Question 3

Describe the factors that influence the speed of ONSET of neuromuscular blockade.

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College Answer

The better candidates had an organised approach to their answer. For example factors could be broadly classified as pharmacokinetic and pharmacodynamic factors or patient and drug factors. For example, pharmacokinetic factors could include dose, the use of a priming dose, patient’s volume status, cardiac output, muscle group and skeletal muscle blood flow. Pharmacodynamic factors expected were those of mechanism of blockade, receptor affinity, agent potency, neuromuscular disorders, age, drug interactions and electrolyte disorders. Many answers listed factors which affect the duration of neuromuscular blockade instead of the onset. Marks were not allocated for information provided by candidates that did not address the question asked. It is important that candidates provide an answer specific to the question asked. Many candidates applied Fick’s Law inappropriately. Lipid solubility and pKa are not relevant as these drugs do not cross the nerve membrane. 

Syllabus - H2a, 2c
Reference: Pharmacology and Physiology in clinical practice, Stoelting Pg 186, Foundations
of Anaesthesia: Basic clinical Science, Hemmings and Hopkins ( 2nd ed)

Discussion

  • Factors that influence the rate of agent delivery to the muscles:
    • Route of administration (IV faster than IM)
    • Site of IV administration (CVC faster than PIVC)
    • Rate of administration (flushed bolus faster than infusion)
    • Cardiac output (faster in pregnancy, slower in cardiogenic shock)
    • Muscle position (those proximal to the heart affected faster)
  • Factors that influence plasma-effect site equilibration
    • Potency of the agent (less potent agents have faster onset)
      (this is the most important determinant and is mainly due to the larger molar concentration of the effective dose of the low potency agents)
    • Factors which influence diffusion to the site (minor influence),
      of which the only one that matters is:
      • Protein binding (less bound drugs have faster onset)
  • Factors that increase the required effective concentration (slowing the onset):
    • Factors that increase acetylcholine concentration
      • Acetylcholinesterase inhibitors
    • Factors that increase the number of receptors
      • Critical illness polyneuromyopathy
      • Burns
      • Tetanus
      • Spinal injury
      • Stroke
      • Antiepileptic agents
    • Factors that reduce the number of acetylcholine receptors, such as myasthenia gravis (for non-depolarising agents, this slows the onset)
    • Factors that hyperpolarise the motor endplate
      • Hyperkalemia (for nondepolarisng agents)
      • Hypercalcemia
      • Malignant hyperthermia
  • Factors that decrease the required effective concentration (hastening the onset):
    • Factors that reduce the synthesis or storage of acetylcholine
      • Hemicholinium
      • Vesamicol
    • Factors that decrease acetylcholine release
      • Foetal/neonatal motor endplates
      • General anaesthetic agents (volatiles)
      • Regional local anaesthesia
      • Frusemide
      • Calcium channel blockers
      • Aminoglycosides
    • Factors that partially depolarise the motor endplate
      • Hypermagnesemia
      • Hypocalcemia
      • Hyperkalemia (for depolarising agents)
    • Pre-curarisation or "priming" with a low dose of non-depolarising agent
    • Factors that reduce the number of acetylcholine receptors, such as myasthenia gravis (for depolarising agents, this slows the onset)

References

Kim, Yong Byum, Tae-Yun Sung, and Hong Seuk Yang. "Factors that affect the onset of action of non-depolarizing neuromuscular blocking agents." Korean journal of anesthesiology 70.5 (2017): 500-510.