Question 3

Outline the factors which affect the onset, duration of action and toxicity of local anaesthetic agents.

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College Answer

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),


  • J is "diffusive flux", the magnitude of flow of the local anaesthetic to the site of action
  • dφ is the concentration difference:
    • A more highly concentrated solution will have faster onset
    • A less potent drug will have faster onset (as the dose of molecules is higher, which increases the concentration gradient) 
  • dx is the distance for diffusion (or the thickness of the membrane)
    • This is the thickness of the nerve axon (thinner and unmyelinated axons have a more rapid onset of effect)
  • D is a diffusion coefficient which is influenced by
    • solution temperature
    • viscosity of the fluid
    • size of the local anaesthetic agent molecules (smaller molecules diffuse faster)

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:

  • Protein-binding determines the total amount of drug available for diffusion, as bound molecules will not be inclined to diffuse anywhere (or to ionise)
  • pKa determines the lipid soluble fraction

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:

  • Could be at body pH, in which case close to 50% of the drug should be in a lipid-soluble form (most of them have a pKa close to that of the body fluids, in the low 8 - high 7 range)
  • Could be hilariously acidic, if:
    • the injectate retains its pH from the ampoule (local anaesthetic solutions are usually stored at a pH of 5.0 or so, in order to maximise the soluble ionised fraction)
    • the site of injection is an abscess, which tend to be quite acidic
  • Could be intentionally alkaline: buffering their infiltrate with sodium bicarbonate to improve lipid solubility seems to be a common practice among anaesthetists

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:

  • Concentration gradient: less potent drugs (higher concentration) diffuse faster = faster onset
  • Optimal pKa: to strike a balance between lipid solubility and receptor binding:
    • Lipid solubility: pKa below body fluid pH = larger lipid-soluble fraction; thus, diffuse  through cell membrane faster for a faster onset
      • But high lipid solubility also leads to sequestration in myelin = slower onset
    • Intracellular ionisation: pKa above intracellular pH = larger ionised fraction = faster onset, as only the ionised drug can bind the sodium channel molecular targets 
  • Protein binding:
    • drugs with less protein binding are more available for diffusion = faster onset
    • patients with less protein (eg. pregnant, child, elderly, critically ill) = 
  • Diffusion distance: unmyelinated C-fibres = shorter diffusion distance = faster onset
  • Molecule size: smaller local anaesthetic molecules (eg. prilocaine) diffuse faster = faster onset
  • Stimulus: more stimulated nerve = more open channels = more blockade ("use-dependence")

Factors which determine the duration of action of local anaesthetics:

  • Concentration gradient: higher gradient = more diffusion away = shorter duration
  • Lipid solubility: myelin sequestration = larger local reservoir = longer duration
  • Intracellular ionisation: ion trapping of ionised agent inside cells = longer duration
  • Protein binding: More protein binding = larger local reservoir = longer duration
  • Molecule size: larger molecules (eg. bupivacaine) diffuse away slowly = longer duration
  • Metabolic breakdown: esters metabolised by local esterases = shorter duration
  • Regional perfusion: 
    • increased cardiac output, or highly vascular area = shorter duration
    • concomitant use of vasoconstrictor (eg adrenaline) = longer duration

Factors which determine the toxicity of  local anaesthetics:

  • Patient risk factors for local anaesthetic toxicity:
    • Acidosis (decreased protein binding, increased availability of active ionised form of agent)
    • Old age: slower clearance, more cardiofragile
    • Young age: lower α1-acid glycoprotein level, higher free fraction
    • Pregnant patients: lower α1-acid glycoprotein level, better perfusion of blocked tissue
    • Hyperkalemia (decreased toxic dose of agent)
  • Pharmacological factors which contribute to local anaesthetic toxicity:
    • Dose (obviously)
    • Choice of agent (some drugs, eg. bupivacaine, have a lower CC/CNS ratio)
    • Site of administration (eg. closer to large vessels, hyperaemic site, epidural)
    • Coadministration of vasoconstrictor (slows systemic absorption)
    • Slower dissociation from sodium channels (eg. bupivacaine)
    • Drug interactions:
      • displacement from protein binding (eg. by phenytoin)
      • decreased metabolism (eg. by cimetidine)

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)
Small molecule
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)
Large molecule
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)
Toxicity Acidosis
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)
Drug interactions:
  • displacement from protein binding (eg. by phenytoin)
  • decreased metabolism (eg. by cimetidine)


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