Pharmacokinetics/Pharmacodynamics

Patient Case

day. Which drug will most likely have an increased absorption secondary to the increased gastric pH?

to the concentration of drug in the serum. A simple mathematical representation of this relationship is the

following equation:

C = dose

Vd

where C is the initial serum concentration of an intravenously administered drug and Vd is the volume of

distribution. However, the distribution of most drugs is more complex and is affected by several factors

such as systemic and tissue perfusion, degree of protein binding, tissue permeability, drug lipid solubility,

drug pKa, and pH of the environment. Critically ill patients may be subjected to one or more changes in the

previously stated factors that could result in an altered Vd for some drugs.

redistribution of blood flow. This results in decreased perfusion of the muscle, skin, and splanchnic organs.

Hydrophilic drugs with a smaller Vd (ones that remain in the plasma water volume) may have decreased

distribution to physiological compartments with decreased blood flow. This is highlighted by animal studies

of septic shock showing lower gentamicin concentrations in the microcirculation than in the central vessels.

intravenous fluid for resuscitation. This often results in increased total body water and interstitial volume. In

addition to fluid administration, diseases such as sepsis, thermal injury, acute respiratory distress syndrome,

AKI, heart failure, and cirrhosis can increase interstitial fluid volumes. Moreover, surgery increases

extracellular volume postoperatively. In this setting, the Vd for hydrophilic drugs is increased, whereas the

Vd for lipophilic drugs is often unchanged. The increased interstitial water provides a larger compartment for

hydrophilic drugs to distribute, thus decreasing the serum concentrations. In addition, because distribution

is into a larger interstitial space (as the result of increased interstitial water), the drug concentration can

be decreased in this space. This has been shown in microdialysis studies evaluating subcutaneous tissue

concentrations for intravenously administered piperacillin. Compared with healthy volunteers, patients with

septic shock had reduced piperacillin tissue concentrations. However, the increased Vd of drugs is not

universally noted with increased interstitial fluid volumes in some critically ill patients. Although one study

found increases in aminoglycoside Vd, another study was unable to correlate fluid shifts with changes in the