Drug Dosing Renal Failure PDF

ANALYTIC REVIEWS
Drug Dosing in Critically Ill Patients with Renal

Failure: A Pharmacokinetic Approach
Ronald J. DeBellis, PharmD,*
Brian S. Smith, PharmD,
Pauline A. Cawley, PharmD,
and Gail M. Burniske, PharmD
DeBellis RJ, Smith BS, Cawley PA, Burniske GM. Drug dosing
in critically ill patients with renal failure: a pharmacokinetic
approach. J Intensive Care Med 2000;15:273313.
Accurate pharmacotherapy management in the intensive

care unit (ICU) patient is crucial to minimize adverse drug
events. Pharmacokinetic principles including absorption,
distribution, metabolism, and excretion (ADME) all play an
important role in determining the fate of medications used
in the critical care setting. Renal failure in this setting further
alters pharmacokinetic parameters, resulting in drug dosing
changes. This article highlights and applies principles of drug
dosing in normal patients and in the pharmacokinetically
challenging environment of critically ill patients with renal
failure. Specific drug dosing tables serve as a guide for the
clinician to renally adjust medication doses in the critically
ill patient with renal failure.
From the *Massachusetts College of Pharmacy and Health Sciences, University of Massachusetts School of Medicine, University of Massachusetts Memorial Health Care, Worcester, MA,
Regional Medical Center at Memphis, Memphis, TN, and University of Maryland Medical Center, Baltimore, MD.
Critically ill patients often have multiple medical

problems and commonly receive complex medication regimens. These factors make critically ill patients highly susceptible to adverse drug events.
Adverse drug events have been shown occur in
1012% of intensive care unit (ICU) patients and
occur approximately two times more frequently
when compared to patients on general medicine
units [1,2]. Patients who are critically ill are also at
increased risk for developing renal failure. Acute
renal failure occurs in 725% of all patients admitted
to ICUs and increases the average mortality from
approximately 15% to more than 60% [39]. Renal
failure is a risk factor for adverse drug events and
likely contributes to the high rate of adverse drug
events in critically ill patients. Up to 45% of patients
with an estimated creatinine clearance less than 40
ml/min receive medications that are dosed 2.5 times
higher than the maximum recommended dose [10].
In addition, adverse drug reactions have been
shown to occur in 9% of patients with blood urea
nitrogen (BUN) level less than 20 mg/dl versus 24%
of patients with a BUN greater than 40 mg/dl [11].
Adverse drug events place critically ill patients
at risk for morbidity and mortality, resulting in the
utilization of tremendous financial resources. It has
been estimated that each adverse drug event increases hospital costs by $2,000$4,600 [1214]. The
cost of adverse drug events in patients admitted to
an ICU have the potential to be higher due to the
augmented cost of an ICU bed. Accurate drug
dosing in a pharmacokinetically challenging environment is essential to ensure optimal pharmacotherapy in critically ill patients. This particularly
applies to patients with renal failure. The following
review will discuss some key concepts and theories
of drug dosing in critically ill patients. In addition,
practical guidelines for drug dosing in the critically
ill patient with renal failure are delineated.
Received Jun 2, 2000, and in revised form Jul 17, 2000. Accepted
for publication Jul 18, 2000.
Pharmacokinetics and Pharmacodynamics
Address correspondence to Ronald J. DeBellis, Department of

Pharmacy, University Campus, 55 Lake Ave. N, Worcester, MA
01655, or e-mail: debellir@ummhc.org
In order to comprehend the disposition of medications in patients with renal failure, the clinician must
Copyright 2000 Blackwell Science, Inc.
273
274 Journal of Intensive Care Medicine Vol 15 No 6 November/December 2000
apply general pharmacokinetic and pharmacodynamic principles in order to construct an effective

and safe medication regimen. Pharmacokinetics describes the processes influencing a drugs transport
through the body to its site of action. The processes
affecting a drugs transport through the body are
absorption, distribution, metabolism, and elimination (ADME). Clinical pharmacokinetics is the application of these principles to individualize drug
therapy based on patient-specific information with
the goal of maximizing therapeutic outcomes while
minimizing the risk of toxicity. Pharmacodynamics
describes the relationship between a drugs concentration at the site of action and the ensuing pharmacologic response. The relationship between
pharmacokinetics and pharmacodynamics can be
described as the dose of a drug that provides a sufficient drug concentration at the site of action in order
to elicit a biologic response (Fig 1). There are many
factors in critically ill patients with renal failure that
will alter the pharmacokinetics and pharmacodynamics of drugs and necessitate modification of the drug therapy regimen. Before we discuss
the changes that occur in critically ill patients with
renal failure, we will briefly review pharmacokinetic
models and pharmacokinetic terminology.
Pharmacokinetic Models
Many mathematical models and equations have
been developed to describe pharmacokinetic processes. The aim is to focus on concepts and ideas
that will provide the practitioner with an understanding of pharmacokinetics as it relates to drug
dosing in the critically ill patient.
Compartmental models are methods to mathematically describe and conceptualize pharmacokinetic processes. A drug can be described in terms
of a one-, two-, or multicompartment model. Onecompartment models do not precisely represent the
pharmacokinetics of most drugs, but the equations
used to describe one-compartment models are clinically most useful. Two- and multicompartment
models more accurately describe the pharmacokinetics of most drugs, but the equations needed to
describe these models are very complex and are
not clinically practical. We will review the concepts
of a one-compartment model because the concepts
are clinically useful and they can be applied to twoand multicompartment models.
In a one-compartment model, the drug enters
the central or vascular compartment either by direct
intravenous injection or by other routes requiring
absorption. Drugs administered intravenously will
have 100% bioavailability or 100% of the administered dose reaches the systemic circulation. Bioavailability refers to both the rate and extent of
absorption and is defined as the relationship between the total amount of drug and how fast that
drug is absorbed from a nonintravenous route compared to the same dose administered intravenously.
Drug absorption can occur through many different
membranes including the gastrointestinal tract,
skin, subcutaneous or intramuscular tissue, lungs,
or any other membrane. The bioavailability of drugs
Fig 1. The relationship between pharmacokinetics and pharmacodynamics.

(Adapted from Chernow B, ed. Critical care pharmacotherapy. Baltimore: Williams & Wilkins, 1995:4.)
DeBellis et al.: Drug Dosing in Renal Failure 275
administered by any route requiring absorption can

be highly variable. Once a drug is in the central
compartment, it can bind to plasma proteins, primarily albumin or 1-glycoprotein, and may be pH
dependent. The drug will then achieve a state of
equilibrium between the unbound and bound state.
Only unbound or free drug is available to exert a
pharmacologic effect, and to be metabolized and/
or eliminated. Unbound drug is primarily metabolized and eliminated from the central compartment
via the liver and kidneys, the major metabolic and
elimination pathways (Fig 2).
In two- and multicompartment models, all the
same processes of a one-compartment model
occur, but the drug will also distribute to peripheral
compartments such as adipose tissue, muscle tissue, or the central nervous system. When the
amount of unbound drug going into and coming
from various compartments is equal, a state of equilibrium is achieved. The phase where drug is
achieving a state of equilibrium between compartments is called the distribution phase. Similar to
one-compartment models, unbound drug in the
central compartment is often metabolized and eliminated through the liver and kidney, though some
drugs can be metabolized and/or eliminated in peripheral compartments as well.
Zero- and First-Order Kinetics

Most drugs used in critically ill patients will follow
principles associated with first-order or linear pharmacokinetics, however, some drugs demonstrate
zero-order or nonlinear kinetics. For example, phenytoin follows zero-order pharmacokinetic principles or MichaelisMenten kinetics. Drugs are
described as exhibiting zero-order pharmacokinetics when a constant quantity or amount of drug is
removed per unit of time. As the plasma concentration of the drug decreases or increases, the quantity
or amount eliminated remains the same. Zero-order
kinetics is a result of metabolism by a saturated
enzyme system eliminating drug at a constant rate
despite the serum concentration of the drug. Clinically this means small increases in the drugs dose
can lead to large increases in the plasma concentration, hence the term nonlinear pharmacokinetics
(Fig 3). Because there are few drugs that follow
zero-order pharmacokinetics, attention will be directed toward drugs following principles of firstorder or linear pharmacokinetics.
Medications that demonstrate first-order or linear
pharmacokinetics eliminate or dispose of a constant
percentage of drug from the plasma per unit of
Fig 2. Compartmental drug model.

