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Local anesthetics have been used for centuries and represent some of the oldest drugs in the armamentarium of anesthesiologists. The story of the coca leaf and its alkaloid derivative, cocaine, is the best-known example of this. Members of the pre-Columbian Inca civilization would chew coca leaves to reduce pain and for its stimulant effects. Coca leaves are still chewed and brewed in teas in present day South American cultures. Research has found traces of coca in mummies from over 3000 years ago.1 It is believed that shamans in the Incan culture would chew coca leaves and that the mixture of juice and saliva would be spit into the surgical site during trepanning operations. Eventually, coca was farmed for exportation to Europe starting in the 16th century. Coca wines, a blend of wine and cocaine, were popularized in the mid-1800s in Europe and eventually made an appearance in America. However, with the onset of prohibition in America, the wine in coca wine was replaced with a syrup, which became the basis for the first recipe of Coca-Cola. During the period of coca wine production in Europe, a German chemist named Albert Niemann in 1859 became the first person to isolate the primary alkaloid of coca, which he termed cocaine.2 The first clinical use of cocaine was as an ophthalmic anesthetic by Karl Koller in 1884. Sigmund Freud, Koller's colleague, had done extensive testing of cocaine and had noted its anesthetic qualities prior to Koller's clinical use. Ultimately, the addictive properties of cocaine were recognized, and an effort was made to synthesize other local anesthetics. Einhorn developed procaine for clinical use in 1905, which became the local anesthetic of choice. Cocaine is still used even today (mostly for head, neck, and ophthalmic procedures), but its popularity is waning in the medical field. Unfortunately, most cocaine use today is as an illegal drug via snorting, smoking, or injection.

Numerous ester and amide formulations have been produced, starting in the 1890s. There was a push in the early to mid-1900s to improve the pharmacokinetics and toxicity profile of local anesthetics. Lidocaine is often considered to be the prototypical local anesthetic, and it was first used clinically in 1944 by Swedish chemist Nils Lofgren and patented in 1948.3 Bupivacaine, another popular local anesthetic in common use today, was first synthesized in 1957 and introduced clinically in 1965. Clinicians have appreciated bupivacaine for its long duration of action but also recognized its troublesome cardiovascular toxicity profile and difficult resuscitation following inadvertent intravenous injection. In response to this, ropivacaine was developed and introduced clinically in 1996.4 Bupivacaine consists of a racemic mixture of both S and R stereoisomers. However, ropivacaine consists of a single S stereoisomer, which shows lower potency at cardiac sodium channels and only slightly decreased anesthetic potency.

There will continue to be further research and development into the production of an ideal local anesthetic. However, ...

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