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Dialysis of Drugs
Curtis A. Johnson, PharmD
CKD Insights, LLC
Verona, Wisconsin
Professor (Emeritus) of Pharmacy and MedicineUniversity of Wisconsin-MadisonMadison, Wisconsin 2008 Dialysis of Drugs
DISCLAIMER—These Dialysis of Drugs guidelines are offered as a general summary of information for pharmacists and other medical professionals. Inappropriate administration of drugs may involve serious medical risks to the patient that can only be identifi ed by medical professionals. Depending on the circumstances, the risks can be serious and can include severe injury, including death. These guidelines cannot identify medical risks specifi c to an individual patient or recommend patient treatment. These guidelines are not to be used as a substitute for professional training. The absence of typographical errors is not guaranteed. Use of these guidelines indicates acknowledgment that neither CKD Insights, LLC. nor Genzyme will be responsible for any loss or injury, including death, sustained in connection with or as a result of the use of these guidelines. Readers should consult the complete information available in the package insert for each agent indicated before prescribing medications. Guides such as this one can only draw from information available as of the date of publication. Neither CKD Insights, LLC. nor Genzyme is under any obligation to update information contained herein. Future medical advances or product information may affect or change the information provided. Pharmacists and other medical professionals using these guidelines are responsible for monitoring ongoing medical advances relating to dialysis. Copyright 2008, CKD Insights, LLC. Printed in the U.S.A. All rights reserved. This material may not be published, rewritten or redistributed. SEE DISCLAIMER REGARDING USE OF THIS GUIDE Drug removal during dialysis is frequently of interest to those caring for patients receiving hemodialysis or peritoneal dialysis. The extent of drug dialyzability determines whether supplemental dosing is necessary during or following dialysis. The accompanying table is a reference regarding the effect of either form of dialysis on drug clearance. This table should be used as a general guideline.
The drugs included in the table are parent drugs. In some cases, these drugs are converted to pharmacologically active or toxic metabolites for which little dialysis information is known. Therefore, for a few drugs, a primary metabolite is also included in the table. When available, serum drug measurements may be appropriate for dosing individual patients. In all cases, patients should be monitored for clinical effi cacy and toxicity.
What Determines Drug
Dialyzability?
The extent to which a drug is affected by dialysis is
determined primarily by several physicochemical
characteristics of the drug that are briefl y described
in the text that follows. These include molecular
size, protein binding, volume of distribution, water
solubility, and plasma clearance. In addition to
these properties of the drug, technical aspects of
the dialysis procedure also may determine the
extent to which a drug is removed by dialysis.
SEE DISCLAIMER REGARDING USE OF THIS GUIDE 2008 Dialysis of Drugs
Molecular Weight
Dialysis is dependent upon the use of a dialytic
membrane: either a synthetic membrane
with fi xed pore size, as in hemodialysis, or
a naturally occurring peritoneal membrane,
as in peritoneal dialysis. The movement of
drugs or other solutes is largely determined
by the size of these molecules in relation to
the pore size of the membrane. As a general
rule, smaller molecular weight substances will
pass through the membrane more easily than
larger molecular weight substances. A common
assumption is that pore size of the peritoneal
membrane is somewhat larger than that of the
hemodialysis membrane. This would explain
the observation that larger molecular weight
substances appear to cross the peritoneal
membrane to a greater extent than the
hemodialysis membrane.
Protein Binding
Another important factor determining drug
dialyzability is the concentration gradient
of unbound (free) drug across the dialysis
membrane. Drugs with a high degree of protein
binding will have a low plasma concentration
of unbound drug available for dialysis. Uremia
may have an effect on protein binding for some
drugs. Through mechanisms not completely
understood, protein binding may decrease in
uremic serum. Should this change in binding be
substantial, increased dialyzability of free drug
may occur.
SEE DISCLAIMER REGARDING USE OF THIS GUIDE Because the primary binding proteins for most drugs (albumin, α -acid glycoprotein) are of large molecular size, the drug-protein complex is often unable to cross the dialysis membrane, especially the hemodialysis membrane. Since the peritoneal membrane does permit the passage of some proteins, there may be some limited drug-protein removal with peritoneal dialysis. Increased protein concentrations often occur in peritoneal effl uent during episodes of peritonitis.
