The document provides an overview of the neuromuscular junction, detailing its structure, function, and the processes involved in muscle contraction such as the release and action of acetylcholine. It discusses the mechanisms by which various drugs can affect neuromuscular transmission, including neuromuscular blockers and stimulators. Additionally, the document describes clinical conditions like myasthenia gravis and Lambert-Eaton syndrome, which impair normal neuromuscular function.

1. NEURO-MUSCULAR
JUNCTIONS
First year MBBS,
THOOTHUKUDI MEDICAL
COLLEGE,
THOOTHUKUDI

2. OBJECTIVES
 Structure of Neuromuscular junction
 Events occurring at Neuromuscular
junction
 Drugs acting on Neuromuscular
junction and their mechanism of action
 Clinical Aspects
1)Myasthenia Gravis
2)Lambert-Eaton Syndrome

3. First of all….What is a
neuromuscular junction??
 Neuromuscular junction refers to the
intimate contact of nerve endings with
the muscle fiber to which they innervate
 The following structures are included in a
typical neuromuscular junction
* Terminal button
* Presynaptic membrane
* Synaptic cleft
* Postsynaptic membrane

4. 1) Terminal Button
 The axon of a neuron supplying a
skeletal muscle loses its myelin sheath
and divides into a number of fine
branches which end in small knobs
called terminal buttons or end feet which
forms a neuromuscular junction, at the
centre of muscle fibre .
 Synaptic knob contain about three lakh
vesicles containing acetylcholine and
mitochondria.
 The acetylcholine is synthesized by the
mitochondria and is stored in the
vesicles

5. Pre synaptic membrane
This refers to the axonal membrane
lining the terminal buttons of the nerve
endings.

6. Synaptic cleft
 It is the space between the
presynaptic and the postsynaptic
membrane
 It is about 50-100nm
 It is filled with ECF with reticular fibers
forming the matrix

7. Post synaptic membrane
 It refers to the sacrolemma of the
muscle fiber which is present in the
neuromuscular junction
 The sacrolemma is thickened and
depressed to form the synaptic trough
where the terminal button fits
 This thickened portion is called the
motor end plate

8. Contd…
 The postsynaptic membrane contains
receptor sites for ACETYLCHOLINE
called as the NICOTINIC
RECEPTORS
 The matrix of cleft contains the
enzyme CHOLINESTERASE which
hydrolyzes the acetylcholine

9. Courtesy: Medical
physiology by Indu Khurana

10. Courtesy: Medical physiology by
Indu Khurana

11. Synthesis of
ACETYLCHOLINE
Raw materials :
The mitochondria requires
 Choline
 Acetyl Co Enzyme-A
 ATP
 Glucose
 Enzyme---} Choline acetylase (or)
Choline transferase

12. Storage :
Acetylcholine once synthesized is
stored temporarily in the vesicles in
small packets called quanta which
consists of about 10^4 molecules of
acetylcholine

13. Sequence of events:
 Release of acetylcholine by the nerve
terminals
 Effect of acetylcholine on the
postsynaptic membrane
 Development of end plate potential
 Miniature end plate potential
 Removal of acetylcholine by
cholinesterase
 Initiation of action potential in the muscle
fiber

14. Release of acetylcholine by the
nerve terminals
 When the nerve impulse travelling in the
nerve fibre (axon) reaches the terminal
buttons, the voltage gated Ca2+
channels present on the presynaptic
membrane open up, increasing its
permeability to Ca2+ ions.
 Consequently, the Ca2+ ions present in
the ECF of the synaptic cleft enter the
cytosol of the terminal buttons which
inturn trigger a marked increase in
exocytosis of vesicles releasing

15. Effect of acetylcholine of the
postsynaptic membrane
The acetylcholine so released diffuses
in the synaptic cleft and binds to the
nicotinic–acetylcholine receptors
located mainly on the junctional folds
of the motor end plate (postsynaptic
membrane) leading to opening up of
the tubular channels.

16. Development of end plate
potential
Due to opening of the acetylcholine-
gated channels in the end plate
membrane, a large number of Na+
ions from the ECF enter inside the
muscle fibre causing a local positive
potential change inside the muscle
fibre membrane called the end plate
potential.

17. Contd…
 The end plate potential is non-
propagative but when a critical level of
−60 mV is reached, it triggers the
development of action potential in the
muscle fibre
 The action potentials are generated on
either side of the end plate and
conducted away from the end plate in
both the directions along the muscle
fibres thus causing muscle contraction

18. Courtesy: Medical physiology
by Indu Khurana

19. Miniature end plate potential
 Even at rest, small quanta of
acetylcholine are released randomly
from the nerve terminal because of
random Brownian movement of
axoplasm.
 Each quantum of acetylcholine
produces a weak end plate potential
about 0.5 mV in magnitude. This is
called miniature end plate potential.

