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Local anesthetics are xenobiotics that block excitation of, and transmission along, a nerve axon in a predictable and reversible manner. The anesthesia produced is selective to the chosen body part in contrast to the nonselective effects of a general anesthetic. Local anesthetics do not require the circulation as an intermediate carrier, and they usually are not transported to distant organs. Therefore, the actions of local anesthetics are largely confined to the structures with which they come into direct contact. Local anesthetics may 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 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 fibers. Toxicity may be local or systemic. With systemic toxicity, the central nervous system (CNS) and cardiovascular systems typically are affected.


Until the 1880s, the only xenobiotics available for pain relief were centrally acting depressants such as alcohol and opioids, which blunted the perception of pain rather than attacking the root cause. The coca shrub (Erythroxylon coca) was brought back to Europe from Peru by Karl Von Scherzer, an Austrian explorer, in the mid-1800s. Some of the coca leaves were analyzed by the chemist Albert Niemann, who in 1860 successfully extracted and named the active principle, the alkaloid cocaine (see Chap. 76). Sigmund Freud studied the use of cocaine to cure morphine addiction. Koller at the Ophthalmological Clinic at the University of Vienna dissolved coca powder in distilled water; instilled the solution in the conjunctival sacs of a frog, a rabbit, a dog, and himself; and noted that their corneas as well as his own could be touched without any evidence of a reflex blink. In 1884, Koller performed an operation for glaucoma with topical cocaine anesthesia, and the news spread rapidly, leading to diversification of use.42


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.66,84 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 they were either highly toxic or irritating or had an impractically brief clinical effectiveness. In 1904, Einhorn synthesized procaine, but its short duration of action limited its clinical utility. Research then focused on synthesis of xenobiotics with more prolonged durations of action.


The potent, long-acting local anesthetics ...

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