What happens when the unbound fraction of a drug increases?

When the unbound fraction of a drug increases, it means that a greater proportion of the drug is present in its active form, as opposed to being bound to plasma proteins. This has important implications for pharmacodynamics and potential toxicity.

Increased unbound drug can heighten potential toxicity because the unbound fraction is responsible for the pharmacological activity of the drug. Since many drugs exert their effects only when they are in free (unbound) form, an increase in this fraction can lead to higher concentrations of the drug at its target sites, enhancing the pharmacological response and possibly resulting in adverse effects or toxicity. For example, in cases of renal or hepatic insufficiency where protein binding may be altered, the increased free drug can lead to exaggerated responses and increased risk of side effects.

Understanding the relationship between drug binding and toxicity is crucial in clinical settings, especially for drugs that have a narrow therapeutic index, where the difference between therapeutic and toxic doses is minimal. Higher levels of unbound drug can significantly increase the risk of reaching toxic levels.