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.
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. When, in 1860, Albert Niemann isolated cocaine, he tasted his newly isolated compound, noted that it numbed his tongue, and a new era began. 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. Subsequently, Einhorn and others developed synthetic substitutes in an attempt to avoid the toxic and addictive qualities of cocaine.
CSF: cerebrospinal fluid
CYP: cytochrome P450
EDTA: ethylenediaminetetraacetic acid
NET: norepinephrine transporter
TRP: transient receptor potential
TRPV channel: TRP vanilloid subtype channel
CHEMISTRY AND STRUCTURE-ACTIVITY RELATIONSHIP
Cocaine is an ester of benzoic acid and the complex alcohol 2-carbomethoxy, 3-hydroxytropane (Figure 25–1). Because of its toxicity and addictive properties (see Chapter 28), 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 lidocaine, bupivacaine, and tetracaine.
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, green). The structures at the top are grouped by the nature of the linker region. Procaine is a prototypic ester-type local anesthetic; esters generally are rapidly 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. There are exceptions, including benzocaine (poorly water soluble; used only topically) and the structures with a ketone, an amidine, and an ether ...