Structure of the neuromuscular junction
Motor nerve fibres are the axons of nerve cells that origi-nate in the anterior horn of the brain stem and the spinal cord. The axon terminals branch extensively, and each an-terior horn cell normally innervates 10–150 muscle fibres (the motor unit). As each terminal branch approaches skeletal muscle it loses its myelin sheath, and the neuro-muscular junction (the ‘final common pathway’ of Charles Sherrington) commences at the non-myelinated nerve ending that is distal to the last node of Ranvier.
Focal innervation
Most axon terminals are situated in a junctional fold on the surface of the muscle fibre (the motor endplate). In most mammalian muscles, each muscle fibre has a single motor endplate near its midpoint (focal innervation). This usu-ally forms an elevation on the surface of the fibre, which is called an en plaque neuromuscular junction. These fibres are supplied by fast conducting A axons, and have rapid rates of contraction and relaxation.
Multiple innervation
A minority of muscle fibres are densely innervated at numerous sites by slower conducting A axons. Multi-ple innervation occurs in extraocular, intrinsic laryngeal and some facial muscles where the termination of mo-tor nerves resembles a bunch of grapes, and is called an en grappe neuromuscular junction. These fibres are un-able to propagate action potentials and require a series of impulses to produce a muscle response. The resultant con-traction and subsequent relaxation is thus slower than in focally innervated fibres, and is sometimes described as a contracture.
The motor endplate
The essential features of focally innervated motor end-plates can be revealed by electron microscopy (Fig. 10.1).
The axon terminal, which is enveloped by processes of Schwann cell cytoplasm, lies in a cleft in the sarcolem-mal membrane and contains numerous mitochondria and synaptic vesicles. Many of these vesicles are associated with specialized zones in the axon membrane that correspond to sites of neurotransmitter release. The synaptic vesicles are synthesized in anterior horn cells of the spinal cord and are transported to the motor nerve terminal by the mi-crotubular system. The terminal axolemmal membrane is separated from the postsynaptic membrane by the tic gap, which is approximately 50 nm wide. The synap-tic gap includes a basement lamina approximately 20 nm wide, which mainly consists of mucopolysaccharides.
Acetylcholine receptors are primarily present in dis-crete groups on the shoulders of the junctional folds. Their maximum density at these sites is approximately 10,000 per square micrometre (m2). The distal valleys contain acetylcholinesterase (AChE), which has a globular struc-ture and is predominantly present in the synaptic gap. The enzyme is firmly attached to the basement membrane by collagen fibres. Both acetylcholine receptors and AChE are also present at presynaptic sites on the motor nerve terminal.
Physiology of neuromuscular transmission
The synthesis, storage and release of acetylcholine
Neuromuscular transmission depends on the synthesis, storage and release of acetylcholine by the motor nerve terminal. At the motor endplate, choline is partly de-rived from plasma and partly produced by the hydrolysis
Principles and Practice of Pharmacology for Anaesthetists, Fifth Edition T.N. Calvey and N.E. Williams 171
© 2008 Norman Calvey and Norton Williams. ISBN: 978-1-405-15727-8
Fig. 10.1 Electron micrograph of part of a normal neuromuscular junction. The axonal terminal (A) lies in a deep indentation of the sarcolemmal membrane and contains abundant mitochondria and synaptic vesicles. The external surface of the axon is covered by processes of Schwann cell cytoplasm (S). There are numerous infoldings (arrowed) of the sarcolemma beneath the axon, and basal lamina material lies between nerve and muscle (M) and fills these subneural folds (×30,000). (Courtesy of Professor L.W. Duchen)
of acetylcholine. Choline is transported from extracellu-lar fluid into the axoplasm by a high affinity carrier sys-tem that is present in all cholinergic nerves (Fig. 10.2).
The active transport of choline across the neurolemma is usually the rate-limiting step in the synthesis of acetyl-choline by acetyl-choline acetyltransferase, according to the reaction:
choline+ acetyl-coenzyme A → acetylcholine + coenzyme A The synthesis of the neurotransmitter in the axoplasm is increased by its release, and it is not usually possible to cause depletion of acetylcholine by rapid rates of nerve stimulation or by choline deficiency.
