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Local anesthetics block excitation of and transmission along a nerve axon in a predictable and reversible manner. In contrast to the nonselective effects of a general anesthetic, the anesthesia produced is selective to the chosen body part. Because local anesthetics do not require the circulation as an intermediate carrier and usually are not transported to distant organs, their actions are largely confined to the structures with which they come into direct contact. Local anesthetics are used to provide analgesia in various parts of the body by topical application, injection in the vicinity of peripheral nerve endings and major nerve trunks, or via instillation within the ophthalmic, epidural or subarachnoid spaces. The various local anesthetics differ with regard to their potency, duration of action, and degree of effects on sensory and motor nerve fibers. Toxicity is either local or systemic. With systemic toxicity, central nervous system (CNS) and cardiovascular effects are of greatest concern.

Until the 1880s, the only available analgesics were centrally acting depressants such as alcohol and opioids, which blunted the perception of pain rather than addressing the underlying cause. In 1860, the chemist Albert Niemann extracted the active alkaloid cocaine (Chap. 75) from the leaves of the coca shrub (Erythroxylon coca). Over the next 2 decades, the local anesthetic properties of the drug were identified. In 1884, Koller performed glaucoma surgery with only topical cocaine anesthesia.54

Although the clinical benefits of cocaine anesthesia were significant, so were its toxic and addictive potential. At least 13 deaths were reported in the first 7 years after the introduction of cocaine in Europe, and within 10 years after the introduction of cocaine as a regional anesthetic, reviews of “cocaine poisoning” appeared in the literature.89,111 The toxicity of cocaine, coupled with the tremendous advantages it provided for surgery, led to a search for less toxic substitutes.

After the elucidation of the chemical structure of cocaine (the benzoic acid methyl ester of the alkaloid ecgonine) in 1895, other amino esters were examined. Synthetic compounds with local anesthetic activity were introduced but were highly toxic or irritating or had an impractically brief clinical effect. In 1904, Einhorn synthesized procaine, but its short duration of action limited its clinical utility. Research turned to focus on synthesis of local anesthetics with more prolonged durations of action.

The potent, long-acting local anesthetics dibucaine and tetracaine were synthesized in 1925 and 1928, respectively, and were introduced into clinical practice shortly thereafter. These anesthetics were not safe for regional anesthetic techniques because of potential systemic toxicity secondary to the combination of high potency, delayed metabolism, and the larger volumes of drug required for regional anesthesia compared with local anesthesia. On the other hand, these anesthetics were very useful for spinal anesthesia, which required much smaller volumes.

Lofgren synthesized lidocaine in 1943 from a series of ...

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