P Chapter 29
Medication Dosing in
LEARNING OBJECTIVES
• State the purpose and intent of a
renal dosing program.
• Describe important concepts related
to renal dosing.
• Calculate appropriate dosing based
on the patient’s degree of renal
impairment.
Patients with Renal
Dysfunction
Curt W. Quap, RPh, MS Pharm, FASHP
The kidneys are a major route of elimination for many
medications and waste products produced by the body.
Therefore, loss of renal function can affect the manage-
ment of medication therapy in patients. Impairment
of renal function can range in severity from mild
renal insufficiency to end-stage renal disease. Renal
failure can be acute (e.g., hypoperfusion of the kidney
resulting from severe hypovolemia or drug-induced
acute tubular necrosis) or chronic in nature. There
are many causes of renal dysfunction, including acute
and chronic diseases, trauma or injury, dehydration,
exposure to medications or other toxic substances, and
advanced age. Because many medications are renally
eliminated, renal dysfunction increases the risk of
adverse drug effects. Pharmaceutical care of patients
with renal dysfunction is improved by individualizing
medication dosing regimens based on the patient’s
renal function.
Renal dosing of medications ensures efficacy
of medication therapy through the achievement of
appropriate drug serum concentrations and avoidance
of overdosing. Failure to adjust dosages in patients
with renal dysfunction can lead to accumulation of
these medications, resulting in toxicity. Examples
of adverse drug effects associated with renal insuf-
ficiency include neurotoxicity with acyclovir and H2
receptor antagonists and seizures with imipenem and
ceftazidime. Renal dosing improves patient safety by
making adjustments in medication dosage that ensure
serum drug concentrations do not reach toxic levels yet
remain at therapeutic levels to maintain efficacy. Renal
dosing programs also reduce costs through reduction
in dosage, avoidance of dose-related adverse effects,
and reduction in personnel time spent in preparing and
administering doses.
330  Competence Assessment Tools for Health-System Pharmacies
Effects of Renal Dysfunction on
Drug Disposition
Changes in drug disposition caused by renal dysfunc-
tion affect the pharmacokinetic and pharmacodynamic
parameters of medications.
Bioavailability
Gastrointestinal tract (GIT) disturbances (e.g., nausea,
vomiting, and diarrhea) associated with renal disease,
including those caused by uremia, uremic gastritis,
and pancreatitis, can inhibit the absorption of medi-
cations. Impaired absorption may occur because of
edema of the GIT in patients with nephrotic syndrome.
Neuropathy associated with uremia can also alter
GIT motility and gastric emptying, causing changes
in drug transit time. Uremia and hyperphosphatemia
can increase the pH of the GIT, impairing the bioavail-
ability of medications requiring acidic conditions for
absorption. Antacids used to treat the GI symptoms
of renal failure can form complexes with medications
and further impair absorption.
Distribution
Hypoalbuminemia resulting from decreased albumin
production, changes in drug-binding sites, and accu-
mulation of substances that inhibit binding alter the
plasma protein binding of medications in patients with
renal dysfunction. Low serum albumin levels are espe-
cially important for highly (greater than 80%) protein-
bound medications (e.g., phenytoin). In general, the
binding of acidic medications is decreased, resulting in
an increase in the unbound, active drug fraction. The
increase in free, unbound drug fraction increases the
volume of distribution. If there is no corresponding
increase in plasma clearance, the half-life of the medi-
cation increases. The presence of uremia also causes
accumulation of acidic byproducts that may displace
acidic medications from albumin binding sites or
inhibit their binding. The binding of basic medications
is usually normal or slightly decreased or increased.
Medications that are not highly protein bound (e.g.,
gentamicin) have little change in their volume of distri-
bution. Digoxin is an exception because its volume of
distribution decreases due to decreased uptake into
myocardial tissue.
Elimination
The extent to which renal dysfunction affects medi-
cation elimination depends on two factors: (1) the
fraction of medication eliminated by the kidney
unchanged, and (2) the degree of renal impairment.
