NEUROMUSCULAR

JUNCTION PHYSIOLOGY &

BLOCKING AGENTS

PROF V K BHATIA
DEPT OF ANAESTHESIOLOGY
KGMU

1
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
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
4
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
6
 Sequence Of Events At Neuromuscular
Junction
Action potential

Ca2+
Presynaptic
terminal
Voltage-gated
Ca2+ channel

Action potentials arriving at the presynaptic

terminal cause voltage-gated Ca2+ channels to 7
 Sequence Of Events At Neuromuscular
Junction (continued)

Ca2+

Synaptic
vesicle

Acetylcholine

Ca2+ uptake into the terminal causes release of the

neurotransmitter
Ca2+ diffuse into theacetylcholine into synaptic
cell and cause synaptic cleft
vesicles , which
to release
has been synthesized
acetylcholine, and stored
a neurotransmitter into synaptic vesicles 8
molecule.
 Sequence Of Events At Neuromuscular
Junction (continued)

Ca2+
Presynaptic
terminal

Synaptic cleft

Acetylcholine

 Ach travels across the synaptic cleft to postsynaptic

membrane
Acetylcholine whichfrom
diffuses is also known asterminal
the presynaptic motoracross
end plate.
the 9
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
Sequence Of Events At Neuromuscular
Junction (continued)
Action potential

Ca2+
1
Presynaptic
Synaptic terminal
vesicle
Voltage-gated
Ca2+ channel Synaptic cleft
2

Acetylcholine Postsynaptic
membrane
Na+
Acetylcholine bound
to receptor site opens
ligand-gated Na+ 44
channel

11
Sequence Of Events At
Neuromuscular Junction
(continued)

Na+
Acetylcholine bound
to receptor site opens
ligand-gated Na+
channel

Acetylcholine molecules combine with their receptor sites and

cause ligand-gated Na+ channels to open. 12
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
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
 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
 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
 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
Objectives
 Mechanism of action
 Monitoring
 Pharmacology
 non-depolarizers
 depolarizers
 Reversal
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

Margin of Safety
 Wide margin of
safety of
neuromuscular
transmission
 70% receptor
occupancy before
twitch depression
 Clinical Use
 Anesthesia:
 facilitate tracheal intubation

 paralysis for surgery + mechanical ventilation

 ICU:
  VO
2
 tetanus
 status epilepticus
  ICP
  shivering

Smith CE, Peerless JR: ITACCS

Monograph 1996
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”

Viby-Mogensen, 1984
Onset + Recovery of NM
Block

A-Nondepolarizing. B- Sux.
Viby-Mogensen: BJA
1982;54:209
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
 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
 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
Prielipp et al: Anesth Analg
1995;81:3-12
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
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
Succinylcholine Adverse
Effects
 Hyperkalemia + cardiac arrest in “at risk
patients”
 denervation, burns, myopathy
 Malignant hyperthermia, masseter spasm
  IOP- blood flow mechanism
 Myalgias,  intragastric pressure
  dose requirement for non-depolarizers after
sux
  ICP- blood flow mechanism; clinically
irrelevant
Bevan DR: Semin Anesth
1995;14:63-70
Head Injury + Sux

Kovarik, Mayberg, Lam:

Anesth Analg 1994;78:469-73
 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

Bevan DR, Bevan JC, Donati F:

1988
 Cholinesterase Inhibitors

•↑ Ach at nicotinic
+ muscarinic
receptors to
antagonize NMB
•Full reversal
depends on
diffusion,
redistribution,
metabolism +
excretion
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
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
Viby-Mogensen, 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
Savarese JJ, Caldwell JE, Lien
CA, Miller RD: 2000
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!
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
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