The neuromuscular junction is the synapse between a motor neuron and a muscle fiber. It contains a presynaptic membrane, synaptic cleft, and postsynaptic membrane. Acetylcholine is synthesized in the motor neuron and stored in vesicles. When an action potential reaches the motor neuron terminal, calcium enters and causes acetylcholine vesicles to fuse with the presynaptic membrane and release acetylcholine into the synaptic cleft. Acetylcholine then binds and opens channels in the postsynaptic membrane of the muscle fiber, generating an endplate potential that triggers a muscle action potential and contraction. Acetylcholinesterase in the cleft rapidly breaks down acetylcholine to terminate its effects.

1. NEUROMUSCULAR JUNCTION
ANATOMY & PHYSIOLOGY

2. • A neuromuscular junction
(NMJ) is the
synapse or junction of the axon
terminal of a
motorneuron with the motor end
plate,
responsible for initiation of action
potentials
across the muscle's surface,
ultimately causing
the muscle to contract.

3. PARTS OF NMJ
The anatomy of NMJ consist of
following parts:
 Pre-synaptic membrane
 Synaptic cleft
 Post-Synaptic membrane

4. • Morphology:
• The neuromuscular junction is specialized on the nerve
side and on the muscle side to transmit and receive
chemical messages.
• Each motor neuron runs without interruption from the
ventral horn of the spinal cord or medulla to the
neuromuscular junction as a large, myelinated axon.
• As it approaches the muscle, it branches repeatedly to
contact many muscle cells and gather them into a
functional group known as a motor unit .

5. • The nerve is separated from the surface of the
muscle by a gap of approximately 20 nm, called
the junctional or synaptic cleft.
• The nerve and muscle are held in tight alignment
by protein filaments called basal lamina that span
the cleft between the nerve and end plate.
• The muscle surface is heavily corrugated, with
deep invaginations of the junctional cleft—the
primary and secondary clefts.

6. A) Axon Terminal: contains
around 300,000 vesicles which
contain the neurotransmitter
acetylcholine (Ach).
B) Synaptic Cleft :
20 – 30 nm ( nanometer ) space
between the axon terminal & the
muscle cell membrane. It contains
the enzyme cholinesterase which
can destroy Ach .
C) Synaptic Gutter ( Synaptic Trough)
It is the muscle cell membrane
which is in contact with the
nerve terminal . It has many folds
called Subneural Clefts , which
greatly increase the surface area ,
allowing for accomodation of large
numbers of Ach receptors . Ach
receptors are located here .

7. • Formation of Neurotransmitter at Motor
Nerve Endings:-
• The axon of the motor nerve carries electrical signals from the
spinal cord to muscles and has all of the biochemical
apparatus needed to transform the electrical signal into a
chemical one.
• All the ion channels, enzymes, other proteins,
macromolecules, and membrane components needed by the
nerve ending to synthesize, store, and release acetylcholine
and other trophic factors are made in the cell body and
transmitted to the nerve ending by axonal transport.

8. • How is Ach released…..

11. Acetylcholine
1)  Ach is synthesized locally in the
cytoplasm of the nerve terminal ,
from active acetate
(acetylcoenzyme A) and choline.
 Then it is rapidly absorbed into
the synaptic vesicles and
stored there.
 The synaptic vesicles themselves
are made by the Golgi Apparatus
in the nerve soma ( cell-body).
 Then they are carried by
Axoplasmic Transport to the
nerve terminal , which contains
around 300,000 vesicles .
 Each vesicle is then filled with
around 10,000 Ach molecules .
Acetylcholine

12. • When a nerve impulse
reaches the nerve terminal ,
• it opens calcium channels 
calcium diffuses from the
ECF int the axon terminal 
Ca++ releases Ach from
vesicles by a process of
EXOCYTOSIS
• One nerve impulse can
release 125 Ach vesicles.
• The quantity of Ach
released by one nerve
impulse is more than
enough to produce one End-
Plate Potential .

13.  Ach combines with its
receptors in the subneural
clefts. This opens sodium
channels  & sodium
diffuses into the muscle
causing a local,nonpropagated
potential called
the “ End-Plate Potential
(EPP)”, whose value is 50 –
75 mV.
 This EPP triggers a muscle
AP which spreads down
inside the muscle to make it
contract .

14. • Fate of Ach….