a
Drugs administered intravenously enter the central compartment directly.
b
Drugs administered by any route other than intravenously must be absorbed before entering the central compartment.
c
Distribution to peripheral compartments only occurs in two or multicompartment models.
d
In a one-compartment model, drug interacts with its receptor directly from the central compartment.
Fig 3. Effect of increasing daily dose on average steadystate drug concentrations for drugs undergoing nonlinear
or zero order pharmacokinetic modeling (
). Effect
of increasing daily dose on average steady-state drug
concentrations for drugs undergoing linear or first order
pharmacokinetic modeling ( _ _ _ _ _ ).
time required for a drug to reach equilibrium between the central and peripheral compartments.
Drug such as gentamicin demonstrate an alpha
elimination phase. It is this phase that is important
in causing acute tubular necrosis. This is important
to keep in mind because most drugs take time to
distribute. When drawing blood levels, it is important to know the time required for the distribution phase to complete. Obtaining plasma drug
concentrations prior to completion of distribution
will yield falsely elevated levels. This will ensure
clinical decisions are not made on falsely elevated
drug levels that have not fully distributed to other
tissues. Once distribution is complete, the slope
changes and is referred to as the beta or elimination
phase. The slope of the elimination phase is the
elimination rate constant (Kel) and can be used to
determine the drugs half-life (t1/2).
Half-Life
time. As the plasma concentration increases, the
amount of drug eliminated increases (a directly proportional relationship). As the plasma concentration decreases, the amount of drug eliminated
decreases. In a clinical sense, if the dose of a drug
is increased, the plasma concentration increases
proportionally as well as the amount eliminated
(Fig 3). Regardless of the plasma concentration, the
percentage that is eliminated remains constant. If
the logarithm of the plasma concentration versus
time for a drug is plotted, one will see two different
slopes (Fig 4). The upper portion is referred to as
the alpha or distribution phase and represents the
Fig 4. Logarithm of plasma concentration (Cp) versus

time plot for a drug following rapid intravenous injection
delineating both the alpha distribution and beta elimination phase.
A drugs half-life (t1/2) is a constant value determined

by the function of the metabolizing and eliminating
processes. The definition of a drugs half-life is the
amount of time required for the concentration of
the drug to decrease by 50%. Half-life is often expressed in minutes or hours. The half-life of a specific drug will remain the same as long as the
function of the metabolizing and eliminating processes remains constant. For example, if it takes 8
hours for the plasma concentration of a drug to
decline from 10 mg/L to 5 mg/L, the plasma halflife is 8 hours. If, however, there is a change in
renal function, the half-life can be significantly prolonged.
The half-life of a drug can be used to determine
the time required for a drug to be eliminated from
the body, as well as the time required to reach
steady state. From a pharmacokinetic perspective, it takes three to five half-lives to achieve
87.596.875% of steady-state drug concentration
(the point where the amount of drug going into the
body equals the amount being eliminated). Concurrently it takes the same period of time for a drug
to be 87.596.875% eliminated from the body. This
is important since a clinician should generally wait
for steady state prior to drawing a blood level or
increasing the dose of a medication. Knowing how
long it will take before a drug is almost completely
removed can help a clinician judge how long it
should take for a pharmacologic or toxic effect to
wear off [15]. It is important for a clinician to keep in
mind that the pharmacodynamic behavior of some
drugs may correlate with pharmacologic activity
regardless of pharmacokinetic drug behavior. Some
drugs can stay at receptor sites and have pharmacologic activity long after the plasma concentration
has decreased. For example, consider the extended
spectrum macrolide antibiotic azithromycin. A patient generally requires 5 days of therapy for most
infections, however, administration of this drug for
5 days is the same as receiving 910 days of therapy
from other antimicrobial agents. Understanding a
drugs pharmacokinetic and pharmacodynamic
profile is necessary to appropriately use its halflife to dose and assess the response in critically ill
patients with renal failure.
Elimination Rate Constant

As mentioned earlier, most drugs follow first-order
models of elimination. The elimination rate constant (Kel) determines the rate of elimination from
the body. With first-order elimination, a constant
percentage of drug is removed from the plasma per
unit of time and is often expressed as per minute
or per hour. The elimination rate constant for a
drug can represent total body elimination (Kel) or
it can be broken down into the specific organs
responsible for elimination, such as renal (Kr) or
metabolic (Km) [15]:
Kel Kr Km.
(1)
The elimination rate constant for a drug can be

determined by plotting the logarithm of the drug
plasma concentration (Cp) over time (t) and determining the slope of the line after distribution has
occurred (Fig 4). The following equation describes
linear or first-order elimination [15]:
Cp(0) Cp(t)e(Kel)(t).
(2)
Cp(0) is the plasma concentration of the drug at

time zero, Cp(t) is the plasma concentration of the
drug at time (t), and (Kel) is the elimination rate
constant. The elimination rate constant is also inversely proportional the drugs half-life (t1/2) [15]:
t1/2 0.693/Kel.
The volume of distribution is most commonly

expressed in terms of liters (L) or liters per kilogram
(L/kg). It is important to remember that the volume
of distribution is a theoretical volume, not a physiological volume. For example, if a 700 mg dose of
a drug administered intravenously to a 70 kg patient
results in a calculated maximum plasma concentration of 7 mg/L, it appears as if the drug is dissolved
in 100 L of fluid. The volume of distribution would
be 100 L or 1.429 L/kg. Obviously under normal
physiologic conditions, a 70 kg adult does not have
100 L of fluid in their body. A drug can have such
a high volume of distribution as a result of plasma
protein binding and/or distribution to other compartments (intracellular space, lipid compartments,
muscle). Protein binding or distribution to peripheral compartments leads to a larger volume of distribution by reducing the amount of measurable drug
in the plasma. Drugs that are not highly bound to
proteins and/or drugs that do not distribute out of
the central (vascular) compartment will tend to
have lower volumes of distribution closer to the
intravascular volume.
In clinical situations it is difficult to calculate a
drugs volume of distribution. The equation above
assumes an intravenous bolus of a drug, instantaneous distribution, and the maximum plasma concentration that immediately results. This cannot be
accomplished in clinical situations. The maximum
plasma concentration (Cpmax) has to be calculated
or back-extrapolated from a measured peak plasma
concentration (Cppeak). The following equation is
commonly used to calculate Cpmax [15]:
Cpmax measured Cp/e (Kel)(t).
(5)
The time (t) is the time difference between when

the dose was administered and when the peak
plasma concentration (measured Cp) was drawn.
Clearance
The volume of distribution (Vd) is a parameter relating the dose of a drug to the maximum plasma
concentration (Cpmax) [15]:
Clearance (Cl) is the term describing the volume

of fluid cleared of drug over time, usually in milliliters per minute. Total body clearance (ClTB) represents all the processes involved in removing a drug
from the body. Clearance can be broken down into
the individual organs or processes that are responsible for the elimination of drug from the body, such
as renal clearance (ClR), metabolic clearance (ClM),
or any other process that eliminates drug (ClX) from
the body. Total body clearance is the sum of all the
clearance processes in the body [15]:
Cpmax dose/Vd or Vd dose/Cpmax.
ClTB ClR ClM ClX.
(3)
The rate of elimination and half-life are constants

and do not change unless the function of the metabolizing and/or eliminating processes change.
Volume of Distribution
(4)
(6)
Clearance through an organ is determined by the

blood flow to the organ (Q) and the extraction
ratio (ER) for the organ. Blood flow to the organ
is expressed as a unit of volume per time, often
milliliters per minute. The extraction ratio is the
percentage or fraction of drug removed from the
blood as a result of passing through the organ and
has no units. The extraction ratio depends on the
fraction of free drug presenting to the organ, the rate
of blood flow through the organ, and the intrinsic
ability of the organ to eliminate drug [15]:
Cl (Q)(ER).
(7)
Changes in blood flow to the organ responsible

