Chapter 15 Marini Pharmacotherapy

334

SECTION I • Techniques and Methods in Critical Care

trauma) or postoperative, have sepsis, are diagnosed with hematologic malignancies, or have significant burn injuries. Although there is no universally accepted definition of augmented renal clearance, a value of 10% above the upper limit of normal (GFR > 160 mL/min/1.73 m 2 in men and >150 mL/ min/1.73 m 2 in women) has been proposed. Optimal dosing of drugs in the acute kidney injury of critical illness is difficult because con- clusive data are lacking. The Kidney Disease: Improving Global Outcomes (KDIGO) work group suggests that drug dosing be adjusted according to FDA-approved labeling. Even less is known about drug dosing in patients undergoing renal replace- ment therapy. In such cases, pharmacists should help specify appropriate schedules. Of course, when available, protocols based on fluctuations in renal function may also assist in dosing adjustments. Half-life After administration, most drugs exhibit a two-phase concentration profile corresponding to initial distri- bution and then elimination. The serum half-life ( t 1/2 ) is the time required for initial drug concentra- tion to fall by 50% without further supplementa- tion. The t 1/2 incorporates distribution and clearance effects to give a useful index for predicting the time required to achieve steady state (usually 5 half-lives) and to determine the dosing interval. With repeated

intermittent dosing, most drugs accumulate and wash out exponentially to their final concentra- tions (first-order kinetics). Drug monitoring before steady state will underestimate the eventual peak, and trough concentrations and should, therefore, be avoided (Fig. 15-1). Unfortunately, the stated half-life of drugs typically is determined in healthy individuals and rarely accurately reflects the kinet- ics of a compound in the critically ill. Commonly, long-term dosing and dysfunction of several organ systems prolongs half-life. For example, drugs that rely on renal elimination may have a prolonged functional half-life in patients with renal dysfunc- tion (e.g., active metabolites of midazolam, carbape- nem antibiotics), and similarly, drugs that rely on metabolism by the liver (e.g., propofol, argatroban) may have prolonged effects in patients with hepatic dysfunction.

ROUTES OF ADMINISTRATION Goals of Drug Administration

The aim of drug therapy is to rapidly achieve and maintain effective, nontoxic tissue drug concentrations. In critically ill patients, these goals are frequently met by combining appropriate loading doses followed by maintenance regimens. During intermittent dosing, drug levels may demonstrate peaks and troughs that potentially expose patients

Single Loading Dose Kinetics

Intermittent Dosing Without Load

Steady State Concentration

100%

Continuous Infusion

50%

DRUG CONCENTRATION (% Steady State Level) 25%

1

2

3

4

5

6

NUMBER OF HALF-LIVES

FIGURE 15-1. Dosing and elimination kinetics. After a single dose, drug concentration falls expo- nentially to undetectable levels over approximately five half-lives ( dashed line ). During continuous infusion or intermittent administration of smaller maintenance doses (without load), a steady-state concentration is not achieved until five half-lives have elapsed ( solid line ). The therapeutic range can be achieved and maintained quickly by combining a large initial loading dose with a maintenance schedule of either type.