Neuromuscular Blockers

Neuromuscular transmission relies on acetylcholine (ACh) acting at the neuromuscular junction (NMJ). ACh is synthesised from choline and an acetyl group from acetyl-CoA. It is stored in vesicles with ATP (which neutralises ACh's positive charge, making vesicles isoelectric). Release is by regulated exocytosis triggered by action potentials.

The nicotinic acetylcholine receptor (nAChR) is a pentameric ionotropic receptor with approximately 20 transmembrane segments surrounding an aqueous ion channel. It has two ACh binding sites; both must be occupied for a conformational change (channel opening) and Na+ influx, generating an end plate potential — depolarisation of the skeletal muscle at the NMJ.

ACh is hydrolysed by acetylcholinesterase (AChE) within 1 ms, releasing inactive choline (recycled) and acetate. The NMJ has a large safety factor — ACh released greatly exceeds what is needed — so 70-80% of receptors must be blocked before transmission fails.

Neuromuscular block can be achieved by: inhibiting presynaptic ACh release; inhibiting AChE; or blocking ACh action postsynaptically (the therapeutic approach). Postsynaptic block uses two strategies:

Non-depolarising block: competitive antagonists (e.g. tubocurarine) block nAChRs. Surmountable — AChE inhibitors restore transmission by increasing ACh concentration.

Depolarising block: agonists (e.g. decamethonium — two positively charged nitrogens that can bind both receptor sites) maintain sustained depolarisation. Non-surmountable — AChE inhibitors worsen it. Phase I block: maintained 0 mV membrane potential; no Na+ entry; muscle unresponsive. Phase II block: prolonged activation causes receptor desensitisation and internalisation (beta-arrestin binding); receptors removed from membrane; returns to -70 mV but muscle remains unresponsive until receptor recycling or resynthesis.

Non-depolarising NMBs are used in surgical anaesthesia. Clinical choice depends on desired onset, duration, and mechanism of termination.