Drugs that are highly protein bound will have ______ active drug available for a pharmacologic response than drugs that have a lower percentage bound to protein.

• A. An equal amount of
• B. More
• C. Greater
• D. Less

Answer: (D)

Only the unbound fraction of a drug can reach receptors, cross membranes, be metabolized, and be cleared. When a drug is highly protein-bound, most of it is held in the bound state and the free, active portion is small. So, at the same total drug concentration, there is less active drug available to produce a pharmacologic response compared with a drug that has lower protein binding. The protein-bound portion acts as a reservoir, which can slow clearance and, if binding is displaced by another substance, temporarily raise the free drug and potentially increase effects or toxicity. For example, with drugs like warfarin or phenytoin, high protein binding means a small free fraction drives the response; if binding is reduced or displaced, the free fraction—and effect—can rise rapidly.