Decreased elimination in renal dysfunction can result
in medication toxicity due to increased elimination
half-life and accumulation of the drug in serum. Clear-
ance of medications primarily eliminated by nonrenal
mechanisms (i.e., hepatic metabolism) is not signifi-
cantly altered in renal dysfunction. However, if the
hepatic metabolites are active or toxic and rely on
renal elimination, accumulation of these metabolites
can occur, resulting in toxicity. Examples of medica-
tions with active or toxic metabolites excreted renally
include allopurinol, cefotaxime, codeine, imipramine,
meperidine, morphine, procainamide, theophylline,
and sulfonamides.
Monitoring Parameters
The renal elimination of waste products and medica-
tions in patients with renal dysfunction is estimated
by measuring the ability of the kidneys to excrete
substances. The glomerular filtration rate (GFR) is used
for this purpose. Determination of GFR involves the
measurement of the amount of a substance excreted
in the urine per unit of time (clearance). Creatinine,
a breakdown product from muscle metabolism, is
primarily eliminated via filtration and is not reab-
sorbed, making its clearance a good indicator for
estimating GFR. Direct measurement of creatinine
clearance (CrCl) through urine collection is an expen-
sive and difficult test to perform. However, estimates
of CrCl can be made through the use of mathemat-
ical equations utilizing certain patient parameters,
including increased, but stable, serum creatinine (SCr)
levels, age, and weight.
Generally, normal renal function is indicated by a
CrCl of greater than 50 mL/min. Patients with renal
dysfunction will have a decrease in CrCl. A CrCl of 11
to 50 mL/min is considered indicative of moderate
impairment of renal function, and a CrCl of less than
10 mL/min indicates severe renal dysfunction.
However, CrCl is also affected by other factors:
• Low muscle mass (e.g., advanced age, malnutrition,
spinal cord injury)
• Unusual diet (e.g., vegetarianism)
• Exercise habits (e.g., performance athletes, body
builders)
• Liver dysfunction
• Morbid obesity

• Ethnicity (e.g., African Americans have higher mean
SCr values and Mexican Americans have lower
mean values)
Other changes in laboratory tests that may be seen
in patients with renal dysfunction include the following:
• Altered serum electrolytes (e.g., hyperkalemia,
hyperphosphatemia, hypermagnesemia, hypo-
calcemia)
• Increased blood urea nitrogen
• Decreased serum albumin
• Metabolic acidosis (decreased blood pCO2 and pH)
• Decreased hematocrit and hemoglobin
• Increased urine osmolality
• Imbalance in fluid input and output (I&O)
• Hematuria and proteinuria
• Increased serum concentrations of medications or
their metabolites
Candidate Patients for Renal
Dosing
The types of patients that should be monitored for
potential renal dosing modifications include the
following:
• Patients with elevated SCr—The normal SCr
concentration for adults is 0.6 to 1.3 mg/dL. All
medications for patients with elevated creatinine
levels should be reviewed for potential dosage
modifications.
• Elderly patients—Elderly patients have decreases
in protein stores and renal function that result in
increased free, unbound serum drug concentra-
tions. When calculating CrCl for this patient popu-
lation, it is important to note that patients with
advanced age and declining muscle mass may have
falsely low creatinine levels that affect estimates of
CrCl. Elderly patients may have a SCr in the normal
range but a decreased CrCl.
• Patients taking high-risk medications—Certain
medications have an increased potential for causing
adverse reactions in patients with renal dysfunction.
The class of medications that most often requires
dosing adjustments for renal function is antimi-
crobials. Other medications often needing dosage
modifications include angiotensin-converting
enzyme (ACE) inhibitors, allopurinol, antineoplastic
agents, digoxin, H2 receptor antagonists, lithium,
meperidine, morphine, and phenytoin.
Medication Dosing in Patients with Renal Dysfunction   331
Estimating Creatinine Clearance
Collecting urine output for 24 hours and directly
measuring creatinine excretion from that sample
is the most accurate measure of CrCl. However,
approximating equations are more commonly used
because incomplete urine collection and laboratory
considerations make 24-hour collections burdensome.
A number of equations have been suggested for use,
each with their own variability in results depending on
the patient being evaluated. The following discussion
will focus on those in common usage.
