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CHAPTER 26 Local Anesthetics 461

Historical Development of Local Anesthesia

Although the numbing properties of cocaine were recognized reducing its common usage to spinal anesthesia. Both procaine
for centuries, one might consider September 15, 1884, to mark and tetracaine shared another drawback: their ester linkage
the “birth of local anesthesia.” Based on work performed by conferred instability, and particularly in the case of procaine, the
Carl Koller, cocaine’s numbing effect on the cornea was dem- free aromatic acid released during ester hydrolysis of the parent
onstrated before the Ophthalmological Congress in Heidelberg, compound was believed to be the source of relatively frequent
ushering in the era of surgical local anesthesia. Unfortunately, allergic reactions.
with widespread use came recognition of cocaine’s significant Löfgren and Lundqvist circumvented the problem of insta-
central nervous system (CNS) and cardiac toxicity, which along bility with the introduction of lidocaine in 1948. Lidocaine was
with its addiction potential, tempered enthusiasm for this appli- the first in a series of amino-amide local anesthetics that would
cation. As the early investigator Mattison commented, “the risk come to dominate the second half of the 20th century. Lidocaine
of untoward results have robbed this peerless drug of much had a more favorable duration of action than procaine, and less
favor in the minds of many surgeons, and so deprived them of systemic toxicity than tetracaine. To this day, it remains one of
a most valued ally.” As cocaine was known to be a benzoic acid the most versatile and widely used anesthetics. Nonetheless,
ester, the search for alternative local anesthetics focused on this some applications required more prolonged block than that
class of compounds, resulting in the identification of benzocaine afforded by lidocaine, a pharmacologic void that was filled with
shortly before the turn of the last century. However, benzocaine the introduction of bupivacaine, a more lipophilic and more
proved to have limited utility due to its marked hydrophobicity, potent anesthetic. Unfortunately, bupivacaine was found to
and was thus relegated to topical anesthesia, a use for which have greater propensity for significant effects on cardiac con-
it still finds limited application in current clinical practice. The duction and function, which at times proved lethal. Recognition
first useful injectable local anesthetic, procaine, was introduced of this potential for cardiac toxicity led to changes in anesthetic
shortly thereafter by Einhorn, and its structure has served as practice, and significant toxicity became sufficiently rare for it
the template for the development of the most commonly used to remain a widely used anesthetic for nearly every regional
modern local anesthetics. The three basic structural elements of technique in modern clinical practice. Nonetheless, this inherent
these compounds can be appreciated by review of Table 26–1: cardiotoxicity would drive developmental work leading to the
an aromatic ring, conferring lipophilicity; an ionizable tertiary introduction of two recent additions to the anesthetic armamen-
amine, conferring hydrophilicity; and an intermediate chain con- tarium, levobupivacaine and ropivacaine. The former is the S(–)
necting these via an ester or amide linkage. enantiomer of bupivacaine, which has less affinity for cardiac
One of procaine’s limitations was its short duration of action, sodium channels than its R(+) counterpart. Ropivacaine, another
a drawback overcome with the introduction of tetracaine in S(–) enantiomer, shares this reduced affinity for cardiac sodium
1928. Unfortunately, tetracaine demonstrated significant toxicity channels, while being slightly less potent than bupivacaine or
when employed for high-volume peripheral blocks, ultimately levobupivacaine.

Thus, pK can be seen as an effective way to consider the ten- anesthetics are less effective when they are injected into infected
a
dency for compounds to exist in a charged or uncharged form, ie, tissues because the low extracellular pH favors the charged form,
the lower the pK , the greater the percentage of uncharged weak with less of the neutral base available for diffusion across the mem-
a
bases at a given pH. Because the pK of most local anesthetics is brane. Conversely, adding bicarbonate to a local anesthetic—a
a
in the range of 7.5–9.0, the charged, cationic form will constitute strategy sometimes used in clinical practice—will raise the effec-
the larger percentage at physiologic pH. A glaring exception is tive concentration of the nonionized form and thus shorten the
benzocaine, which has a pK around 3.5, and thus exists solely as onset time of a regional block.
a
the nonionized base under normal physiologic conditions.
This issue of ionization is of critical importance because the
cationic form is the most active at the receptor site. However, the Pharmacokinetics
story is a bit more complex, because the receptor site for local When local anesthetics are used for local, peripheral, and central neur-
anesthetics is at the inner vestibule of the sodium channel, and axial anesthesia—their most common clinical applications—systemic
the charged form of the anesthetic penetrates biologic membranes absorption, distribution, and elimination serve only to diminish or
poorly. Thus, the uncharged form is important for cell penetra- terminate their effect. Thus, classic pharmacokinetics plays a lesser
tion. After penetration into the cytoplasm, equilibration leads to role than with systemic therapeutics, yet remains important to the
formation and binding of the charged cation at the sodium chan- anesthetic’s duration and critical to the potential development of
nel, and hence the production of a clinical effect (Figure 26–1). adverse reactions, specifically cardiac and CNS toxicity.
Drug may also reach the receptor laterally through what has been Some pharmacokinetic properties of the commonly used
termed the hydrophobic pathway. As a clinical consequence, local amide local anesthetics are summarized in Table 26–2. The