for clearing the drug or any factor altering the extraction ratio of a drug will alter a drugs clearance.
For example, a patient experiencing septic or cardiogenic shock may have impaired blood flow to
the liver or kidneys impairing the clearance of a
particular drug. In addition, if a pharmacologic vasopressor is added to the therapy, blood flow to
the gastrointestinal tract may be compromised, resulting in a decreased transport of drug to target
site. Clearance is also equal to the product of the
elimination rate constant (Kel ) and the volume of
distribution (Vd ) [15]:
Cl (Kel)(Vd).
Glomerular Filtration
Plasma flow to the kidney is approximately 650700
ml/min in a healthy adult. Of this amount, about
20% is filtered at the glomerulus. Glomerular filtration is the most common means of drug excretion
by the kidneys [1618]. Drug excretion via glomerular filtration is a passive, first-order process. Drug
excretion is a function of the glomerular filtration
rate (GFR) and the percentage of free unbound
drug. The unbound drug is filtered through pores
in the glomerular capillaries called fenestrae. The
pores in the glomerular capillaries are much larger
than pores found in other capillaries, making them
much more permeable to solutes. The GFR for an
average healthy adult is 100125 ml/min [1618].
The GFR depends on the hydrostatic pressure or
renal plasma flow and osmotic pressure gradients
between the glomerulus and Bowmans capsule.
There are many factors influencing the amount of
drug filtered at the glomerulus. Table 1 lists these
factors and how they influence drug filtration.
Effects of Impaired Glomerular Filtration

on Drug Elimination
(8)
Using pharmacokinetics to calculate Kel and Vd, it

is possible to calculate a drugs clearance from the
body. Again, it is easy to see that changes in the elimination rate constant and/or volume of distribution
will affect a drugs clearance from the body.
Renal Drug Excretion

The kidney is the primary organ responsible for the
excretion of drugs and their metabolites. The three
main processes by which the kidney excretes drugs
include glomerular filtration, tubular secretion, and
tubular reabsorption.
Impairment of glomerular filtration can lead to a

clinically significant accumulation of drug and/or
its metabolites. To assess the likely impact of decreased glomerular filtration, it is important to know
what fraction of a drug is renally eliminated, as well
as the excretion method for any active or toxic
metabolites [16,17]. Drugs excreted primarily by
glomerular filtration will be filtered at a rate that is
proportional to the patients GFR (first order) and
the percentage of free drug in the plasma, since
only free, unbound drug can be filtered:
Rate of
(GFR) (free drug in plasma) (9)
drug filtration
Table 1. Factors Influencing Glomerular Filtration of Drugs [1618]

Factor
Effect on Glomerular Filtration
Hydrostatic pressure
Plasma protein binding
Volume of distribution
Molecular size
Drug filtration decreases as hydrostatic pressure decreases

Drug filtration decreases as plasma protein binding increases
High volume of distribution decreases the amount of drug available to be filtered
Drug filtration decreases as molecular size increases (MW less than 5 kDa and
radii less than 15 A)
Drug filtration increases as membrane integrity decreases
Drug filtration decreases as the number of functioning nephrons decreases
Glomerular integrity
Number of functioning nephrons
For example, if a drug is excreted solely by filtration and the GFR decreases by 50%, drug excretion
will also decrease by 50%. There are many mechanisms by which GFR is altered. Table 2 summarizes
the major factors and mechanisms.
Tubular Secretion
As mentioned before, 20% of the plasma flow is
filtered at the level of the glomerulus. The remaining 425600 ml/min of renal plasma flow not
filtered at the glomerulus is directed to the peritubular capillaries, where drugs may be secreted. Tubular secretion is an active process where drugs are
transported by membrane proteins from the interstitial fluid surrounding the proximal tubule and secreted into the lumen. Tubular secretion rate
depends on the intrinsic activity of the transporter,
proximal tubule blood flow, and the percentage of
free or unbound drug. There are two main transport

systems for drugs in the proximal tubule. One transport system is for anions and the other transport
system is for cations [16,2227]. These secretory
transport systems are not fully understood and there
may be more than one transport subtype for each
system responsible for eliminating different substances. Drugs can compete for secretion with other
drugs and endogenous substances secreted by the
same transporter, since they are saturable [2427].
An example of competition for secretion via an
anionic transporter is probenecid with penicillins
or cephalosporins [28]. This combination has been
used to prolong the half-life of penicillin. Table 3
is a list of drugs actively secreted by the kidney.
It is difficult to study drug secretion interactions
because most drugs are metabolized and eliminated
by multiple processes. This makes it difficult to
study the effects of secretion alone with all these
other processes occurring simultaneously. Studies
Table 2. Factors Affecting Glomerular Filtration in Critically Ill Patients with Renal Failure [1821]
Factor
Mechanism
Cardiac output
Decreased cardiac output leads to decreased GFR. Homeostatic mechanisms attempt

to maintain blood flow to the heart, brain, and muscle at the expense of the
kidney.
Decreased plasma flow to the kidney resulting in proportional decrease in GFR.
Increased permeability results in increased clearance rate of protein bound-drugs.
For example, with membrane permeability in nephrotic syndrome the glomerular
basement membrane loses negative charge, allowing albumin and other large
molecules to cross the barrier.
Tubular blockage with casts, cellular debris, or cellular swelling leading to decreased
GFR.
Decreased GFR with luminal fluid back-leak into the interstitium and renal venous
blood; caused by damaged epithelium in moderate to severe acute renal failure.
Decreased GFR due to either afferent arteriolar vasoconstriction or efferent arteriolar
capillary hydraulic pressure vasodilation.
Decreased GFR by drug-mediated prostaglandin inhibition.
Renal plasma flow

Glomerular basement
Renal tubule obstruction

Reabsorption via back-leak
Decreased glomerular filtration
Drug induced
Table 3. Drugs Secreted by Anionic and Cationic Transport Systems [2227]

Organic Anion Transport
Acyclovir
Acetazolamide
Captopril
Cephalosporins
Folic acid
Furosemide
Moxalactam
Nafcillin
Penicillin G
Phenobarbital
Sulfonamides
Thiazides
Organic Cation Transport
Acetylcholine
Amantadine
-blockers
Cimetidine
Ephedrine
Epinephrine
Methadone
Morphine
Procainamide
Pseudoephedrine
Serotonin
Ampicillin
Cisplatin
Ibuprofen
Naproxen
Probenecid
Uric acid
Ascorbic acid
Clofibrate
Indomethacin
Nitrofurantion
Quinolones
Zidovudine
Benzylpenicillin
Ethacrynic acid
Methotrexate
Oxalate
Salicylates
Amiloride
Creatinine
Ethambutol
Nicotine
Quinidine
Amphetamines
Digoxin
Famotidine
Norepinephrine
Quinine
Atropine
Disopyramide
Metformin
Pindolol
Ranitidine
evaluating changes in drug elimination in renal failure look at changes in total body clearance and/or
increases in blood concentration rather than excretion changes via secretion alone [2426].
Pharmacokinetic Changes in Critically Ill

Patients with Renal Failure
There are many physiological changes that can
occur in a critically ill patient that will alter the
pharmacokinetics of drugs. Overall, studies looking
at specific pharmacokinetic changes in drugs in
critically ill patients are limited. Most pharmacokinetic studies are performed in healthy volunteers
or in patients with a specific disease state who are
not critically ill. Critically ill patients are very dynamic and often have multiple organ dysfunction
or age-specific parameters potentially altering all
aspects of drug therapy. Some ADME changes that
can occur in critically ill patients, specifically those
with renal failure, will be addressed.
Effects of Impaired Tubular Secretion on

