Why are ester drugs generally shorter acting than amide drugs?

Ester drugs are generally shorter acting than amide drugs primarily because esterases, the enzymes responsible for hydrolyzing and inactivating ester drugs, are predominantly found in the plasma. This means that when an ester drug is administered, it is rapidly broken down in the bloodstream, leading to a quick decline in its pharmacological effects. The swift metabolism results in a shorter duration of action for ester drugs compared to amide drugs.

In contrast, amide drugs are metabolized more slowly, primarily in the liver, which provides them with a longer duration of action. The increased stability of amides contributes to their longer half-life as well, allowing them to remain effective in the system for extended periods. Therefore, the distribution of esterases in the plasma is a critical factor in the pharmacokinetics of ester versus amide drugs, directly influencing their duration of action.