2007B06 Describe how suxamethonium produces neuromuscular blockade.
What is the mechanism of recovery of neuromuscular function and what mechanisms may be involved in Phase 2 block?

Structure

·  Pentameric ligand-gated ion channel

·  Central ionophore

·  ααβδε in adults

·  ααβγδ in utero, or denervated adults as extrajunctional type

Function

·  Activation -> Na⁺ influx > K⁺ efflux = Ca²⁺ influx -> depolarisation i.e. mini end-plate potential

·  Spatial and temporal summation -> action potential

·  Rapid cycling through resting->activated->inactivated states when bound by agonist

Of action

·  Diffuses from plasma to NMJ

·  Agonist at muscle type nAChR

·  Binds both alpha subunits

·  Depolarisation of motor endplate -> fasciculation

·  Remote metabolism -> prolonged receptor binding -> failure to repolarize junctional and peri-junctional membrane -> flaccid paralysis

Of recovery

·  Diffusion from NMJ to plasma down concentration gradient to plasma
(cf. ACh metabolized by AChE at NMJ)

·  Gradient established by metabolism in plasma/liver by plasma cholinesterase

·  Two stage:

o Suxamethonium -> succinylmonocholine + choline

o Succinylmonocholine -> succinic acid + choline

·  10% renal elimination unchanged (more important if enzyme polymorphism)

·  High capacity, high concentration enzyme. Offset usually 5 mins.

Features

·  Similar to non-depolarising blockade

·  TOF ratio <0.3, fade during tetany, post-tetanic facilitation, antagonism by AChEi

Cause

·  Big dose >3-5mg/kg
(or conventional dose if significant plasma cholinesterase polymorphism)

Mechanisms

·  Post-junctional receptor densitisation

o Continuous agonist binding

o Large Na⁺, K⁺, Ca²⁺ flux

o Phosphorylation of tyrosine unit

o Conformational change in receptor

o Dysfunction of receptor and membrane

o Flux between resting and desensitized state

o Does not adopt activated state

o Impervious to agonist binding

·  Pre-synaptic receptor blockade (lower affinity)

·  Activation of Na⁺K⁺ATPase by initial depolarisation