Drug Elimination
Tubular secretion is an extremely efficient process
that is capable of eliminating relatively large
amounts of drug substances from the blood in a
short period of time [27]. When drugs are excreted
from the body via tubular secretion, the rate of drug
clearance is greater than drug clearance via filtration
[26]. A decline in renal function impacts tubular
secretion, as both endogenous and exogenous organic acids and bases accumulate and compete for
transporters. This competition for the transporters
required for active secretion may lead to either drug
toxicity or lack of efficacy, however, it is not possible to predict which is most likely to occur or the
extent of the interaction [19].
Absorption
There is a lack of abundant discussion concerning
drug absorption in patients with renal failure [30].
Drug absorption in patients with renal failure may
be altered secondary to gastrointestinal edema,
nausea and vomiting due to uremia, and delayed
gastric emptying [31,32]. Comorbid illnesses or conditions that commonly occur with renal disease
such as diabetic gastroparesis may also have a
significant effect on drug absorption. Patients receiving peritoneal dialysis may experience complications leading to peritonitis, which has been
shown to decrease gastrointestinal peristalsis, thus
impairing the absorption process [19].
In general, the average number of medications
taken by a patient in renal failure is eight [33,34].
This setting provides the framework for multiple
drug interactions. Specific drug interactions involving decreased absorption secondary to chelation
manifest in patients taking phosphate binding antacids containing aluminum or calcium. Other enterally administered medications need to be spaced
around the antacid by at least 2 hours to minimize
chelation. Although these antacids are administered
for the sole purpose of phosphate binding in renal
failure patients, a subsequent increase in gastric pH
Tubular Reabsorption
Tubular reabsorption of drugs can occur by active
and/or passive processes. When ultrafiltrate passes
through the nephron, up to 99% of the filtered volume is reabsorbed. This can lead to a dramatic
increase in a drugs concentration in the tubule
as the volume decreases. This high concentration
gradient of drug between the renal tubule and
plasma promotes passive diffusion from inside the
tubule into the plasma. The properties that effect
passive tubular reabsorption are listed in Table 4.
Altering urine pH has long been used to decrease
the amount of drug reabsorbed and enhance excretion. Alkalinizing the urine can be used to enhance
the elimination of barbiturates (weak acids) by increasing the fraction of ionized drug, which decreases the amount available for reabsorption [29].
Table 5 lists some drugs with pH-dependent elimination.
Table 4. Factors Influencing Tubular Reabsorption [16,22,26]

Factor
Effect on Tubular Reabsorption
Lipid solubility of the drug

Degree of ionization of the drug
Urine pH
Urine flow
Concentration gradient
Increased reabsorption with increased lipid solubility

Decreased reabsorption with increased ionization
Variable depending on if drug is acidic or basic
Decreased reabsorption as urine flow increases
Increased reabsorption as concentration gradient increases
Table 5. Drugs with pH-Dependent Elimination [16]

Weak Acids
Weak Bases
Phenobarbital
Salicylates
Sulfonamides
Amphetamines
Ephedrine
N-acetylprocaninamide
Procanamide
Pseudoephedrine
Quinidine
Tocanide
Tricyclic antidepressants
occurs [19]. The elevated gastric pH may impair the

dissolution process of other enterally administered
medications, leading to incomplete drug absorption, particularly with acidic drugs. In addition, the
onset of drug action may be delayed secondary to
decreased gastric emptying. The effects of enterally
administered analgesics are often impaired in this
situation. Caution must be exercised in renal failure
patients with concomitant diabetic gastroparesis.
Metoclopramide or erythromycin are frequently administered to enhance the motility of the gastrointestinal tract. When these agents are administered,
enteral absorption of medications is often decreased due to an increase in gastrointestinal transit
[35].
Bioavailability studies, for the most part, are lacking in critically ill patients. Most bioavailability studies are conducted in healthy adults versus critically
ill patients, however, it is known that in a majority
of medications, the bioavailability in patients with
renal failure is either unchanged or increased
(Table 6).
Distribution
Altered plasma protein binding in critically ill patients with renal failure can significantly change
drug distribution. Drugs that bind to plasma proteins exist in a state of equilibrium between
unbound (free) and bound drug (not free), and
since the unbound drug exerts a pharmacologic
effect, decreased binding increases the amount of
drug available to exert a pharmacologic effect and
therefore increases the risk of toxicity. Drug-drug
interactions can occur when two highly plasma protein-bound drugs compete for binding with the
same plasma protein. A drug is considered to be
highly plasma protein bound when more than 90%
is bound to plasma proteins. Drugs that are bound
to plasma proteins less than 90% are not considered
to be clinically significant binders. Anionic or acidic
drugs tend to bind to albumin, while cationic or
basic drugs tend to bind to 1-glycoprotein. Drugs

like warfarin, phenytoin, valproic acid, and salicylates are highly bound to albumin and can lead to
displacement-mediated drug interactions if administered together [4345]. Even though drug displacement interactions occur, their clinical significance
tends to be low. Drug-drug interactions do not
occur primarily due to alteration in plasma protein
binding, but they also occur in patients with poor
renal function due to changes in the configuration
of albumin [4648]. For example, the pharmacodynamic effects of phenytoin and warfarin are increased in patients with renal failure. The decreased
binding of drugs to albumin in patients with renal
failure is thought to be due to the accumulation of
small acidic molecules displacing these drugs from
binding sites or alterations in binding sites on the
albumin molecules [49,50]. Critically ill patients
often have low albumin due to malnutrition and/
or acute illness [52]. This can lead to higher free
fractions of drugs and potentially increase the risk
of toxicity. Drugs binding to 1-glycoprotein appear to be less affected in critically ill patients with
renal failure, even though it is an acute-phase reactant that increases with trauma, surgery, or acute
illness [49]. Any of these protein binding changes
may alter a drugs volume of distribution. For example, if plasma protein concentrations experience a
sudden decrease, and a patient is taking warfarin,
the volume of distribution for that medication becomes significantly smaller since warfarin is bound
to plasma proteins more than 90%. This occurrence
becomes significant by having warfarin exert more
of a pharmacodynamic effect by having less drug
bound to proteins that may result in an adverse
event such as bleeding.
In addition, fluid status can be highly variable in
a critically ill patient with renal failure, leading to
changes in a drugs volume of distribution. Accumulation of fluid in renal failure patients can result in
lower drug concentrations [52]. The clearance of
drugs can be affected by changes in the volume
Table 6. Bioavailability of Drugs in Patients with Renal

Disease [19,2932,3642]
Decreased
Unchanged
Increased
D-Xylose
Furosemide
Pindolol
Cimetidine
Ciprofloxacin
Codeine
Digoxin
Labetalol
Trimethoprim
Sulfamethoxazole
Bufuralol
Dextropropoxyphene
Dihydrocodeine
Oxprenolol
Propranolol
Tolamolol
Adopted from [23].
of distribution and protein binding by altering the

