2. NMJ
• The NMJ is a highly specialized synapse at which
presynaptic motor nerve endings meet the
postsynaptic membranes of skeletal muscles (motor
end plates).
• The NMJ is designed to transmit electrical impulses
from the nerve terminal to the skeletal muscle via the
chemical transmitter, acetylcholine.
• The NMJ comprises portions of three structures—
motor neuron, muscle fiber, and glial cells known as
Schwann cell.
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3. NMJ
• The NMJ is consisted of a three components:
1. Presynaptic (or prejunctional) nerve terminal synaptic
vesicles (SVs) (acetylcholine) and mitochondria.
2. Synaptic cleft that contains acetylcholinesterase enzyme
responsible for hydrolysis of free acetylcholine.
3. Postsynaptic (or postjunctional) muscle membrane that is
highly infolded and these foldsc (left).
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5. The Nicotinic Acetylcholine Receptor(nAChR) at NMJ
• In the adult skeletal muscle, the nAChRs are highly
concentrated at the crests of junctional folds.
• The nAChR is a complex of two α subunits in association with
a single β, δ, and ε subunit.
• The two α subunits has an acetylcholine-binding site.
• The fetal nAChRs contains a γ subunit instead of an ε adult
subunit.
• The mature nAChR has a higher conductance to Na+, K+, and
Ca 2+ than the fetal nAChR.
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6. • Upregulation of nAChRs, found in states of functional or
surgical denervation, is characterized by the spreading of
predominantly fetal type nAChRs.
• In some pathologic states such as:
– Denervation
– Burns immobilization
– Inflammation or sepsis
• These receptors are resistant to nondepolarizing
neuromuscular blockers and more sensitive to
succinylcholine (SCh).
• When depolarized, the immature isoform has a prolonged
open channel time that exaggerates the K+ efflux.
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7. Presynaptic Structure and Function
• Is responsible for neurotransmitter (ACh) synthesis, uptake
and storage into synaptic vesicles.
• ACh release and reuptake of choline after its hydrolysis.
• Motor neuron is a large myelinated axon that extends from
the ventral horn of the spinal cord to the NMJ.
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8. Nerve Terminal Action Potential
• During the nerve action potential:
– Na+ from outside the nerve flows resulting depolarizing
voltage opens voltage-gated Ca2+ channels, which permit
Ca2+ to enter the nerve triggering the release of ACh.
• The Ca2+ current persists until the channels inactivate and
outward fluxes of K+ from inside the nerve return the
membrane potential to normal.
• These K+ channels limit the duration of nerve terminal
depolarization.
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9. Synaptic Cleft Structure and Function
• The junctional or synaptic cleft is the gap (~50 nm) between
the nerve terminal ending and the muscle membrane.
• The cleft contains molecules include acetylcholinesterase.
• After release from the nerve terminal, ACh diffuses the short
distance across the synaptic cleft to the postsynaptic
membrane.
• Approximately 50% of the released ACh is degraded by
acetylcholinesterase.
• Acetylcholinesterase degrades ACh into acetate and choline.
• Choline is then taken up into the presynaptic terminal by a
specific transporter for re-synthesis of ACh within the nerve
terminal.
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10. Electrical transmission
• As an electrical signal motor nerve (presynaptic) terminal
depolarization of Ca2+channels, and ACh is released from synaptic
vesicles.
• The cleft is home to acetylcholinesterase, the enzyme that breaks
down ACh.
• 50% of the released ACh is cleaved by acetylcholinesterase, and the
remaining bind to postsynaptic nAChRs on the motor end plate
open ion channels Na+ influxes .
• When enough channels are opened, the myocyte is depolarized and
muscle contraction occurs muscle is allowed to repolarize.
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11. Postsynaptic Membrane
• The shoulders of the folds contain high densities of AChRs (~
5 million in each junction).
• AChRs contain a high density of voltage-gated Na+ channels
for amplification of AChR induced depolarization.
• It serves the critical function of transducing the signal from the
junction into deeper regions of the muscle cell.
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12. Mechanism of action
• Normal physiology:
• nAChRs are ionotropic (are ion channels).
• N1 nAChR location: NMJ (end plate) on skeletal
muscles.
• Activation of nAChRs by acetylcholine (ACh):
• Ion channel opens → net Na+ influx →
depolarization at postsynaptic membrane → action
potential in muscle fiber → muscle contracts.
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13. Mechanism of action:
Depolarizing muscle relaxant(DMRs)
• DMRs:
– ACh-receptor agonists.
– Bind to the ACh receptors and transmit the nerve impulse
to the muscle cell
– Similar to normal neuromuscular transmission.
