What best explains the faster onset of alfentanil compared to fentanyl?

The faster onset of alfentanil compared to fentanyl can be attributed to its lower pKa. Alfentanil has a lower pKa, which means that a greater proportion of the drug is non-ionized at physiological pH. Since the non-ionized form of a drug is more readily able to cross cell membranes, this allows alfentanil to enter the central nervous system more quickly than fentanyl.

In contrast, fentanyl with a higher pKa has a lower fraction of non-ionized drug at the same pH, resulting in a slower penetration into the central nervous system. This property directly influences the speed at which the drug effects are felt after administration.

Other factors such as protein binding, lipid solubility, and clearance can affect drug distribution and duration of action, but they do not specifically explain the rate of onset in the same direct way that pKa does. Thus, the lower pKa of alfentanil is key to understanding why it has a faster onset compared to fentanyl.