Pharmacokinetics/Pharmacodynamics

Pharmacokinetics (PK) refers to the movement of a drug throughout the body, particularly absorption, distribution,

metabolism, and excretion (ADME) of a drug, whereas pharmacodynamics (PD) addresses the biochemical and

physiologic effects of a drug on the body. Physiologic changes in critically ill patients cause alterations that affect

the PK and PD of drugs. Although few studies evaluate the effect of these changes, clinicians must consider the

general principles when making drug dosing decisions in critically ill patients. The most important consideration in

critically ill patients is that changes can occur rapidly and with high frequency. A patient may have an altered PK

variable on one day, only to experience changes that alter that variable in a completely different way on the following

day. An example is a critically ill patient with augmented renal clearance (ARC) who then develops an acute kidney

injury (AKI). The patient may have increased renal elimination of a specific drug, followed by decreased elimina-

tion when AKI occurs. Therefore, the critical care pharmacist should know how the principles can be altered and

continually anticipate changes during a patient’s stay in the ICU.

The intravenous route is the most widely used method of drug administration in the critically ill

population. The bioavailability of an intravenously administered drug is 100%, thus ensuring the

entire dose reaches the systemic circulation. As such, this route is preferred over other routes subject

to reduced absorption.

several potential problems. The intravenous route does not guarantee penetration of the drug into

sites outside the circulatory system. Examples of this include poor penetration of hydrophilic drugs

into various tissues such as the meninges, pulmonary tissue, and bone. In conditions such as septic

shock, drug penetration into muscle and subcutaneous tissue is lower than expected. Finally, there are

reports documenting the severe adverse effects of inadvertent extravascular administration of a drug.

There are several reports of drug (vesicants or non-vesicants, which can be cytotoxic or noncytotoxic)

extravasation, which highlights this potential complication of intravenous administration. For example,

extravasation of norepinephrine creates local vasoconstriction and tissue necrosis, which is sometimes

severe enough to cause loss of a limb.

bioavailability. The predominant concern for this route of administration in critically ill patients pertains

to alterations in drug absorption. The issues pertaining to altered drug absorption are discussed in the next

section. Of note, not all drugs show reduced absorption when administered enterally/orally to critically ill

patients. One example comes from a study investigating the PK of atorvastatin, administered enterally.

Compared with healthy volunteers, patients in the ICU had a significantly higher area under the curve (AUC)

(110.5 ng/mL vs. 5.9 ng/mL, p<0.01) after a single dose of atorvastatin 20 mg. The increased AUC could

factor with enteral administration is first-pass metabolism, which can significantly affect the bioavailability of

hepatically metabolized drugs (discussed later in the chapter). As such, critical care clinicians should evaluate

the use of the enteral/oral route because of both increased and decreased bioavailability with different enteral

medications.