Approximately 50% of acetylcholine synthesized in the axoplasm is transferred to small synaptic vesicles about 50 nm in diameter and stored as molecular pack-ages or quanta. Each synaptic vesicle contains 10,000–
12,000 molecules of acetylcholine, as well as Ca2+, ATP and various protoglycans. Some of the remaining acetyl-choline leaks across the axonal membrane and may be present in significant amounts in Schwann cells and in the sarcoplasm of muscle fibres, although its function at these sites is unknown. A few large dense-core vesi-cles can also be detected at motor nerve endings, and contain calcitonin gene-related peptide (CGRP), which is released into the synaptic gap following high frequency stimulation.
Drugs that Act on the Neuromuscular Junction 173
SV (ACh)
SV (ACh)
AChR
↓ EPP↓ MAP
T-tubule T-tubule
membrane
DHPR RR
SR membrane AChE
Acetate + Choline CAT
ACh
Ca2+
Ca2+
Synapsin IC-PK
Cytoskeleton (Actin)
Synaptobrevin/
Synaptophysin Synaptotagmin
Syntaxin/Neurexin
Ca2+
Fig. 10.2 Diagrammatic representation of neuromuscular transmission. Acetylcholine (ACh) is synthesized in the axoplasm by choline acetylase (CAT) and is then stored in the synaptic vesicles (SV), which are anchored to cytoskeletal elements by Synapsin I.
After depolarization Ca2enters the axoplasm (via P/Q channels) and activates a Ca2+/calmodulin-dependent protein kinase (C-PK), causing the phosphorylation of Synapsin I and the release of SVs from the cytoskeleton. SVs migrate to the axonal membrane, and vesicular proteins (synaptotagmin, synaptobrevin and synaptophysin) are bound by docking sites in the membrane (syntaxin and neurexin). Synaptotagmin is activated by Ca2+entry, resulting in the release of ACh into the synaptic gap. ACh is rapidly hydrolysed by acetylcholinesterase (AChE) and the choline formed is recycled by active transport. Released ACh combines with binding sites on the-subunits of the acetylcholine receptor (AChR), opening the ion channel. Na+entry results in an endplate potential (EPP), and a muscle action potential (MAP) is propagated along the muscle fibre. At the end of the sarcomere, the MAP depolarizes the T-tubule membrane and activates a dihydropyridine receptor (DHPR) in the membrane. This in turn activates the ryanodine receptor (RR), the Ca2+release channel of the sarcoplasmic reticulum (SR). The released Ca2+is rapidly bound by Troponin-C, resulting in myosin–actin interaction and muscle contraction.
About 1% of the acetylcholine vesicles are located at re-lease sites on the axolemma of the motor nerve terminal, and constitute the ‘easily available’ store of the neurotrans-mitter (Fig. 10.1). The remaining vesicles are distributed throughout the axoplasm, where they are bound to micro-tubules, actin filaments and other cytoskeletal elements, forming a large reserve store. They can be rapidly mobi-lized and can readily migrate to docking sites on the termi-nal axolemmal membrane during repetitive nerve activity.
After the release of the neurotransmitter, synaptic vesicles are retrieved and recycled by endocytosis.
Integral proteins contained in the nerve terminal ap-pear to play an important role in the docking of vesicles
at the release site, and in the formation of an extrusion pore, which allows the escape of acetylcholine into the synaptic gap. Several integral proteins are involved in this process:
rSynapsin I is a phosphoprotein which encircles synaptic vesicles in the axoplasm and anchors them to cytoskele-tal elements. After depolarization of the terminal plasma membrane, calcium P/Q channels open, allowing Ca2+to enter the axoplasm and combine with calmodulin. This results in the activation of a Ca2+/calmodulin-dependent protein kinase that phosphorylates serine residues in the tail of synapsin I, resulting in the release of the vesicles (Fig. 10.2).
rSynaptobrevin, synaptotagmin and synaptophysin are vesicular membrane proteins that are bound by specific receptor docking sites (e.g. syntaxin, neurexin) in the presynaptic membrane. Synaptotagmin appears to be ac-tivated by Ca2+entry, allowing it (and the synaptic vesi-cles) to combine with the presynaptic docking proteins, and to release quanta of acetylcholine into the junctional gap.
Acetylcholine receptors
During the past 40 years, there has been considerable progress in the isolation and purification of acetylcholine receptors, and their precise structure has been deter-mined by molecular biological techniques. Similar recep-tors are present in abundance in the electroplaque organs of certain fishes, such as the South American freshwater eel and the giant electric ray. These receptors are irre-versibly bound by the toxins of certain snakes, such as
-bungarotoxin derived from the Taiwan banded krait and-cobra toxin. Consequently, they can be isolated and purified by affinity chromatography. In addition, recep-tors have been sequenced and inserted into artificial and amphibian oocyte membranes by molecular biological techniques.