Volume of Distribution
A drug with a large volume of distribution
is distributed widely throughout tissues and
is present in relatively small amounts in the
blood. Factors that contribute to a large volume
of distribution include a high degree of lipid
solubility and low plasma protein binding.
Drugs with a large volume of distribution are
likely to be dialyzed minimally.
Water Solubility
The dialysate used for either hemodialysis or
peritoneal dialysis is an aqueous solution. In
general, drugs with high water solubility will
be dialyzed to a greater extent than those with
high lipid solubility. Highly lipid-soluble drugs
tend to be distributed throughout tissues, and
therefore only a small fraction of the drug is
present in plasma and accessible for dialysis.
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Plasma Clearance
The inherent metabolic clearance—the sum of
renal and nonrenal clearance—is often termed
the “plasma clearance” of a drug. In dialysis
patients, renal clearance is largely replaced
by dialysis clearance. If nonrenal clearance
is large compared to renal clearance, the
contribution of dialysis to total drug removal
is low. However, if renal (dialysis) clearance
increases plasma clearance by 30% or more,
dialysis clearance is considered to be clinically
important.
Dialysis Membrane
As mentioned previously, the characteristics
of the dialysis membrane determine to a
large extent the dialysis of drugs. Pore size,
surface area, and geometry are the primary
determinants of the performance of a given
membrane. The technology of hemodialysis
has evolved, and new membranes have been
introduced for clinical use. Interpretation of
published literature should be tempered with
the understanding that newer hemodialysis
membranes may have different drug dialysis
characteristics. Little can be done to alter the
characteristics of the peritoneal membrane.
SEE DISCLAIMER REGARDING USE OF THIS GUIDE Blood and Dialysate
Flow Rates
The hemodialysis prescription includes the
desired blood and dialysate fl ow rates. As drugs
normally move from blood to dialysate, the
fl ow rates of these two substances may have a
pronounced effect on dialyzability. In general,
increased blood fl ow rates during hemodialysis
will deliver greater amounts of drug to the
dialysis membrane. As the drug concentration
increases in the dialysate, the fl ow rate of the
dialysis solution also becomes important in
overall drug removal. Greater dialysis can be
achieved with faster dialysate fl ow rates that
keep the dialysate drug concentration at a
minimum.
During peritoneal dialysis, little can be done to alter blood fl ow rates to the peritoneum. However, dialysate fl ow rates are determined by the volume and frequency of dialysate exchange in the peritoneum. At low exchange rates, drug concentrations in the dialysate will increase during the time in which the dialysate resides in the peritoneum, thus slowing additional movement of drug across the membrane. More frequent exchanges will favor increased drug dialyzability, provided the drug’s physicochemical characteristics permit its movement across the peritoneal membrane.
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Special Considerations
HIGH PERMEABILITY DIALYSIS
Much of the information contained in this guide has been obtained from studies conducted under conditions of standard hemodialysis that employed conventional dialysis membranes. Changes in dialysis technology have led to more permeable dialysis membranes and the opportunity to employ higher blood and dialysate fl ow rates. These new technologies are often referred to as “high permeability,” “high-effi ciency,” and “high-fl ux” dialysis. The United States Food and Drug Administration has classifi ed high permeability dialysis membranes as those whose in vitro ultrafi ltration coeffi cient (KUf) is greater than 8 mL/hour/mm Hg. Commonly included in this group of dialysis membranes are polysulfone, polyacrylonitrile, and high-effi ciency cuprammonium rayon dialyzers. Changes in dialysis membranes and changes in blood and dialysis fl ow rates may have clinically important effects on drug removal through the membrane.
