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The pharmacokinetics and pharmacodynamics of many drugs are altered
in patients with impaired renal function (e.g., declining glomerular
filtration rate) or who are on renal replacement therapy.
Clinicians should be aware of drugs that require dosage adjustment in the
setting of renal dysfunction to avoid adverse drug events and poor
Dosages of drugs that are cleared by the kidneys should be adjusted
according to the patient’s renal function (e.g., creatinine clearance).
The initial dose can be determined using the manufacturer’s prescribing
information, published guidelines, or published literature.
Many drugs have a narrow therapeutic window (range of drug
concentrations that will achieve the desired effect), for which there may
be lack of efficacy with subtherapeutic levels and adverse events
associated with elevated levels. Therapeutic drug concentration
monitoring should be performed to achieve the desired target
Renal replacement therapy (e.g., hemodialysis, continuous venovenous
hemofiltration) can have a significant influence on the extracorporeal
removal of drug. Clinicians should be aware of the method of renal
replacement therapy and its impact on drug dosing.
Biotransformation of drugs may be altered in patients with renal failure.
Active or toxic metabolites may accumulate in patients with renal
failure, leading to adverse effects. Excipients such as diluents can also
accumulate in the setting of renal failure, resulting in toxicity.
The kidneys play an important role in the disposition of many drugs. It is important to
design specific pharmacotherapeutic regimens for patients with renal impairment.
Without careful dosing and therapeutic drug monitoring for select medications in
these patients, accumulation of drugs or toxic metabolites can occur, resulting in
serious adverse effects. Many patients are treated with multiple medications, which
may require even greater attention to dosage adjustment.
In addition to altered drug elimination, numerous other factors associated with
kidney disease predispose patients to potential drug toxicity by altering the
pharmacokinetic disposition and the pharmacodynamic effects of drugs. For example,
the physiologic changes associated with uremia can change drug absorption, protein
binding, distribution, or elimination. These physiologic effects can alter drug
concentrations in the plasma or blood, and at the targeted tissue site of activity,
thereby affecting drug efficacy and toxicity.
Less is known about the effect of renal disease on drug pharmacodynamics, i.e.,
the pharmacologic or toxicologic effects
produced relative to the drug concentration. Patients with renal disease can be
more sensitive to some drugs, and experience an increased frequency of adverse drug
Effect of Renal Failure on Drug Disposition
Although several factors can potentially affect drug absorption in patients with
kidney disease, limited data are available describing altered bioavailability. For
example, drug absorption could be impaired in uremia by nausea, vomiting, diarrhea,
gastritis, and edema of the gastrointestinal (GI) tract, the latter condition being a
complication of nephrotic syndrome. Gastric and intestinal motility, as well as
gastric emptying time, can be altered by the neuropathy associated with uremia.
Uremia also can increase gastric ammonia, leading to an increased gastric pH, which
may affect the bioavailability of drugs that require an acidic environment for
absorption such as ferrous sulfate.
1 Similarly, calcium-containing antacids used by
patients with renal failure for GI symptoms and hyperphosphatemia neutralize
hydrochloric acid in the stomach and increase gastric pH. Patients with end-stage
renal disease (ESRD) often take oral phosphate binders, such as sevelamer and
lanthanum carbonate, which can impair the absorption of other medications.
The bioavailability of orally administered drugs also depends on the extent to
which the drug is eliminated by first-pass (presystemic) metabolism. The first-pass
hepatic metabolism of oral propranolol was found to be reduced in patients with
renal disease, leading to increased bioavailability.
4 Subsequent studies, however,
attributed the observed increased concentrations of propranolol in renal failure to a
significant increase in the blood to plasma ratio.
Intestinal P-glycoprotein activity
6 Other drugs exhibiting increased bioavailability in renal
disease include cloxacillin, propoxyphene, dihydrocodeine, encainide, and
zidovudine (AZT). For example, the area under the concentration–time curve of
dihydrocodeine is increased by 70% in those patients with impaired renal function.
PROTEIN BINDING AND VOLUME OF DISTRIBUTION
The extent to which a drug exerts its pharmacologic effects is related to the amount of
free or unbound drug available for distribution to target tissues. Patients with renal
failure often have alterations in plasma protein binding, which can increase the
8 Clinically, this is most important for highly protein-bound
acidic drugs (>80%), whereas the binding of basic drugs is usually unchanged or
possibly decreased in renal disease. Decreased protein binding of affected drugs
results in increases in the free fraction of drug, an increase in the apparent volume of
distribution (Vd), and higher plasma clearance (Cl) for drugs with a low-extraction
ratio. However, the simultaneous increase in both the Vd and clearance results in
little or no change in the elimination half-life (t1/2
) of these drugs. Alternatively, the
Vd of high-extraction ratio drugs can increase without a concomitant change in
clearance. In this situation, the t1/2 would increase, based on the following
relationships, where Kd is the elimination rate constant of the drug:
In patients with renal failure, the accumulation of uremic toxins may also alter
protein binding. When the free fraction of drugs that are highly protein bound
changes, the interpretation of the total drug concentration must also be considered.
