Could alkalinization worsen local anesthetic systemic toxicity?

Some weak acids, such as salicylic acid, have increased toxicity in the setting of low systemic pH because they become uncharged and lipophilic, cross the cell membrane, and reach their intracellular site of toxicity [8-10]. Most local anesthetics are weak bases, therefore the ratio of freebase to salt is increased by raising pH. Since local anesthetics access their site of action via a pH-modulated pathway, this raises the question: does increased pH increase local anesthetic toxicity? The model is based on the Henderson-Hasselbach equation, which yields the relative concentrations of a weak base [B] and its conjugate acid [B+] from the pH and the weak base's pKa. Since the sum of [B] and [B+] is equal to 100%, it is possible to manipulate the equation to derive the percentage of total local anesthetic existing as freebase as a function of pH [Fig. 1].