amount of unbound drug available to be metabolized and/or eliminated. Despite the potential for
many changes in the distribution of drugs in critically ill patients with renal failure, it is often difficult
or impossible to predict these interactions. It is important for the clinician to be aware of the potential
for interaction and monitor for the signs of efficacy
and toxicity so interactions are recognized and corrected.
Metabolism
Most drug dosage changes in patients with renal
failure are necessary due to reduced renal elimination, however, some drugs can have altered metabolic elimination due to renal failure. The kidneys
have been found to have many drug metabolizing
systems, and it is likely that renal disease alters
renal drug metabolism as well as hepatic metabolism [5356]. The exact mechanisms are not completely defined, but one study suggested drugs
oxidized by the cytochrome P-450 2D6 isozyme are
more likely to be affected [57]. The clinical significance of these effects in critically ill patients with
renal disease remains to be further explored. Critically ill patients often have impaired metabolic
function from nonrenal causes; either from direct
damage to the liver (cirrhosis), decreased blood
flow to the liver (shock, elderly), or as a result
of other medications that are enzyme inhibitors or
inducers [5860]. Clearance flow extraction
ratio (Equation 7) mathematically delineates this
concept. Careful drug dosing and monitoring is essential to ensure drug therapy is achieving the
desired pharmacologic effects without causing adverse events.
Elimination
Studies to determine drug pharmacology and clearance in critically ill patients are usually performed
on patients undergoing anesthesia. Occasionally
the study population includes patients with chronic
disease to one organ that is stable. It is therefore
difficult to apply these study results to critically
ill patients with unstable, multiple organ disease.
Critically ill patients each have a unique combination of factors that can affect renal drug clearance
[61]. In addition to renal failure, which is relatively
common in this patient population, the impact of
other organ dysfunction such as liver, cardiovascular, or respiratory failure, as well as malnutrition,
must be assessed [62,63].
Acute renal failure is often accompanied by metabolic acidosis and respiratory alkalosis. Depending
on the pKa value of drugs, the pH difference between plasma and tissue compartments may alter
the ionization of drug molecules and therefore affect tissue redistribution versus clearance [64]. Renal
failure also impacts total body water and therefore
drug volume of distribution. Patients who have a
low level of serum albumin via decreased hepatic
synthesis, protein loss through increased vascular
permeability, or malnutrition will have a corresponding decrease in plasma protein binding of
drugs [65]. This can lead to an increase in clearance
of drugs that are normally highly plasma protein
bound. Plasma protein binding can also be reduced
in conditions such as the nephrotic syndrome, proteinuria, conditions that alter the molecular structure of albumin, and with accumulation of uremic
toxins that compete with drugs for protein binding
sites [64,66].
Cardiovascular failure contributes to the reduction in renal drug clearance by two mechanisms:
reduction in cardiac output and therefore reduction
in renal plasma flow and increased hepatic congestion, and increased sympathetic drive leading to
shunting of blood away from the kidney in order
to protect blood flow to the heart, brain, and muscle. This reduction in the supply of oxygenated
blood may further affect drug clearance if anaerobic
metabolism and metabolic acidosis ensue, potentially causing changes in the ionization of drugs.
Retention of fluid may then increase the drug volume of distribution, further reducing drug clearance
[64,66]. Other conditions with profound vasodilation such as sepsis, systemic inflammatory response
syndrome (SIRS), multiple organ dysfunction syndrome (MODS), pancreatitis, and liver failure will
also cause a decrease in renal drug elimination due
to decreased GFR and renal plasma flow [65]. Patients with respiratory failure who are placed on
mechanical ventilation may have reduced cardiac
output (due to increased mean intrathoracic pressure) and volume of distribution changes, in addition to possible alkalosis or acidosis which can
affect drug disposition if clearance is pH sensitive
[65,66].
Principles of Drug Elimination Via Dialysis

Drug elimination via dialysis deserves specific attention since there are many variables unique to
dialysis that can affect drug clearance. Dialysis patients, on average, take more than eight different
medications [33,34]. It is therefore extremely important to adjust the drug dosing schedules cor-
rectly according to the degree, if any, of residual

renal function, together with the dialyzability of
the drugs. The way in which drug dosing should
optimally be adjusted depends on the particular
drug characteristics and the type of dialysis to be
used.
side of the membrane, a negative pressure on the

dialysate side, or a combination of the two [68]. In
our drug tables we provide dosing information for
hemodialysis (HD) and continuos arteriovenous/
venovenous hemodialysis (CAVHD/CVVHD). Information on drug dosing in peritoneal dialysis is
not included since this is not a common dialysis
modality in the critically ill patient population.
Types of Dialysis
There are two main types of dialysisdiffusive and
convectivewith many variations or combinations
of these principles (Table 7). Diffusive dialysis involves the system of dialysate and blood separated
by a semipermeable membrane, with selective
movement of substances down a concentration gradient. In this way drugs that are capable of being
dialyzed can be cleared from the blood, and electrolytes can be simultaneously replaced from the dialysate if needed. In convective dialysis, however,
solutes are removed from blood via solvent drag
that is independent of concentration gradients and
is not limited by drug molecule size. Conventional
hemodialysis describes a process that is primarily
diffusive with minimal convective losses, whereas
hemofiltration describes primarily convective solute clearance. The terms high efficiency and
high flux are used to indicate large membrane
surface area and pore size, respectively [67]. Hemodiafiltration indicates one-third convection and
two-thirds high-flux diffusion [34]. Ultrafiltration refers to removal of fluid volume from the patient
[68]. In arteriovenous dialysis the driving force is
the mean arterial pressure of the patient, whereas
for venovenous dialysis the system relies on the
use of a mechanical blood pump. The driving pressure for ultrafiltration is established by one of three
ways: a positive pressure gradient on the blood
Table 7. Types of Dialysis
Dialysis Types
Hemodialysis
Hemofiltration
Hemodiafiltration
Ultrafiltration
Conventional hemodialysis (HD)

Continuous arteriovenous
hemodialysis (CAVHD)
Continuous venovenous
hemodialysis (CVVHD)
hemofiltration (CAVH)
hemofiltration (CVVH)
hemodiafiltration (CAVHD)
hemodiafiltration (CVVHD)
Slow continuous ultrafiltration (UF)
Dialysis Drug Clearance

Drug clearance via hemodialysis can be estimated
as follows:
ClHD (Clurea)(60/MWdrug)
(10)
where ClHD is the drugs clearance by hemodialysis,

Clurea is the clearance of urea by the dialyzer (typically about 150 ml/min for standard dialyzers), and
MWdrug is the molecular weight of the drug [33]. If
a drug has negligible clearance via dialysis, then
a postdialysis replacement dose is not necessary;
however, if clearance is more efficient, then the
percentage of the drug removed is usually calculated and a replacement dose provided. In addition
to taking into account the amount of drug removal,
it is also important to consider the degree of residual
renal function of the patient, since additional dosage may need to be administered to take this into
account.
Components of Dialysis System and

Factors That Affect Drug Removal
There are three main components to the dialysis system: blood, dialysate, and membrane. Changes to
each of these will affect drug removal. Table 8 summarizes how drug removal is affected by changes to
the respective components [33,34,67,68]. Since information pertaining to drug dosing in patients receiving different types of dialysis is not always
available, assessing the patient-specific dialysis
method together with an analysis of the variables
discussed above should provide a basis from which
to make clinical decisions on drug dosing regimens.
Serum Drug Monitoring with Dialysis

If there is a known relationship between serum
drug level and efficacy/toxicity, serum drug monitoring can be a useful tool in drug dosing for dialysis
patients. If a replacement dose of drug is provided
postdialysis then an appropriate period of time
Table 8. Factors Affecting Drug Removal During Dialysis [33,34,6769]

Drug Characteristic
Comments
Molecular weight
Larger MW decreases the likelihood that the drug will pass through the dialyzer membrane,
depending on membrane type. This is one of the most predictive characteristics of a
drugs dialyzability. Generally if MW > 1,000 Da, then convection is required rather than
diffusion to clear the drug.
Increased PPB results in a decreased amount of free drug available for dialysis. Note that
with dialysis heparinization, lipoprotein lipase is induced which increases levels of free
fatty acids (FFA). These FFA compete with certain drugs for protein binding sites.
Drugs with a Vd < 1 L/kg are more likely to be dialyzed than those with a higher Vd,
providing the MW and PPB conditions are favorable. A drug with a Vd of 12 L/kg will
be marginally dialyzable, and > 2 L/kg is unlikely to be dialyzable.
Plasma protein binding
Volume of distribution
Membrane
Membrane type
Surface area
Dialyzer system
Flow rate
Duration of dialysis
Synthetic membranes tend to have higher ultrafiltration coefficients than those produced
from biologic materials. Modified biologic materials include cellulose and cuprane
derivatives. Synthetic materials include polysulfone, polycarbonate,
polymethylmethacrylate, and polyacrylonitile-based materials.
Increased surface area leads to increased efficiency of drug clearance. However, as the
MW increases drug clearance becomes more reliant on convection techniques rather
than diffusion.
An increase in dialysate flow rate to > 500 ml/min has only a modest increase in solute
clearance due to increased turbulence within the membrane.
Longer duration of dialysis increases the likelihood of clearance; however, reequilibration
of high Vd drugs must be considered.
MW molecular weight, PPB plasma protein binding, Vd volume of distribution.
must be established before measuring the drug

