Chemically, most local anaesthetics consist of a lipophilic and a hydrophilic group which are connected by either an ester linkage or an amide bond. Within the body, they exist as weak bases. A certain proportion is in a non-ionized lipid form and it is this which penetrates the lipid bilayer of neuronal axons.
Within the axon, the local anaesthetic is ionized again. In this form it is capable of interacting with membrane sodium channels to alter the kinetics of opening. It is thus harder for the neurone to depolarize in response to a given stimulus. Indeed, when the sodium channels do open, more protonated local anaesthetic is thought to gain access to the neurone and impulse transmission is inhibited to a greater extent - 'use dependence'.
Highly lipophilic local anaesthetics, e.g. benzocaine, may act by the same final common path - disruption of sodium channels - but do not seem to require entry into the ionized state.
Local anaesthetics differ markedly in their properties and one gauge of their potency is by means of the minimum concentration of drug necessary to block conduction in fibres of a certain diameter. All agents tend to affect small-diameter fibres first and so sensory block of mixed nerves can be achieved: pain, temperature and autonomic loss without change in motor function.
The non-specific effect of local anaesthetics on sodium channels and hence all excitable tissues is responsible for many of their side-effects.
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