2. Neuromuscular junction
(example of chemical synapse)
Neuromuscular junction : the synapse
between motor neuron and muscle fiber is
called the neuromuscular junction
Motor neurons : are the nerves that
innervate muscle fibers
Motor unit : single motor neuron and the
muscle fibers it innervate
2
3. Physiologic anatomy of N.M
junction (continued)
As axon approaches muscle , it divides
into many terminal branches and loses
its myelin sheath
Each of these axon terminal forms
special junction ,a neuromuscular
junction with one or more muscle fiber
3
5. Physiologic anatomy of N.M
junction (continued)
The axon terminal is enlarged into a knoblike
structure ,the terminal botton,which fits into
shallow depression in underlying muscle fiber
5
7. Sequence Of Events At Neuromuscular Junction
Action potential
Action potential
Ca2+
Ca2+
Presynaptic
terminal
Presynaptic
terminal
Voltage-gated
Ca2+ channel
Voltage-gated
Ca2+ channel
7
Action potentials arriving at the presynaptic terminal
cause voltage-gated Ca2+ channels to open.
8. Sequence Of Events At Neuromuscular Junction
(continued)
Ca2+ diffuse into the cell and cause synaptic vesicles to release
acetylcholine, a neurotransmitter molecule.
Ca2+
Ca2+
Synaptic
vesicle
Synaptic
vesicle
Acetylcholine
Acetylcholine
8
Ca2+ uptake into the terminal causes release of the
neurotransmitter acetylcholine into synaptic cleft , which has
been synthesized and stored into synaptic vesicles
9. Sequence Of Events At Neuromuscular Junction
(continued)
Ach travels across the synaptic cleft to postsynaptic
membrane which is also known as motor end plate.
Acetylcholine diffuses from the presynaptic terminal across the
Synaptic cleft
Synaptic cleft
Acetylcholine
Acetylcholine
Presynaptic
terminal
Presynaptic
terminal
Ca2+
Ca2+
9
10. Sequence Of Events At
Neuromuscular Junction (continued)
Motor end plate contains nicotinic receptors
for Ach , which r ligand gated ion channels
Ach binds to the alpha subunits of nicotinic
receptors and causes conformational change.
When conformational changes occurs ,the
central core of channels opens & permeability
of motor end plate to Na+ & K+ increases
10
12. Sequence Of Events At
Neuromuscular Junction (continued)
Acetylcholine molecules combine with their receptor sites and
cause ligand-gated Na+ channels to open.
Na+
Na+
Acetylcholine bound
to receptor site opens
ligand-gated Na+
channel
Acetylcholine bound
to receptor site opens
ligand-gated Na+
channel
12
13. End plate potential
When the ion channel on post synaptic membrane
opens both Na+ & K+ flow down their concentration
gradient.
At resting potential net driving force for Na+ is much
greater than K+ ,when Ach triggers opening of these
channels more Na+ moves inwards than K+ out
wards, depolarizing the end plate.this potential
change is called end plate potential (EPP).
EPP is not an action potential but it is simply
depolarization of specialized motor end plate
13
14. End plate potential (continued)
Small quanta (packets) of Ach are released randomly
from nerve cell at rest, each producing smallest
possible change in membrane potential of motor end
plate, the MINIATURE EPP.
When nerve impulse reaches the ending, the number
of quanta release increases by several folds and
result in large EPP.
EPP than spread by local current to adjacent muscle
fibers which r depolarized to threshold & fire action
potential
14
15. Acetyl cholinesterase ends Ach
activity at N.M junction
To ensure purposeful movement ,muscle cell
electrical response is turned off by
acetylcholinestrase(AchE), which degrade Ach to
choline & acetate
About 50%of choline is returned to the
presynaptic terminal by Na+choline transport to
be reused for Ach synthesis.
Now muscle fiber can relax ,if sustained
contraction is needed for the desired movement
another motor neuron AP leads to release of
more Ach 15
16. Myasthenia gravis
A disease involving N.M junction is characterized by the
extreme muscular weakness (myasthenia=muscular &
gravis=severe)
It is an auto immune condition (auto immune means
immunity against self) in which the body erroneously
produces antibodies against its own motor end plate ach
receptors.
Thus not all Ach molecules can find functioning receptors
site with which to bind.
As a results ,AchE destroys much of Ach before it ever
has a chance to interact with receptor site & contribute to
EPP.
16
17. Treatment :
it is treated with long acting
anticholinesterase inhibitor
pyridostigmine or neostigmine.
Which maintains the Ach levels at N.M
junction at high levels thus prolonging
the time available for Ach to activate its
receptors.
