The development of local anesthetics

Abstract

Koller's 1884 report that cocaine induced corneal insensibility enabled ophthalmological procedures and marked the birth of clinical local anesthesia. Soon thereafter, Halsted and Hall produced peripheral nerve blocks while Corning and Bier used cocaine for spinal anesthesia. Toxicity stimulated the search for alternatives. The first new useful local anesthetic was the ester procaine, but its short duration of action limited clinical utility, a limitation overcome by tetracaine. Lidocaine, introduced in 1948, had an amide rather than an ester linkage, imparting greater stability and eliminating concern of allergic reactions from an ester breakdown product. Ironically, chloroprocaine reverted to the ester linkage, as its rapid degradation decreased risk of systemic toxicity. Regrettably, neural injury occurred when a large doses intended for the epidural space was apparently administered intrathecally. Bupivacaine, a longer-acting amide anesthetic was released in 1963. Associated untoward cardiac effects led to modifications in practice, while stereochemical strategies produced levobupivacaine and ropivacaine that have less affinity for cardiac sodium channels. Toxic reactions with spinal lidocaine resulted in its near abandonment as a spinal anesthetic. In 1998, Weinberg suggested that intravenous infusion of lipid could decrease the availability of local anesthetics and thereby treat systemic toxicity. As apparent from this history, toxicity, rather than efficacy, has directed the evolution of these compounds.