Pharmacokinetics/Pharmacodynamics

Effect of Changes in Intrinsic Clearance

Drug interactions – A major mechanism for altered intrinsic clearance is not caused by changes in critical

illness, but still poses a significant threat to altered metabolism of drugs. The CYP enzymes play an

important role in phase I metabolism. Many drugs used in critically ill patients are substrates, inducers,

inhibitors, or combinations of these. Critically ill patients often have complex pharmacotherapeutic

regimens that create the potential for drug interactions through the CYP system. As in other patient

populations, drug concentrations are increased when substrates are coadministered with inhibitors of

the same CYP and decreased when substrates are coadministered with inducers.

cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor alpha decrease the expression and activity

of CYP enzymes. Similarly, patients in early sepsis would have increased inflammatory cytokines

with the resultant depressed CYP activity. This is supported by studies showing that endotoxin

administration results in decreased CYP-mediated drug metabolism in healthy volunteers. However,

studies have not characterized a time course for the cytokine-mediated changes. Clinicians are left to

use patient response and monitoring for toxicity to determine whether drug metabolism is altered or

has returned to normal.

Hypothermia – Animal models have shown that hypothermia affects drugs metabolized through

the CYP system. Drugs studied in animal models include fentanyl, pentobarbital, propranolol, and

morphine. Human studies have investigated the effect of hypothermia on low extraction ratio drug

kinetics. One example showed changes in phenytoin PK during mild hypothermia. Specifically,

increased concentrations and reduced metabolism, but no changes in protein binding, were noted

during hypothermia (Ther Drug Monit 2001;23:192-7). Other drugs noted to have decreased hepatic

clearance during hypothermia are midazolam, fentanyl, remifentanil, phenobarbital, and vecuronium.

AKI – One study investigated the effects of AKI on the hepatic metabolism of midazolam. Patients with

worsening AKI, as determined using the RIFLE (risk, injury, failure, loss, end-stage kidney disease)

criteria, had increasing midazolam concentrations. The authors hypothesized that the increased

hepatic blood flow, intrinsic clearance, and fraction of unbound drug. Essentially, intermediate extraction

ratio drugs depend on the same variables as both the low extraction ratio and high extraction ratio drugs. As

such, they are the most complex drugs for determining how hepatic clearance will be affected in critically

ill patients. This is important because critically ill patients usually have more than one change occurring at

the same time. For example, patients with septic shock may have increased hepatic blood flow secondary

to increased cardiac output while having a decreased intrinsic clearance secondary to increased circulating

inflammatory cytokines. Quantifying the overall effect is difficult in the ever-changing critically ill patient.

The clinician is often left to monitor for the expected therapeutic outcome while being aware of the potential

toxicities. Table 1 lists select intermediate extraction ratio drugs.

TBI increases the hepatic clearance of some drugs.

One study found that patients with TBI had increased hepatic clearance of phenytoin during the

first 7–14 days. The authors alluded to the possibility that the increased clearance was associated

with changes in protein binding, induction of metabolism, or stress on hepatic metabolic capacity

Another study noted a correlation between nutritional protein intake and increased phenytoin

metabolism in patients with TBI.