Which anesthetic has the most rapid onset based on its pKa?

Benzocaine is characterized by a unique property; it is an ester local anesthetic with a pKa of about 3.5. This relatively low pKa means that a significant proportion of the drug exists in its un-ionized form at physiological pH. The un-ionized form of a local anesthetic can readily cross neuronal membranes, resulting in a rapid onset of action.

In contrast, the other local anesthetics listed—mepivacaine, lidocaine, and bupivacaine—have higher pKa values, which means that a larger fraction of these agents exists in a charged, ionized form at physiological pH. While they still provide effective anesthesia, their onset of action is slower compared to benzocaine. The ionized form is less able to penetrate lipid membranes, thus delaying the onset of the anesthetic effect.

Considering these factors, benzocaine's low pKa and its ability to exist predominantly in its un-ionized form at physiological pH contribute significantly to its rapid onset of action among the anesthetics listed.