Local Anaesthetics

Mechanism of Action

Local anaesthetic agents consist of a lipid-soluble (hydrophobic) aromatic ring joined to a basic (hydrophilic) amide group. The linkage between the two groups may be either an ester linkage or an amide linkage. Examples of ester-linked drugs include procaine and cocaine. Drugs linked in this way are less stable in solution, and are metabolised by tissue esterases, hepatic esterases and hydrolysis to be subsequently excreted by the kidney. The metabolism of ester-linked local anaesthetics produces para-amino benzoic acid (PABA), which may cause allergic reactions. Amide linked drugs include lidocaine and bupivicaine. These are can be stored longer than ester-linked drugs and are heat stable. They are metabolised by hepatic amidases and excreted by the kidney.

Local anaethetic drugs reversibly interfere with action potential generation and conduction in the neurons around which they are administered. To reach the neuronal plasma membrane where they act, local anaethetic drugs must first enter the nerve sheath. Only molecules lacking ionic charge may do this, and so local anaesthetic agents work more effectively in an alkaline pH when charge is neutral. Once inside the sheath, the drug gains charge and can then bind to voltage-gated Na⁺ channels, preventing depolarisation of the cell. Local anaesthetics also infiltrate and change the composition of the cell membrane to take effect. However, they do NOT alter resting membrane potential.

Pharmacokinetic Considerations

Local anaesthetics are weak bases and so at body pH of 7.4, more molecules are ionised than unionised. This makes it more difficult for drugs to cross the plasma membrane. Infected tissue has a lower pH than healthy tissue, causing the ratio of ionised:unionised molecules to increase. Because of this, there is poorly cellular uptake of local anaethetics in infected tisse, as they cannot cross the cell membrane. For more about the effect of pH on drugs, see the pharmacokinetics page.