Postsynaptic receptors
The acetylcholine receptor on the postsynaptic brane of the neuromuscular junction is an integral mem-brane protein with a molecular weight of approximately 250 kDa. It is the classical example of a receptor that contains an intrinsic ion channel. In adults, it consists of five glycoprotein subunits (1, 1, , ε, ), which cross the postsynaptic membrane and surround a cen-tral cation channel (Fig. 10.3).1The-subunits have a molecular weight of approximately 40 kDa, and each contains an acetylcholine-binding site at the interface with a different subunit (ε or ). Each acetylcholine-binding site is adjacent to specific amino acid residues (cys-teines 192 and 193, tyrosines 93 and 190 and tryptamine 149), and the phospholipid composition of the sur-rounding membrane may influence combination of the
-subunits with acetylcholine and subsequent receptor activation.
1In the fetus, denervated muscle, and many other species the ε-subunit is replaced by the -subunit, which has a lower ionic conductance but a longer channel opening time.
β α
γ / ε δ
α β δ
Outside
Inside
β δ
α α γ/ε
α
(a)
(b)
Fig. 10.3 Diagrammatic representation of the nicotinic receptor at the neuromuscular junction. The receptor consists of five subunits (1,1,, or ε, and ) surrounding the central transmembrane ion channel. It has two binding sites for acetylcholine (at the–/ε and – interfaces). (a) View of the receptor from above; (b) vertical cross-section of the receptor in the muscle cell membrane. Acetylcholine-binding sites (◦); ion channel (•, ↓↓↓↓).
Presynaptic receptors
Acetylcholine receptors at the neuromuscular junction are also present on the presynaptic motor nerve terminal and the most distal node of Ranvier, although their molecu-lar structure is slightly different, consisting of3-, 3-,
-, ε- and -subunits. Presynaptic receptors on the mo-tor nerve terminal play an important part in maintaining transmitter output at high rates of nerve stimulation (‘pos-itive feedback’), and their blockade by non-depolarizing agents is responsible for the phenomenon of decrement or fade (page 183). In contrast, acetylcholine receptors on the most distal node of Ranvier can induce retrograde (antidromic) firing of the motor nerve. The injection of acetylcholine into the popliteal artery of experimental an-imals not only produces activity of the appropriate muscle groups, but also gives rise to antidromic nerve action po-tentials that are conducted in a retrograde direction, and can be recorded from ventral nerve roots by appropriate
Drugs that Act on the Neuromuscular Junction 175
electrophysiological methods. Similar effects are produced by anticholinesterase drugs and suxamethonium, indicat-ing that drugs actindicat-ing at the neuromuscular junction may also affect the motor nerve terminal.
Neuromuscular transmission Miniature endplate potentials
In the absence of nerve impulses, postsynaptic receptors display spontaneous electrical activity. This occurs as dis-crete, randomly distributed miniature endplate potentials (MEPPs), which have an amplitude of 0.5–1.5 mV. Each MEPP is considered to arise from the release of a single molecular packet or quantum of acetylcholine, and re-flects the random spontaneous activity of isolated vesicles that have collided or lined up with extrusion sites on the membrane.
Acetylcholine release
When a nerve action potential reaches the axon ter-minal, the contents of 200–300 synaptic vesicles, each containing 10,000–12,000 molecules of acetylcholine, are released from the terminal into the synaptic gap. The re-leased acetylcholine diffuses across the synaptic cleft and combines with the-subunits close to their / and /ε interfaces, resulting in conformational changes that open the ion channel. The probability of this occurring is con-siderably increased when both sites are occupied by acetyl-choline (‘positive cooperativity’).
Ion channel opening
Ion channel opening is an extremely rapid ‘all or none’
phenomenon that results in the entry of 10,000–20,000 cations (mainly Na+, but also K+ or Ca2+) during the 1–2 milliseconds that each channel is open.2These ionic changes result in multiple single channel currents, each of which has an amplitude of approximately 4 pA (4× 10−12 A), which summate to produce an endplate current. If the small and localized endplate potential reaches a critical amplitude (a depolarization of≈10–15 mV), voltage-sensitive Na+channels open, and a muscle action potential (MAP) is propagated along the muscle fibre. The amount of acetylcholine released is normally greater than that required to produce minimal endplate depolarization, i.e. there is a considerable safety margin in neuromuscular transmission.
