In patients with normal renal function, piperacillin is primarily excreted
unchanged by the kidney with a clearance of 2.6 mL/minute/kg, and a half-life of
90,91 Doses of piperacillin/tazobactam can be as high as 4.5 g
every 6 hours for the treatment of serious Pseudomonas species infections. In patients
with ESRD, mean piperacillin clearance and half-life values are 0.7 mL/minute/kg
90–92 Although these parameters are significantly different,
they are less than those expected for a drug primarily cleared by the kidneys,
suggesting that some other compensatory mechanism for elimination must be present.
Piperacillin is partially cleared by biliary excretion, a route of elimination that is
increased in patients with renal failure.
92,93 Therefore, aggressive dosage reductions
in M.H. are unnecessary. An appropriate dose of piperacillin/tazobactam for M.H.
would be 3.375 g every 8 hours. Widely used drug references such as Facts and
Comparisons can be used for dosing guidelines for drugs commonly used in patients
PHARMACOKINETIC DOSAGE CALCULATIONS
CASE 31-5, QUESTION 2: In addition to the aforementioned regimen for M.H., vancomycin therapy is
penicillins, such as nafcillin. Is this an appropriate dosing regimen for M.H.?
Streptococcus species, including some isolates of Enterococcus species. It is used
empirically in febrile neutropenic patients because the incidence of infection
secondary to resistant organisms is much greater in this patient population. However,
cases of vancomycin-resistant enterococci have emerged at rates as high as 50%,
raising concern and reducing its empiric use.
Vancomycin is poorly absorbed by the oral route and must be administered IV
when used to treat systemic infections. As with many other antibiotics, vancomycin
primarily is cleared by the kidneys.
95 Significant toxicities have been associated with
elevated serum concentrations, making careful dosing modification in renal failure
As with the aminoglycosides, pharmacokinetic calculations can be used to
individualize a dosing regimen to produce the desired peak and trough plasma levels.
Unlike the aminoglycosides, the therapeutic range for vancomycin is less clear.
Normally, doses are designed to achieve peak levels of 25 to 40 mg/L and trough
97,98 The correlation between vancomycin toxicity (e.g.,
ototoxicity) and plasma levels is not well defined. Some clinicians have suggested,
however, that plasma levels of 80 mg/L or more may correlate with auditory
Vancomycin has an elimination half-life of 3 to 9 hours in patients with normal
99 This increases to 129 to 189 hours in patients with ESRD.
Using pharmacokinetic principles and considering that the plasma clearance of
vancomycin is approximately 60% to 70% of CrCl
the estimated Vdvanco and Clvanco can be calculated using the following
Based on estimated values for Clvanco and Vdvanco
, the elimination rate constant
can be calculated using the following equation:
Because M.H.’s estimated peak concentration is less than 40 mg/L and her trough
falls within the range of 10 to 15 mg/L, the starting dose of 500 mg every 24 hours is
Routine monitoring of plasma vancomycin concentrations in patients with normal
renal function is controversial because the likelihood that toxicity will develop in
this group is relatively low. However, in patients with renal failure, such as M.H., it
is advisable to measure vancomycin levels several days after initiation of therapy to
ensure that they are within an acceptable range.
99,101,102,104 This is prudent if an
extended course of therapy is anticipated. Vancomycin is usually infused over the
CASE 31-5, QUESTION 3: M.H.’s renal function begins to deteriorate to the point where she requires
hemodialysis. How should her regimen now be altered?
Patients with ESRD may have measurable vancomycin levels for up to 3 weeks
after a single dose despite conventional hemodialysis.
102 This suggests that the ability
of these patients to eliminate vancomycin is minimal and that little of the drug is
removed by conventional hemodialysis. The elimination half-life for vancomycin in
these individuals averages 5 to 7 days, which is consistent with a residual
vancomycin clearance of 3 to 4 mL/minute.
100–102 Only about 5% of vancomycin is
metabolized hepatically in patients with normal renal function.
Conventional hemodialysis removes about 7% of vancomycin during a typical 4-
105 The elimination half-life on and off dialysis and plasma levels of
the drug before and after hemodialysis do not differ significantly. The poor removal
of vancomycin by conventional hemodialysis is attributable to its large MW of 1,400.
