Pharmacology for Anaesthesia and Intensive Care

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Muscle relaxants and

anticholinesterases

Physiology

The neuromuscular junction (NMJ) forms a chemical bridge between the motor neu-

rone and skeletal muscle. The final short section of the motor nerve is unmyelinated

and comes to lie in a gutter on the surface of the muscle fibre at its mid-point –

each being innervated by a single axonal terminal from a fast Aαneurone (en plaque

appearance). However, for the intra-occular, intrinsic laryngeal and some facial mus-

cles the pattern of innervation is different with multiple terminals from slower Aγ

neurones scattered over the muscle surface (en grappeappearance). Here, muscle

contraction depends on a wave of impulses throughout the terminals.

The post-synaptic membrane has many folds; the shoulders contain ACh receptors

while the clefts contain the enzyme acetylcholinesterase (AChE), which is responsi-

ble for the hydrolysis of ACh (Figure11.1).

Acetylcholine

Synthesis

The synthesis of ACh (Figure11.2)isdependent on acetyl-coenzyme A and choline,

which is derived from the diet and recycled from the breakdown of ACh. Once syn-

thesized in the axoplasm it is transferred into small synaptic vesicles where it is stored

prior to release.

Release

When an action potential arrives at a nerve terminal it triggers Ca^2 +influx, which

then combines with various proteins to trigger the release of vesicular ACh. About 200

such vesicles (each containing about 10 000 ACh molecules) are released in response

to each action potential.

Acetylcholine receptor

Nicotinic ACh receptors are in groups on the edges of the junctional folds on the

post-synaptic membrane. They are integral membrane proteins with a molecular

weight of 250 000 Da and consist of five subunits (twoα, and a singleβ,andδ

in adults). They are configured with a central ion channel that opens when theα

subunits (each of 40 000 Da) bind ACh. Binding the initial molecule of ACh increases

the affinity of the secondαsubunit for ACh. These receptors are also present on