Local anesthetics bind reversibly to a specific receptor site within the pore of the Na+ channels in nerves and block ion movement through this pore. When applied locally to nerve tissue in appropriate concentrations, local anesthetics can act on any part of the nervous system and on every type of nerve fiber, reversibly blocking the action potentials responsible for nerve conduction.
CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP. The most widely used agents today are procaine, lidocaine, bupivacaine, and tetracaine (Figure 20-1). These agents were synthesized as substitutes for cocaine, preserving the local anesthetic effect of cocaine but avoiding its toxicity and addictive properties. The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage. The hydrophilic group usually is a tertiary amine but also may be a secondary amine; the hydrophobic moiety must be aromatic. The nature of the linking group determines some of the pharmacological properties of these agents. For example, local anesthetics with an ester link are hydrolyzed readily by plasma esterases. Hydrophobicity increases both the potency and the duration of action of the local anesthetics; association of the drug at hydrophobic sites enhances the partitioning of the drug to its sites of action and decreases the rate of metabolism by plasma esterases and hepatic enzymes. In addition, the receptor site for these drugs on Na+ channels is thought to be hydrophobic, so that receptor affinity for anesthetic agents is greater for more hydrophobic drugs. Hydrophobicity also increases toxicity, so that the therapeutic index is decreased for more hydrophobic drugs.
Structural formulas of selected local anesthetics. Most local anesthetics consist of a hydrophobic (aromatic) moiety (black), a linker region (orange), and a substituted amine (hydrophilic region, in red). Procaine is a prototypic ester-type local anesthetic; esters generally are well hydrolyzed by plasma esterases, contributing to the relatively short duration of action of drugs in this group. Lidocaine is a prototypic amide-type local anesthetic; these structures generally are more resistant to clearance and have longer durations of action. Figure 20-1 in 12th edition of the parent text shows additional variations on the basic structure.
Molecular size influences the rate of dissociation of local anesthetics from their receptor sites. Smaller drug molecules can escape from the receptor site more rapidly. This characteristic is important in rapidly firing cells, in which local anesthetics bind during action potentials and dissociate during the period of membrane repolarization. Rapid binding of local anesthetics during action potentials causes the frequency- and voltage-dependence of their action.
MECHANISM OF ACTION. Local anesthetics act at the cell membrane to prevent the generation and the conduction of nerve impulses. The major mechanism of action of local anesthetics involves their interaction with 1 or more specific binding sites within the Na+ channel (...