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Chapter: Basic & Clinical Pharmacology : Local Anesthetics

Historical Development of Local Anesthesia

One of procaine’s limitations was its short duration of action, a drawback overcome with the introduction of tetracaine in 1928.

Historical Development of Local Anesthesia

Although the numbing properties of cocaine were recognized for centuries, one might consider September 15, 1884, to mark the “birth of local anesthesia.” Based on work performed by Carl Koller, cocaine’s numbing effect on the cornea was demonstrated before the Ophthalmological Congress in Heidelberg, ushering in the era of surgical anesthesia. Unfortunately, with widespread use came recognition of cocaine’s significant CNS and cardiac toxicity, which along with its addiction potential, tempered enthusiasm for this application. As the early investigator Mattison com-mented, “the risk of untoward results have robbed this peerless drug of much favor in the minds of many surgeons, and so deprived them of a most valued ally.” As cocaine was known to be a benzoic acid ester, the search for alternative local anesthetics focused on this class of compounds, resulting in the identification of benzocaine shortly before the turn of the last century. However, benzocaine proved to have limited utility due to its marked hydrophobicity, and was thus relegated to topical anesthesia, a use for which it still finds limited application in current clinical practice. The first useful injectable local anesthetic, procaine, was introduced shortly thereafter by Einhorn, and its structure has served as the template for the development of the most com-monly used modern local anesthetics. The three basic structural elements of these compounds can be appreciated by review of Table 26–1: an aromatic ring, conferring lipophilicity, an ionizable tertiary amine, conferring hydrophilicity, and an intermediate chain connecting these via an ester or amide linkage.


One of procaine’s limitations was its short duration of action, a drawback overcome with the introduction of tetracaine in 1928. Unfortunately, tetracaine demonstrated significant toxicity when employed for high-volume peripheral blocks, ultimately reducing ts common usage to spinal anesthesia. Both procaine and tetra-caine shared another drawback: their ester linkage conferred insta-bility, and particularly in the case of procaine, the free aromatic acid released during ester hydrolysis of the parent compound was believed to be the source of relatively frequent allergic reactions.


Löfgren and Lundqvist circumvented the problem of instabil-ity with the introduction of lidocaine in 1948. Lidocaine was the first in a series of amino-amide local anesthetics that would come to dominate the second half of the 20th century. Lidocaine had a more favorable duration of action than procaine, and less sys-temic toxicity than tetracaine. To this day, it remains one of the most versatile and widely used anesthetics. Nonetheless, some applications required more prolonged block than that afforded by lidocaine, a pharmacologic void that was filled with the intro-duction of bupivacaine, a more lipophilic and more potent anes-thetic. Unfortunately, bupivacaine was found to have greater propensity for significant effects on cardiac conduction and func-tion, which at times proved lethal. Recognition of this potential for cardiac toxicity led to changes in anesthetic practice, and sig-nificant toxicity became sufficiently rare for it to remain a widely used anesthetic for nearly every regional technique in modern clinical practice. Nonetheless, this inherent cardiotoxicity would drive developmental work leading to the introduction of two recent additions to the anesthetic armamentarium, levobupiva-caine and ropivacaine. The former is the S(–) enantiomer of bupi-vacaine, which has less affinity for cardiac sodium channels than its R (+) counterpart. Ropivacaine, another S(–) enantiomer, shares this reduced affinity for cardiac sodium channels, while being slightly less potent than bupivacaine or levobupivacaine.

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