Which statement correctly explains why some local anesthetics have a faster onset of action?

Which statement correctly explains why some local anesthetics have a faster onset of action?

• A. Higher molecular weight
• B. Higher pKa
• C. Lower pKa leading to more non-ionized form at physiologic pH
• D. Higher protein binding

Answer: (C)

Onset speed depends on how quickly the drug can cross the nerve membrane to reach and block the intracellular Na+ channel. Only the non-ionized (lipid-soluble) form readily diffuses through the lipid nerve membrane, so the fraction of drug that is non-ionized at physiologic pH determines how fast it starts working. A lower pKa means more of the drug is non-ionized at pH 7.4, so more drug can penetrate the nerve quickly and produce a faster onset. In contrast, higher molecular weight slows diffusion, higher pKa reduces the non-ionized fraction and slows onset, and higher protein binding mainly affects duration rather than how fast the drug works.

Onset speed depends on how quickly the drug can cross the nerve membrane to reach and block the intracellular Na+ channel. Only the non-ionized (lipid-soluble) form readily diffuses through the lipid nerve membrane, so the fraction of drug that is non-ionized at physiologic pH determines how fast it starts working. A lower pKa means more of the drug is non-ionized at pH 7.4, so more drug can penetrate the nerve quickly and produce a faster onset. In contrast, higher molecular weight slows diffusion, higher pKa reduces the non-ionized fraction and slows onset, and higher protein binding mainly affects duration rather than how fast the drug works.