15. • After ACh acts on the receptors , it is hydrolyzed by the
enzyme Acetylcholinesterase (cholinesterase ) into Acetate &
Choline . The Choline is actively reabsorbed into the nerve
terminal to be used again to form ACh. This whole process of
Ach release, action & destruction takes about 5-10 ms .

16. 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

18. POSTSYNAPTIC STRUCTURE
Consists of two area :-
(1 ) Juctional :- inveginated to form multiple
fold and rich in Ach receptors
(2) peri-junctional:- rich in Na+
channels>Ach channels

22. Different pools of acetylcholine in the
nerve terminal
VP2:(active zone) small size ,very close to
synaptic nerve terminal ,ready to release
VP1: (reserve storage zone) large size
,majority in number ,vesicle have been
recycled after their use
When nerve is repeatedly stimulated
these vesicles are mobilized from zone 2
to zone 1 and more ach become available
for impulse transmission

23. • Ach formed is stored in cytoplasm
until
it is transported into vesicles for the
release.

24. Sequence Of Events At Neuromuscular Junction
Action potentialAction potential
Ca2+Ca2+
Presynaptic
terminal
Presynaptic
terminal
Voltage-gated
Ca2+ channel
Voltage-gated
Ca2+ channel
24
Action potentials arriving at the presynaptic terminal cause voltage-
gated Ca2+ channels to open.

25. 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
AcetylcholineAcetylcholine
25
Ca2+ uptake into the terminal causes release of the
neurotransmitter acetylcholine into synaptic cleft , which has
been synthesized and stored into synaptic vesicles

26. Aneasthtic Implication of Ca channels
entry of calcium inside nerve ending via a
special type of protein calcium channels
Calcium channels two type :-
(1) L type
(2) P type
P channels are found on in motor nerve
ending adjacent to the active zone of the
nerve terminal and is responsible (not L type
calcium channel) for entry and subsequent
transmitter release for neuromuscular
transmission

27. They are voltage dependent
They are opened and closed by changes in membrane
voltage caused by propagated nerve action potential
Many bivalent organic cations such as magnesium
(Mg+2),cadmium , Mn+2 etc. can also block this
ca+ channel and impair the neuromuscular transmission.
Significance:- this is mechanism for muscle weakness in
mother and foetus when magnesium sulfate is
administreted to treat the pre-eclampsia..

28. Calcium channel blockers effect
Normally calcium p channel cannot be blocked by organic
calcium channel blocker such as drugs:- verapamil ,
diltiasem ,nifedipine etc.
Because these drugs have only profound effect on slower
L type of calcium channel present in the cvs . So L-type
calcium channel blocker at therapeutic doses have no
significant effect on the normal release of ACH from
nerve terminal or on the strength of the normal
neuromuscular transmission.

29. Ach receptors
Synthesized inside the muscle fibre
Composed of 5 subunit
On the basis of these subunits they classified
as:-
1 Adult/mature/juctional
2 fetal/extra juctional

30. Adult/mature ach
 • Present in the post junctional membrane of the motor end plate & are of nicotinic
type. Thesereceptors exist in pairs.
 • It consists of protein made up of 1000 amino acids,
 made up of 5 protein subunits designated as alpha (α), beta (β) , delta (δ) and
epsilon (ε)
 joined to form a channel that penetrates through and projects on each side of the
membrane.

31. • Each receptor has central funnel shaped core
which
is an ion channel, 4 nm in diameter at entrance
narrowing to less than 0.7nm within the
membrane.
• The receptor is 11 nm in length and extends
2nm
into the cytoplasm of the muscle cell.
• The receptor has 2 gates, an Upper
voltagedependent
and a Lower time-dependent.

32.  When acetylcholine receptors bind to the pentameric
complex, they induce a conformational change in the
proteins of the alpha (α) subunits which opens the
channel and it occurs only if it binds to both the alpha
(α) binding sites.
 For ions to pass through the channel both the gates
should be open.
Cations flow through the open
channel, Na+ and Ca+2 in
and K+ out, thus generating end
plate potential.
Na+ ions are attracted to the
inside of the cell which induces
depolarisation.

33. Fetal/extra-juctional Ach receptor
 During prolonged immobilization neuromuscular disease burn extra-juctional ach
receptors are synthesized by muscle.
 They are composed of 2a , 1β ,1γ , 1δ subunits. In them, the adult epsilon (ε)
subunit is replaced by the fetal gamma (γ) subunit.

