muscle relaxants

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MUSCLE RELAXANTS MUSCLE RELAXANTS ESSAM A.EID, M.D ESSAM A.EID, M.D DEPARTEMENT OF ANESTHESIA, KKUH DEPARTEMENT OF ANESTHESIA, KKUH

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Page 1: Muscle Relaxants

MUSCLE RELAXANTSMUSCLE RELAXANTS

ESSAM A.EID, M.DESSAM A.EID, M.D

DEPARTEMENT OF ANESTHESIA, KKUHDEPARTEMENT OF ANESTHESIA, KKUH

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INTRODUCTIONINTRODUCTION

The neuromuscular junction is made up of a motor neuron and a motor endplate with a synaptic cleft or junctional gap dividing them

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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.

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-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.

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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.

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-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 .

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-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.

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Acetylcholine Receptors

- Nicotinic acetylcholine receptors: ~ 50 million acetylcholine receptors

.-Five polypeptide subunits surround an ion channel . * adult receptor has two identical α subunits, one β one δ and one ε

subunit. * In the foetus a γ (gamma) subunit replaces the ε.

. -Acetylcholine molecules bind to the α 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).

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-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.

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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 .

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Classification Of Skeletal Muscle RelaxantsA- Neuromuscular blocking agents:

1 .According to their mechanism of action into:a) Competitive orb) depolarizing neuromuscular blockers.

2 .According to their duration of action: into:a) Long-acting agents (more than 35 minutes) e.g. d-tubocurarineb) Intermediate-acting agents (20-35 minutes) e.g. gallamine, atracuriumc) 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.

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B- Antispasticity agentsWhich are used to decrease painful muscle spasms. According to theirsite 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 actdirectly on skeletal muscles e.g. dantrolene

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.ANEUROMUSCULAR BLOCKING AGENTS

•All of the neuromuscular blocking drugs has a chemical structuralresemblance to acetylcholine.

•They are:

a) poorly soluble in lipidb) They do not enter into the CNS.c) They do not affect consciousness.

d) All are highly polar and inactive when given by mouthe) Intravenously.

I-

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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 “Hofmann’s 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

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Drug Interactions

A- Synergists:a) inhalational anaesthetics e.g. ether, halothane, isoflurane, actsynergistically with competitive blockers. Consequently their doses should be

reduced..b) Some antibiotics, e.g. aminoglycosides as streptomycin,

neomycin inhibit acetylcholine release from cholinergic nervesby competing with calcium ions. The paralysis could bereversed by administration of calcium ions.

.c) Local anaesthetics e.g. procaine may block neuromusculartransmission through a stabilizing effect on the nicotinic receptor ionchannels.

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Mechanism Of ActionDepolarization block

■Succinylcholine has a similar effect to acetylcholine on the motor endplate receptors (open the sodium channel and cause depolarization of themotor end plate) but instead of producing transient depolarization, itproduces prolonged depolarization which is associated with transmissionfailure.

Thus it produces initial stimulation of the muscle which is manifestedas fasciculation of the muscle followed by muscle paralysis

■Succinylcholine stimulates the nicotinic receptors in sympathetic andparasympathetic ganglia (NN) and the muscarinic receptors (M2) in the SAnodeof the heart.

■Histamine release, particularly in larger doses.

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Side Effects:

1 -Succinylcholine apnoea:Occasionally succinylcholine produces prolonged apnoea due to lack ofnormal plasma (pseudo) cholinesterase levels.This may be the result of:a) Genetic abnormality in the enzyme:

i- Its activity may be lower than normal orii- Abnormal variant of pseudocholinesterase (atypical form of theenzyme) 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 cholinesteraseenzyme level.c) No specific antidote is available.

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RESIDUAL NEUROMUSCULARBLOCKADETrain-of-four (TOF)

stimulation has been established as the pattern of stimulationfor clinical monitoring of neuromuscular blockade.

Thisstimulation mode allows for convenient and reliable tactile

evaluation of moderate degrees of non-depolarizingBlockade and is of special value in the adjustment of

individual dose regimens for neuromuscular blocking drugsduring anesthesia .

A TOF ratio of > 0.7 (ratio of theheight of the fourth twitch to that of the first twitch) has

been shown to correlate with recovery from neuromuscularblockade.

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Peripheral nerve stimulator electrodes were positionedover the ulnar nerve on the volar side of the wrist, so that

the distal electrode was positioned where the proximal skincrease crossed the radial side of the flexor carpi ulnarismuscle .

The proximal electrode was placed 2-3 cm proximalto 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 TOFratio of 75% correlated well with adequate clinical recoverincluding sustained head lift for 5 seconds or more .