Neuromuscular Blocking Agents Flashcards
What are neuromuscular blocking agents? Where do they originate?
agents used in clinical medicine that act by interfering with the action of the endogenous neurotransmitter ACh on the nicotinic cholinergic receptor at the neuromuscular junction (NMJ)
discovery of curare, a mixture of naturally occurring alkaloids in South American plants used in arrow poison by Indians causing death by paralysis of respiratory muscles
- paralysis by blocking neuromuscular transmission
What is the most important component of curare?
tubocurarine
What are the 2 types of neuromuscular blocking agents?
- competitive nondepolarizing agents - occupy the receptor so that ACh cannot access its binding site and fail to trigger transmembrane ion movement, resulting in muscle paralysis (competes with ACh)
- depolarizing agents - causes initial membrane depolarization (muscle fasciculation) before the blockade and muscle paralysis occurs
Neuromuscular blocking agents:
What happens at the neuromuscular junction?
- ACh is released into the synaptic cleft and binds to specialized nicotinic receptors
- nicotinic cholinergic receptors located on the plasma membrane surface of the muscle cell are clustered in high densities
- they require the activation of a large number to excite a single muscle fiber —> muscle contraction
How much ACh is located in a single vesicle? How many vesicles can be released at once? What is the relative ratio of binding site for ACh on nicotinic cholinergic receptors to AChE binding sites?
7000-12000
single AP may trigger the fusion of 40-300 vesicles
10:1
What are 3 structural characteristics of nicotinic cholinergic receptors? What happens upon activation?
- 5 subunits (α1, α2, β, δ (ε in adults), γ)
- anionic binding site on α subunits where 2 ACh binds to induce a conformational change
- central transmembrane channel for ion fluxes instigated by agonist activation (ACh)
Na+ moves into cells and K+ moves out
What happens when the binding site of nicotinic cholinergic receptors is occupied by competitive nondepolarizing agents? What happens upon depolarizing agent binding?
receptor is stabilized —> membrane channel is not activated
allows the initial channel activation and ion flow, but it results in a persistent interruption in ion flow through the receptor
What are Tetrodotoxin and Saxitoxin commonly found in? How do they act as neuromuscular blocking agents?
fish and shellfish poisons
decrease the permeability of excitable membrane to Na+ (but not K+), resulting in no generation of axonal action potentials —> muscle paralysis
How do local anesthetics work as neuromuscular blocking agents?
inactivate Na+/K+ channels —> propagation of AP is halted
How does Hemicholinium work as a neuromuscular blocking agent?
interferes with the choline reuptake into cholinergic neurons used for ACh synthesis
- no clinical application; research
How do magnesium ions (Mg2+) act as neuromuscular blocking agents?
interfere with the release of ACh by competing for transport mechanisms responsible for mobilization of Ca2+ into the nerve, which lowers the sensitivity of postsynaptic membrane to ACh
What aminoglycoside antibiotics can be used as neuromuscular blocking agents? How do they work?
Neomycin, Streptomycin, Kanamycin, Gentamycin
- inhibit the release of ACh from motor nerves
- lowers availability of Ca2+ at axonal terminals
- lowers sensitivity of the postsynaptic membrane to ACh
Competitive nondepolarizing vs depolarizing neuromuscular blocking agents:
What is the historical prototype of competitive nondepolarizing neuromuscular blocking agents? What drugs are used now?
d-tubocurarine - binds cholinergic receptors, but does not exhibit receptor-activating properties —> any motor end-plate potential
Atracurium, Cisatracurium, Mivacurium, Doxocurium, Pancurium, Vecuronium, Rocuronium, Gantacurium
(don’t absorb well, given IV)
What are the 2 types of competitive nondepolarizing neuromuscular blocking agents?
- pachycurares
- bulky molecyles
What are the 3 groups of pachycurares used as neuromuscular blocking agents?
- benzylisoquinoliniums - Atracurium, Cisatracurium (Mivacurium, Doxocurium)
- aminosteroids - Vecuronium, Rocuronium, Pancuronium
- asymmetric mixed-onium chlorofumarate - Gantacurium (new!)
What is Atracurium most commonly used for? Why is it safe to use for patients with significant renal and hepatic insufficiency? What affects its elimination?
produces muscle relaxation during surgery, most commonly to facilitate endotracheal intubation
Hofmann elimination - reaction in the plasma without enzymes accelerated by high pH and high temperatures
How is Atracurium used in cats?
used in male cats with urethral plugs to increase obstruction removal
What is Cisatracurium? How does it compare to Atracurium?
neuromuscular blocking agent; cis-isomer of Atracurium
similar duration and clinical effects
What was the first aminosteroid introduced as a neuromuscular blocking agent? How is it used? How does it affect the cardiovascular system?
