College Answer
There were a number of possible factors that candidates could have selected. Examples
include drug interactions (anticholinesterases, aminoglycoside antibiotics, local anaesthetics, steroids, antiarrhythmic drugs, anticonvulsants (phenytoin), diuretics, magnesium, lithium), hypothermia / hyperthermia, acidosis, [k+], burn injury, allergic reactions, gender, altered elimination due to renal or hepatic dysfunction and disease states (adrenocortical dysfunction, myasthenia, myopathies, denervation injury). Also extremes of age and pregnancy. Areas of weakness for the candidates were failure to include sufficient factual knowledge for their selected factors, and as a result, a failure to illustrate sufficiently the mechanisms by which the pharmacodynamic response of nondepolarising neuro-muscular blocking drugs may be affected.
Discussion
There was a huge number of possibilities here, in terms of factors which the candidates might have picked, which would all have yielded potentially passing answers. One cannot imagine a marking rubric sufficiently inclusive to account for all possible variants, which suggests that the examiners would have had to be generous, or prepared to do a lot of googling to supplement their own understanding.
Pharmacokinetic factors that influence the potency of NMJ blockers:
- Storage:
- Prolonged storage at room temperature degrades the potency of most NMJ blockers, especially atracurium and cisatracurium
- Dose
- There is a minimum dose requirement: 70-80% of the NMJ receptors need to be occupied by a nondepolarising agent to produce a clinically relevant response
- Absorption
- Zero oral availability; nil potency unless parenteral
- Distribution
- Extremely low protein can increase the potency of highly protein boundNMJ blockers (which is mainly just pancuronium)
- Extremely reduced extracellular fluid volume will increase the potency of NMJ blockers by decreasing their volume of distribution
- More lipophilic NMJ blockers (eg. vecuronium) may have lower potency in patients with greater adipose tissue
- Monoquaternary NMJ blockers (notably rocuronium and vecuronium), weakly basic drugs, will have greater solubility at acidic pH, which will decrease their potency (and, conversely, alkalinisation will increase their potency, as demonstrated by Lee et al, 2010)
- Metabolism:
- Hepatic failure can potentiate the effects of NMJ blockers by increasing the duration of action
- Extremes of pH and temperature can change the rates of Hoffmann degradation of NMJ blockers such as cisatracurium, increasing their potency and duration of action
- Elimination:
- Renal failure can potentiate the effects of NMJ blockers by increasing the duration of action of renally excreted agents
Pharmacodynamic factors that influence the potency of NMJ blockers:
- Altered concentration of acetylcholine at the synapse
- Decreased concentration increases the potency of competitive (nondepolarising) NMJ antagonists, for example in:
- Immature foetal/neonatal NMJ synapses
- General anaesthetic agents (volatiles)
- Regional local anaesthesia
- Frusemide
- Calcium channel blockers
- Aminoglycosides
- Hemicholinium
- Vesamicol
- Increased concentration decreases the potency of competitive (nondepolarising) NMJ antagonists, for example:
- Acetylcholinesterase inhibitors
- Altered number/availability of acetylcholine receptors
- Immature (foetal/neonatal) receptors have a higher affinity, result in increased potency
- Numerically fewer receptors (eg. myasthenia gravis)
- increase potency of nondepolarisng agents
- decrease potency of depolarising agents
- Fewer available receptors
- Pre-curarisation or "priming" with a low dose of non-depolarising agent
- More receptors decrease potency:
- Critical illness polyneuromyopathy
- Burns
- Tetanus
- Spinal injury
- Stroke
- Antiepileptic agents
- Altered post-synaptic NMJ performance:
- Partially depolarising factors:
- Hypermagnesemia
- Hypocalcemia
- Hypokalemia
- Hyperpolarsing factors:
- Hyperkalemia
- Hypercalcemia
- Malignant hyperthermia