17
20. Classical Mechanism of Action
Non-depolarizers:
bind to AchR, post junctional nicotinic
receptor
competitively prevent binding of Ach to
receptor
ion channel closed, no current can flow
Depolarizers- succinylcholine:
mimic action of Ach
excitation of muscle contraction followed
by blockade of neuromuscular transmission
21. Margin of Safety
Wide margin of
safety of
neuromuscular
transmission
70% receptor
occupancy before
twitch depression
22. Smith CE, Peerless JR: ITACCS
Monograph 1996
Clinical Use
Anesthesia:
facilitate tracheal intubation
paralysis for surgery + mechanical ventilation
ICU:
VO2
tetanus
status epilepticus
ICP
shivering
23. Viby-Mogensen, 1984
TOF Monitoring
TOF:
4 supramaximal stimuli at
2 Hz, every 0.5 sec
observe ratio of 4rth
twitch to first
Loss of all 4 twitches:
profound block
Return of 1-2 twitches:
sufficient for most
surgeries
Return of all 4 twitches:
easily “reversible”
25. Vecuronium
ED90: 0.04 mg/kg
intubating dose: 0.1-0.2 mg/kg
onset: 2-4 min, clinical duration: 30-60 min
Maintenance dose: 0.01-0.02 mg/kg, duration: 15-30
min
Metabolized by liver, 75-80%
Excreted by kidney, 20-25%
½ life : 60 minutes
Prolonged duration in elderly + liver disease
No CV effects, no histamine release, no vagolysis
May precipitate after thiopental
26. Rocuronium
ED90: 0.3 mg/kg
intubating dose: 0.6-1.0 mg/kg
onset: 1-1.5 minutes, clinical duration: 30-60 min
Maintenance dose: 0.1-0.15 mg/kg, duration: 15-30
min
Metabolized by liver, 75-80%
Excreted by kidney, 20-25%
½ life : ~ 60 minutes
Mild CV effects- vagolysis, no histamine release,
Prolonged duration in elderly + liver disease
Only non-depolarizer approved for RSI
27. Prielipp et al: Anesth Analg
1995;81:3-12
Cisatracurium
ED90: 0.05 mg/kg
intubating dose: 0.2 mg/kg
onset: 2-4 minutes, clinical duration: 60 min
Hofmann elimination: not dependent on liver or
kidney for elimination
Predictable spontaneous recovery regardless of dose
½ life : ~ 60 minutes
No histamine release
CV stability
Agent of choice for infusion in ICU
28. Succinylcholine
ED90: 0.3 mg/kg
intubating dose: 1.0-1.5 mg/kg
onset: 30-45 sec, clinical duration: 5-10 min
can be given IM or sublingual
dose to relieve laryngospasm: 0.3 mg/kg
Maintenance dose: no longer used
Metabolized by pseudocholinesterase
prolonged duration if abnormal pc (dibucaine #
20)
Prolonged effect if given after neostigmine
29. Succinylcholine: Key Concepts
Bradycardia + nodal rhythms after “2nd
dose” in adults + after initial dose in children
Hyperkalemia + cardiac arrest likely 1 week
after major burns, or in children with
Duchenne’s muscular dystrophy
Not contraindicated in patients with head
injury
May cause malignant hyperthermia or
masseter spasm
Duration increased by prior administration of
neostigmine
32. Bevan DR, Bevan JC, Donati F:
1988
Sux + Hyperkalemia
Burns, Hemiplegia, Paraplegia, Quadraplegia:
extrajunctional receptors after burn or
denervation
Danger of hyperkalemia with sux: 48 hrs post
injury until …?
Muscular Dystrophy
Miscellaneous
severe infections, closed head injury, crush,
rhabdo, wound botulism, necrotizing pancreatitis
Renal failure: pre-existing hyperkalemia
Acidosis: extracellular K
33. Cholinesterase Inhibitors
•↑ Ach at nicotinic +
muscarinic receptors
to antagonize NMB
•Full reversal depends
on diffusion,
redistribution,
metabolism +
excretion
34. Key Concepts of NMBA Reversal
Cholinesterase inhibitors indirectly reverse
NMB
Head lift x 5 sec- reliable sign of reversal
Teeth clenching x 5 sec- reliable sign of
reversal
Usually not difficult to reverse block if 2
twitches are visible in response to TOF
Neostigmine is a minor risk factor for PONV
Anticholinergic agents should never be
omitted with reversal
35. Viby-Mogensen, 2000
Double Burst
TOF fade: difficult to
detect clinically until
< 0.2
Use double burst:
2 short bursts of
tetanic stimulation
separated by 750 ms
Easier to detect fade
+ residual block, 0.2-
0.7
36. Savarese JJ, Caldwell JE, Lien CA,
Miller RD: 2000
Clinical Evaluation
Reliable signs of adequate NM
transmission
Head lift x 5 s
Leg lift x 5 s
Hand grip as strong as preop x 5 s
Sustained bite
Helpful, but unreliable
Normal Vt , Vc, + cough
37. Reversal of NM Block
Clinical practice:
if no evidence block + 4 half-lives: omit reversal
if still evidence block: give reversal
if unsure: give reversal
Rule of thumb:
if 2 twitches of TOF visible, block is usually
reversible
if no twitches visible, best to wait (check battery)
Neostigmine 2.5 mg/Glycopyrolate 0.5 mg
do not omit anti-cholinergic!
38. Suggamadex (Org 25969): Safer way to reverse NMB
Gijsenbergh et al, Anesthesiology
2005;103;695-703. Belgium. Phase 1
study
Modified cyclodextrin
Encapsulates roc
Promotes dissociation of roc from AchR
No recurarization
39. Summary
Indications: tracheal intubation, surgery, mech ventilation
Choice of drug: pharmacology + other factors (histamine)
Onset of action:
sux is fastest
roc is suitable alternative
Duration:
non-depolarizing block easily reversible if 2 twitches
residual block: incidence with intermediate rx
Monitoring + Reversal: TOF, double burst, clinical signs
Suggmadex: will likely replace neostigmine for reversal
