Module 3. Effects of altered clearance on plasma concentrations.

Objectives

Having completed this exercise and based on pharmacokinetic constants and data, students should be able to:

Significance

Dysfunction of the organs of elimination (renal failure, hepatic failure, etc.) is associated with reduced clearance. Changes in volumes of distribution are usually small. Reduced total clearance changes the drugs half-life, average concentration and peak and trough concentration. Dosing in such patients should be done with some understanding of the effect of organ failure on the pharmacokinetics of the drug. In the specific case of gentamicin, lower than normal clearance greatly increases the incidence of toxicity.

Exercise

Download clt.xlsx, the worksheet for this exercise. Depending on your settings, you may have to "enable editing" in order to make the changes suggested by the exercise.

Pharmacokinetic variables and doses on the spreadsheet are preset for a typical adult horse given gentamicin according to original (and still often cited) doses and eight hour intervals.

Half-lives of aminoglycoside antibiotics are very short (roughly an hour). Concentrations of these drugs decline very rapidly after they are administered. Traditionally, they have been administered with dose intervals of 6 - 8 hours. Unfortunately, the renal elimination of aminoglycosides is often reduced when renal dysfunction cannot be detected clinically. Current recommendations for dosing aminoglycosides are based on principles that were originally referred to as "pulse dosing." In essence 3 or 4 doses (original dosage) are combined into one daily dose. The practice is so common now that the phrase "pulse dosing" has essentially been abandoned.

Target Concentrations

Manipulate dosage and pharmacokinetic parameters

Inspect

Calculated values

Steady-State Concentrations (for repeated doses during therapy).

Graph(s)

Assess