There are an increasing number of studies that examine the effects of high permeability dialysis on drug dialyzability. Results of these studies confi rm predictions that drug removal from plasma is often enhanced as compared with more traditional dialysis membranes. Studies with high permeability dialysis also demonstrate that removal of drug from plasma often exceeds the transfer of drug from tissues to plasma. As a result, a rebound of plasma drug concentrations SEE DISCLAIMER REGARDING USE OF THIS GUIDE I SPECIAL CONSIDERA
following the conclusion of dialysis may occur as blood-tissue drug equilibration occurs. Patients receiving high permeability dialysis may require more drug compared with those receiving standard hemodialysis. Due to the many technical and physiological variables, individualized therapeutic drug monitoring may be necessary. The reader is referred to the primary literature for further details.
CONTINUOUS RENAL REPLACEMENT
THERAPY

Another therapeutic development that will affect drug dialyzability is continuous renal replacement therapy (CRRT), known in its various forms as continuous arteriovenous hemofi ltration (CAVH), continuous venovenous hemofi ltration (CVVH), continuous arteriovenous hemodialysis (CAVHD), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafi ltration (CVVHDF), continuous arteriovenous hemodiafi ltration (CAVHDF), slow continuous ultrafi ltration (SCUF), continuous arteriovenous high-fl ux hemodialysis (CAVHFD), and continuous venovenous high-fl ux hemodialysis (CVVHFD). These various techniques are used in the management of acute renal failure in critically ill patients.
Continuous renal replacement therapies differ considerably from intermittent hemodialysis. Relying heavily upon continuous ultrafi ltration of plasma water, CRRT has the potential for the removal of large quantities of ultrafi lterable SEE DISCLAIMER REGARDING USE OF THIS GUIDE 2008 Dialysis of Drugs
drugs contained in plasma. Unfortunately, few in vivo studies have been published, and very few drugs have been studied pharmacokinetically in intensive care patients. Therefore, many guidelines for drug dosing during CRRT are extrapolated from experiences with chronic hemodialysis or from theoretical considerations based upon general principles of drug removal derived from the physicochemical characteristics of the drug and the CRRT technique employed.
Molecular weight of a drug has been an important determinant of drug dialyzability in conventional hemodialysis. This drug characteristic becomes less important during CRRT because of the use of high-fl ux hemofi lters that permit passage of larger molecules up to 5000 Da. As is true with conventional hemodialysis, drugs with a large volume of distribution are unlikely to be removed to a great extent during CRRT. Most of the body stores of such drugs are outside the vascular compartment and not accessible to the hemofi lter for removal. Similarly, drugs that are highly bound to plasma proteins are not subject to signifi cant removal during CRRT because the molecular weight of drug-protein complexes usually hinders passage of the complex across the fi lter. The fraction of unbound drug may change during renal failure, however, thus altering the likelihood of drug removal. If the unbound fraction increases, more drug clearance may occur. If the unbound fraction becomes less, there is likely to be less drug removal during CRRT.
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A useful tool to predict the likelihood of a drug to cross the hemofi lter membrane is the sieving coeffi cient. This term is defi ned as the ratio of drug concentration in the ultrafi ltrate to the prefi lter plasma water concentration of the drug. If the sieving coeffi cient is close to 1.0, the drug has relatively free passage across the fi lter. The following table presents sieving coeffi cient data from in vitro and in vivo evaluations.
SIEVING COEFFICIENT
Drug Name
Predicted Measured Condition
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Drug Name
Predicted Measured Condition
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Drug Name
Predicted Measured Condition
aAmicon diafi lter (polysulfone)bRenal System (polysulfone)cHospal (AN69)dGambro (polyamide) The above table was published in the following article: Joy MS, Matzke, GR, Armstrong DK, Marx MA, Zarowitz BJ. A primer on continuous renal replacement therapy for critically ill patients. Ann Pharmacother. 1998;32:362-75. Reprinted with permission. Harvey Whitney Books Company.
