++
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
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
++