2In practice, the ion channel opens for about 0.4 milliseconds, and then briefly closes 4–5 times during this 1–2 millisecond interval.
MAPs and excitation–contraction coupling
The MAP is conducted as a wave of depolarization along the sarcolemma, and enters the transverse or T-tubular system at the end of the sarcomere. Depolarization of the T-tubular system, which is perpendicular to the sar-colemma, results in conformational changes in the dihy-dropyridine receptor in the T-tubular membrane. These allosteric changes activate the Ca2+ release channel in the adjacent sarcoplasmic reticulum (the ryanodine re-ceptor), and the subsequent release of Ca2+from the sar-coplasmic reticulum initiates contraction of the muscle fibre (Fig. 10.2). The released Ca2+ are bound by tro-ponin C, resulting in conformational changes in trotro-ponin I, troponin T and tropomyosin. Cross-bridges are then formed between myosin and actin, resulting in the phe-nomenon of muscle contraction. The sequence of physi-ological and biochemical changes between depolarization of the T-tubular system and muscle contraction are known as excitation–contraction coupling.
Acetylcholinesterase
The action of acetylcholine at the motor endplate is rapidly terminated by the hydrolytic enzyme AChE. The enzyme is predominantly associated with the basement membrane in the distal valleys of the synaptic space, where it is an-chored by connective tissue fibres (collagen Q). AChE combines with acetylcholine at two sites approximately 0.5 nm apart, called the anionic and the esteratic site (Fig. 10.4). The anionic site mainly consists of a negatively charged glutamate group, which forms a reversible ionic bond with the positively charged quaternary nitrogen in acetylcholine. The esteratic site consists of the amino acids serine and histidine. The terminal hydroxyl group in serine attacks and splits acetylcholine at its ester link, resulting in the release of choline and the transient acetylation of the serine residue in AChE (Fig. 10.4). The acetylated enzyme reacts with water extremely rapidly (half-life of hydrolysis
= 40 s) resulting in the regeneration of AChE and the release of the acetate group (as acetic acid).
AChE is present at all cholinergic junctions and is prob-ably synthesized at these sites. It is also found in red blood cells and in many regions of the CNS. Erythrocyte AChE may play an important part in the hydrolysis of certain drugs (e.g. diamorphine, esmolol).
Butyrylcholinesterase
In contrast, butyrylcholinesterase (BChE), also known as plasma cholinesterase or pseudocholinesterase, is synthe-sized in the liver, and is also present in many other tissues.
Anionic site Esteratic site
(1) Glutamate Serine Histidine
⏐ ⏐ ⏐
COO−
COO−
CH2 :N
⏐
CH3 H⎯ O
+⏐
CH3⎯ N ⎯ CH2⎯ CH2⎯ O ⎯ C ⎯ CH3 Acetylcholine
⏐CH3 O
(2) Glutamate Serine Histidine
⏐ ⏐
⏐
⏐
⏐
CH2 + N⏐
CH3 H O
+⏐
Choline CH3 N CH2 CH2 O C CH3 Acetylated AChE
⏐CH3 O
+ H2O (half-life of hydrolysis = 40 μs)
(3) Glutamate Serine Histidine
⏐ _
COO CH2 : N
H O Regenerated AChE
+
OH C⎯ CH3 Acetic acid O
Fig. 10.4 The hydrolysis of acetylcholine by AChE. (1) The quaternary nitrogen atom in acetylcholine (N+) forms a reversible ionic bond with the negatively charged glutamate group (COO−) at the anionic site, and electron donation occurs from histidine to the carbonyl carbon atom in acetylcholine at the esteratic site ( ); (2) The terminal hydroxyl group in serine attacks and splits acetylcholine at its ester link, resulting in the formation of choline and the transient acetylation of the esteratic site; (3) Choline is released, and the acetylated enzyme is rapidly hydrolysed (half-life of hydrolysis = 40s) resulting in the regeneration of AChE and the release of the acetate group (as acetic acid).
Although BChE can slowly metabolize acetylcholine, it may have a more important function in the regulation and hydrolysis of other choline esters that are present in the gut wall (e.g. propionylcholine, butyrylcholine).
