All medications have specific disease states and conditions that change the pharmacokinetics of the drug and warrant dosage modification. However, the dosing of most drugs will be altered by one or more of the important factors discussed in this chapter. Renal or hepatic disease will decrease the elimination or metabolism of the majority drugs and change the clearance of the agent. Dialysis procedures, conducted using artificial kidneys in patients with renal failure, removes some medications from the body while the pharmacokinetics of other drugs are not changed. Heart failure results in low cardiac output which decreases blood flow to eliminating organs, and the clearance rate of drugs with moderate-to-high extraction ratios are particularly sensitive to alterations in organ blood flow. Obesity adds excessive adipose tissue to the body, which may change the way that drugs distribute in the body and alter the volume of distribution for the medication. Finally, drug interactions can inhibit or induce drug metabolism, alter drug protein binding, or change blood flow to organs that eliminate or metabolize the drug.
Most water-soluble drugs are eliminated unchanged to some extent by the kidney. In addition to this, drug metabolites that were made more water soluble via oxidation or conjugation are typically removed by renal elimination. The nephron is the functional unit of the kidney that is responsible for waste product removal from the body and also eliminates drug molecules (Figure 3-1). Unbound drug molecules that are relatively small are filtered at the glomerulus. Glomerular filtration is the primary elimination route for many medications. Drugs can be actively secreted into the urine, and this process usually takes place in the proximal tubules. Tubular secretion is an active process conducted by relatively specific carriers or pumps that move the drug from blood vessels in close proximity to the nephron into the proximal tubule. Additionally, some medications may be reabsorbed from the urine back into the blood by the kidney. Reabsorption is usually a passive process and requires a degree of lipid solubility for the drug molecule. Thus, tubular reabsorption is influenced by the pH of the urine, the pKa of the drug molecule, and the resulting extent of molecular ionization. Compounds that are not ionized in the urine are more lipid soluble, better able to pass through lipid membranes, and more prone to renal tubular reabsorption. The equation that describes these various routes of renal elimination is
where fB is the free fraction of drug in the blood, GFR is glomerular filtration rate, RBF is renal blood flow, Cl′sec is the intrinsic clearance for tubular secretion of unbound drug, and FR is the fraction reabsorbed.1
The nephron is the functional unit of the kidney responsible for drug elimination. Unbound drug is filtered freely at the glomerulus (shown by arrow). Active tubular secretion of drug (denoted by ...