A pharmaceutical company is testing four new drugs in the same class; all are weak acids. Which of the following is likely to have the most rapid onset of action at physiologic pH?
a) pKa = 3
b) pKa = 5
c) pKa = 7
d) pKa = 9
Answer d.
Weak acids may exist as either A- or as HA species. Based on the Henderson-Hasselbalch equation, a weak acid with a pKa above the present pH would be more likely to be found in the non-ionized HA form (and thus cross membranes and have a shorter onset of action) than one with a pKa below pH. Thus, a drug with pKa of 9 would have the fastest onset at physiologic pH (7.4) of the available choices.