In anaesthetic practice BChE has an essential role in the hydrolysis of certain muscle relaxants (e.g. suxametho-nium, mivacurium) which are unaffected by AChE. Ge-netic variants of BChE can prolong the action of suxam-ethonium and mivacurium (Chapter 6). BChE also con-tains two binding sites, and the serine group at the ester-atic site combines with choline esters in a similar manner to AChE (Fig. 10.4). However, at the anionic site, BChE forms a dipolar bond rather than an ionic bond with many substrates.
Drugs that inhibit the synthesis of acetylcholine
The synthesis of acetylcholine is dependent on the active transport of choline from the extracellular fluid to the ax-oplasm. Several drugs, including hemicholinium and tri-ethylcholine, inhibit this process and impair the synthesis of acetylcholine. In addition to its effects on choline trans-port, triethylcholine is also converted by choline acetyl-transferase to a ‘false transmitter’ (acetyltriethylcholine), which is stored in synaptic vesicles and released by nerve stimulation, but does not produce depolarization of the motor endplate. The experimental drug vesamicol also
Drugs that Act on the Neuromuscular Junction 177
impairs neuromuscular transmission by preventing the uptake of acetylcholine by synaptic vesicles.
Although all of these drugs have been extensively inves-tigated, none of them have any clinical applications.
Drugs that modify the release of acetylcholine
Several drugs can modify the release of acetylcholine from the motor nerve terminal, including:
r Drugs that affect calcium entry
r Local anaesthetics
r General anaesthetics
r Neurotoxins
r Guanidine and aminopyridine
r Miscellaneous drugs
Drugs that modify calcium entry
The release of acetylcholine from the motor nerve termi-nal is dependent upon the passive entry of Ca2+through P/Q Ca2+channels, which is induced by depolarization of the neuronal membrane (Fig. 10.2). Consequently, al-terations in extracellular Ca2+might be expected to affect neurotransmitter release. In practice, although hypocal-caemia and hypercalhypocal-caemia have important effects on the excitability of tissues and cardiac contraction, they do not usually modify acetylcholine release, except in experimen-tal conditions.
Nevertheless, drugs that prevent Ca2+entry into the motor nerve terminal can impair neuromuscular trans-mission and prolong non-depolarizing neuromuscular blockade. This phenomenon has been mainly reported with the aminoglycosides and polymyxins, but may also occur with various other antibiotics (e.g. colistin, tetra-cyclines, lincomycin). In the past, neuromuscular func-tion was occasionally impaired in patients on long-term streptomycin therapy for tuberculosis, and neostigmine-resistant curarization sometimes occurred after abdom-inal surgery when large doses of aminoglycosides were insufflated to the peritoneal cavity. Similar problems have been observed when antibiotics are given to patients with myasthenia gravis.
Although this problem is rarely encountered in current anaesthetic practice, calcium salts (e.g. calcium gluconate) can reverse antibiotic-induced neuromuscular blockade.
Less commonly, anticholinesterase drugs are useful.
Magnesium salts can also prolong non-depolarizing blockade, since Mg2+compete with Ca2+for transport
into the motor nerve terminal, and thus decrease the re-lease of acetylcholine. Parenteral magnesium sulphate or magnesium-containing antacids may reduce neurotrans-mitter release and prolong the action of muscle relaxants, particularly in patients with renal failure.
Local anaesthetics
Local anaesthetics decrease Na+entry into motor nerve fibres and prevent conduction of the nervous impulse (Chapter 9). Consequently, they decrease Ca2+entry into the motor nerve terminal and prevent the release of acetyl-choline. After systemic administration or absorption, they affect conduction in unmyelinated nerve endings, and conduction blockade of major or minor nerve trunks may prevent transmission of nerve impulses from ante-rior horn cells.
Inhalational anaesthetics
Inhalational anaesthetic agents may also decrease the re-lease of acetylcholine and can profoundly affect the de-gree of neuromuscular blockade. They induce depression of the CNS, decrease the generation of nerve impulses and have direct effects on the muscle cell membrane.
The cardiovascular effects of inhalational anaesthetics may also modify the pharmacokinetic behaviour of muscle relaxants.
