Pharmacokinetics/Pharmacodynamics

activity of the low-molecular-weight heparin certoparin in critically ill patients, of whom 40.3% were

receiving vasopressors. Less than 50% of patients receiving standard doses of certoparin had anti-Xa

This correlates with an abnormal lactulose-mannitol test, indicating increased gut permeability. Splanchnic

hypoperfusion can further worsen gut hypoxia, exacerbating gut permeability. However, the effect of

intestinal atrophy on drug absorption has not been systematically evaluated. Atrophy and the corresponding

loss of integrity of the tight junctions could lead to an increased absorption of drugs that are absorbed through

passive diffusion. Conversely, cellular dysfunction caused by atrophy might decrease the absorption of

drugs that require active transport for absorption. Unfortunately, studies addressing the clinical significance

of intestinal atrophy are difficult to conduct, thereby leaving a void in the current literature.

as 60%. Box 1 shows the factors in critically ill patients that are associated with delayed gastric emptying

caused by dysmotility. Acetaminophen kinetics show that GI dysmotility causes a delay in absorption and

a reduced peak concentration in most studies. Concern regarding PK changes in the presence of delayed

gastric emptying is a major factor contributing to the avoidance of orally or enterally administered drugs in

critically ill patients. GI dysmotility is usually treated using prokinetic agents such as metoclopramide or

erythromycin. No data exist regarding the effect of prokinetics on drug absorption in critically ill patients

with dysmotility. However, one study found that, in healthy individuals, coadministration of erythromycin

and the controlled-release formulation of pregabalin resulted in a 17% decrease in AUC and a 13% decrease

in peak plasma concentrations of pregabalin (Clin Drug Investig 2015;35:299-305). This suggests that

prokinetics can affect the absorption of other medications. In the critically ill patient, the effect of prokinetics

on the PK of orally or enterally administered remains unclear.

Box 1. Reasons for Delayed Gastric Emptying

Burns

Electrolyte abnormalities

GLP-1 agonists

Hyperglycemia

Ileus

Mechanical ventilation

Opioid analgesics

Postoperative ileus

Sepsis

Shock

Surgery

Trauma

Traumatic brain injury

P450 (CYP) enzymes play an integral role in drug absorption. In general, these transporters reduce the

absorption of drug substrates. Therefore, decreased activity of these enzymes will theoretically increase the

absorption of drugs that are substrates. Conversely, several intestinal transporters facilitate drug absorption

and therefore decrease activity, which would decrease drug absorption. However, no PK studies evaluate

changes in drug absorption caused by changes in intestinal transporters that are specifically related to

critical illness or conditions often present in these patients. Increased proinflammatory cytokines in patients

with conditions such as systemic inflammatory response syndrome and sepsis affect P-gp expression and

activity. Therefore, enteral drug absorption can be altered in these states. However, no studies have directly

investigated the effects of inflammatory states, or systemic inflammatory response syndrome, on drug

absorption changes mediated by changes in P-gp activity.

Physical Incompatibilities – Drugs administered through enteral feeding tubes come in contact with gastric

secretions, intestinal secretions, and enteral nutrition formulas, all of which may pose a problem for drug

absorption.