MUSCLE RELAXANTS

ESSAM A.EID, M.D

DEPARTEMENT OF ANESTHESIA, KKUH
 INTRODUCTION
The neuromuscular junction is made up of a
motor neuron and a motor endplate with a
synaptic cleft or junctional gap dividing them
 The Motor Neuron
-Control skeletal muscle activity.
- Originate in the ventral horn of the spinal cord

- Axons are surrounded by a myelin sheath

- Each motor neuron connects to several skeletal muscle fibers

- As the motor neuron enters a muscle, the axon divides into

telodendria, the ends of which, the terminal buttons, synapse
with the motor endplate.
- The junctional gap, release of the neurotransmitter
acetylcholine occurs with consequent binding to the receptors .
 - The surface of motor endplate is is deeply folded with
multiple crests and secondary clefts. The nicotinic
acetylcholine receptors are located on the crests.

- The clefts of the motor endplate contain

acetylcholinesterase.

- peri-junctional zone. It is here that the potential

developed at the endplate is converted to an action
potential.

- The peri-junctional zone has an enhanced ability to

produce a wave of depolarisation to the muscle from that
produced by the post-synaptic receptors.
 Acetylcholine synthesis, storage and release

- choline and acetyl-coenzyme A (mitochondria)

- 50% of the choline is by a sodium dependant active transport

system, the other 50% is from acetylcholine breakdown
.
- Choline acetyltransferase is produced on the ribosomes in the cell
body of the motor neurone from where it is transported distally by
axoplasmic flow to the terminal button and can be found in high
concentrations. The activity of choline acetyltransferase is inhibited
by acetylcholine and increased by nerve stimulation.

- Once synthesised the molecules of acetylcholine are stored in

vesicles within the terminal button, each vesicle containing
approximately 10,000 molecules of acetylcholine. These vesicles
are loaded with acetylcholine via a magnesium dependent active
transport system in exchange for a hydrogen ion.
 - The vesicles then become part of one of
three pools, each varying in their
availability ability for release.
- 1% are immediately releasable,
- 80% are readily releasable and
- 19% the stationary store.
 - Miniature endplate potentials of 0.5-1mV,

- Muscle action potential, wlth the arrival of a nerve impulse,

P-type calcium channels open, allowing calcium to enter the cell.
The combination of depolarization of the presynaptic terminal and
influx of calcium triggers 100-300 vesicles to fuse with the
presynaptic membrane and release acetylcholine into the synaptic
cleft (exocytosis).

- The depleted vesicles are rapidly replaced with vesicles from the
readily releasable store and the empty vesicles are recycled.
 Acetylcholine Receptors
- Nicotinic acetylcholine receptors: ~ 50 million acetylcholine receptors

-. Five polypeptide subunits surround an ion channel.

* adult receptor has two identical subunits, one one and one
subunit.
* In the foetus a (gamma) subunit replaces the .
.
- Acetylcholine molecules bind to the subunits and the ion channel is
opened for just 1 msec. This causes depolarisation,
- the cell becomes less negative compared with the extracellular
surroundings. When a threshold of 50mV is achieved (from a resting
potential of 80mV), voltage- gated sodium channels open, thereby
increasing the rate of depolarisation and resulting in an end plate potential
(EPP) of 50-100mV.
-This in turn triggers the muscle action potential that results in muscle
contraction. By this method the receptor acts as a powerful amplifier and a
switch (acetylcholine receptors are not refractory).
 - In addition to the post-junctional receptors , there are extra-
junctional receptors, and pre-junctional receptors.

-. Denervation injuries and burns are associated with large

increases in the number of extra-junctional receptors .. The extra-
junctional receptors have the structure of immature foetal receptors

- Pre-junctional receptors have a positive feedback role. In very

active neuromuscular junctions acetylcholine binds to these
receptors and causes an increase in transmitter production via a
second messenger system. These receptors may also play a role in
the fade seen in non-depolarising muscle relaxant blockade by
inhibiting replenishment of acetylcholine.
 Acetylcholinesterase
- Hydrolysis of acetylcholine to choline and acetate by
acetylcholinesterase (AChE).

- AchE has , an ionic site possessing a glutamate residue and an esteratic

site containing a serine residue. Hydrolysis occurs with transfer of the acetyl
group to the serine group resulting in an acetylated molecule of the enzyme
and free choline. The acetylated serine group then undergoes rapid,
spontaneous hydrolysis to form acetate and enzyme ready to repeat the
process.

This enzyme is secreted by the muscle cell but remains attached to it by thin
collagen threads linking it to the basement membrane.

Acetylcholinesterase is found in the junctional gap and the clefts of the post-
synaptic folds and breaks down acetylcholine within 1 msec of being
released. Therefore the inward current through the acetylcholine receptor is
transient and followed by rapid repolarisation to the resting state.
Classification Of Skeletal Muscle Relaxants
A- Neuromuscular blocking agents:

1. According to their mechanism of action into:

a) Competitive or
b) depolarizing neuromuscular blockers.

