Local anaesthetic agents are used directly to block neuronal transmission. They also stabilise other electrically excitable membranes, and some examples, such as lidocaine, have clinically useful antiarrhythmic activity.

Structure

Local anaesthetic agents comprise a hydrophilic tertiary amine group linked to a lipophilic aromatic group. They are divided into esters and amides, based on the linking group. Figure LA1 shows examples of these two types of local anaesthetic agent. Protonation of the highlighted amine nitrogen atom confers activity on the molecule once it is inside the cell.

Local anaesthetic agents exist in two states, acid (protonated) and basic (non-ionised) in equilibrium according to their pKa and ambient pH, as determined by the Henderson–Hasselbalch equation (Figure LA2).

Local anaesthetic agents are weak bases. At physiological pH, there exists a mixture of non-ionised and ionised drug. This is important, as only the non-ionised drug passes through the membrane, yet it is only the ionised drug that is active. Small changes in pH have marked effects on the proportion of drug that is ionised, and therefore markedly influence the effect.

Mechanism of action

Injectable local anaesthetics must be soluble and stable in water. This is achieved by creating hydrochlorides of the drug. These drugs exist within ampoules in acid solution with a high degree of ionisation, which maintains solubility.

Local anaesthetic agents act by blocking the fast sodium channel in neuronal membranes.