Patients 20 years of age or older
CrCl can be estimated with the Cockcroft-Gault
equation1:
Males
IBW (140 – Age)
CrCl (mL/min) = 72 × SCr
Females
IBW (140 – Age)
CrCl (mL/min) = × 0.85
72 × SCr
where ideal body weight (IBW) is calculated as follows2:
Patients greater than 60 inches tall
Males
IBW (kg) = 50 kg + (2.3 × inches in height >60)
Females
IBW (kg) = 45.5 kg + (2.3 × inches in height >60)
Patients less than 60 inches tall
Males
IBW (kg) = 50 kg – (2.3 × inches in height <60)
Females
IBW (kg) = 45.5 kg – (2.3 × inches in height <60)
If actual body weight (ABW) is less than IBW, then
use the ABW to calculate CrCl. An adjusted body weight
(AdjBW) is used when IBW is thought to underestimate
the patient’s weight and actual weight is thought to
overestimate the drug distribution in the body. In the
overweight or obese patient, where the ABW is 20% to
40% greater than the IBW, then the AdjBW is calculated
using the following equation:
AdjBW = IBW + [0.4 (ABW – IBW)]
332  Competence Assessment Tools for Health-System Pharmacies
It has been suggested that if ABW is greater than
TABLE
IBW 29-2.than
by more Oral200%
Bioavailability of Selected
(morbid obesity), Medications
then use multipliedAvailable in Bothbody
AdjBW, calculated
the Formulations a 3
as follows : to obtain eGFR in units of mL/min (eGFR/1.73m2 ×
AdjBW (kg) = IBW + [(0.2) (ABW – IBW)]
If the patient’s weight and height are not available,
CrCl can be estimated with the Jellife equation4:
98 – [0.8 (Age in yrs – 20)]
CrCl (mL/min) = SCr (mg⁄dL)
In debilitated, cachectic, and/or elderly patients
with decreased muscle mass, if SCr is less than
0.8 mg/dL, it has been suggested that the actual SCr be
adjusted to 0.8 mg/dL. (Note that some practitioners
will choose to round the SCr to 1.0 mg/dL to simplify
calculations. However, the calculated values overesti-
mate clearance by 25%.)
These equations cannot be used for patients
receiving dialysis. Factors that affect estimates of
CrCl using these equations include advanced age,
fluctuating SCr, high SCr (i.e., greater than 5 mg/dL),
declining muscle mass, presence of liver dysfunction,
and hydration status.
Recently, the National Kidney Foundation (NKF)
recommended the use of the revised Modification of
Diet in Renal Disease (MDRD4revised) study equation for
estimating GFR in patients with chronic kidney disease
and a GFR less than 90 mL/min per 1.73 m2 as follows5:
eGFR = 175 × Cr–1.154 × age–0.203 × (0.742, if female)
× (1.212, if black)
where Cr is the SCr in mg/dL. The revised version
accounts for the change in laboratory creatinine
measurements standardized to the isotope dilution
mass spectrometry (IDMS) reference measurement
procedure, which has been recently adopted by labora-
tories adhering to the Clinical and Laboratory Standards
Institute (CLSI) recommendations.
It is important to note that FDA-approved drug
labeling provides adjustments of drug dosages for
patients with impaired kidney function based on
estimated CrCl using the Cockcroft-Gault equation.
However, the Cockcroft-Gault equation was not devel-
oped using IDMS-traceable creatinine values. NKF
advises that the use of IDMS-traceable SCr values in
the Cockcroft-Gault equation will lead to higher CrCl
values than were determined prior to laboratory stan-
dardization of SCr testing. The National Kidney Disease
Education Program advises that, if practitioners choose
to use eGFR for drug dosing purposes, in very large
or very small patients the reported eGFR should be
by the estimated IV and PO area (BSA)
surface
estimated BSA = eGFR for drug dosing).6 In all cases,
whether practitioners continue to use Cockcroft-Gault
or adopt the use of eGFR, the patient’s clinical condi-
tion should be taken into consideration whenever the
calculated result falls close to the CrCl “breakpoints”
for dosing adjustment.
