Physiology of drugs acting at neuromuscular juction i/v/o anesthesia

1. Neuromuscular Physiology
Presented by: Dr. Vishal kr. Kandhway
Jawaharlal Nehru Medical College, Sawangi, Wardha

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. • 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 .

4. Neuromuscular Junction (NMJ)

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. The Neuromuscular junction consists of
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. • Ach formed is stored in cytoplasm until it is
transported into vesicles for the release.

9. • How is Ach released…..

10. Ach release
Ca entry into the nerve
Opening of Ca channels
P channels L Channels (slow)
Na influx
Depolarisation
Nerve Action Potential

11. Muscle Contraction
Transmission of AP along sarcolemma to open Tubular Ca Channels
Generation of Action Potential
depolarisation
Opening of Na channels
Ach binds to the post junctional receptors

12. • 1.Upon the arrival of an action potential at the presynaptic
neuron terminal, voltage-dependent calcium channels open
and Ca2+ ions flow from the extracellular fluids into the
presynaptic neuron's cytosol
• 2.This influx of Ca2+ causes neurotransmitter-containing
vesicles to dock and fuse to the presynaptic neuron's cell
membrane. Fusion of the vesicular membrane with the
presynaptic cell membrane results in the emptying of the
vesicle's contents (acetylcholine) into the synaptic cleft, a
process known as exocytosis.
• 3.Acetylcholine diffuses into the synaptic cleft and binds to
the nicotinic acetylcholine receptors bound to the motor end
plate.
• 4.These receptors are ligand-gated ion channels, and when
they bind acetylcholine, they open, allowing sodium ions to
flow in and potassium ions to flow out of the muscle's cytosol.

13. • 5.Because of the differences in electrochemical gradients across the
plasma membrane, more sodium moves in than potassium out, producing
a local depolarization of the motor end plate known as an end-plate
potential (EPP).
• 6.This depolarization spreads across the surface of the muscle fiber into
transverse tubules, eliciting the release of calcium from the sarcoplasmic
reticulum, thus initiating muscle contraction.
• 7.The action of acetylcholine is terminated when the enzyme
acetylcholinesterase degrades part of the neurotransmitter (producing
choline and an acetate group) and the rest of it diffuses away.
• 8. The choline produced by the action of acetylcholinesterase is
recycled — it is transported, through reuptake, back into the presynaptic
terminal, where it is used to synthesize new acetylcholine molecules.

14. 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 .

15. Acetylcholine (2)
• 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 .

16.  Ach combines with its
receptors in the subneural
clefts. This opens sodium
channels  & sodium
diffuses into the muscle
causing a local,non-
propagated 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
cntract .

17. • Fate of Ach….

18. • 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 .

19. Anaesthetic Implication of Ca channels
• Higher than normal concentrations of cations (e.g.,
magnesium, cadmium, manganese) can also block entry of
calcium through P channels and decrease neuromuscular
transmission.
• This is the mechanism for muscle weakness in the mother and
fetus when magnesium sulfate is administered to treat
preeclampsia.
• P channels are not affected by CCB”s– verapamil, diltiazem,
and nifedipine. (These drugs have profound effects on the
slower L channels present in CVS.)
• As a result, the L-type calcium channel blockers have no
significant effect at therapeutic doses on the normal release of
Ach

20. Post-junctional Acetylcholine
Receptors
• 3 types:
• 1) a junctional or mature receptor,
• 2) an extrajunctional or immature (fetal)
receptor
• 3) neuronal α7 receptor (recently described)

21. • Mature receptor - α, β, δ, and ε
• Fetal (immature/extrajunctional)- α, β, δ, and
γ; there are two subunits of α and one of each
of the others.
• Neuronal α7 AChR consists of five α7-subunits

22. Drug Effects on Postjunctional
Receptors
• Nondepolarizing Muscle Relaxants
• All NDMRs impair or block neurotransmission
by competitively preventing the binding of
acetylcholine to its receptor.
• The final outcome (i.e., block or transmission)
depends on the relative concentrations of the
chemicals and their comparative affinities for
the receptor.

23. • 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.

24. • Actions of Depolarizing Muscle Relaxants
• have a biphasic action on muscle—an initial
contraction, followed by relaxation lasting minutes to
hours.
• Not susceptible to hydrolysis by
acetylcholinesterasethe depolarizing relaxants are
not eliminated from the junctional cleft until after they
are eliminated from plasma.
• The time required to clear the drug from the body is
the principal determinant of how long the drug effect
lasts.
• Because relaxant molecules are not cleared from the
cleft quicklyreact repeatedly with receptors
repeatedly depolarizing the end plate and opening
channels.(basis of hyperkalemia)

25. Anaesthetic Implication of DMR”s
• Ocular muscles express both mature and fetal
receptors.
• Accommodation (when synapse area is
inexcitable through nerve) does not occur, and
these muscles can undergo a sustained
contracture in the presence of succinylcholine.
• The tension thus developed forces the eye
against the orbit  increased IOP by depolarizing
relaxants.

26. Nonclassic and 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.

27. • If the channel is prevented from opening,
transmission is weakened.
• If, however, the channel is prevented from or
slowed in closing, transmission may be
enhanced.
• Basis is two clinically important reactions:
receptor desensitization and channel
blockade.

28. Desensitization Block
• Some receptors that bind to agonists do not
undergo the conformational change to open
the channel.
• Receptors in these states are called
desensitized (i.e., they are not sensitive to the
channel-opening actions of agonists).

29. Anaesthetic Implication
• The drugs acting by this route can decrease
neuromuscular transmission.
• They can cause an apparent increase in the
capacity of nondepolarizing agents to block
transmission.

30. Drugs Causing Desensitization of Nicotinic
Cholinergic Receptors
• Volatile anesthetics : Halothane ,Sevoflurane ,Isoflurane.
• Antibiotics : Polymyxin B.
• Barbiturates: Thiopental, Pentobarbital.
• Agonists: Acetylcholine, Succinylcholine.
• Local anesthetics: Dibucaine ,Lidocaine,Prilocaine.
• Phenothiazines:Chlorpromazine,Trifluoperazine,Prochlorperaz
ine.

31. Channel Block
• Block channels at Ach receptors.
• The normal flow of ions through the receptor
is impaired, thereby resulting in prevention of
depolarization of the end plate and a weaker
or blocked neuromuscular transmission.
• Anaesthetic Implication:
• Channel block is believed to play a role in cocaine, quinidine,
piperocaine, tricyclic antidepressant, naltrexone, naloxone
induced alterations in neuromuscular function.

32. Extrajunctional, or fetal form of AChR
• is expressed when there is decreased activity in
muscle, as seen in the fetus before innervation or
• after chemically or physically induced
immobilization;
• after lower or upper motor neuron injury, burns,
or sepsis; or
• after other events that cause increased muscle
protein catabolism, including sepsis or
generalized inflammation.

33. Anaesthetic Implication
• Depolarizing or agonist drugs such as
succinylcholine and acetylcholine depolarize
immature receptors more easily,
• thereby resulting in cation fluxes; doses one
tenth to one hundredth of those needed for
mature receptors can effect depolarization.

34. Anaesthetic Implication
• most serious side effect with the use of
succinylcholine in the presence of upregulated
AChRs in one or more muscles is hyperkalemia.
• (immature) receptor channels stay open for a
longer timethe amount of potassium that
moves from muscle to blood can be considerable.
The resulting hyperkalemia can cause dangerous
disturbances in cardiac rhythm, including
ventricular fibrillation.

35. 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

36. Thank you