3. Old stuff
          3.1. Old pharm stuff (pre 2009)
              3.1.3. Pharmacology
                  3.1.3.7. Neuromuscular blocking drugs
 3.1.3.7.3. Neuromuscular blockade 

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