Local anaesthetic agents

Local anaesthetic agents cause a pharmacologically induced reversible neuropathy characterized by axonal conduction blockade. They act by blocking the sodium ionophore and exhibit membrane stabilizing activity by inhibiting initiation and propagation of action potentials. They are weak bases consisting of three components: a lipophilic aromatic ring, a link, and a hydrophilic amine. The chemical link classifies them as esters or amides. Local anaesthetics diffuse through the axolemma as unionized free-base and block the ionophore in the quaternary ammonium ionized form. The speed of onset of block is therefore dependent on the pKa of the agent and the ambient tissue pH. Esters undergo hydrolysis by plasma esterases and amides are metabolized by hepatic microsomal mixed-function oxidases. Local anaesthetics are bound in the blood to α‎1-acid glycoproteins. Pharmacological potency is dependent on the lipid solubility of the drug as is the potential for systemic toxicity. The blood concentrations required to cause cardiovascular system (CVS) collapse and early central nervous system (CNS) toxicity are used to quantify the CVS:CNS toxicity ratio. Local anaesthetics also have the potential to induce direct neuronal damage. Intravenous lipid emulsion is used for the treatment of systemic toxicity but the scientific evidence is inconsistent. With regard to the pipecoloxylidine local anaesthetics, early evidence indicated that the S- was less toxic than the R-enantiomer. However, clinical research using minimum local analgesic concentration designs suggests that reduced systemic toxicity and motor block sparing is mainly explained by potency rather than enantiomerism.