level to allow adequate tissue distribution. A peak
level is typically drawn 12 hours after oral drug
administration, and about 30 minutes after parenteral administration. A trough level is drawn at the
end of a dosing interval. For example, if a drug is
to be administered every 12 hours, a trough level
should be drawn after 11.5 hours from the time that
the dose was administered, or just prior to the next
dosage administration. In most instances, if a maintenance dose has been given, then care must be
taken to ensure that three to four doses are given
before checking the drug level to ensure a steadystate level is established [33]. However, by definition, steady state is based on the half-life of the
drug and the dosing schedule is partially based on
the half-life. Given this, steady state can occur well
before the third or fourth doses or well after. For
example, digoxin can be administered on a once
a day dosing interval. It takes 57 days to achieve
steady state with this drug, drawing a level after
the third dose will in fact not truly reflect steady
state. It is important to note that the drugs volume
of distribution must also be taken into account
when considering serum drug monitoring. Drugs
with a high volume of distribution (e.g., digoxin)
will be extensively distributed into tissues and
therefore are not available in the circulation for
clearance via dialysis. Thus intracellular drug con-
centrations may only decrease by 12% after

dialysis, with intercompartmental reequilibration
taking place after dialysis completion. This means
that if serum drug levels are monitored, it is important to allow sufficient time for reequilibration
before measuring the drug level, generally 4 hours
after hemodialysis is complete [69]. High ultrafiltration can increase the level of reequilibration rebound.
Measuring Renal Function

Assessing the degree of renal function in a critically
ill patient is a crucial step toward being able to
select appropriate medication dosages for drugs
that are renally eliminated. Since it is not possible
to directly measure the GFR, indirect measurements
to estimate GFR utilizing either exogenous or endogenous marker substances can be used. The
gold standard for estimating GFR is the measurement of clearance of an exogenous substance called
inulin. This sugar is considered to provide the most
accurate GFR estimation because it is filtered freely
through the glomerulus and is not subject to renal
metabolism, reabsorption, or secretion. Clinically
inulin is not commonly used because the administration technique is cumbersome and impractical.
An intravenous bolus followed by a maintenance
infusion is provided to maintain a certain plasma

concentration, and then serial venous blood and
urine collections are taken at specific time intervals
[69].
The alternative to using inulin in estimating GFR
is to utilize the endogenous substance, creatinine.
Creatinine is a product of muscle creatine decomposition. Daily, a constant rate of approximately
1.62.0% of the total amount of creatine (or approximately 20 mg/kg/day depending on age, gender,
diet, and physical condition) in the body is converted spontaneously to creatinine [70]. This constant production means that urinary excretion rate
varies by only a small amount in a healthy person.
In addition, creatinine is freely filtered across the
glomerulus. However, in contrast to inulin, creatinine undergoes a small degree of renal tubular secretion, which means that the use of creatinine as
a GFR estimation marker is considered to be less
accurate than inulin. Clinically, however, creatinine
is commonly used to estimate GFR because measurement of either serum or urine creatinine are
more practical. However, whether or not to measure creatinine in the blood or urine is subject to
practitioner debate. Traditionally a 24-hour urine
collection is conducted to measure the amount of
creatinine collected over this time period and assessed with serum creatinine levels taken at the
beginning and end of the 24 hours. The most common problem with this method is that urine collections are often incomplete, and therefore the
amount of creatinine collected is inaccurate. One
possible method to assess whether or not a urine
collection is complete is to compare the amount of

creatinine collected to the usual rate of production
of about 20 mg/kg/day to see how these two values
compare. Perhaps a more reliable method of measuring urine creatinine is to collect consecutive
carefully timed urine samples over time periods of
a couple of hours instead of 24 hours. However, a
shortened collection period may serve to increase
the inaccuracy in measuring urine volume if the
bladder is not completely emptied [70].
Since the early 1970s many researchers have developed nomograms or formulas to more easily
estimate GFR using serum creatinine without the
need to perform urine collections. There are many
equations available to clinicians, and some are less
cumbersome and more practical to use than others.
Six of the main methods used clinically to estimate
GFR, and therefore renal function in adults, are
outlined in Table 9, with the relative positive and
negative aspects of each of the formulas listed in
Table 10.
Clinically the Cockcroft and Gault equation (or
a variation of this equation) is the most commonly
used in both the clinical and research settings where
urine collection is not deemed practical or necessary. When utilizing the Cockcroft and Gault equation to determine creatinine clearance, the value
obtained is most likely an overestimation of the
GFR, because between 10 and 60% of creatinine
undergoes renal tubular secretion, and therefore
appropriate clinical judgment should be exercised
[7072]. It is also important to note that the Jaffe
reaction used to measure serum creatinine is based
Table 9. Equations Used to Estimate Creatinine Clearance [16,73]

Equation
Formula
CockcroftGault (males)a
CockcroftGault (females)a
Jelliffe (males)b
Jelliffe (females)b
Walsera,c
Mawer (males)a
Mawer (females)a
Mawer (males)a
Mawer (females)a
Wagner (males)a
Wagner (females)a
Hull (males)d
Hull (females)d
CrCl [(140 - age) IBW]/SCr 72

Male value 0.85
CrCl [98 - 16 (age - 20)/20]/SCr
Male value 0.90
(GFR)(3/ht2) a b(cr)1 c(age) d(wt)
CrCl TBW [29.3 - (0.203 age)]
CrCl TBW [25.3 - (0.175 age)]
CrCl IBW [29.3 - 0.203(age)][1 - 0.03(SCr)]/[14.4(SCr)]
CrCl IBW [25.3 - 0.175(age)][1 - 0.03(SCr)]/[14.4(SCr)]
Log CrCl 2.008 - 1.19 log SCr
Log CrCl 1.888 - 1.20 log SCr
CrCl 145 - age - 3/SCr
Male value 0.85
CrCl creatinine clearance; GFR glomerlar filtration rate; SCr serum creatinine; IBW ideal body weight (in kilograms); TBW
total body weight (in kilograms); IBW males 50 2.3(each inch > 60 inches); IBW females 45 2.3(each inch > 60 inches).
a
CrCl in ml/min.
b
CrCl in ml/min/1.73 m2.
c
For the Walser equation: a 6.66 (males) or 4.81 (females); b 7.57 (males) or 6.05 (females); c 0.103 (males) or
0.080 (females); d 0.096 (males) or 0.080 (females); cr SCr in millimoles; wt kilograms; ht meters.
d
CrCl in ml/min/70 kg.
Table 10. Positive and Negative Aspects of Equations Used to Estimate Creatinine Clearance [16,73]
Equation
Positive Aspects
Negative Aspects
CockcroftGault
Considered standard method for estimating

GFR
Not complicated, therefore rapid bedside
estimation of CrCl
Attempts to measure GFR and not CrCl
Overestimates GFR; does not consider nonrenal

clearance
No adjustment for body size, estimates CrCl,
urinary creatinine is constant
Number of variables and correlation factors
needed for each gender
Does not consider age, IBW, nonrenal clearance
Does not consider IBW and nonrenal clearance
Jelliffe
Walser
Wagner
Hull
CrCl creatinine clearance, IBW ideal body weight.
on the red color that is produced when creatinine is

