Thus, pKa can be seen as an effective way to consider the tendency for compounds to exist in a charged or uncharged form, ie, the lower the pKa, the greater the percentage of uncharged weak bases at a given pH. Because the pKa of most local anesthetics is in the range of 7.5–9.0, the charged, cationic form will constitute the larger percentage at physiologic pH. A glaring exception is benzocaine, which has a pKa around 3.5, and thus exists solely as 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 story is a bit more complex, because the receptor site for local anesthetics is at the inner vestibule of the sodium channel, and the charged form of the anesthetic penetrates biologic membranes poorly. Thus, the uncharged form is important for cell penetration. After penetration into the cytoplasm, equilibration leads to formation and binding of the charged cation at the sodium channel, and hence the production of a clinical effect (Figure 26–1). Drug may also reach the receptor laterally through what has been termed the hydrophobic pathway. As a clinical consequence, local anesthetics are less effective when they are injected into infected tissues because the low extracellular pH favors the charged form, with less of the neutral base available for diffusion across the membrane. Conversely, adding bicarbonate to a local anesthetic—a strategy sometimes used in clinical practice—will raise the effective concentration of the nonionized form and thus shorten the onset time of a regional block.
When local anesthetics are used for local, peripheral, and central neuraxial anesthesia—their most common clinical applications—systemic absorption, distribution, and elimination serve only to diminish or terminate their effect. Thus, classic pharmacokinetics plays a lesser role than with systemic therapeutics, yet remains important to the anesthetic’s duration and critical to the potential development of adverse reactions, specifically cardiac and CNS toxicity.
Some pharmacokinetic properties of the commonly used amide local anesthetics are summarized in Table 26–2. The pharmacokinetics of the ester-based local anesthetics have not been extensively studied owing to their rapid breakdown in plasma (elimination half-life < 1 minute).
ExtracellularIntracellularSodiumchannel+LA+HLAH+LA+H+LAH+LAFIGURE 26–1 Schematic diagram depicting paths of local anesthetic (LA) to receptor sites. Extracellular anesthetic exists in equilib-rium between charged and uncharged forms. The charged cation penetrates lipid membranes poorly; intracellular access is thus achieved by passage of the uncharged form. Intracellular re-equilibration results in formation of the more active charged species, which binds to the receptor at the inner vestibule of the sodium channel. Anesthetic may also gain access more directly by diffusing laterally within the membrane (hydrophobic pathway).
A. Absorption
Systemic absorption of injected local anesthetic from the site of administration is determined by several factors, including dosage, site of injection, drug-tissue binding, local tissue blood flow, use of a vasoconstrictor (eg, epinephrine), and the physicochemical properties of the drug itself. Anesthetics that are more lipid soluble are generally more potent, have a longer duration of action, and take longer to achieve their clinical effect. Extensive protein binding also serves to increase the duration of action.