The specifi c CRRT technique employed will infl uence the ultrafi ltration rate and hence, the potential rate of drug removal. When CRRT relies solely on spontaneous blood fl ow without extracorporeal blood pumping, an ultrafi ltration rate of 10-15 mL/min is anticipated. The addition of blood pumps and continuous dialysis may increase the ultrafi ltration rate to 50 mL/min. Higher rates of ultrafi ltration may lead to greater drug removal with a need for more frequent replacement doses. Drug removal can be determined by collection of the total volume of dialysate/ultrafi ltrate and measurement of the concentration of drug in the effl uent. SEE DISCLAIMER REGARDING USE OF THIS GUIDE 2008 Dialysis of Drugs
Because of the multiple techniques employed in CRRT, the variability in individual patient circumstances, and the lack of in vivo data, the tables in this guide do not contain information on drug removal during CRRT. Once again, the reader is referred to the primary literature for assistance with the dosing of specifi c drugs.
PLASMAPHERESIS
Plasmapheresis is another special consideration in which drug removal from plasma may be of concern. This technique is used for the treatment of certain immunologic, infectious, and metabolic diseases, as well as for the removal of toxins that cannot be removed by hemodialysis or peritoneal dialysis. Plasmapheresis removes plasma from the patient with replacement by crystalloid or colloid solutions. Solutes such as drug molecules that are present in the plasma may be removed from the patient. Unfortunately, little is known about the specifi c pharmacokinetic effects of plasmapheresis. The procedure may be most likely to remove substances that are lipophilic, that are highly protein-bound, and that have a small volume of distribution. The reader is referred to reference 5.
Drug dialyzability is determined by a complex interaction of many factors, including the characteristics of the drug and the technical aspects of the dialysis system. Published studies on drug dialyzability should specify the conditions that pertain during dialysis. Results SEE DISCLAIMER REGARDING USE OF THIS GUIDE I ABOUT THIS
from these studies should be applied with caution to other dialysis conditions. About This Guide
These guidelines are designed to provide
extensive, easy-to-read information regarding
the dialyzability of drugs. Numerous literature
sources have been used in preparing the
guidelines. For many drugs, including newly-
approved medications, no studies have been
done to determine the effect of dialysis on drug
removal. In some cases, the available data may
confl ict. Conditions of dialysis used in published
studies may not necessarily refl ect current
dialysis procedures and technology. Variations
in the duration of dialysis, fl ow rates, dialysis
membranes, and whether peritoneal dialysis is
continuous or intermittent will all affect drug
removal. This educational review will distinguish
between conventional hemodialysis and high
permeability (often called high-fl ux) hemodialysis
where such data are available. However,
the review does not contain information on
drug dialyzability with CRRT (See “Special
Considerations,” page 9) or with plasmapheresis.
For additional information on specifi c drugs, the
reader should consult the primary literature.
A designation of “Yes” in the Hemodialysis and Peritoneal Dialysis columns indicates that dialysis enhances plasma clearance by 30% or more. Supplemental dosing may be required or dosing after dialysis should be considered. “No” indicates that dialysis does not have a clinically important effect on plasma clearance. SEE DISCLAIMER REGARDING USE OF THIS GUIDE 2008 Dialysis of Drugs
Supplemental dosing is usually not required. As a general principle, usual methods of continuous ambulatory peritoneal dialysis (CAPD) provide relatively low drug clearances during any given dialysate exchange. However, cumulative drug removal may require dosage supplementation at appropriate intervals. Relatively little research has examined peritoneal drug clearance in PD techniques that utilize automated systems employing large volumes of short dwells at night, often accompanied by one or more longer daytime dwells (APD). Similarly, little data exists on the effects of tidal peritoneal dialysis on drug clearance. A few studies have confi rmed that clearance of some drugs is increased by APD due to the increased drug concentration gradient between blood and dialysate. Increased drug dialyzability may occur with increased peritoneal dialysate fl ow rates or in the presence of peritonitis. A designation of “U” indicates that no dialysis studies have been published, but that the author of this guide has concluded that signifi cant drug removal during dialysis is unlikely based upon the physicochemical characteristics of the drug, which are primarily a high degree of protein binding, a large molecular weight, or a large volume of distribution. A designation of “L” indicates that no published data exist on the removal of the drug during high permeability dialysis. However, the author has extrapolated data from studies using conventional dialysis to conclude that signifi cant drug removal is likely to occur during high permeability dialysis. A designation of “ND” indicates that no data are available on drug dialyzability. In some cases, the literature reports the use of a high permeability, or SEE DISCLAIMER REGARDING USE OF THIS GUIDE I ABOUT THIS
high-fl ux, dialysis membrane, however the type of membrane is not specifi ed. A designation of “NS” indicates membrane type is not specifi ed.
