(A) Lipid solubility
(B) Longer onset of action
(C) pKa
(D) Protein binding
(E) Vasoconstrictor activity

The correct response is Option D.

The pharmacokinetic properties of local anesthetics, including lipid solubility, pKa, protein binding, and nonspecific tissue binding, determine their clinical characteristics. The duration of action correlates directly with protein binding; ie, greater protein binding results in a longer duration of action. This best explains the long duration of action of bupivacaine when compared with lidocaine; bupivacaine has been shown to be 96% protein-bound, while lidocaine is 64% protein-bound.

The lipid solubility of a local anesthetic determines its potency. Higher solubility leads to a higher potency drug.

Bupivacaine has a longer onset of action (5 to 8 minutes) than lidocaine (2 to 4 minutes), but its duration of action (up to 10 hours) is much longer than that of lidocaine (up to 3 hours). This small difference in onset of action does not account for the prolonged duration of action.

The pKa is defined as the negative logarithm of the acid ionization constant. This determines the onset of action of a local anesthetic because the uncharged (or base) form is the active component. Local anesthetics with a high pKa have the slowest onset of action because the pKa varies more greatly from the physiologic pH of the drug. Lidocaine, with a pKa of 7.9, has a more rapid onset of action than bupivacaine, which has a pKa of 8.1.

Addition of epinephrine, a vasoconstrictor, to a local anesthetic prolongs the duration of action of the anesthetic and decreases its toxicity. However, all local anesthetics, with the exception of cocaine, have natural vasodilator activity.