Neuromuscular Relaxants Flashcards
Describe the mechanisms by which skeletal muscle nicotinic receptor activation stimulates skeletal muscle contraction, including the agonists, receptors, and postsynaptic mechanisms that initiate contraction.
- pre-synaptic neuron releases ACh into the synaptic cleft
- muscle nicotinic receptors (Nm) act as binding sites for the ACh
- activation of Nm receptors opens up Na+ channels for depolarization
- sufficient Na+ influx causes depolarization to travel down the T-Tubules (requires enough Na channels in the resting state)
- calcium influx leads to muscle contraction
Compare the 2 distinct mechanisms by which depolarizing and non-depolarizing neuromuscular blockers mediate their effects on the motor end plate.
NON-DEPOLARIZING = competitive antagonists
- block the nicotinic ACh receptors (curare crayons)
- overcome by excess ACh via tetanic stimulation or cholinesterase inhibitors (neostigmine store owner yells at curare kid)
- at higher concentrations, nicotinic channel pore is blocked => not as sensitive to excess ACh
DEPOLARIZING = agonists
Compare the pharmacokinetics of the 2 classes of neuromuscular blockers.
NON-DEPOLARIZING
- competitive binding of nicotinic receptors prevents membrane depolarization and end-plate potential
- rapid distribution
- t1/2 depends on route of elimination (kidney > liver > plasma cholinesterase (metabolic))
=> avoid drugs metabolized by the liver if the patient has liver failure
=> avoid drugs metabolized by the kidney if the patient has renal failure
- biological half-life is longer than therapeutic effect due to receptor reserve
DEPOLARIZING
- more rapid onset that ND
- rapidly metabolized by plasma cholinesterases
- action terminated by diffusion out of the synapse
- genetic variations in cholinesterase can prolong drug effect
- clinical manifestation: arm => neck => leg => diaphragm
Describe how cholinesterase inhibition affects the paralysis produced by each type of neuromuscular blocker.
NON-DEPOLARIZING
- overcome paralysis when given ChE inhibitors
DEPOLARIZING
- Phase I - exacerbation
- Phase II - overcome paralysis
List the mechanisms by which the action of both classes of neuromuscular blockers are terminated.
ND
- AChE inhibitors
D
- Phase I - diffusion
- Phase II - AChE inhibitors
Describe the prominent side effects of each class of skeletal muscle relaxants.
NON-DEPOLARIZING
- non-analgesic
- apnea
- drug interactions with inhalant anesthetics (enhanced effect)
DEPOLARIZING
- non-analgesic
- apnea
- muscle pain
- stimulation of nicotinic autonomic and muscarinic cardiac receptors (arrhythmia, HTN, bradycardia)
- hyperkalemia due to K+ release from motor end plate
- malignant hyperthermia
- drug interactions with local anesthetics (enhanced effect)
- drug interactions with cholinesterase inhibitors (enhances Phase I)
List the antidote for either class of neuromuscular blockers.
NON-DEPOLARIZING
- cholinesterase inhibitors (neostigmine store owner yells at curare kid)
- muscarinic blockers to minimize cholinesterase inhibitor action on the muscarinic receptors (glycopyrrolate)
DEPOLARIZING
- Phase I = none; rapidly hydrolyzed by plasma cholinesterase
=> atropine for bradycardia due to muscarinic effects
- Phase II = cholinesterase inhibitors
Describe the characteristics of phase I and phase II block with depolarizing neuromuscular blockers and describe why phase II should be avoided.
- Phase I - succinylcholine binds to the nicotinic ACh receptor and causes motor end plate depolarization => transient contraction => succinylcholine is NOT degraded by acetylcholinesterase (requires plasma cholinesterase) => continuous depolarization of the AChR => not enough time for Na+ channels to return to resting => inactivated Na+ channels => no further AP => flaccid paralysis
=> tx with ChE inhibitors will augment blockade - Phase II - succinylcholine enters the pore => membrane becomes repolarized, but receptor is desensitized;
=> acts like non-depolarizing muscle block
=> overcome by treatment with cholinesterase inhibitors or tetanic stimulation
=> but must confirm that Phase I is over b/c ChE inhibitors will augment muscle block when in Phase I
=> monitor patient for muscle action
=> avoid this phase by co-treatment with ChE inhibitors
Describe the characteristics of pancuronium, rocuronium, and vecuronium. Why is one agent preferable over another in long term ventilation, intubation of a healthy patient, or patient with renal failure for a short procedure or a moderate lengthy orthopedic surgery.
- long-term ventilation - roc
- intubation of a health patient - roc
- patient with renal failure for a short procedure - roc, mivac
- longer orthopedic surgery = pan
- avoid drugs metabolized by the liver if the patient has liver failure
- avoid drugs metabolized by the kidney if the patient has renal failure
Describe the mechanisms by which baclofen and benzodiazepines alter somatic motor neuron excitation.
- reduce activity of Ia fibers that excite the primary motor neuron
- enhance activity of the internuncial inhibitory neuron
List the major side effects of baclofen and benzodiazepines and discuss how the route of delivery can reduce side effects.
major SE = drowsiness
List the following for Tizanidine.
- MOA
- SE
- use
TIZANIDINE
- MOA: alpha-2 agonist (promotes inhibition of sympathetic activity in spinal cord)
- SE: drowsiness, hypotension
- use: MS and spinal spasticity
Define muscle twitch, clonus, and tetany.
twitch - action potential-dependent increase in intracellular calcium followed by reduction (sequestered in SR)
clonus - increased frequency of stimulation leads to incomplete relaxation;
tetany - no reduction in calcium between stimuli => muscle contraction
Describe how receptor reserve relates to the pharmacodynamics of curare compounds (non-depolarizing competitive antagonists).
- high receptor occupancy is required before an effect is observed
- % receptors occupied to inhibit contraction is proportional to (~) receptor reserve
- ex: 75% receptor occupancy is required before seeing any detriment in function, while 100% is required for full muscle relaxation
- biological half-life of curare compounds is longer than their therapeutic effect
Describe how receptor reserve creates a characteristic onset of drug effect for curare compounds (non-depolarizing competitive antagonists).
- different muscle beds have different receptor reserve and thus require different plasma concentration of curare to inhibit contraction
=> respiratory muscles > larger limb and trunk > fine muscles
EFFECTS
extraocular => hands and feet => head and neck => abdomen and extremities => diaphragm and respiratory muscles
This is because the lower the receptor reserve, the quicker therapeutic effects are reached (muscle weakness and paralysis)
