3. The Neuromuscular Junction

ACh is formed in the motor nerve terminal (by the acetylation of choline, catalyzed by choline-O-acetyltransferase). Much of the synthesized ACh is stored in vesicles containing around 10,000 molecules and which lie just within the axonal prejunctional membrane.

ACh release is triggered by the motor nerve action potential. In response to depolarization, voltage-gated channels permit an inward flux of calcium which stimulates release into the junctional gap.. Prejunctional nicotinic cholinergic receptors modulate further ACh mobilization and release via a positive feedback mechanism.

ACh acts at the postjunctional nicotinic receptor, whose structure has been fully identified. It consists of five glycoprotein subunits characterized as α (2), β, δ and ε which form a central ionophore (ion channel). Binding of one molecule of ACh to one of the two α units facilitates the binding of a second, during which the receptor undergoes an evanescent conformational change and the ionophore opens. A net influx of sodium ions then depolarizes the muscle cell membrane.

The ACh in the cleft will interact with an α unit only once before being broken down within 100 μsec by the acetylcholinesterase in the junctional folds of the muscle membrane.

Structures: all are quaternary amines, whose potency is increased if the molecule contains two quaternary ammonium radicals. (Pancuronium is bisquaternary, whereas vecuronium is monoquaternary.)

suxamethonium is the only therapeutic depolarizing neuromuscular blocker, but agonists at nicotinic cholinergic receptors can have a similar effect. Anticholinesterases given in the absence of non-depolarizing block, for example, may themselves cause blockade. Following depolarization of the muscle membrane, suxamethonium remains bound to the receptor for some minutes, during which time muscle action potentials are prevented.

Phase II block: this is a postjunctional non-depolarizing ion channel block, which accompanies the prolonged action or accumulation of suxamethonium. The block is also characterized by impairment of prejunctional ACh release. This probably explains why anticholinesterases may reverse the block, although the advice to do so is not universal.

non-depolarizing blockers are competitive inhibitors of ACh at the postjunctional nicotinic receptors. They bind to one or both of the α units to prevent ACh access, but they induce no conformational change in the receptor. Receptor occupancy needs to be at least 80%, depending on the surgery that is planned, a nd it is important to recognize that the sensitivity of muscle groups is very different. The pattern appears to be the same across all mammalian species such that the muscles of facial expression, including the ocular muscles, and the muscles of the distal limb (including the tail) are much more sensitive than the diaphragm. Thus, only 20% receptor blockade is sufficient to paralyze the tibialis anterior muscle, whereas the diaphragm requires 90%.

non-depolarizing blockers are competitive inhibitors of ACh at the postjunctional nicotinic receptors. They bind to one or both of the α units to prevent ACh access, but they induce no conformational change in the receptor. Receptor occupancy needs to be at least 80%, depending on the surgery that is planned, a nd it is important to recognize that the sensitivity of muscle groups is very different. The pattern appears to be the same across all mammalian species such that the muscles of facial expression, including the ocular muscles, and the muscles of the distal limb (including the tail) are much more sensitive than the diaphragm. Thus, only 20% receptor blockade is sufficient to paralyze the tibialis anterior muscle, whereas the diaphragm requires 90%.

this is an autoimmune disease in which antibodies are formed to the postjunctional acetylcholine (ACh) receptor. The resulting decrease in the population of effective receptors means that muscles fatigue rapidly on repetitive exertion Clinically, this can be demonstrated by asking a patient to chew gum; the muscles of mastication do not fatigue in normal individuals. Electromyographic stimulation of myasthenic patients will reveal fade. The diagnosis can be supported by testing with edrophonium, and first-line treatment is with another anticholinesterase, pyridostigmine

patients clinically may be weak, and postoperative ventilatory support may be required in as many as 30% of subjects. Myasthenic patients demonstrate some resistance to depolarizing neuromuscular blockers, but a dose of suxamethonium 2 mg kg1 will allow good conditions for intubation. Acute sensitivity to the effects of non-depolarizing blockers means that initial doses should be around one-tenth of normal. In practice, combinations of drugs such as propofol and remifentanil mean that muscle relaxants can usually be avoided.

Crises: a myasthenic crisis, which can be precipitated by various physical and emotional stresses or which can be spontaneous, is manifest by an exacerbation of symptoms severe enough to cause respiratory failure. cholinergic crisis is precipitated by an overdose of anticholinesterase. In addition to stimulating muscarinic receptors, the excess ACh acts as a neuromuscular blocker at the diminished number of receptors, thereby leading to muscle weakness and respiratory compromise. Edrophonium, which is a short-acting anticholinesterase with effects which last for about 5 minutes, will transiently improve a myasthenic, and transiently worsen a cholinergic crisis.

in around two-thirds of cases this condition is associated with malignancy, classically with bronchogenic carcinoma. It appears to reduce the number of pre-synaptic quanta of ACh that are released (possibly by antibodies to voltage-gated calcium channels and to the associated protein synaptotagmin), but the post-synaptic membrane sensitivity is normal. Unlike myasthenia gravis, the muscle weakness improves with activity; however, these patients are acutely sensitive to the effects both of depolarizing and non-depolarizing muscle relaxants.