MUSCLE RELAXANTS ESSAM A.EID, M.D DEPARTEMENT OF ANESTHESIA, KKUH
INTRODUCTION <ul><li>The neuromuscular junction is made up of a motor neuron and a motor endplate with a synaptic cleft or junctional gap dividing them </li></ul>
The Motor Neuron <ul><li>- Control skeletal muscle activity. </li></ul><ul><li>- Originate in the ventral horn of the spinal cord </li></ul><ul><li>- Axons are surrounded by a myelin sheath </li></ul><ul><li>- Each motor neuron connects to several skeletal muscle fibers </li></ul><ul><li>- As the motor neuron enters a muscle, the axon divides into telodendria, the ends of which, the terminal buttons, synapse with the motor endplate. </li></ul><ul><li>- T he junctional gap, release of the neurotransmitter acetylcholine occurs with consequent binding to the receptors . </li></ul>
<ul><li>- The surface of motor endplate is is deeply folded with multiple crests and secondary clefts. The nicotinic acetylcholine receptors are located on the crests. </li></ul><ul><li>- The clefts of the motor endplate contain acetylcholinesterase. </li></ul><ul><li>- peri-junctional zone. It is here that the potential developed at the endplate is converted to an action potential. </li></ul><ul><li>- 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. </li></ul>
Acetylcholine synthesis, storage and release <ul><li>- choline and acetyl-coenzyme A (mitochondria) </li></ul><ul><li>- 50% of the choline is by a sodium dependant active transport system , the other 50% is from acetylcholine breakdown </li></ul><ul><li>. </li></ul><ul><li>- 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. </li></ul><ul><li>- 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. </li></ul>
<ul><li>- The vesicles then become part of one of three pools , each varying in their availability ability for release. </li></ul><ul><li>- 1% are immediately releasable, </li></ul><ul><li>- 80% are readily releasable and </li></ul><ul><li>- 19% the stationary store. </li></ul>
<ul><li>- Miniature endplate potentials of 0.5-1mV, </li></ul><ul><li>- M uscle 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). </li></ul><ul><li>- The depleted vesicles are rapidly replaced with vesicles from the readily releasable store and the empty vesicles are recycled. </li></ul>
Acetylcholine Receptors <ul><li>- Nicotinic acetylcholine receptors: ~ 50 million acetylcholine receptors </li></ul><ul><li>-. Five polypeptide subunits surround an ion channel. </li></ul><ul><li>* adult receptor has two identical α subunits, one β one δ and one ε subunit. </li></ul><ul><li>* In the foetus a γ (gamma) subunit replaces the ε. </li></ul><ul><li>. </li></ul><ul><li>- Acetylcholine molecules bind to the α subunits and the ion channel is opened for just 1 msec. This causes depolarisation, </li></ul><ul><li>- 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. </li></ul><ul><li>-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). </li></ul>
<ul><li>- In addition to the post-junctional receptors , there are extra-junctional receptors , and pre-junctional receptors. </li></ul><ul><li>-. 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 </li></ul><ul><li>- 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. </li></ul>
Acetylcholinesterase <ul><li>- Hydrolysis of acetylcholine to choline and acetate by acetylcholinesterase (AChE ). </li></ul><ul><li>- 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. </li></ul><ul><li>This enzyme is secreted by the muscle cell but remains attached to it by thin collagen threads linking it to the basement membrane. </li></ul><ul><li>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. </li></ul>
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
<ul><li>NEUROMUSCULAR BLOCKING AGENTS </li></ul><ul><li>• All of the neuromuscular blocking drugs has a chemical structural </li></ul><ul><li>resemblance to acetylcholine. </li></ul><ul><li>• They are : </li></ul><ul><li>a) poorly soluble in lipid </li></ul><ul><li>b) They do not enter into the CNS . </li></ul><ul><li>c) They do not affect consciousness. </li></ul><ul><li>d) All are highly polar and inactive when given by mouth </li></ul><ul><li>e) Intravenously . </li></ul><ul><li>I- </li></ul>
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
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 <ul><li>Train-of-four (TOF) </li></ul><ul><li>stimulation has been established as the pattern of stimulation </li></ul><ul><li>for clinical monitoring of neuromuscular blockade. </li></ul><ul><li>This </li></ul><ul><li>stimulation mode allows for convenient and reliable tactile </li></ul><ul><li>evaluation of moderate degrees of non-depolarizing </li></ul><ul><li>Blockade and is of special value in the adjustment of </li></ul><ul><li>individual dose regimens for neuromuscular blocking drugs </li></ul><ul><li>during anesthesia. </li></ul><ul><li>A TOF ratio of > 0.7 (ratio of the </li></ul><ul><li>height of the fourth twitch to that of the first twitch) has </li></ul><ul><li>been shown to correlate with recovery from neuromuscular </li></ul><ul><li>blockade. </li></ul>
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.
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