Patients receiving conventional hemodialysis are typically given a single, 1-g dose
99,102,104 Based on M.H.’s estimated Vd of 49 L, this dose will
produce an initial peak plasma level of approximately 20 mg/L. If vancomycin is
administered weekly, steady-state peak and trough levels of 40 and 16 mg/L,
respectively, would be predicted.
Vancomycin is removed to a greater extent by high-flux hemodialysis than by
conventional hemodialysis. As a result, more frequent dosing is necessary to maintain
therapeutic vancomycin concentrations. High-flux dialysis clearance of vancomycin
using the Fresenius polysulfone dialyzer is 45 to 160 mL/minute and varies with
60,106 Up to 50% of a dose of vancomycin is removed in 4
hours by high-flux hemodialysis compared with 6.9% using conventional dialysis. A
rebound phenomenon after dialysis suggests that the total amount of drug removed
may be less than initially reported.
In any case, the efficiency of high-flux
procedures in removing vancomycin is greater than that of conventional dialysis.
Therefore, plasma levels should be monitored carefully in these patients, and the
necessity for postdialysis replacement doses of around 500 mg (~10–15 mg/kg)
CASE 31-5, QUESTION 4: M.H. continues to be febrile despite her triple antimicrobial regimen.
Caspofungin is an echinocandin antifungal agent that is slowly metabolized by
hydrolysis and N-acetylation, with little being excreted unchanged in the urine.
Caspofungin is not removed significantly by hemodialysis or continuous
hemofiltration. No dosage adjustment is necessary in patients with renal failure or on
110 The maintenance dose needs to be reduced in the setting
of moderate liver failure however.
CASE 31-5, QUESTION 5: What factors need to be considered when other antifungal agents are used in
Amphotericin B is a polyene antifungal agent that has activity against a wide
variety of fungi. Amphotericin B is extensively distributed into the peripheral tissue,
and has a long elimination half-life of approximately 15 days.
significant change in the disposition of amphotericin B in patients with liver or
kidney disease. The utility of amphotericin B has been limited due to its
113 Lipid-based formulations are associated with a lower incidence of
nephrotoxicity and other systemic side effects.
114 Triazole antifungal agents (e.g.,
fluconazole, posaconazole, voriconazole) or an echinocandin class (e.g.,
anidulafungin, caspofungin, micafungin) are alternative choices that are not
potentially nephrotoxic, nor do they need to be dose adjusted in the setting of renal
dysfunction (with the exception of fluconazole). The oral as opposed to the IV
formulation of voriconazole and posaconazole should be used in the setting of renal
dysfunction or for patients with a CrCl of less than 50 mL/minute to prevent
accumulation of sulfobutyl ether β-cyclodextrin, the solvent vehicle found in the IV
has no allergies, and weighs 52 kg. How should M.J.’s PD-related infection be managed?
Gram-positive cocci such as S. aureus are common causes of PD-related
infections. The selection of empiric antibiotics should be made based on the patient’s
and program’s history of microorganisms and sensitivities. A first-generation
cephalosporin such as cefazolin would be a reasonable choice for M.J. Programs
with a high rate of methicillin-resistant organisms should use vancomycin.
IP antibiotics can be given with each exchange (continuous dosing). In this
situation, a single 500-mg/L loading dose of cefazolin is given followed by a
maintenance dose of 125 mg/L with subsequent exchanges. Antibiotics can also be
given intermittently (once daily per exchange). With intermittent dosing, the
antibiotic-containing dialysis solution should dwell for at least 6 hours to allow for
adequate absorption. Cefazolin 15 mg/kg (rounded off to 750 mg) is typically given
in one exchange. For patients on automated PD, the dose of cefazolin is 20 mg/kg
every day in a long-day dwell. For patients with residual renal function (e.g., >100
mL/day of urine output), empirically, the dose is increased by 25%. The management
of PD-related infections and dosing of various antibiotics is discussed in the
International Society for Peritoneal Dialysis guidelines.
laboratory work includes the following:
Eight hours after administration, his phenytoin level is 5 mg/L. Is this levelsubtherapeutic?
R.S. has severe renal disease, which will affect the total (bound plus free)
phenytoin concentration achieved and how this concentration is interpreted.