20. Giant end plate potential
 Due to increased releasing of
Acetylcholine the end plate potential
rises to 12mV.
 This is known as giant end plate
potential
 This is not sufficient to generate
action potential

21. Removal of acetylcholine
 The acetylcholine released in the
synaptic cleft stays for a short time
and is removed within 1 ms by the
enzyme acetylcholinesterase present
in the matrix of synaptic cleft.
 A small amount of ACh diffuses back
into nerve terminals from the synaptic
cleft.
 The rapid removal prevents repeated
excitation of the muscle fibre

22. Drugs affecting neuromuscular
juncton
These drugs are classified as :
*Drugs which block transmission,
known as NEUROMUSCULAR
BLOCKERS
*Drugs that stimulate transmission,
the NEUROMUSCULAR
STIMULATORS

23. NEUROMUSCULAR
BLOCKERS
 CURAE
 BUNGAROTOXIN
 SUCCINYLCHOLINE
 CARBAMYLCHOLINE
 BOTULINUM TOXIN

24. Curare
 Curare combines with the
aceytlcholine receptors
 Thus there will be no sites for the
acetylcholine to combine and hence
end plate potential will not develop
 This is the active principle of
D-tubocurarine

25. Curare obtained is
from Strychnos
toxifera
Courtesy:Köhler's
Medicinal Plants

26. Bungarotoxin
 This is obtained from venom of deadly
snakes
 This also binds with the Acetylcholine
receptors and block the transmission

27. Obtained from a krait (snake)
Bungarus multicinctus
Courtesy: PubChem and
Thomas Brown

28. Succinylcholine &
carbamylcholine
 Succinylcholine and carbamylcholine
act like acetylcholine and cause
depolarization of the postsynaptic
membrane.
 But, these are not destroyed by
cholinesterase and so the muscle
remains in a depolarized state for a
long time.
 Thus, these drugs block the
myoneural junction by keeping the

29. Succinylcholine
Courtesy: pharmacopeia.cn

30. Carmabylcholine (carbachol)
Courtesy:
Chembase

31. Botulinum toxin
 It is obtained from Clostridium
botulinum
 It prevents the release of acetylcholine
from the terminal branches of the
nerve endings

32. Courtesy: Centre for Food safety, Hong Kong

33. Neuromuscular stimulators
• Methacholine
• Carbachol
• NicotineDrugs acting
like Ach
• Neostigmine
• Physostigmine
• Diisopropyl
flurophosphate(DFP)
Drugs that
inactivate
cholinesterase

34. Drugs acting like Ach
 These act like acetylcholine and
produce end plate potential exciting
the muscle fibre.
 However, these drugs are either not
destroyed or are destroyed very slowly
by the enzyme acetylcholinesterase.
 So they cause repeated stimulation
and continuous action of muscle,
thereby causing a state of muscle
spasm.

35. Drugs that inactivates the
enzyme cholinesterase:
 These stimulate the neuromuscular
junction by inactivating this enzyme due
to which the acetylcholine released at
the nerve terminal cannot be hydrolysed,
this leads to repeated stimulation and
continuous action of muscle.
 The effect of neostigmine and
physostigmine lasts for several hours
while that of DFP lasts for several
weeks.
 The DFP is thus a lethal poison which
can cause death due to laryngeal spasm.

36. Clinical aspects :
•Myasthenia
gravis
•Lambert-Eaton
syndrome

38. AntibodiesattacktheseACHreceptors

39. Lambert-Eaton syndrome
 Here, antibodies are produced against
the calcium channels present on the
presynaptic membrane which destroy the
channels.
 Consequently, Ca2+ influx into the nerve
terminal is markedly decreased and
thereby release of acetylcholine is also
reduced.
 Scanty amount of acetylcholine is not
able to produce adequate end plate
potential to excite the muscle fibres
producing muscular weakness.

40. Symptoms
 Weak muscles – weakness is often
relieved temporarily after exercise or
exertion
 Trouble walking
 Tingling sensation in the hands or feet
 Eyelid drooping
 Fatigue
 Dry mouth
 Trouble speaking and swallowing
 Trouble breathing
 Bladder and bowel changes
 Erectile dysfunction

41. References:
 Medical physiology for Undergraduate
students by Indu Khurana 1st Edition
 Textbook of Medical physiology by
Guyton and Hall , 2nd South Asia
Edition
 Johns Hopkins Medical library(online)

42. First year MBBS
THOOTHUKUDI MEDICAL COLLEGE, THOOTHUKUDI