How can changes in distribution from CKD alter the pharmacokinetic behavior of drugs?
The volume of distribution (V D ) represents the ratio of administered dose to the resulting plasma drug concentration.
The calculated V D is a theoretic representation of the size of the anatomic space occupied by the drug if it were present throughout the body in the same concentration as that in the plasma.
Drugs with a large V D , such as digoxin, are distributed widely throughout the tissues and are present in relatively small amounts in the blood. In patients with CKD, changes in drug distribution may arise from either fluid retention or reductions in the extent of protein binding in tissue and plasma. CKD has very limited effects on drugs with large volume distribution.
Conversely, drugs that are less lipid soluble and highly protein bound will tend to have a lower V D because they are more restricted to the vascular compartment. Kidney impairment and hemodialysis has a significant effect on drugs with small V D .
For example, in critically ill patients with CKD, for a drug like vancomycin with a small V D , higher than recommended loading and daily doses are needed to rapidly achieve therapeutic serum concentrations.
Malnutrition and proteinuria reduce the amount of protein available for protein binding, and uremic stage may alter the affinity of many drugs to albumin. Thus the concentration of free drug will increase in these settings, which can result in increased free fraction and potential adverse drug reactions.
Therapeutic drug monitoring (TDM) for free or unbound drug concentrations in patients with kidney insufficiency or heavy proteinuria (e.g., free phenytoin levels) is an important consideration.