Decreased plasma protein binding will result in lower measured total phenytoin
concentrations, and the calculated apparent Vd may increase. In patients with normal
renal function, approximately 90% of the measured phenytoin is bound to albumin,
and 10% is free. The free fraction of phenytoin is increased to about 20% to 25% in
11,117–121 Because the free fraction for phenytoin is increased in
patients with uremia, lower plasma concentrations will produce therapeutic effects
that will be equivalent to those produced by higher phenytoin concentrations in
patients with normal renal function.
8,122 Phenytoin is an acidic drug that is bound
primarily to albumin. A number of mechanisms have been proposed that account for
the decreased binding, including (a) decreased albumin concentration, (b)
accumulation of uremic by-products that displace acidic drugs from their binding
sites, and (c) alteration in the conformation or structure of albumin in uremic patients,
resulting in a reduced number of binding sites or decreased affinity for drugs (see
Chapter 60, Seizure Disorders). Other acidic drugs with altered protein binding in
renal disease are listed in Table 31-1.
J Med. 1971;285:648. Copyright © 2001 Massachusetts Medical Society. All rights reserved.)
Figure 31-2 illustrates changes in phenytoin levels when uremic and nonuremic
patients are given equivalent doses.
The following equation should be used to correct for R.S.’s altered binding owing
to his renal dysfunction and hypoalbuminemia
where Cp′ is the measured plasma concentration reported by the laboratory, and
is the corrected plasma concentration that would be seen if the patient
had normal renal function and normal albumin. Alpha (α) is the normal free fraction
(0.1), P′ is the patient’s serum albumin, and PNL
is normal albumin (4.4 g/dL). The
factor 0.48 was derived from patients on hemodialysis and represents the decreased
affinity of phenytoin for albumin.
For R.S., a total plasma phenytoin concentration of 5 mg/L is comparable to 13
mg/L in a patient without renal failure. Because this falls within the phenytoin’s
therapeutic range of 10 to 20 mg/L, his measured level is not subtherapeutic.
The factor 0.48 should be used only to estimate changes in protein binding for
patients with ESRD receiving hemodialysis. Data for patients with moderate renal
disease are limited, and it is unclear what changes exist in the binding of phenytoin to
118 For patients with normal or moderate renal impairment, the following
equation should be used only if the serum albumin is low; the factor 0.48 should be
Fosphenytoin, a prodrug of phenytoin, does not need to be dissolved in propylene
glycol, and therefore can be administered more quickly. This offers an important
advantage for seizures that must be controlled quickly. In patients with renal failure,
the conversion of fosphenytoin to phenytoin was equally efficient in patients with
renal disease and healthy subjects.
124 Once fosphenytoin is converted to phenytoin,
the impact of renal disease on protein binding is expected to be similar to that seen
with phenytoin and thus the same considerations should be made for patients with
EFFECT OF RENAL FAILURE ON METABOLIZED
QUESTION 1: F.G., a 56-year-old woman, is admitted for a cervical laminectomy. She has a history of
laboratory values are as follows:
history of seizures. What might be responsible for this sudden event?
Meperidine is a narcotic analgesic commonly used to control acute pain. It is
metabolized hepatically via N-demethylation to normeperidine, a metabolite known
to accumulate in renal insufficiency.
15,125 Although meperidine has both CNS
excitatory and depressant properties, normeperidine is a very potent CNS stimulant
that can cause seizures in patients with renal failure who are receiving multiple doses
126 Patients with renal dysfunction given merperidine experience
126 Because the renal clearance of normeperidine correlates
significantly with CrCl, renal dysfunction can lead to its accumulation, resulting in
neurologic toxicity. The normeperidine to meperidine plasma concentration ratio was
consistently higher in patients with renal failure, averaging 2.0 compared with a
mean of 0.6 for patients with good renal function.
126 Table 31-3 lists examples of
additional drugs that have active or toxic metabolites that may accumulate in renal
CASE 31-8, QUESTION 2: Are the pharmacokinetics or pharmacodynamics of other narcotic analgesics
altered in patients with renal insufficiency?