complexed with alkaline picrate. Other substances
present in the blood sample such as glucose, protein, and ascorbic acid are also picked up by the
test and provide a reading that is approximately
15% higher than it should be. This inaccuracy can
serve to offset some of the overestimation of GFR
that is obtained when using the Cockcroft and Gault
formula [73].
Limitations of glomerular filtration estimates
using creatinine clearance calculations may exist in
certain patient populations. Patients who are elderly, cachetic, obese, fluid overloaded, or burned
require special attention. In these patients, body
weight may not accurately reflect true muscle mass
and/or creatinine production. In addition, clearance of aminoglycosides and vancomycin in patients with burns are often enhanced by extrarenal
mechanisms and may not correlate well with creatinine clearance [74].
Estimated creatinine clearance may change due
to many factors. One is diurnal fluctuations in serum
creatinine of up to about 25%, therefore it is desirable to measure serum creatinine at the same time
every day [73]. Certain drugs such as cimetidine,
trimethoprim, and probenecid can also affect creatinine clearance because they interfere with tubular
secretion [70]. Patient factors such as disease state
and age (i.e., production of creatinine via muscle
mass) need to be considered [17]. In addition, as
renal function declines, tubular secretion and GFR
are not altered at the same rate. A critically ill patient
may experience rapid changes in renal function,
making quantitative estimation of GFR extremely
difficult. The estimation of creatinine clearance by
the formulas listed assumes that creatinine production is stable and that extrarenal elimination of creatinine does not exist. A patient in renal failure does
not meet these assumptive criteria [68]. In addition,
there can be a considerable lag time between rapid
renal function decline and a reflection in increased
serum creatinine level [71].
The clinician should be aware of the limitations
of the currently available methods of GFR estimation and use of clinical judgment in order to assess
the level of renal function that will be assumed in
order to use the medication dosage tables in the
appendix.
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Appendix: Creatinine Clearance Calculated According to Cockroft and Gault
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Notes
Pharmacologic vasopressors
Dobutamine
(Dobutrex)
2.515 g/kg/
min titrate for
response
No change
No change
No change
No change
No change
Liver
metabolized;
increased doses
may lead to
more frequent
atrial and
ventricular
arrhythmias
Dopamine
(Intropin)
25 g/kg/min
(low); 510 g/
kg/min
(medium);
titrate for
response up to
50 g/kg/min
No change
No change
No change
No change
No change
Increased doses
may lead to
more frequent
atrial and
ventricular
arrhythmias
Epinephrine
(Adrenaline)
0.11 g/kg/
No change
min in refractory
hypotension;
210 g/min in
septic or
cardiogenic
shock; all doses
to be titrated for
response
No change
No change
No change
No change
Used as a
second- or thirdline agent in
refractory
hypotension
Isoproterenol
(Isuprel)
210 g/min;
titrate for
desired heart
rate
No change
No change
No change
No change
No change
5080% of drug
is excreted
renally, no dose
adjustment data
available [76]
Norepineprhine
(Levophed)
212 g/min;
titrate for blood
pressure
No change
No change
No change
No change
No change
Doses may
drastically
exceed 12 g/
min; titrate to
desired blood
pressure [78]
Phenylephrine
(Neosynephrine)
2560 g/min;
titrate for blood
pressure
No change
No change
No change
No change
No change
8086%
excreted
renally; no data
on dose
adjustment [79]
0.75 mg/kg
load; 510 g/
kg/min; titrate
for effect
No change
No change
0.37 mg/kg
load; 2.55
g/kg/min;
titrate for
effect
No data
No change
40% of
amrinone is
excreted
unchanged in
urine [78]
Inotropes
Amrinone
(Inocor)
Appendix: Continued
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
IV 0.41 mg/day
LD, 0.1250.375
mg/day MD; PO
0.751.25 mg/
day LD,
0.1250.375 mg/
day MD (IV and
PO loading
doses are to be
administered
every 68 hr)
Same LD; IV/

PO MD
0.1250.375 mg
every 36 hr
Same LD; IV/

PO MD
0.1250.375 mg
every 36 hr
0.625 mg LD; No
IV/PO MD
supplement
0.1250.375
for HD
mg every 48
hr
Normal LD; IV/

PO MD
0.1250.375 mg
every 36 hr
Glucagon
15 mg IV bolus
every 3060
min, or 110
mg/hr IV
infusion
No change
No change
No change
No change
No change
Milrinone
(Primacor)
5075 g/kg
load over 10
minutes,
0.3750.75 g/
kg/min infusion
based on clinical
response
0.330.43 g/
kg/min based
on CrCl 3050
ml/min,
respectively
0.230.28 g/
kg/min based
on CrCl 3050
ml/min,
respectively
2550 g/kg
load, 0.19
0.56 g/kg/
min infusion
based on
clinical
response
No data
Use normal
dose
85% of dose
eliminated
unchanged in
urine within 24
hr [80]
Drug
Normal Dose
Digoxin
(Lanoxin)
Notes
The Vd of
digoxin can
decrease by up
to 50% in
patients with
renal failure,
necessitating
dose adjustment
[80]
Preload reducers (diuretics/nitrates)

Acetazolamide
(Diamox)
500 mg IV 1
dose
No change
No change
Not effective
Not effective
Not effective
Use in
nonchloride
responsive
metabolic
alkalosis [81]
Amiloride
(Midamor)
520 mg/day
PO
2.510 mg/day
PO
2.510 mg/day
PO
Not effective
Not effective
Not effective
Diuretic effect
plateaus when
doses exceed 40
mg/day [82]
Bumetanide
(Bumex)
12 mg IV every No change
812 hr or 1 mg
bolus followed
by 0.912 mg/hr
continuous
infusion 12 hr
No change
810 mg PO No change
or IV single
dose; or an
infusion of 12
mg over 12 hr
yields
maximal
response
No change
Maximum dose
not to exceed 10
mg intermittent,
or 12 mg/
infusion/24 hr in
patients with
normal renal
function
Chlorothiazide
(Diuril)
0.51 g IV every No change

1224 hr
No change
Not effective
Not effective
Not effective
Thiazide
diuretics are not
recommended
for use alone
where CrCl is
<30 ml/min;
demonstrate
synergism with
loop diuretics in
renal failure
Ethacrynic acid
(Edecrin)
50100 g IV
every 8 hr
50100 mg IV
every 812 hr
Do not use
Do not use
Do not use
Ototoxicity
prevalent in
patients with
GFR <10 ml/min
[83]
Furosemide
(Lasix)
4080 mg IV
No change
every 12 hr;
higher doses
may be required
for desired urine
output
No change
No change
Not effective
Not effective
Doses up to
1,500 mg/day IV
have been used
and are
recognized as
such in the
package insert;
continuous
infusion may
also be used
50100 mg IV
every 812 hr
Appendix: Continued
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
No change
No change
Not effective
Not effective
Not effective
Isosorbide
dinitrate (Isordil)
1040 mg PO tid No change
No change
No change
Administer
1040 mg PO tid Dose alteration
dose after HD
not necessary in
renal failure [84]
Metolazone
(Zaroxylyn)
520 mg/day
PO
No change
No change
No change
Not effective
Not effective
Nitroglycerin
(Nitro Bid,
Nitrostat, Nitrol,
Nitrodur)
Many methods
and routes of
dosing
No change
No change
No change
Guidelines
not
determined
No change
Spironolactone
(Aldactone)
25200 mg/day
PO in 24
divided doses
for edema;
50100 mg/day
for essential
hypertension;
100 mg/day PO
to start, increase
to 200400 mg/
day PO in 24
divided doses
for ascites
12.5100 mg PO 12.5100 mg PO Not effective

every 24 hr
every 24 hr
Not effective
Not effective
Use should be
avoided in
patients with
GFRs <10 ml/
min; risk of
increased
potassium
Torasemide
(Demadex)
1020 mg IV/PO
every 24 hr,
doses may be
titrated for
clinical
response
No change
No change
No change
Not effective
Not effective
Doses should
not exceed 200
mg/day
Triamterene
(Dyrenium)
50100 mg PO
bid
No change
No change
Not effective
Not effective
Not effective
Avoid in
patients with
serum
creatinine >2.5
mg/dl; risk of
hyperkalemia
520 mg PO
every 24 hr
520 mg PO
every 24 hr
520 mg PO
every 24 hr
520 mg PO
every 24 hr
Maximum dose
should not
exceed 40 mg;
fixed doses of
benazepril and
amlodipine
together should
not be given to
patients with
SCr >3.0 mg/dl
Drug
Normal Dose
Hydrochlorothiazide
(Hydrodiuril)
2550 mg PO
bid for
hypertension;
25200 mg/day
PO in 13
divided doses
for edema
Notes
Hydrochlorothiazide should
not be used in
patients with
SCr >2.5 mg/dl
Although
thiazides may
not be effective
in renal failure,
metolazone has
demonstrated
efficacy with
GFRs at 20 ml/
min
Angiotensin converting enzyme (ACE) inhibitors

