Muscle Function and Neuromuscular Blockade
PHYSIOLOGY OF NEUROMUSCULAR TRANSMISSION
FIGURE 6.1 The neuromuscular junction with an axon terminal, containing vesicles of acetylcholine. The neurotransmitter is released on arrival of an action potential and crosses the junctional cleft to stimulate the postjunctional receptors on the shoulders of the secondary clefts. (Reproduced with kind permission of Professor WC Bowman.)
The nicotinic acetylcholine receptors on the postsynaptic membrane are organized in discrete clusters on the shoulders of the junctional folds (Fig. 6.1). Each cluster is about 0.1 μm in diameter and contains a few hundred receptors. Each receptor consists of five subunits, two of which, the alpha (α; MW = 40 000 Da), are identical. The other three, slightly larger subunits, are the beta (β), delta (δ) and epsilon (ε). In fetal muscle, the epsilon is replaced by a gamma (γ) subunit. Each subunit of the receptor is a glycosated protein – a chain of amino acids – coded by a different gene. The receptors are arranged as a cylinder which spans the membrane, with a central, normally closed, channel – the ionophore (Fig. 6.2). Each of the α subunits carries a single acetylcholine binding region on its extracellular surface. They also bind neuromuscular blocking drugs.
FIGURE 6.2 Two postjunctional receptors, embedded in the lipid layer of the postsynaptic muscle membrane. The α, β, ε and δ subunits are demonstrated on the surface of one receptor and the ionophore is seen in cross-section on the other receptor. On stimulation of the two α subunits by two molecules of acetylcholine, the ionophore opens to allow the passage of the end-plate current. (Reproduced with kind permission of Professor WC Bowman.)
FIGURE 6.3 Acetylcholine receptors are present on the shoulders of the axon terminal, as well as on the postjunctional membrane. Stimulation of the prejunctional receptors mobilizes (MOB) the vesicles of acetylcholine to move into the active zone, ready for release on arrival of another nerve impulse. The mechanism requires Ca2 + ions. (Reproduced with kind permission of Professor WC Bowman.)
PHARMACOLOGY OF NEUROMUSCULAR TRANSMISSION
Depolarizing Neuromuscular Blocking Agents
Succinylcholine Chloride (Suxamethonium)
FIGURE 6.4 The chemical structures of acetylcholine and succinylcholine. The similarity between the structure of succinylcholine and two molecules of acetylcholine can be seen. The structure of decamethonium is also shown. The quaternary ammonium radicals N+(CH3)3 cling to the α subunits of the postsynaptic receptor.
Inherited Factors: The exact structure of plasma cholinesterase is determined genetically, by autosomal genes, and this has been completely defined. Several abnormalities in the amino acid sequence of the normal enzyme, usually designated , are recognized. The most common is produced by the atypical gene,
, which occurs in about 4% of the Caucasian population. Thus a patient who is a heterozygote for the atypical gene
demonstrates a longer effect from a standard dose of succinylcholine (about 30 min). If the individual is a homozygote for the atypical gene
, the duration of action of succinylcholine may exceed 2 h. Other, rarer, abnormalities in the structure of plasma cholinesterase are also recognized, e.g. the fluoride
and silent
genes. The latter has very little capacity to metabolize succinylcholine and thus neuromuscular block in the homozygous state
lasts for at least 3 h. In such patients, non-specific esterases gradually clear the drug from plasma.
keep the patient anaesthetized and the lungs ventilated artificially, and
monitor neuromuscular transmission accurately, until full recovery from residual neuromuscular block.
Acquired Factors: In these instances, the structure of plasma cholinesterase is normal but its activity is reduced. Thus, neuromuscular block is prolonged by only minutes rather than hours. Causes of reduced plasma cholinesterase activity include:
liver disease, because of reduced enzyme synthesis.
carcinomatosis and starvation, also because of reduced enzyme synthesis.
pregnancy, for two reasons: an increased circulating volume (dilutional effect) and decreased enzyme synthesis.
anticholinesterases, including those used to reverse residual neuromuscular block after a non-depolarizing muscle relaxant (e.g. neostigmine or edrophonium); these drugs inhibit plasma cholinesterase in addition to acetylcholinesterase. The organophosphorus compound ecothiopate, once used topically as a miotic in ophthalmology, is also an anticholinesterase.
other drugs which are metabolized by plasma cholinesterase, and which therefore decrease its availability, include etomidate, propanidid, ester local anaesthetics, anti-cancer drugs such as methotrexate, monoamine oxidase inhibitors and esmolol (the short-acting β-blocker).
cardiopulmonary bypass, plasmapheresis.
Side-Effects of Succinylcholine
Muscle Pains: These occur especially in the patient who is ambulant soon after surgery, such as the day-case patient. The pains, thought possibly to be caused by the initial fasciculations, are more common in young, healthy patients with a large muscle mass. They occur in unusual sites, such as the diaphragm and between the scapulae, and are not relieved easily by conventional analgesics. The incidence and severity may be reduced by the use of a small dose of a non-depolarizing muscle relaxant given immediately before administration of succinylcholine, e.g. gallamine 10 mg (which is thought to be most efficacious in this respect) or atracurium 2.5 mg. However, this technique, termed pre-curarization or pretreatment, reduces the potency of succinylcholine, necessitating administration of a larger dose to produce the same effect. Many other drugs have been used in an attempt to reduce the muscle pains, including lidocaine, calcium, magnesium and repeated doses of thiopental, but none is completely reliable.
Increased Intraocular Pressure: This is thought to be caused partly by the initial contraction of the external ocular muscles and contracture of the internal ocular muscles after administration of succinylcholine. It is not reduced by pre-curarization. The effect lasts for as long as the neuromuscular block and concern has been expressed that it may be sufficient to cause expulsion of the vitreal contents in the patient with an open eye injury. This is unlikely. Protection of the airway from gastric contents must take priority in the patient with a full stomach in addition to an eye injury, as inhalation of gastric contents may threaten life.
Increased Intragastric Pressure: In the presence of a normal lower oesophageal sphincter, the increase in intragastric pressure produced by succinylcholine should be insufficient to produce regurgitation of gastric contents. However, in the patient with incompetence of this sphincter from, for example, hiatus hernia, regurgitation may occur.
Hyperkalaemia: It has long been recognized that administration of succinylcholine during halothane anaesthesia increases the serum potassium concentration by 0.5 mmol L–1. This effect is thought to be caused by muscle fasciculation. It is probable that the effect is less marked with the newer potent inhalational agents, e.g. isoflurane, sevoflurane. A similar increase occurs in patients with renal failure, but as these patients may already have an elevated serum potassium concentration, such an increase may precipitate cardiac irregularities and even cardiac arrest.