2. According to their duration of action: into:

a) Long-acting agents (more than 35 minutes) e.g. d-tubocurarine
b) Intermediate-acting agents (20-35 minutes) e.g. gallamine, atracurium
c) Short-acting agents (less than 20 minutes) e.g. succinyl choline,
mivacurium

3. According to their route of elimination from the body into:

a) Agents eliminated via kidney e.g. gallamine (95%), pancuronium (80%)
b) Agents eliminated via liver e.g. d-tubocuranine (60- 70%)
c) Agents eliminated via plasma cholinesterase enzyme, e.g.succinylcholine.
d) Agents spontaneously broken down (Hofmann elimination) e.g. atracurium.
B- Antispasticity agents
Which are used to decrease painful muscle spasms. According to their
site of action, they are divided into
:
1- Central muscle relaxants:
Their site of action is the spinal cord and subcortical areas of the brain. They
do not directly relax spastic muscles. They include benzodiazepine

2- Direct muscle relaxants:

They do not act on central synapses or neuromuscular junction. They act
directly on skeletal muscles e.g. dantrolene
A. NEUROMUSCULAR BLOCKING AGENTS

All of the neuromuscular blocking drugs has a chemical structural

resemblance to acetylcholine.
They are :
a) poorly soluble in lipid
b) They do not enter into the CNS.
c) They do not affect consciousness.
d) All are highly polar and inactive when given by mouth
e) Intravenously.
I-
 ATRACURIUM (TRACIUM):

1- potent as tubocurarine
2- It has a shorter duration of action (~30 min).
3- It is spontaneously broken down in the plasma by a
non-enzymatic chemical process Hofmanns degradation.
Thus it is non-cumulative. It could be used in patients with
either liver and/or kidney disease.
4- It is the relaxant of choice in fragile patients and in renal
failure.
5- It is a weak histamine releaser, but has no effect on
autonomic ganglia or on cardiac muscarinic receptor
6- Dose: 0.5 mg/kg
Drug Interactions
A- Synergists:
a) inhalational anaesthetics e.g. ether, halothane, isoflurane, act
synergistically with competitive blockers. Consequently their doses should be
reduced..
b) Some antibiotics, e.g. aminoglycosides as streptomycin,
neomycin inhibit acetylcholine release from cholinergic nerves
by competing with calcium ions. The paralysis could be
reversed by administration of calcium ions.
.
c) Local anaesthetics e.g. procaine may block neuromuscular
transmission through a stabilizing effect on the nicotinic receptor ion
channels.
Mechanism Of Action
Depolarization block

Succinylcholine has a similar effect to acetylcholine on the motor end

plate receptors (open the sodium channel and cause depolarization of the
motor end plate) but instead of producing transient depolarization, it
produces prolonged depolarization which is associated with transmission
failure.
Thus it produces initial stimulation of the muscle which is manifested
as fasciculation of the muscle followed by muscle paralysis

Succinylcholine stimulates the nicotinic receptors in sympathetic and

parasympathetic ganglia (NN) and the muscarinic receptors (M2) in the SAnode
of the heart.

Histamine release, particularly in larger doses.

Side Effects:
1- Succinylcholine apnoea:
Occasionally succinylcholine produces prolonged apnoea due to lack of
normal plasma (pseudo) cholinesterase levels.
This may be the result of:
a) Genetic abnormality in the enzyme:
i- Its activity may be lower than normal or
ii- Abnormal variant of pseudocholinesterase (atypical form of the
enzyme) that may be totally unable to split succinylcholine.
b) Acquired low level of pseudocholinesterase activity occurs in:
i- Severe liver disease.
ii- Malnutrition.
iii- Exposure to insectisides.
iv- Cancer patients.

Treatment:
a) Artificial respiration until the muscle power returns.
b) Fresh blood or plasma transfusion to restore cholinesterase
enzyme level.
c) No specific antidote is available.
 RESIDUAL NEUROMUSCULAR
BLOCKADE
Train-of-four (TOF)
stimulation has been established as the pattern of stimulation
for clinical monitoring of neuromuscular blockade.

This
stimulation mode allows for convenient and reliable tactile
evaluation of moderate degrees of non-depolarizing
Blockade and is of special value in the adjustment of
individual dose regimens for neuromuscular blocking drugs
during anesthesia.
A TOF ratio of > 0.7 (ratio of the
height of the fourth twitch to that of the first twitch) has
been shown to correlate with recovery from neuromuscular
blockade.
Peripheral nerve stimulator electrodes were positioned
over the ulnar nerve on the volar side of the wrist, so that

the distal electrode was positioned where the proximal skin

crease crossed the radial side of the flexor carpi ulnaris
muscle.

The proximal electrode was placed 2-3 cm proximal

to the distal electrode.
Viby Mogensen first reported that the use of neuromuscular
blocking agents was followed by residual paralysis in 42%
patients even after administration of reversal.

Study conducted by Ali showed that TOF

ratio of 75% correlated well with adequate clinical recover
including sustained head lift for 5 seconds or more.