine
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
Succinylcholine may cause increased pressure in which 2 locations as an AE?
↑ intraocular pressure and ↑ intragastric pressure
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 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
The combination of Succinylcholine and volatile anesthetics can result in what; how is this treated?
Malignant hyperthermia (rare); tx with Dantrolene
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
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
Which 5 AChE inhibitors are tertiary/uncharged; well absorbed from all sites and have CNS distribution?
Physostigmine + Donepezil + Tacrine + Rivastigmine + Galantamine
Which AChE inhibitor of the organophosphate type is charged and does not have CNS distribution?
Echothiophate
What is the effect on arteries/veins with normal dose of AChE inhibitor vs. high-dose?
- Normal: dilation (via EDRF)
- High-dose: constriction
What are the 3 standard AChE inhibitors used in the symptomatic tx of myasthenia gravis; why?
- Pyridostigmine, neostigmine, and ambenonium
- Do not cross BBB
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
Which AChE inhibitor is commonly used to reverse neuromuscular blocking drug-induced paralysis?
Neostigmine
Which 3 AChE inhibitors are used to tx Alzheimers and Dementia associated with Parkinsons?
Donepezil, Rivastigmine, and Galantamine
Which AChE inhibitor is preferred as an antidote for anticholinergic intoxication?
Physostigmine - can cross the BBB
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
AChE inhibitors may enhance which effect of beta-blockers?
Bradycardia
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 are the dominant initial signs of AChE intoxication?
Those of mAChR stimulation: miosis, salivation, sweating, bronchial constriction, vomiting, and diarrhea
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
Which centrally-acting spasmolytic is as effective as diazepam in reducing spasticity and causes less sedation?
Baclofen
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
The precise MOA for the centrally-acting spasmolytic, Carisprodol, is unknown but it acts as what?
CNS depressant
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
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)
What is the action of the centrally-acting spasmolytic, Cyclobenzaprine?
Reduces tonic somatic motor activity by influencing both alpha and gamma motor neurons
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
What is significant about the metabolism of the centrally-acting spasmolytic, Cyclobenzaprine?
Metabolized by CYP450; use with caution with CYP inhibitors
What are 3 AE’s of the the centrally-acting spasmolytic, Cyclobenzaprine?
Drowsiness + dizziness + xerostomia
What is the MOA of Diazepam?
Promotes binding of GABA to GABAA receptor = ↑ frequency of channel openings –> ↑ inhibitory transmission and ↓ spasticity
What 4 effects does Diazepam have?
- Sedation
- Muscle relaxation
- Anxiolytic
- Anticonvulsant
What are the effects of the α2-adrenergic agonist, Tizanidine?
Drowsiness + hypotension + dry mouth + asthenia/muscle weakness
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 3 AE’s associated with Dantrolene?
- Generalized muscle weakness
- Sedation
- Occasionally hepatitis
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
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
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 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
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)