The pharmacokinetic disposition of morphine does not appear to be altered in
; however, its active metabolite, morphine-6-
glucuronide, as well as its principal metabolite, morphine-3-glucuronide, do
accumulate in renal disease. The elimination half-life of morphine-6-glucuronide
increases from 3 to 4 hours in normal subjects to 89 to 136 hours in subjects with
128 This metabolite penetrates the blood–brain barrier more readily, has
a greater affinity for CNS receptors, and has analgesic activity that is 3.7 times
129 Therefore, accumulation of morphine-6-glucuronide may be
responsible for the morphine-induced narcosis reported in patients with severe renal
Other analgesics that have been associated with CNS toxicity in patients with renal
failure include codeine, propoxyphene, and dihydrocodeine.
orally administered codeine does not appear to be altered in renal failure; however,
there have been case reports of codeine-induced narcosis.
codeine did not exceed 120 mg/day, CNS and respiratory depression persisted for up
to 4 days after discontinuing codeine and initiating naloxone administration. The
elimination half-life of codeine is prolonged in patients on chronic hemodialysis.
Although the Vd of codeine was twice as large, the total clearance was not
131 A lower initial dose should be used because codeine is
Drugs with Active or Toxic Metabolites Excreted by the Kidney
Bupropion Threo/erythro-hydrobupropion
Cefotaxime Desacetylcefotaxime
Chlorpropamide Hydroxy metabolites
Clofibrate Chlorphenoxyisobutyrate
Cyclophosphamide 4-Ketocyclophosphamide
Methyldopa Methyl-O-sulfate-α-methyldopamine
Morphine Morphine-3-glucuronide
Phenylbutazone Oxyphenbutazone
Procainamide N-acetylprocainamide (NAPA)
Rifampicin Deacetylated metabolites
Sodium nitroprusside Thiocyanate
Sulfonamides Acetylated metabolites
Tramadol O-Demethyl-N-demethyltramadol
Hydromorphone is metabolized in the liver to hydromorphone-3-glucuronide,
dihydroisomorphone, dihydromorphine, and small amounts of hydromorphone-3-
sulfate, norhydromorphone, and nordihydroisomorphone.
eliminated are excreted by the kidneys. Hydromorphone can be used in patients with
renal failure; however, smaller initial doses may be warranted.
Enoxaparin is a low MW heparin that is used to prevent and treat various
thromboembolic disorders, such as deep venous thrombosis, unstable angina, and
non–Q wave myocardial infarction. The kidneys play a major role in the clearance of
133 and a higher incidence of bleeding complications is associated
with the use of enoxaparin in patients with renal dysfunction.
half-life of enoxaparin is prolonged in patients with ESRD, although the other
pharmacokinetic parameters are similar to those in healthy subjects.
increased incidence of bleeding complications cannot be completely attributed to
pharmacokinetic changes, but may also be related to the effects of enoxaparin on
antifactor IIa and antithrombin III, as well as the effects of uremia on hemostasis.
Enoxaparin should be used cautiously in patients with a CrCl less than 30
mL/minute, with a recommended lower dosage of 30 mg subcutaneously daily.
Although monitoring of the anticoagulant effect by anti-Xa activity is not necessary in
clinically stable patients, it may be warranted in patients with renal dysfunction as
well as in those who have other factors that may increase the risk of bleeding
ASSESSING RENAL FUNCTION IN THE ELDERLY
Renal function declines physiologically with advancing age and as the result of
comorbidities such as hypertension and diabetes.
138 This decrease in renal function
can have significant consequences on drug excretion, metabolism, and the potential
for adverse drug reactions, particularly in the elderly population that is often
prescribed multiple medications.
adverse drug events in elderly patients.
140 Sulfonylurea antidiabetic agents such as
glyburide that are eliminated primarily by the kidneys can lead to prolonged
hypoglycemia in patients with decreased renal function.
should be used with caution in patients with kidney dysfunction due to the increased
Formulas that estimate renal function use the serum creatinine. In elderly adults, a
low serum creatinine may not always be indicative of normal renal function. Older
adults tend to have lower muscle mass than younger people, and a low serum
creatinine may not be indicative of normal renal function, but rather reduced muscle
mass. Differences in the estimated GFR between the MDRD and Cockcroft–Gault
formulas may result in discordant dosing recommendations in an elderly
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