Local anesthetics (LAs) have been used for more than a century to block nociceptive signals. They bind to the specific receptor sites on the sodium (Na+) channels in nerve cells to interrupt nerve conduction by blocking the entrance of ions across the cell membrane. LAs also activate a number of downstream pathways in neurons by G protein-coupled receptors and interact with calcium, potassium, and hyperpolarization-gated ion channels, ligand-gated channels. The clinical properties of the LAs are determined by their chemical and pharmacologic properties with a significant variation in individual patients’ responses. The current developments in LAs focus on formulations of local anesthetic that prolong the duration of the action. Formulations of encapsulated slow-release LAs, on-demand release, and those with a selective nociceptive block are being developed. This chapter discusses the mechanism of action of LAs and their clinical use. The prevention and treatment of toxicity and allergy by LAs are explained in Chapter 9.
Nerve conduction is the transmission of an electrochemical signal from one neuron to another. The axon, a prolongation of the soma of the neuron, plays an essential role in nerve conduction. Axons can be myelinated or unmyelinated depending on the type of nerve fiber. Myelin is the fatty substance that insulates the nerves and surrounds the axon. The myelin sheath, however, is not continuous. The section where no myelin is present is called a node of Ranvier. A high concentration of ion channels at the level of these nodes in myelinated nerve fibers results in high conduction speeds. The greater the internodal distance, the greater the conduction speed. Unmyelinated fibers, lacking the saltatory mechanism, conduct more slowly than myelinated fibers.
The propagation of an electrical impulse in nerve conduction is generated by the rapid movement of small amounts of cations, sodium (Na+) and potassium (K+), across the nerve membrane. The ionic gradient caused by Na+ (high extracellular; low intracellular) and K+ (high intracellular; low extracellular) is maintained by a Na+/K+-adenosine triphosphate (ATPase) pump mechanism within the cell membrane of the nerve. In the resting state, the nerve membrane is more permeable to K+ ions than to Na+ ions. This results in the continuous, slow leakage of K+ ions out of the nerve cell. This leakage of cations, in turn, creates a negatively charged interior relative to the exterior, producing an electric potential of –60 to –70 mV across the nerve membrane, also called the resting potential (Figure 2-1).
Resting membrane potential. The Na+/K+ pump is responsible for maintaining the ionic gradient between Na+ and K+ ions within the nerve. Typically, the resting membrane potential is between –60 and –70 mV.