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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. Thus, a local anesthetic in contact with a nerve trunk can cause both sensory and motor paralysis in the area innervated. These effects of clinically relevant concentrations of local anesthetics are reversible with recovery of nerve function and no evidence of damage to nerve fibers or cells in most clinical applications.

History. The first local anesthetic, cocaine, was serendipitously discovered to have anesthetic properties in the late 19th century. Cocaine occurs in abundance in the leaves of the coca shrub (Erythroxylon coca). For centuries, Andean natives have chewed an alkali extract of these leaves for its stimulatory and euphoric actions. Cocaine was first isolated in 1860 by Albert Niemann. He, like many chemists of that era, tasted his newly isolated compound and noted that it caused a numbing of the tongue. Sigmund Freud studied cocaine's physiological actions, and Carl Koller introduced cocaine into clinical practice in 1884 as a topical anesthetic for ophthalmological surgery. Shortly thereafter, Halstead popularized its use in infiltration and conduction block anesthesia.

Chemistry and Structure-Activity Relationship. Cocaine is an ester of benzoic acid and the complex alcohol 2-carbomethoxy, 3-hydroxy-tropane (Figure 20–1). Because of its toxicity and addictive properties (Chapter 24), a search for synthetic substitutes for cocaine began in 1892 with the work of Einhorn and colleagues, resulting in the synthesis of procaine, which became the prototype for local anesthetics for nearly half a century. The most widely used agents today are procaine, lidocaine, bupivacaine, and tetracaine.

The typical local anesthetics contain hydrophilic and hydrophobic moieties that are separated by an intermediate ester or amide linkage (Figure 20–1). A broad range of compounds containing these minimal structural features can satisfy the requirements for action as local anesthetics. 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.

The structure-activity relationship and the physicochemical properties of local anesthetics have been reviewed by Courtney and Strichartz (1987). 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 (see Mechanism of Action), so that receptor ...

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