What factors affect the potency, onset, and duration of action of local anesthetics?

What factors affect the potency, onset, and duration of action of local anesthetics?

Anesthetic potency correlates with lipid solubility as lipophilic local anesthetics more easily cross nerve membranes. In general, lengthening the connecting hydro-carbon chain or increasing the number of carbon atoms on the tertiary amine or aromatic ring often results in a more potent drug. For example, adding a halide to the aromatic ring (2-chloroprocaine vs. procaine), an ester linkage (tetracaine vs. lidocaine), and large alkyl groups on the tertiary amine (tetracaine vs. procaine) increases potency.

Onset of action of local anesthetics depends primarily on the pKa of the drug. Drugs with a lower pKa or pKa closer to physiologic pH will have a higher concentration of the nonionized, lipophilic form which easily diffuses across nerve membranes and thus have a faster onset. Likewise, the addition of a small amount of sodium bicarbonate to the local anesthetic solution may speed onset and improve qual-ity of blockade by increasing the amount of the nonionized form of the drug. However, lower tissue pH, as seen in infected tissue, results in delayed onset of action because of a decreased proportion of the nonionized form.

Duration of action is associated with plasma α₁-acid lipoprotein binding. A high degree of this protein binding results in prolonged duration of effect. Bupivacaine, etido-caine, and prilocaine are more highly protein-bound than most other agents and thus have a longer duration of action. The addition of vasoconstrictors, such as epineph-rine, also prolongs duration of action by decreasing local blood flow and consequently decreasing drug absorption. This enhances neuronal uptake leading to a greater degree and duration of blockade.