NMJ — MRCS Part B Applied surgical science and critical care

The neuromuscular junction, approached through myasthenia gravis and the drugs that act on it.

Myasthenia gravis

An autoimmune disease in which antibodies against the nicotinic acetylcholine receptor (or, in a minority, muscle-specific kinase) reduce the number of working receptors on the muscle. The result is weakness that worsens with use and improves with rest, first in the eye and bulbar muscles. It matters to surgeons because of the thymus (thymoma in about a tenth, hyperplasia in most), because of the risk of respiratory failure in a crisis, and because these patients are unusually sensitive to non-depolarising muscle relaxants and resistant to suxamethonium.

Transmission

The action potential reaches the motor nerve terminal and opens voltage-gated calcium channels. Calcium entry makes vesicles fuse with the presynaptic membrane and release acetylcholine into the cleft. Acetylcholine binds nicotinic receptors on the folded postsynaptic membrane, opening a cation channel that depolarises the end-plate; when the end-plate potential reaches threshold, voltage-gated sodium channels fire a muscle action potential that spreads along the fibre and down the T-tubules to release calcium from the sarcoplasmic reticulum. Acetylcholinesterase in the cleft breaks the transmitter down within milliseconds and choline is taken back up.

Summation

At a normal junction a single nerve impulse releases far more transmitter than needed, so every impulse produces a contraction and summation is not required; the terms come from synapses in the central nervous system. Temporal summation is a second input arriving before the first end-plate potential has decayed, adding to it; spatial summation is inputs at different sites adding together. At the junction the concept that matters is the safety margin, which is what myasthenia erodes: each impulse releases enough acetylcholine, but too few receptors are available to reach threshold, so repeated stimulation fatigues.

Cholinergic receptors

Nicotinic receptors are ligand-gated ion channels: the muscle type at the junction, and the neuronal type at autonomic ganglia and in the brain. Muscarinic receptors are G-protein coupled, at the parasympathetic end organs (heart, glands, smooth muscle) and sweat glands; there are five subtypes.

Atropine

A competitive antagonist at muscarinic receptors. It does nothing at the junction; it is given with neostigmine to block the muscarinic effects of the extra acetylcholine (bradycardia, salivation, bronchospasm) when a block is reversed, and for organophosphate poisoning.

Muscle relaxants

Depolarising: suxamethonium, which binds the receptor and holds the end-plate depolarised, giving fasciculations then a short paralysis, broken down by plasma cholinesterase. Non-depolarising: the competitive antagonists rocuronium, vecuronium, atracurium and pancuronium, reversed with neostigmine (with glycopyrrolate or atropine) or, for rocuronium and vecuronium, with sugammadex.

Treating myasthenia at the junction

Acetylcholinesterase inhibitors (pyridostigmine) let the transmitter act longer, so more of the remaining receptors are occupied. Beyond the junction: steroids and other immunosuppression, plasma exchange or intravenous immunoglobulin in a crisis, and thymectomy.

Tetanus toxin

It does not act at the junction itself. Taken up at the motor terminal, it travels up the axon to the spinal cord and blocks release of glycine and GABA from the inhibitory interneurones that normally restrain the motor neurone, so the motor neurones fire without inhibition and the muscles go into spasm. Botulinum toxin is the opposite: it cleaves the proteins that let vesicles fuse at the terminal, so no acetylcholine is released and the muscle is paralysed.