Neuromuscular blockade

[CEACCP 2004 Vol 4(1) "Pharmacology of neuromuscular blocking drugs"; SH4:p216-217]

Neuromuscular junction

• NMJ contains 3 types of nicotinic acetylcholine receptors (nAChR)
  * Junctional (post-synaptic)
  * Extrajunctional (post-synaptic)
  * Presynaptic

Phase I block (depolarising blockade)

• aka accommodation block
• Often preceded by muscle fasciculation
• [CEACCP article] Suxamethonium stimulates prejunctional ACh receptors
  --> Repetitive firing and release of neurotransmitter
  --> Fasciculation
• [SH4:p217] Skeletal muscle fasciculation reflects the generalised depolarisation of postjunctional membranes produced by suxamethonium

Mechanism of phase I block

• Also see previous section
• Basically, due to suxamethonium's longer action (than ACh)
  --> Junctional nAhRs stay open
  --> Membrane potential cannot be restored
  --> Inactivated voltage-sensitive Na+ channels cannot revert back to resting state
  --> Action potential cannot be generated

Characteristics of phase I block

• Decreased contraction in response to single twitch stimulation
• Decreased amplitude but sustained response to continous stimulation
• TOF ratio of >0
• Absence of post-tetanic facilitation
• Augmentation of neuromuscular blockade after anticholinesterase drug
  * i.e. block increases, rather than decrease, as with non-depolarising NMBDs
• Onset of phase I block is accompanied by skeletal muscle fasciculations

Recovery from Phase I block

Recovery from phase I block occurs when

• Suxamethonium diffuse away from the neuromuscular junction (down the concentration gradient)
• Plasma concentration decreases when suxamethonium is metabolised by plasma cholinesterase (pseudocholinesterase)

Phase II block (desensitisation blockade)

• Prolonged exposure to suxamethonium or large doses of suxamethonium (>2mg/kg IV)
  --> Postjunctional membrane does not respond to ACh even when resting membrane potential is restored
  * i.e. Desensitisation blockade or Phase II block.
  * May be a safety mechanism to prevent overexcitation of the NMJ
• According to CEACCP article, desensitisation block and phase II block are two different things.
• According to [SH4:p217], these two are the same thing.
• Transition from phase I to phase II block is fairly abrupt
  * Initial manifestation as tachyphylaxis
• At any one time there could be varying degrees of phase I and phase II blockade present at the same time

Mechanism of phase II block

Exactly mechanism is UNKNOWN.

Possible mechanisms include:

• Presynaptic block
  --> Reduction in synthesis and mobilisation of ACh
• Postjunctional receptor desensitisation
• Initial depolarisation activates the Na-K ATPase pump
  --> Repolarisation

Characteristics of phase II block

Resembles that of nondepolarising NMBDs
* But mechanism is likely to be different

• Fade of the train-of-four twitch response
• Tetanic fade
• Post-tetanic potentiation
• Anticholinesterase drugs will antagonise effects of a phase II blockade

Characteristics of nondepolarising neuromuscular blockade

[SH4:p222]

• Decreased twitch response to a single stimulus
• Unsustained response (fade) during continuous stimulation
• TOF ratio of <0.7
• Posttetanic potentiation
• Potentiation of other nondepolarising NMBDs
• Antagonism by anticholinesterase
• NOT accompanied by fasciculations

NB.

• Twitch response is decreased because some fibres are contracting normally and others are blocked
• Fade in response to continuous electrical stimulation - some fibres are more susceptible to being blocked by NMBDs and need greater sustained release of ACh to trigger their response