Pancuronium - use today is rare
muscle relaxation during surgery to facilitate endotracheal intubation
inconsistent among species (blocks muscarinic receptors)
How is Vencuronium commonly used? How is it metabolized? How can this affect recovery time?
adjunct to general anesthesia to produce muscle relaxation
partially metabolized in the liver
prolonged recovery time can result in patients with renal or hepatic disease
How does Vencuronium compare to other aminosteroid neuromuscular blocking agents?
- minimal cardiac effects
- potency lower in horses
How does Rocuronium compare to other neuromuscular blocking agents?
- rapid onset compared to Atracurium and Vecuronium
- similar duration of action
- devoid of cardiovascular side effects
What is the duration of action of Gantacurium? How is it eliminated? How can recovery be accelerated?
ultrashort
Hofmann elimination - degraded in plasma by pH-sensitive chemical hydrolysis
AChE inhibitors
What is the only depolarizing neuromuscular blocking agent available for use in veterinary medicine? What is its onset of action and duration like?
succinylcholine
rapid onset and short duration —> requires frequent redosing or constant-rate infusion
Why is succinylcholine use limited in small animal patients? How does it work?
dog and cat larynx does not routinely exhibit excessive laryngospasm
stimulated cholinergic receptors at NMJ and elicited a prolonged depolarization of neuromuscular end-plate
What is the biphasic mechanism of depolarization induced by succinylcholine like?
PHASE I - nonselective cation channel associated with nicotinic muscle receptor is opened and the receptor is depolarized, resulting in an increase in the persistent permeability to Na+ and K+ and fasciculations
PHASE II - nonselective cation channel closes and repolarization occurs, rendering the NMJ resistant to depolarization, resulting in flaccid paralysis
Why does succinylcholine cause persistent alteration during Phase I block?
it is not hydrolyzed and must slowly diffuse away from the NMJ
How does muscle paralysis progress after the administration of neuromuscular blocking agents? How does recovery proceed?
- extraocular muscles, facial muscles, head and neck muscles
- limbs muscles, deglution and laryngeal muscles (glottis)
- abdominal muscles, intercoastal muscles, diaphragms
recovers in the reverse direction
Why is the correct dosage of neuromuscular blocking agents crucial? What is imperative to be available while using NMB agents?
need to use a dosage adequate to paralyze ambulatory muscle, but is insufficient to affect the diaphragm, or else respiratory insufficiency will occur
apparatus for administering mechanical ventilation
What are 5 common clinical uses of neuromuscular blocking agents?
- facilitates tracheal intubation in an unanesthetized animal immediately after administration of the paralyzing dose has taken effect (+ sedation/tranquilization)
- increase muscle relaxation to facilitate surgical access to difficult anatomical regions
- evoke muscle relaxation to facilitate orthopedic manipulations
- improve ocular positioning for surgery
- reduce the amount of general anesthesia
How does the presence of neuromuscular blocking agents in cholinergic receptors relate to muscle twitch failure? How does this work for recovery?
large percentage of receptors must be occupied before muscle twitch fails
only a small percentage (5% in dogs, 18% in cats) is needed to regain muscle contraction control
What are the steps to reverse neuromuscular paralysis?
- initiate positive pressure ventilation (PPV) so allow for adequate time for the drug to be metabolized
- withdraw administration of involved NMB agent
- avoid using drugs that work synergistically with NMB agents
- reverse the neuromuscular blockade with AChE inhibitors or sugammadex (cyclodextrin)
How do AChE inhibitors reverse the neuromuscular blockade? Which 3 are used to reverse NMB agents? What agent do they not work on?
inhibits AChE, which is responsible for the hydrolysis of ACh into choline and acetic acid
edrophonium**, neostigmine, pyridostigmine
- rapid onset, milk muscarinic effects
depolarizing NMB agents —> succinylcholine
What is the first selective relaxant binding agent (SRBA)? How does it work?
Sugammadex, a cyclodextrin
tightly encapsulates aminosteroid-based nondepolarizing NMB agents
- hydrophobic cavity and hydrophilic exterior
- hyrdophobic interaction traps NMB agent in cavity and the complex is readily available for elmination
Administration of which of the following NMB drugs will cause transient and painful skeletal muscle contractions?
a. Atracurium
b. Pancuronium
c. Vencuronium
d. Succinylcholine
e. Tubocurarine
D
Which of the following agents would you administer to reverse the action of nondepolarizing NMB drugs?
a. Gentamycin
b. Neomycin
c. Hemicholinum
d. Neostigmine
D
True or false: AChE inhibitors act by preventing ACh release.
FALSE
True or false: In patients with liver and renal disease, you would rather choose Atracurium as a NMB agent.
TRUE
