FIGURE 14-1 Structural formulas of selected local anesthetics. Most local anesthetics consist of a hydrophobic (aromatic) moiety (black), a linker region (light blue), and a substituted amine (hydrophilic region, in dark blue). The structures above are grouped by the nature of the linker region. Procaine is a prototypic ester-type local anesthetic; esters generally are well hydrolyzed by plasma esterases, contributing to the relatively short duration of action of drugs in this group. Lidocaine is a pro-totypic amide-type local anesthetic; these structures generally are more resistant to clearance and have longer durations of action. There are exceptions, including benzocaine (poorly water soluble; used only topically) and the structures with a ketone, an amidine, and an ether linkage. See 11th edition of the parent text, Figure 14—1, for additional details and structures.

myelinated AS fibers (mediating pain and temperature sensations) are blocked before the larger myelinated Ag, Ab, and Aa fibers (mediating postural, touch, pressure, and motor information). This differential rate of block exhibited by fibers mediating different sensations is of considerable practical importance in the use of local anesthetics; the mechanisms responsible for this apparent specificity are not known.

EFFECT OF pH Local anesthetics tend to be only slightly soluble as unprotonated amines. Therefore, they generally are marketed as water-soluble salts, usually hydrochlorides. Since local anesthetics are weak bases (typical p^a values range 8-9), their hydrochloride salts are mildly acidic. This property increases the stability of the local anesthetic esters and catecholamines added as vasoconstrictors. Following administration, the pH of the local anesthetic solution rapidly equilibrates to that of the extracellular fluids.

Although the unprotonated species of the local anesthetic is necessary for diffusion across cellular membranes, it is the cationic species that interacts preferentially with Na+ channels.

PROLONGATION OF ACTION BY VASOCONSTRICTORS The duration of action of a local anesthetic is proportional to the time of contact with nerve. Consequently, maneuvers that keep the drug at the nerve prolong the period of anesthesia. Thus, catecholamines, acting at a-adrenergic receptors in the vasculature, cause vasoconstriction and reduced absorption of local anesthetics in vascular beds where a adrenergic effects predominate (see Chapters 6 and 10). In clinical practice, a vasoconstrictor, usually epinephrine, is often added to local anesthetics. The vasoconstrictor performs a dual service. By decreasing the rate of absorption, it not only localizes the anesthetic at the desired site, but reduces systemic toxicity by slowing systemic absorption, thereby favoring metabolism rather than accumulation of absorbed drug. Note, however, that epinephrine dilates skeletal muscle vascular beds through actions at b2 adrenergic receptors and therefore has the potential to increase systemic toxicity of anesthetic deposited in muscle tissue.

CHAPTER 14 Local Anesthetics 243 A f}^ Subunit arSubunit ^2Subunit

CHAPTER 14 Local Anesthetics 243 A f}^ Subunit arSubunit ^2Subunit

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