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