Neurotoxins
Certain neurotoxins can prevent the release of acetyl-choline, for example:
r-Latrotoxin
rBotulinus toxin
r-Bungarotoxin
α-Latrotoxin
Latrotoxin is a constituent of black widow spider venom and affects the release of acetylcholine from all choliner-gic nerves. At the neuromuscular junction,-latrotoxin initially produces the irreversible fusion of synaptic vesi-cles with the terminal axonal membrane. Subsequently, the vesicles become disorganized and lose their ability to concentrate newly synthesized acetylcholine, partly due to disruption of the vesicular membrane protein synaptotag-min, which fuses synaptic vesicles to the docking proteins in the nerve terminal.
Botulinus toxin
Botulinus toxin, which also affects all cholinergic nerves, is a zinc endopeptidase. The toxin consists of a num-ber of distinct enzymes that break down synaptobrevin and synaptotagmin and thus prevent the release of acetyl-choline from synaptic vesicles (although the neurotrans-mitter content of the motor nerve terminal is unaffected).
Botulinus toxin typically causes progressive parasympa-thetic and motor paralysis (botulism), resulting in a high mortality due to respiratory failure. Although botulinus antitoxin may be lifesaving, it must be administered before the appearance of any clinical signs of botulism in order to be of therapeutic value.-Bungarotoxin has a similar action to botulinus toxin.
Guanidine and aminopyridine
Both guanidine and aminopyridine prolong the duration of the neuronal action potential and increase the cal-cium channel opening time. Consequently, they increase Ca2+entry into the motor nerve terminal and thus facil-itate the release of acetylcholine. Their mode of action is slightly different, since guanidine delays the inactivation of Na+channels, while aminopyridine tends to inactivate K+ channels and thus prevent repolarization. Both drugs have been used to increase the release of acetylcholine from the motor nerve terminal in botulism and the Eaton–Lambert syndrome, a rare disorder of neuromuscular transmis-sion usually associated with a small cell carcinoma of the bronchus. Unfortunately, both guanidine and aminopyri-dine readily cross the blood–brain barrier and can cause convulsions, and this has severely restricted their clinical use.
Other drugs
Theophylline and other xanthine derivatives can enhance the release of acetylcholine, either by adenosine receptor blockade or by phosphodiesterase inhibition and accumu-lation of cAMP. This phenomenon may also explain the improvement that occurs in myasthenia gravis when sym-pathomimetic drugs (e.g. ephedrine) are administered.
Drugs that modify the action of acetylcholine
Drugs that modify the action of acetylcholine by com-bining with postsynaptic cholinergic receptors are tradi-tionally referred to as neuromuscular blocking agents or
muscle relaxants. They are commonly divided into two groups:
rDepolarizing agents
rNon-depolarizing agents
Depolarizing agents
Suxamethonium chloride is the only depolarizing agent that is in current clinical use. In the past, decamethonium was used but is now only of historical interest. As their name implies, these drugs produce depolarization of the motor endplate immediately before the onset of neuro-muscular blockade.
Suxamethonium
CH3 CH3
⏐+ ⏐ + CH3⎯ N ⎯ CH2⎯ CH2⎯ O ⎯ C ⎯ CH2⎯ CH2⎯ C ⎯ O ⎯ CH2⎯ CH2⎯ N ⎯ CH3
⏐ ⏐
CH3 O O CH3
Suxamethonium is a quaternary amine ester consisting of two molecules of acetylcholine linked by their acetyl groups at their non-quaternary ends. It is a slender, elon-gated and flexible molecule (a leptocurare) with three methyl groups attached to each quaternary head, which are separated by a distance of approximately 1.2 nm.
The ability of suxamethonium to produce depolariza-tion blockade in humans was first recognized in 1949–
1951, although its pharmacological properties were ini-tially investigated in curarized animals in 1906. After the intravenous injection of suxamethonium, profound mus-cle relaxation preceded by observable musmus-cle fascicula-tions normally occurs within 1 minute. The duration of neuromuscular blockade after normal doses (1.0–1.5 mg kg−1) is usually 4–6 minutes.
It is usually the agent of choice for rapid sequence induc-tion and this remains the main indicainduc-tion for its clinical use.
Mode of action
Since suxamethonium is not hydrolysed by AChE, it can produce prolonged and repetitive depolarization of the motor endplate. Depolarization activates voltage-sensitive Na+channels in the adjacent muscle fibre, resulting in the generation and propagation of MAPs and producing mus-cle fasciculations. However, the persistent depolarization produced by suxamethonium is rapidly followed by the generation of local current circuits in the adjacent mus-cle fibre, which cause conformational changes in voltage-sensitive Na+ channels, resulting in their inactivation.