34. Fetal/extra-juctional Ach receptor
They are more sensitive to Ach and remain open for
more prolonged duration after its use.
They are not found in normal active muscle, but
appear very rapidly after injury or whenever muscle
activity has ended.
 They can appear within 18 hrs of injury and an
altered response to neuromuscular blocking drugs
can be detected in 24 hrs of the insult.
As a result patient with high density of fetal
receptors become prone for hyperkalemic response
after succinylcholine.

35. SIGNIFICANCE:-
 When a large number of extrajunctional receptors are
present, resistance to non-depolarising muscle
relaxants develops, yet there is an increased
sensitivity to depolarising muscle relaxants.
In most extreme cases, increased sensitivity to
succinylcholine results in lethal hyperkalemic receptors
with an exaggerated efflux of intracellular potassium.
 The longer opening time of the ion channel on the
extrajunctional receptor also results in larger efflux.

36. Conditions predisposing for the
development of fetal Ach receptors:-
Prolonged immobilization
Massive trauma
Massive Burns
Sepsis
Neuromuscular disorder
Upper/Lower motor neuron lesion

37. ACETYLCHOLINESTERASE
 Acetylcholinesterase is a type B carboxylesterase enzyme.
 A smaller concentration of the enzyme is found in the extrajunctional area.
 The enzyme is secreted from the muscle but remains attached to it by thin stalks of
collagen to the basement membrane.
 Most of the molecules of acetylcholine released from the nerve initially pass
between the enzymes to reach the postjunctional Receptors
.
 Under normal circumstances, a molecule of acetylcholine
reacts with only one receptor before it is hydrolyzed.
 Acetylcholine is a potent messenger.
 its actions are very short lived because it is destroyed in less than 1 millisecond
after it is released.

38. Acquired cholinesterase deficiency
Conditions:
• Liver failure
• Renal insufficiency
• Burn injury
• Pregnancy (high
estrogen levels)
Inhibitory drugs:
• Anti cholinesterases
• Pancuronium
• Metoclopramide
• Insecticides
• Drugs for Glaucoma,
myasthenia
• Chemotherapeutic agents

39. Action of drugs on neuromuscular
transmission
 NM transmission can be blocked by two ways
 (1)inhibiting of release of Ach (ex:-botulinus toxin)
 (2)inhibiting of action of Ach on its receptors on motor end
plate (a) depolarising muscle relaxant (b) non-depolarizing
muscle relaxants
 Botulinum toxin:
botulinum toxin exerts its lethal effect by blocking the
release of Ach .
Toxin claves SNARE proteins→ prevent releasing vesicles
 Clostridium botulinum poisoning most frequently result from
improperly canned food contaminated with clostridia
bacteria

40. Non-depolarizing Muscle Relaxants
 All NDMRs impair or block neurotransmission By
competitively preventing the binding of acetylcholine to its
receptor
 NDMRs bind with same receptors and close the channels
 Two molecules of Ach per receptor are needed to open the
channels
 Single molecule of NDMR for single receptor is adequate to
prevent the opening of channels
 The final outcome (i.e., block or transmission)
depends on the relative concentrations of the chemicals
and their comparative affinities for the receptor.

41. • Reversal
• Normally, acetylcholinesterase destroys
acetylcholine and removes it from competition
for a receptor.
• Inhibitor of acetylcholinesterase such as
neostigmine, blocks it acetylcholine conc rises.
• High concentration shifts the competition
between acetylcholine and NDMR in favor of the
former, thereby improving the chance of two
acetylcholine molecules binding to a receptor.
• This causes reversal of NDMR effect.

42. Actions of Depolarizing Muscle
Relaxants
 DMRs act same as Ach by binding same α-subumit and
initiates depolarization
 Ach destroyed by enzyme acetylcholinestrase in less than 1
miliseconds.
 Succinylcholine(structurally two molecules of Ach) elimination
by hydrolysis by plasma or pseudocholine-esterase circulating
in plasma.
 Peri-juctional area of end-plate have two different type of
membrane (a)endplate memb.→ open channel by contact
with ach or sch. (Ach receptors )
(b)True muscle memb.→ which only responds to
depolarization impulse (Na channels)

43. SODIUM CHANNEL
• Sodium channels are present in muscle
membrane.
• Peri-junctional areas of muscle membrane
have a higher density of these sodium channels
than other parts of the
membrane.
• These sodium channels have two types of
gate
Activation gate- voltage dependent
Inactivation gate- time dependent
• Sodium ions pass only when both gates are
open.