Patients less than 20 years of age
CrCl can be estimated using the Schwartz equation7:
(K value)(Height in cm)
CrCl (mL/min) =
SCr
where the K value is
• Low birth weight infant
(less than or equal to 1 year old) 0.33
• Full-term infant
(less than or equal to 1 year old) 0.45
• Children (1 to 13 years old) and
adolescent females 0.55
• Adolescent males 0.70
A study comparing three methods of estimating
GFR (including MDRD) suggests that the Schwartz
equation, while routinely resulting in a 20% to 25%
overestimate of GFR, is both more accurate than the
Cockcroft-Gault in children less than 12 years of age
and the most accurate of the three methods evalu-
ated in that population. The Cockcroft-Gault method
is the better predictor of GFR in children greater than
12 years old.8
Modifying Medication Dosage
Once the CrCl has been estimated and evaluated,
the patient’s current medications are reviewed and
those for which dosage adjustments are necessary are
identified. Dosage adjustments can be made as recom-
mended in the published literature. Factors to consider
when evaluating a patient’s CrCl and recommending
dosage adjustments include the following:
• Medication’s route(s) of elimination
• Percentage of unchanged drug that is cleared by
the kidneys
• Presence of active or toxic hepatic metabolites that
are eliminated renally
• Therapeutic window of the medication

• Presence of concurrent disease states
• Presence of fluid overload or dehydration
Pharmacokinetic calculations may also be useful in
dosing some medications, such as aminoglycoside anti-
biotics, vancomycin, and medications with a narrow
therapeutic window. Dosing modifications may involve
changes in dose, dosing frequency, or both.
After medication dosing adjustments are made, the
patient should be monitored for medication response
and toxicity. Drug serum concentrations should be
monitored, if applicable (e.g., aminoglycosides). Addi-
tional dosage adjustments may be necessary based on
the patient’s response to the medication or a change
in the patient’s status, including renal function.
References
1. Cockcroft DW, Gault MH. Prediction of creatinine clear-
ance from serum creatinine. Nephron. 1976;16(1):31-41.
2. Devine BJ. Clinical pharmacy case studies. Case
number 25: gentamicin therapy. Drug Intell Clin Pharm.
1974;8:650-656.
3. Erstad BL. Which weight for weight-based dosage
regimens in obese patients? Am J Health-Syst Pharm.
2002;59(21):2105-2110.
4. Jellife RW. Creatinine clearance: bedside estimate. Ann
Intern Med. 1973;79:604.
5. Levey AS, Coresh J, Greene T, et al. Expressing the
MDRD study equation for estimating GFR with IDMS
traceable (gold standard) serum creatinine values. J Am
Soc Nephrol. 2005;16:69A. Abstract.
Medication Dosing in Patients with Renal Dysfunction   333
6. Estimation of Kidney Function for Prescription Medica-
tion Dosage in Adults. http://nkdep.nih.gov/resources/
CKD-drug-dosing.shtml. Accessed February 28, 2014.
7. Schwartz GJ, Brion LP, Spitzer A. The use of plasma
creatinine concentration for estimating glomerular filtra-
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Clin North Am. 1987;34(3):571-590.
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in children and adults: a comparison of the Cockcroft-
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disease formulas. Kidney Int. 2003;64(4):1425-1436.
Resources
• Dowling TC. Clinical assessment of kidney function. In:
DiPiro J, Talbert RL, Yee G, et al., eds. Pharmacotherapy:
A Pathophysiologic Approach. 8th ed. New York, NY:
McGraw-Hill Medical; 2011:713-740.
• Laroche ML, Charmes JP, Marcheix A, et al. Estimation of
glomerular filtration rate in the elderly: Cockcroft-Gault
formula versus modification of diet in renal disease
formula. Pharmacotherapy. 2006;26(7):1041-1046.
• Matzke GR. Drug therapy individualization for patients
with chronic kidney disease. In: DiPiro J, Talbert RL, Yee
G, et al., eds. Pharmacotherapy: A Pathophysiologic
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2011:861-872.
• Rule AD, Larson TS, Bergstralh EJ, et al. Using serum
creatinine to estimate glomerular filtration rate: accuracy
in good health and in chronic kidney disease. Ann Intern
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• Stevens LA, Coresh J, Greene T, et al. Assessing kidney
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