Chemistry Reference
In-Depth Information
The site of action of most local anaesthetics is a Na
ion channel
found in the cell membrane of nerve cells (or
neurons
). This sodium
channel, as its name suggests, allows Na
ions to travel through the cell
membrane to depolarise the resting membrane potential and allow the
nerve cell to fire. Local anaesthetics block nerve conduction by attaching to
the protein of the sodium channel and disrupting the flow of Na
ions.
Recent research using radiolabelled local anaesthetics has shown that the
local anaesthetic attaches to a structure at the
intracellular
opening of the
sodium channel, and that the form of the drug active at the receptor is
the positively charged
conjugate acid
, which prompts the question 'How
does an ionised drug get to the internal opening of the ion channel?' The
apparently obvious answer is that the cationic form of the local anaesthetic
gains entry to the nerve cell by the same route as the Na
ions, i.e. down the
open sodium channel. Although this may explain part of local anaesthetic
action, it cannot be the full story, since most local anaesthetics are too large
to pass through the channel. The answer lies within the properties of
equilibria and can be predicted from the pH partition hypothesis (see
Figure 2.9).
Na
+
channel
BH
+
B + H
+
Lipid
cell
membrane
Lipid
cell
membrane
BH
+
H
+
+ B
Local
anaesthetic
receptor
Figure 2.9
A diagram of local anaesthetic equilibrium.
The important thing to remember in this situation is that although 99
out of every 100 local anaesthetic molecules are ionised, there exists an
equilibrium between the cation and the unionised free base. This unionised
free base (B) can diffuse easily through the cell membrane, where it will
become instantly ionised due to the H
ions present within the cell. Once
ionised to the cation (BH
), the local anaesthetic cannot easily diffuse back
outside the cell, but it can approach the receptor situated at the internal
opening of the sodium channel. Once the 1% of free base has diffused into