44. Action of depolarizing
muscle relaxant (sch)

45. When Sch bind with receptors
Depolarization impulse
voltage changes
resting state convert to active state(both gate
are open and Na move across the channel
→time gated channel close its fixed time
active state convert to inactive state (no Na
flow) and no resting sates come (because no
repolarization occurs).
voltage dependent → responses only to voltage changes
time dependent → close at fixed time period
(1 to 2 millisecond )

46. During active state a depolarization impulse generated and
moves along the whole muscle memb. and triggers the muscles
contraction → seen Ms fasciculation

47. Phase block
Phase 1 block
After administration of DMRs (sch) , act as an agonist of ach to
bind with receptors at NMJ-membrane depolarization-than
trainsient fasciculation followed by paralysis
Muscle end plate dose not repolarise and continue depolarization till
sch is present and thus maintain the muscle relaxation
Phase 2 block
If depolarization of muscle end plate is prolonged due to repeated
injection and large dose of sch than receptors at motor end-plate
undergo an ionic and conformational changes and become
insensitive to ach(desensitization)
Phase 2 block mainly seen when sch given large single
dose>(5mg/kg), repeated doses, or a continuous infusion

48. Noncompetitive
Actions of Neuromuscular Drugs
• Several drugs can interfere with the receptor, directly or through its
lipid environment, and change transmission.
• These drugs react with the neuromuscular receptor to change its
function and impair transmission but do not act through the
acetylcholine binding site.
• These reactions cause drug-induced changes in the dynamics of the
receptor, and instead of opening and closing sharply, the modified
channels are sluggish.
• These effects on channels cause corresponding changes in the flow
of ions and distortions of the end-plate potential.
• For example, procaine, ketamine, inhaled anesthetics, or other
drugs that dissolve in the membrane lipid may change the opening
or closing characteristics of the channel.

49. Channel Block
The molecules of many drugs enter the nicotinic
receptors channels and block the flow of ions
preventing depolarization.
Mainly two type (a)open channel blockade
(b)Close channel blockade

50. NMDR blocked channels by ach recognition site
directly and open receptors channel
pancuronium→acts ach site
Gallamine →acts equally both site
Tubocurarine →low dose >acts on ach
high dose > both site
Open channel blocked
Some ms relaxant also enter upto
the middle of the channel while it is
open by Ach and block it.
Best example is NDMR

51. Close channel blockade
Drug block the mouth of channel while it is closed
Ex:- cocaine , quinidine

52. Myasthenia gravis
Myasthenia gravis (MG) is an autoimmune disorder characterized by
fatigable weakness of skeletal muscles. Weakness results from an
antibody-mediated immunological attack directed at acetylcholine
receptors (or receptor-associated proteins) in the postsynaptic membrane
of the neuromuscular junction.
Patients with MG are sensitive to non-depolarizing NMBAs and are
resistant to succinylcholine a depolarizing NMB

53. ANESTHESIA MANAGEMENT —
●Use of ultrashort- or short-acting sedatives, hypnotics, and anesthetic agents
to minimize respiratory depression on emergence from anesthesia
Premedication —premedication with sedatives can be avoided by reassurance
and explanation of expected procedures.
Depolarizing NMBAs — MG are resistant to neuromuscular blockade with
depolarizing NMBAs (eg, succinylcholine),because they have decreased
number of acetylcholine receptors
Choice of anesthetic technique — When possible, local or regional anesthesia
should be used. Regional anesthesia should be considered for peripheral
procedures that can be done with relatively low-level neuraxial anesthesia,
either epidural or spinal, or with peripheral nerve blocks
Avoidance of the use of neuromuscular blocking agents (NMBAs)

54. Lambert-Eaton Syndrome
Myasthenic Syndrome (Lambert-Eaton) is caused by IgG
antibodies to voltage-gated Ca++ channels in the musculature,
which leads to increased sensitivity to both SCh and
nondepolarizing muscle relaxants
Myasthenic Syndrome (Lambert Eaton)
•IgG antibodies to voltage-gated Ca++ channels
•Associated with small-cell carcinoma of the lung, sarcoidosis,
thyroiditis, collagen-related vascular disease
Proximal muscle weakness, improves with repetitive effort
•More susceptible to both SCh and non-depolarizing
NMBDs
•Titrate small doses of NMBDs to quantitative twitch monitoring
•Beware orthostatic hypotension in these patients