Yes Indicates that dialysis enhances plasma clearance by
30% or more. Supplemental dosing may be required or dosing after dialysis should be considered.
No Indicates that dialysis does not have a
clinically important effect on plasma clearance. Supplemental dosing is usually not required.
Indicates signifi cant drug removal is unlikely based on physicochemical characteristics of the drug such as protein binding, molecular size or volume of distribution Indicates no published data exist, but information extrapolated from studies using conventional dialysis techniques suggests signifi cant drug removal is likely during high permeability dialysis ND Indicates there are no data on drug dialyzability
NS Indicates the type of membrane was not specifi ed
* Removed with hemoperfusion
Note: In these tables, conventional hemodialysis is
defi ned as the use of a dialysis membrane whose in
vitro coeffi cient of ultrafi ltration (KUf) ≤8 mL/hour/mm
Hg. Data also are placed in the conventional column
if the literature does not specify the type of dialysis
membrane employed. High permeability hemodialysis
is defi ned as the use of a dialysis membrane whose
KUf >8 mL/hour/mm Hg. In the tables, the KUf of the
membrane(s) used is included in parentheses.

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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
streptokinase activator complexAnistreplase SEE DISCLAIMER REGARDING USE OF THIS GUIDE HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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HEMODIALYSIS
Conventional High Permeability Peritoneal
Dialysis
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References
1. Aronoff GR, Berns JS, Brier ME, Golper TA, Morrison
G, Singer I, Swan SK, Bennett WM. Drug prescribing in renal failure, 4th ed. Philadelphia: American College of Physicians; 1999.
2. Böhler J, Donauer J, Keller F. Pharmacokinetic principles during continuous renal replacement therapy: drugs and dosage. Kidney Int. 1999;56 (Suppl 72):S-24-S-28.
3. Bressolle F, Kinowski JM, de la Coussaye JE, Wynn N, Eledjam JJ, Galtier M. Clinical pharmacokinetics during continuous haemofi ltration. Clin Pharmacokinet. 1994;26:457-471.
4. Joy MS, Matzke GR, Armstrong DK, Marx MA, Zarowitz BJ. A primer on continuous renal replacement therapy for critically ill patients. Ann Pharmacother. 1998;32:362-375.
5. Kale-Pradham PB, Woo MH. A review of the effects of plasmapheresis on drug clearance. Pharmacotherapy. 1997;17:684-695.
6. Keller E, Reetze P, Schollmeyer P. Drug therapy in patients undergoing continuous ambulatory peritoneal dialysis: Clinical pharmacokinetic considerations. Clin Pharmacokinet. 1990;18:104-117.
7. Keller F, Böhler J, Czock D, Zellner D, Mertz AKH. Individualized drug dosage in patients treated with continuous hemofi ltration. Kidney Int. 1999;56 (Suppl 72):S-29- S31.
8. Bugge JF. Pharmacokinetics and drug dosing adjustments during continuous venovenous hemofi ltration or hemodiafi ltration in critically ill patients. Acta Anaesthesiol Scand. 2001; 45:929-934.
9. Olyaei AJ, DeMattos A, Bennett WM. Principles of drug usage in dialysis patients, in Nissenson AR, Fine RN (eds). Dialysis therapy. Philadelphia: Hanley & Belfus; 2002.
10. Taylor CA, Abdel-Rahman E, Zimmerman SW, Johnson CA. Clinical pharmacokinetics during continuous ambulatory peritoneal dialysis. Clin Pharmacokinet. 1996;31:293-308.
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Source: http://www.wilbertjellema.nl/pdf/DialysisDrugs2008.pdf

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