Pharmacokinetics/Pharmacodynamics

and cortisol-binding protein. Albumin and AAG are particularly important in critically ill patients because

albumin usually binds to acidic drugs (e.g., diazepam, phenytoin), whereas AAG binds to basic drugs

(e.g., lidocaine, diltiazem). Of importance, albumin concentrations usually decrease (negative acute phase

reactant) under stress, while AAG concentrations increase (positive acute phase reactant). The following

equation represents the calculation of Vd:

Vd = ( ) Vt + Vp

fu

fut

where fu is the fraction unbound in the plasma, fut is the fraction unbound in the tissues, Vt is the volume

of tissue, and Vp is the volume of plasma. When the plasma concentration of albumin decreases, the fu of a

drug increases. This increase results in an increased Vd. Conversely, increases in AAG plasma concentra-

tions decrease the fu of a drug bound to AAG due to increased protein binding, ultimately decreasing the

Vd for that drug.

The clinical relevance of this was noted when a decrease in the Vd of lidocaine correlated with an

increase in AAG in post-cardiac surgery patients. It was suspected that arrhythmias were caused by

these PK changes (Clin Pharmacol Ther 1984;35:617-26). A similar effect has been reported where

development of hypoalbuminemia was associated with elevated free valproate concentrations (Crit

Care Explor 2022;4:e0746).

Protein Binding

High ER Drugsa

Intermediate ER Drugsa

Low ER Drugsa

Albumin

Diltiazem

Morphine

Propofol

Propranolol

Verapamil

Aspirin

Carvedilol

Midazolam

Omeprazole

Carbamazepine

Ceftriaxone

Dexamethasone

Diazepam

Itraconazole

Phenytoin

Valproic acid

Warfarin

AAG

Diltiazem

Fentanyl

Lidocaine

Propranolol

Verapamil

Midazolam

Carbamazepine

aER is addressed in section V. Metabolism.

AAG = α1-acid glycoprotein.

treatable, they create plasma pH changes that could affect drug distribution. Most drugs are either weak acids

or bases and exist in either the ionized or the nonionized state, depending on the surrounding environment.

Nonionized drugs penetrate cell membranes more easily than do ionized drugs. Therefore, a drug in the

ionized state would be expected to have a smaller Vd than when in the nonionized state. Theoretically, a

drug that is a weak acid in a patient experiencing acidemia would be expected to have a larger Vd, whereas

a basic drug would have a smaller Vd in the same patient. Although the potential exists to correlate plasma

pH changes with changes in drug Vd, evidence in humans is lacking.