Nicotinic Agonists and Antagonists Flashcards
What are ways to modulate transmission of the neuromuscular junction at presynpatic sites?
Block Ca2+ transport (some aminoglycosides)
Block ACh secretion (Botulinum toxin)
Block choline uptake (hemicholinium)
What are ways to modulate transmission of the neuromuscular junction at postsynpatic sites?
Block nicotinic acetylcholine receptor (using nicotinic agonists and antagonists)
How does botulinum toxin prevent ACh secretion from the presynaptic site?
Enzymatically cleave the snare proteins (SNAP-25, syntaxin, synaptobrevin/VAMP)
Snare proteins are required for docking and release of ACh from synaptic vesicles
Which subunit of the nicotinic acetylcholine receptor does ACh bind to?
Alpha
How many molecules of ACh are needed to activate nicotinic receptor?
2
What are the two groups of neuromuscular blocking agents?
Nondepolarizing
Depolarizing
What drugs are in the non-depolarizing (antagonist) group?
d-Turbocurarine Pancuronium Vecuronium Cisatracurium Rocuronium
What drugs are in the depolarizing (agonist) group?
Succinylcholine
Why non-depolarizing and depolarizing drugs are used for intubation and why?
Non-depolarizing: rocuronium
Depolarizing: succinylcholine
Have short onset and short duration
Which drugs increase histamine release?
d-Tubocurarine
Succinylcholine
What is unique about the elimination of cisatracurium?
Hoffman elimination (spontaneous cleavage)
What are potential side effects of succinylcholine?
Malignant hypothermia
Increased intraocular pressure
What is the mechanism of action of the nondepolarizing neuromuscular antagonists?
Binds nicotinic receptor and blocks it
Do the following characteristics increase, decrease, or stay the same when a nondepolarizing agent is used:
- mini-EPP and EPP amplitude
- Resting membrane potential
- Action potential threshold
Decreased mini-EPP amplitude, decreased EPP amplitude
No change in RMP
No change in action potential threshold
How can an action potential be achieved in the presence of a nondepolarizing agent?
Temporal summation
Repetitive stimulation causes release of enough ACh to displace the blocker (changes the EPP enough to cause action potential)
What is the mechanism of action of the depolarizing neuromuscular agonists?
Binds nicotinic receptors and causes activation of these receptors below threshold, causing small local depolarization of the membrane
Do the following characteristics increase, decrease, or stay the same when a depolarizing agent is used:
- mini-EPP and EPP amplitude
- Resting membrane potential
- Action potential threshold
No change in mini-EPP and EPP amplitude
Increased (aka more positive) resting membrane potential (due to depolarization of membrane)
Increased action potential threshold (due to inactivation of Na+ channels with the increasing RMP)
Can succinylcholine be inactivated by AChE?
No
Can succinylcholine be inactived by butyryl-cholinesterase?
Yes
What is a potential side effect if succinylcholine is applied quickly in a large dose?
Muscle contracture
Must apply slowly and in low doses
What is ‘dual block’ and how does it occur?
Dual block = extended depolarization with succinylcholine leads to permanent desensitization of the ACh receptor
This happens because the ACh receptor changes conformation to a state where it cannot be activated
How is the effectiveness of a neuromuscular block measured in the OR?
Train of 4 stimulation, measure response of adductor pollicis to stimulation of ulnar nerve
How does AGE influence response to neuromuscular block?
Infants - more sensitive to non-depolarizing, less sensitive to depolarizing
Young infants have fewer receptors at neuromuscular junction, and this number increases with age
How does TEMPERATURE influence response to neuromuscular block?
Hypothermia - more sensitive to depolarizing, less sensitive to non-depolarizing
Decreased temp = decreased efficiency of Na/K pump = reduced membrane potential (aka more positive) = more sensitive to depolarizing block that reduces membrane potential even more
How do GENETIC VARIANTS influence response to neuromuscular block?
Genetic mutation can cause deficiency in butyrylcholinesterase
Cannot degrade succinylcholine (but would not affect anything else in life)
How does HYPOKALEMIA influence response to neuromuscular block?
Reduced K+ = hyperpolarized membrane = enhanced effect of non-depolarizing blocker, decreased effect of depolarizing blocker
How does HYPERKALEMIA influence response to neuromuscular block?
Increased K+ = depolarized membrane = decreased effect of non-depolarizing blocker, enhanced effect of depolarizing blocker
Are myasthenia gravis patients particularly sensitive to depolarizing or nondepolarizing blocks?
Nondepolarizing
Decreased # of ACh receptors = extremely sensitive to nondepolarizing block
Are bronchiogenic carcinoma patients particularly sensitive to depolarizing or nondepolarizing blocks?
Both! Sensitive to nondepolarizing and depolarizing
Reduced number of calcium channels (similar to Lamber Eaton autoimmune dx) = reduced ACh release
How does liver disease influence response to neuromuscular block?
Liver metabolizes many of the blockers and produces plasma butyrylcholinesterase
Results in decreased succinylcholine, vecuronium ,and rocuronium metabolism
How does succinylcholine induce malignant hyperthermia?
Inherited mutation in ryanodine receptor (calcium release in sarcoplasmic reticulum of muscle)
Succinylcholine binds mutated receptor and causes it to stay open = massive release of intracellular Ca2+ = rapid rise in body temp