That is, with an increase in the free fraction, the total drug concentration necessary to
exert the desired pharmacologic effect is lower than that needed under normal
Plasma Protein Binding (%) of Acidic Drugs in Renal Failure
Hypoalbuminemia is a common complication of renal failure. Because acidic
rather than basic drugs are bound to albumin, their protein binding tends to be altered
in patients with renal failure (Table 31-1).
9 Patients with uremia accumulate acidic
by-products that may inhibit binding or displace acidic drugs from albumin binding
sites. This is supported by the observed improvement in protein binding after
removal of uremic by-products by hemodialysis. Finally, the structural conformation
of albumin is altered in renal disease, which may reduce the number or affinity of
binding sites for drugs. Studies have demonstrated differences in the amino acid
composition of albumin between healthy people and patients with uremia.
anticonvulsant, phenytoin, is a classic example of a drug whose protein binding is
11 This is discussed in more detail later in this chapter.
Renal disease can change the Vd of various drugs. The Vd or “apparent volume of
distribution” is the “volume” or size of a compartment necessary to account for the
total amount of drug in the body if it were present throughout the body at the same
concentration as that found in plasma. A decrease in the plasma protein binding of
highly protein-bound drugs, such as phenytoin, leads to an increase in the apparent
Drugs that are not highly protein bound (e.g., gentamicin, isoniazid) have little
change in their Vd in renal disease. Digoxin is a unique exception in that its Vd is
decreased in renal disease. This is attributed to a decrease in myocardial tissue
uptake of digoxin, leading to a decrease in the myocardial or tissue to serum
The extent to which renal disease affects the elimination of a drug depends on the
amount of drug normally excreted unchanged in the urine and the degree of renal
impairment. As kidney disease progresses, the kidney’s ability to excrete uremic
toxins diminishes. Consequently, the ability to eliminate certain drugs that are renally
excreted also decreases. If the dose of these drugs is not modified for the patient’s
degree of renal dysfunction, these drugs will accumulate, potentially leading to an
increase in the pharmacologic effect and toxicity.
The kidney eliminates drugs primarily by filtration or active secretion.
Characteristics of a drug that determine its ability to be filtered include its affinity for
protein binding and its molecular weight (MW). Drugs with low protein binding or
displaced from proteins in the setting of renal disease are filtered more readily.
Molecules with a high MW (>20,000 Da) are not readily filtered because of their
large size. The reasons for how renal disease selectively alters the process of
glomerular filtration or tubular secretion of specific drugs are not well understood.
The elimination of drugs by the kidneys in patients with renal disease usually can be
estimated by measuring the ability of the kidney to eliminate substances such as
creatinine (i.e., creatinine clearance [CrCl]) (see Chapter 29, Acute Kidney Injury).
Organic anion transporters (OATs) are predominantly found in the basolateral
membrane of the renal tubules. OATs facilitate the uptake of small organic anions
into renal tubular cells. Decreased OAT activity as a result of acute kidney injury can
decrease the renal secretion of various drugs such as methotrexate, nonsteroidal
antiinflammatory drugs, and acetylsalicylic acid.
Renal disease can also have an important impact on the elimination of drugs that
are primarily metabolized by the liver.
14 Metabolic processes, such as hydroxylation
and glucuronidation, often produce inactive, more polar compounds that can be
eliminated by the kidney. The metabolites of some drugs (e.g., meperidine, morphine,
procainamide) are pharmacologically active or toxic. In patients with renal disease,
these metabolites may accumulate, leading to an increase in pharmacologic activity
15,16 For example, the central nervous system (CNS) toxicity
observed in renal disease has been attributed to accumulation of the morphine
metabolite, morphine-6-glucuronide. Therefore, careful dosing modifications or
avoidance of these drugs is warranted in patients with renal impairment. Metabolic
enzymes have been found within renal tissue, and may play a role in the metabolism
17,18 For example, the nonrenal clearance of drugs (e.g., acyclovir)
decreases in patients with renal impairment, and is believed to be caused by a
decrease in “renal” metabolism.
Excipients used to formulate medications should also be considered. For example,
the pharmacokinetics of itraconazole and voriconazole are not significantly altered in
the setting of renal dysfunction. However, the parenteral formulations of itraconazole,
posaconazole, and voriconazole contain the solubilizing agent, β-cyclodextrin, which
is normally rapidly eliminated by glomerular filtration but can accumulate in patients
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