Onset of Action

The structural domain of LAs responsible for their hydrophilicity is the amine group. As mentioned earlier, in aqueous solution LAs exist as a mixture of protonated or positively charged (ionized) and deprotonated or neutral (unionized) forms.14,18-25 Only the deprotonated or neutral forms of LA molecules can translocate across neuronal membranes. The ratio of protonated to deprotonated forms is predicated on the drugs’ dissociation constant (pKa) and the pH at the site of drug administration.14,18-25

The closer is a LA's pKa to the pH at the site of its administration (physiologic pH of 7.4), greater is its fraction of deprotonated molecules (free base) that can translocate across neuronal membranes.14,18-25 Therefore, the primary determinant of a LA’s onset of action is its dissociation constant (Table 3). Once in the cytoplasm, most of the deprotonated molecules are rapidly protonated, which tend to bind voltage-gated sodium channels with higher affinity than the deprotonated molecules.

Table 3. Dissociation Constant, Percent Free Base at pH 7.4, and Onset of Action of LAs.14,18‑25
LidocaineMepivacainePrilocaineArticaineBupivacaine
Dissociation constant (pKa)7.97.77.97.88.1
Percent free base at pH 7.4253325291.7
Onset of action in minutes2-42-42-42-44-8