Outline the factors which affect the onset, duration of action and toxicity of local anaesthetic agents.
Marks were equally divided between all three parts. Structure to the answer using a table and list of facts gained credit. Factors affecting onset would be well described by stating Ficks law of diffusion and followed with an explanation of the equation. Factors affecting duration such as protein binding, regional blood flow, metabolism and use of vasoconstrictors scored marks. Regarding toxicity, an explanation of the CC/CNS ratio was required (the ratio of plasma levels at which CVSCollapse vs. Convulsions occur). Other factors included structure of
agents, accumulation e.g. due to liver disease. A mention of features of particular agents’ toxicity such as prilocaine and methaemoglobinaemia was expected.
Syllabus G2b 2a-c
References: Peck, Hill and Williams 2nd edition p163-174
Stoelting and Hillier 4th edition p179-203
Evers and Maze p507-533
The 10% pass rate suggests that this caught a lot of people off-guard. Particularly the Fick thing: it is extremely unlikely that a stressed exam candidate would intuitively guess that the examiners wanted the answer to be framed in this specific way.
A Fickian answer, which is what the examiner apparently wanted, would look like this:
Onset of action of local anaesthetics is governed by Fick's law: "The molar flux due to diffusion is proportional to the concentration gradient", or
J = -D (dφ / dx),
But, the attentive reader would object that this answer contains a lot of pointless wank. In what universe would you be injecting your patient with a thick viscous glug, chilled or heated to some abnormal non-room temperature? Also, local anaesthetic molecules do not vary dramatically in their molecular weight, they range from 220 Daltons (prilocaine) to 288 (bupivacaine). And, probably most importantly: there's no convenient place to discuss the influence of pKa, lipid solubility and protein binding. That dφ concentration difference in the equation: that is a is gradient is of the nonionized particle concentration, as we are really describing the diffusion of a local anaesthetic between two aqueous compartments (extracellular water and cytosol) which are separated by a lipid compartment. Thus, the concentration we need to consider is the lipid-soluble non-ionised concentration. This concentration depends on pKa and protein binding:
And then, the degree to which pKa influences the diffusion of a local anaesthetic agent also depends on the prevailing conditions of the extracellular fluid, which:
In summary, it would appear that any earnest effort to shove this information into the answer through the Fick equation would result in some unpleasant spiral tears. An alternative is offered, which would have hopefully satisfied the examiners by hitting all the important notes without sounding insane, and hopefully with the absolute minimum of words wasted:
Factors which determine the onset of action of local anaesthetics:
Factors which determine the duration of action of local anaesthetics:
Factors which determine the toxicity of local anaesthetics:
Yes, at 373 words, this answer is far, far too long, and in ten minutes one could really only be expected to write about a third of this. Moreover, even a patient reader may at this stage complain that this answer is not tabulated, and the college examiners said it should be tabulated, so why isn't it tabulated. The best table-shaped response to this question would actually have to be by Gladwin (2016), and it would be rather difficult to improve on it, in terms of information density and clarity. All one can hope to do here is present Ben's work rearranged to make it look like one's own, hoping nobody will notice. Also, all the possible explanatory notes have been resected, skeletonising the answer into something which has absolutely no educational benefit.
|Drug property:||Factors which increase this drug property:|
|Onset||Low potency (high drug concentration, more diffusion gradient)|
|Alkaline local pH|
|Drug pKa lower than extracellular pH|
|Drug pKa higher than intracellular pH|
|Less protein-bound fraction|
|Stimulated nerve (use dependence)|
|Thin unmyelinated fibres|
|Duration||High potency (lower drug concentration, less diffusion gradient)|
|Drug pKa lower than intracellular pH (intracellular ion trapping)|
|High lipid solubility (myelin sequestration)|
|High protein binding (regional reservoir)|
|Amide drugs (hepatic metabolism)|
|Poor regional perfusion (eg. use of vasoconstrictor)|
|Extremes of age|
|Choice of agent (eg. bupivacaine)|
|Slower dissociation from sodium channels (eg. bupivacaine)|
|Site of administration (eg. closer to large vessels, hyperaemic site, epidural)|
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