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

Inspect

Graph(s)

Assess

Questions (Key)

  1. Describe the effect that renal dysfunction might have on antibacterial activity (assume the infection is in the lungs).
  2. Is gentamicin given according to pulse dosing principles (3x dose, 24 hour interval) safe for patients with clinically normal renal function (based on BUN, Creatinine falues)?
  3. Is gentamicin given according to pulse dosing principles (3x dose, 24 hour interval) safe for patients with any level of renal function (including overt renal failure)?
  4. Which of the following statements is true?
    1. Incorrect dosing of aminoglycosides can be effective against the bacteria and toxic to the patient.
    2. Incorrect dosing of aminoglycosides can be ineffective against the bacteria and not toxic to the patient.
    3. Correct dosing of aminoglycosides can be effective against the bacteria and not toxic to the patient.