Local anaesthetic is very useful stuff. We all know that it blocks pain signalling somehow, but how exactly? And why do some people insist on mixing bicarbonate into their local before injecting?
How They Work ⚡️
Consider the classic case of the Lego brick versus the plantar aspect of the foot.
At the moment of impact, free nerve endings in the epidermis depolarise to create an action potential that will be transmitted to the dorsal horn of the spinal cord (and then on to the brain) via Aδ (fast) and C (slow) pain fibres.
Local anaesthetics block the voltage-gated sodium channels that facilitate propagation of the action potential, so the noxious stimulus never makes it to the spinal cord. When the axon of interest is myelinated (like Aδ ones), the anaesthetic needs to bind in at least three adjacent nodes of Ranvier to work.
The binding site is inside the ion channel and the majority of the binding happens from the intracellular side. The molecules get into the cell like this…
- Passive diffusion across the cell memebrane in the un-ionised form.
- Re-ionisation in the relatively more acidic intracellular environment.
- Binding to the protein structure of the ion channel.
- They need to be un-ionised because it is all-but-impossible for charged molecules diffuse through the cell membrane unaided.
- A small minority will get distracted on their way through and bind directly to the channel, which is fine. But the main show is the intracellular route.
About Ionisation 📈
All local anaesthetics are weak bases that are mostly ionised at physiological pH, so only the (small) uncharged fraction is able to cross the cell membrane. If you want a science-y way to predict just how small that fraction will be, look no further than the Henderson-Hasselbalch equation:
\[ pH = pK_{a} + \log(\frac{[A^{-}]}{[AH]}) \]
- pH = power of hydrogen
- pKa = power of dissociation constant (more on this below)
- [AH] = concentration of a weak acid
- [A-] = concentration of its conjugate base
This little equation introduces us to pKa: the pH at which 50% of molecules in a weak acid (or base) are ionised and 50% are unionised. Each acid and base has its own unique pKa.
As we decrease pH (increase the concentration of free hydrogen ions), bases will become more ionised as they accept the now-abundant protons. The opposite happens when we increase the pH.
For acids, it’s the other way around: at high pH (low hydrogen ion concentration), they are more ionised and at low pH (hydrogen ion-rich) they are less ionised.
Acids are ionised above their pKa, bases are ionised below their pKa.
So… How can we apply this to a dose of local anaesthetic?
A Worked Example
Consider the case of lignocaine, a weak base with a pKa of 7.8. To stop it from precipitating out of solution (and otherwise chemically degrading), lignocaine is packaged with hydrochloric acid acid to keep the pH at about 6.0.
Let’s plug these values into the Henderson-Hasselbalch equation and see if we can figure out what percentage of the lignocaine we inject will be un-ionised (and therefore able to cross the cell membrane)…
\[ 6.0 = 7.8 + \log(\frac{[A^{-}]}{[AH]}) \]
Which we can re-arrange to…
\[ \log(\frac{[A^{-}]}{[AH]}) = -1.8 \]
For our purposes the weak acid [AH] is ionised lignocaine, and the conjugate base [A-] is unionised lignocaine… \[ \log(\frac{[unionised]}{[ionised]}) = -1.8\]
Get rid of the logarithm my raising ten to the power of both sides…
\[ \frac{[unionised]}{[ionised]} = 10^{-1.8} ≈ 0.016 \]
With a bit of high school algebra, we can now work out the percentage of the total dose that will be un-ionised…
\[ F_{ionised} = \frac{0.016}{1 + 0.016} = 1.56\% \]
A measly 1.56%! Pitiful. We could get the local anaesthetic to diffuse across the cell membrane a lot faster if more of it was un-ionised. I wonder…
Adding Bicarbonate
What if we were to increase the pH of the solution by adding some bicarbonate? From experimental data, we know that if you add 1 mL of standard-issue 8.4% sodium bicarbonate to 10 mL of 1% lignocaine1, the pH comes out around 7.4.
If we repeat our sums with that figure in mind…
\[ 7.4 = 7.8 + \log(\frac{[A^{-}]}{[AH]}) \] \[ \log(\frac{[A^{-}]}{[AH]}) = -0.4 \] \[ \frac{[unionised]}{[ionised]} = 10^{-0.4} ≈ 0.40 \] \[ F_{ionised} = \frac{0.40}{1 + 0.40} = 28.5\% \]
We have upped the un-ionised portion of lignocaine to 28.5%, an 18-fold increase! All other things being equal, that means local anaesthetic will diffuse into the neuronal cells 18 times fast than if you didn’t use bicarbonate.
In practice, this verifiably translates into a more rapid onset of anaesthesia. Given the necessity of a sharp needle for subcutaneous administration, this effect is generally interpreted as an overall-less-unpleasant experience with the needle.
Not that Gas Notes is in the business of giving clinically-applicable advice (doubly so in the Nerd Box), but 11 mL of liquid (1 mL of 8.4% bicarbonate and 10 mL of 1% or 2% lignocaine) will easily fit in a (supposedly) 10 mL syringe and seems to be the accepted practice where the author works. ↩