The higher the pKa, the ____________ the onset.

The higher the pKa, the ____________ the onset.

• A. Faster
• B. Slower
• C. Quicker
• D. Unchanged

Answer: (B)

Onset depends on how much drug is in the non-ionized form, because only the non-ionized form readily crosses the nerve membrane to reach its site of action. For bases like local anesthetics, the Henderson-Hasselbalch relationship can be written as [base]/[protonated form] = 10^(pH − pKa). At physiological tissue pH around 7.4, increasing pKa lowers this ratio, so less non-ionized drug is available to diffuse into the neuron. That means the drug reaches its target more slowly, producing a slower onset. If the pKa were lower, a larger fraction would be non-ionized at the same pH, cross membranes faster, and have a quicker onset. In acidic environments, the non-ionized fraction decreases for bases in general, and the effect is more pronounced for higher pKa drugs, reinforcing the slower onset with higher pKa.

Onset depends on how much drug is in the non-ionized form, because only the non-ionized form readily crosses the nerve membrane to reach its site of action. For bases like local anesthetics, the Henderson-Hasselbalch relationship can be written as [base]/[protonated form] = 10^(pH − pKa). At physiological tissue pH around 7.4, increasing pKa lowers this ratio, so less non-ionized drug is available to diffuse into the neuron. That means the drug reaches its target more slowly, producing a slower onset. If the pKa were lower, a larger fraction would be non-ionized at the same pH, cross membranes faster, and have a quicker onset. In acidic environments, the non-ionized fraction decreases for bases in general, and the effect is more pronounced for higher pKa drugs, reinforcing the slower onset with higher pKa.