Pharmacokinetics/Pharmacodynamics

drugs, altered hepatic blood flow affects both the Css and the Cssu, whereas changes in fu affect only the

Cssu.

↓  Css

↓  Cssu

↑  Q

↓  Q

↑  CLint

↓  CLint

↑  fu

↓  fu

↑  Css

↑  Cssu

↔  Css

↔  Cssu

↔  Css

↔  Cssu

↔  Css

↑  Cssu

↔  Css

↓  Cssu

CLH = Q

Css = Dose

Q

Cssu = fu × Dose

Q

ratio drug.

perfusion during the hyperdynamic phase of sepsis. Critically ill patients in the hyperdynamic phase

of sepsis or septic shock have an increased cardiac output and increased hepatosplanchnic blood flow.

However, no correlation directly relating cardiac output (or an increase in cardiac output) with an

increase in splanchnic blood flow could be established in some studies. Therefore, quantification of

the increase in blood flow and the resultant increase in hepatic metabolism cannot be established. The

clinician is left to assume the potential for increased metabolism of high extraction ratio drugs and the

expected decrease in unbound steady-state concentration and possibly a reduced clinical efficacy.

Any condition or therapy that increases cardiac output could theoretically improve hepatic blood

flow. Although data in humans are lacking, an animal model of endotoxemia showed improved

hepatic blood flow after dobutamine.

Effect of decreased hepatic blood flow

Conditions with a low cardiac output such as hypovolemic or hemorrhagic shock, decompensated

sepsis, myocardial infarction with or without cardiogenic shock, and acute heart failure exacerbation

would be expected to cause a decrease in hepatic blood flow. Human studies to verify this assertion

are lacking. Animal models of decompensated sepsis and cardiogenic shock show reduced hepatic

blood flow, which would be expected to increase the Cssu and potentially increase the effect of, or

produce toxicity for, drugs with high extraction ratios.

Mechanical ventilation has been noted to increase or decrease cardiac output and subsequently hepatic

blood flow, depending on the patient’s condition. Mechanical ventilation may also decrease cardiac

output and subsequently hepatic blood flow because of increased intrathoracic pressure. This pressure

causes a decrease in venous return to the heart, compresses the ventricles, and reduces ventricular

filling. The result is a decrease in cardiac output (N Engl J Med 1981;304:387-92) and hepatic blood