– Are not metabolized by cholinesterase
• DMRs remain bound to the ACh receptor which stays open
inhibiting repolarization persistent depolarization of the
motor endplate and flaccid paralysis of the skeletal muscles.
• Cessation of the effect of depolarizing muscle relaxants are
cleared off by blood.
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14. Depolarizing neuromuscular blockers:
• Succinylcholine is degraded by plasma
pseudocholinesterase.
• Cholinesterase inhibitors do not reverse effects → may
prolong depolarization due to plasma pseudocholinesterase
inhibition.
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15. Nondepolarizing neuromuscular blockers:
• Competitively block ACh from binding to the nAChR and
keep the ion channel closed → prevents muscle contraction
• Effects reversed by cholinesterase inhibitors (e.g.,
physostigmine, neostigmine).
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18. Depolarizing muscle relaxants
• Pharmacodynamics
• Depolarizing and nondepolarizing muscle relaxants only target nicotinic
receptors at the NMJ; they do not target autonomic N. receptors.
• Succinylcholine (suxamethonium)
– Binds to ACh receptors → depolarization of motor end plate →
skeletal muscle fasciculations
– Persistent depolarization of the motor end plate → unresponsiveness of
the motor end plate to subsequent nerve impulses (depolarized block) →
flaccid paralysis of the skeletal muscles
– Within 5–10 minutes plasma cholinesterases metabolize succinylcholine.
• Enzymes that catalyze the breakdown of choline esters
(acetylcholinesterase and butyrylcholinesterase).
• Patients with atypical plasma cholinesterase: prolonged paralysis
– Succinylcholine has no antagonist.
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19. • Phase I blockade
– Persistent depolarization of the acetylcholine receptors of
the NMJ.
– There is currently no antidote.
– Phase I blockade is potentiated by the effects
of cholinesterase inhibitors.
• Phase II blockade
– Despite continued depolarization by succinylcholine,
the postsynaptic membrane repolarizes and becomes
desensitized, (i.e., resistant
to depolarization by acetylcholine) leading to prolonged
muscle relaxation.
– Cholinesterase inhibitors may reverse the effects of phase II
blockade.
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20. Nondepolarizing muscle relaxants
• Compete with ACh to bind with the (nicotinic) ACh receptors at the motor
end plate.
• Competitive antagonists) → prevents depolarization of the motor end
plate.
• Antagonists
– Neostigmine, pyridostigmine, and edrophonium are usually
coadministered with anticholinergics, such
as atropine or glycopyrrolate, to counter muscarinic effects
like bradycardia, nausea, and bronchospasm.
– Sugammadex: a selective relaxant binding agent and rapid-
acting antidote for rocuronium and vecuronium
• Paralysis affects the small muscles of the face first, progresses to the
extremities and trunk, and affects the intercostal muscles and diaphragm
last.
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21. Adverse effects
• Depolarizing NMJ blocker (succinylcholine)
• Hyperkalemia
– Efflux of potassium ions into the extracellular space
– A high-risk of hyperkalemia, including:
• Burn injuries
• Rhabdomyolysis
• Demyelinating disorders (e.g., Guillain-Barré syndrome, multiple
sclerosis, ALS)
• Stroke
• Spinal cord injury
• Postoperative muscle pain due to muscle fasciculations.
• Prolonged muscle paralysis, respiratory depression and/or apnea in patients with a
congenital deficiency of plasma cholinesterase
• Malignant hyperthermia
• Cardiac arrhythmias
• Raised intragastric pressure → emesis
• Raised IOP, ICP
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23. Indications
• Skeletal muscle relaxants are used as adjuncts to anesthetic
agents:
– Laryngeal intubation and rapid sequence induction of
anesthesia : drugs with fast onset of action
(e.g., succinylcholine, rocuronium)
– Artificial ventilation (during anesthesia or in
intubated ICU patients)
– Abdominal muscle relaxation during laparotomy
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24. Monitoring
• Patients who have been given NMJ blockers should be
monitored.
• Clinical assessment:
– ability of the patient to spontaneously open the eyes
– Lift the head/legs, or
– The presence of spontaneous ventilation help determine the
degree of paralysis
• Neuromuscular monitoring:
– Objectively determines degree of muscle paralysis with the
help of a peripheral nerve stimulator
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25. • Method: train-of-four response
– Four electric stimuli are administered along the ulnar
nerve every 2 seconds
– The number of twitches of the adductor pollicis muscle are
counted.
• Interpretation
– 0 twitches indicates profound NMJ block
– 1–2 twitches indicate a partial block.
– 1 twitch per electric stimulus indicates no NMJ block.
• Inadequate reversal can lead to upper airway obstruction
(pharyngeal muscle weakness) and inadequate ventilation.
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