Benazepril
(Lotensin)
1040 mg PO
every 24 hr
520 mg PO
every 24 hr
Captopril
(Capoten)
25100 mg PO
every 8 hr
18.7575 mg PO 18.7575 mg PO 12.550 mg

every 1218 hr every 1218 hr PO every 24
hr
Supplement
18.7575 mg PO
2530% of
every 1218 hr
dose after HD
Appendix: Continued
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Enalapril
(Vasotec)
510 mg PO
every 12 hr
2.57.5 mg PO
every 12 hr
Start at 2.5 mg
PO every 24 hr
and titrate up
for BP control
Start at 2.5
mg PO every
24 hr and
titrate up for
BP control
Enalaprilat
(Vasotec)
1.255 mg IV
every 6 hr
1.252.5 mg IV
every 6 hr
0.625 mg IV
1; if after 1 hr
there is an
inadequate
response, up to
1.25 mg may be
given at 6-hr
intervals
0.625 mg IV
0.625 mg IV
1; if after 1 every 6 hr
hr there is an
inadequate
response, up
to 1.25 mg
may be given
at 6-hr
intervals
0.625 mg IV
1; if after 1 hr
there is an
inadequate
response, up to
1.25 mg may be
given at 6-hr
intervals
Fosinopril
(Monopril)
1040 mg PO
every 24 hr
1040 mg PO
every 24 hr
1040 mg PO
every 24 hr
7.530 mg
PO every 24
hr
No change
1040 mg PO
every 24 hr
Lisinopril
(Zestril)
1040 mg PO
every 24 hr
530 mg PO
every 24 hr
530 mg PO
every 24 hr
2.520 mg
PO every 24
hr
Start at 2.5 mg 530 mg PO

for initial
every 24 hr
dose; if
patient has
dosing
regimen
administer
20% patients
dose after HD
Fixed dose
combinations of
lisinopril and
hydrochlorothiazide should
not be used
where the GFR
is less than 30
ml/min
Quinapril
(Accupril)
1080 mg PO
every 24 hr
7.560 mg PO
every 24 hr
7.560 mg PO
every 24 hr
7.560 mg
PO every 24
hr
Start at 2.5 mg
for initial
dose; if
patient has
dosing
regimen
administer
2535% of
patients dose
after HD
7.560 mg PO
every 24 hr
2.5 mg in HD
patients
provides up to
90% inhibition
of ACE 24 hr
after dose [86]
Ramipril (Altace)
2.520 mg PO
every 24 hr
1.2515 mg PO
every 24 hr
1.2515 mg PO
every 24 hr
1.2510 mg
PO every 24
hr
20% of the
patients dose
should be
supplemented after
HD
1.2515 mg PO
every 24 hr
2.5 mg three
times a week
after a 4-hr
hemodialysis
session was safe
and effective in
controlling BP
in HD patients
[87]
Administer
25% of
current dose
in regimen
after HD
2.57.5 mg PO
every 12 hr
Notes
Reduced initial
doses are
required in
patients with
CrCl <30 ml/min
[85]
Hepatobiliary
elimination,
compensates for
lack of renal
elimination,
dose
adjustments are
minimal
Angiotensin II receptor blockers

Candesartan
(Atacand)
832 mg PO
every 24 hr
No change
No change
No data
No change
No change
Start with lower

doses in patients
with renal
failure and
slowly titrate
Losartan
(Cozaar)
25100 mg PO
every 1224 hr
No change
No change
No change
No data
No change
Losartan is not
better tolerated
than ACE
inhibitors in
causing renal
toxicity [88]
Irbesartan
(Avapro)
150300 mg PO
every 24 hr
No change
No change
No change
No change
No change
Appendix: Continued
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
No change
No change
No data
No data
No change
Diazoxide
(Proglycem)
50100 mg IV
No change
every 515 min
for severe
hypertension,
repeat every
424 hr to
maintain blood
pressure
control; or
1530 mg/min
IV infusion to a
total dose of 5
mg/kg or
adequate blood
pressure control
is achieved
No change
No change
No change
No change
Hydralazine
(Apresoline)
10100 mg IV/
No change
PO every 68 hr
No change
10100 mg
IV/PO every
12 hr
10100 mg
IV/PO every
12 hr
10100 mg IV/
PO every 812
hr
Minoxidil
(Loniten)
2.540 mg PO
every 12 hr
No change
No change
No change
No change
No change
Smaller doses
may be required
in RF or HD;
doses on HD
days should be
administered
after HD or 8 hr
prior to next HD
if late in the day
Nitroglycerin
(see above)
See above
Nitroprusside
(Nipride,
Nitropress)
0.2510 g/kg/
min; titrate for
blood pressure
control
No change
No change
No change
No change
No change
Thiocyanate, a
toxic
metabolite,
accumulates in
RF causing
seizure and
coma,
thiocyanate is
HD [89]; check
thiocyanate
levels every
2448 hr with
normal renal
function and
daily with
impaired renal
function
Drug
Normal Dose
Valsartan
(Diovan)
80320 mg PO
every 24 hr
Notes
Direct-acting vasodilators
-adrenergic receptor blockers

Acebutolol
(Sectral)
400800 mg PO
every 1224 hr
200400 mg PO
every 1224 hr
200400 mg PO
every 1224 hr
100200 mg
PO every
1224 hr
100200 mg
PO every
1224 hr
200400 mg PO
every 1224 hr
Elimination
half-life of
acebutolol is
unchanged,
active
metabolite
(diacetolol) is
prolonged,
warranting dose
adjustment
Atenolol
(Tenormin)
50100 mg PO
every 24 hr
2550 mg PO
every 48 hr
2550 mg PO
every 48 hr
2550 mg PO
every 96 hr
2550 mg PO
every 96 hr,
supplement
by 12.525
mg post-HD
2550 mg PO
every 48 hr
In patients with
CrCl <10 ml/
min, doses >25
mg should
rarely be used
Appendix: Continued
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
6.2550 mg PO
every 12 hr
No change
No change
No change
No data
No change
CHF dosing
should begin at
3.125 mg every
12 hr and be
increased to
6.25 mg as soon
as tolerated and
doubled every 2
weeks to
maximum
tolerated dose
Esmolol
(Brevibloc)
50200 g/kg/
min; titrate for
heart rate
No change
No change
No change
No change
No change
The half-life is 2
min, once drip is
off; no lingering
effects
Metoprolol
(Lopressor)
50450 mg/day No change

PO in two or
three divided
doses; or 515
mg IV every 6 hr
titrated for heart
rate
No change
No change
Supplement
50 mg PO
after HD
No change
Nadolol
(Corgard)
40320 mg/day
PO in single or
divided doses
20160 mg/day
in single or
divided doses;
or use normal
dose and
change interval
to every 2436
hr
20160 mg/day
in single or
divided doses;
or use normal
dose and
change interval
to every 2448
hr
1080 mg/
day in single
or divided
doses; or use
normal dose
and change
interval to
every 48 hr
Supplement
40 mg after
HD
20160 mg/day
in single or
divided doses;
or use normal
dose and
change interval
to every 2448
hr
Alteration of the
interval instead
of dose is an
option
Pindolol
(Visken)
1040 mg PO
every 12 hr
No change
No change
No change
No change
No change
The half-life in
renal failure
increases by a
factor of 1.41.5;
dose
adjustments are
not deemed
necessary [90]
Propranolol
(Inderal)
80320 mg PO
every 612 hr
No change
No change
No change
No change
No change
Sotalol
(Betapace)
80320 mg PO
Lengthen
every 12 hr; start dosing interval
with 80 mg PO to every 24 hr
every 12 hr
Lengthen
dosing interval
to every 3648
hr based on
clinical
response
Dose
according to
clinical
response
Supplement
80 mg after
HD
Lengthen
dosing interval
to every 3648
hr based on
clinical
response
Data suggests
that HD patients
need both a
decrease in dose
and increase in
interval [91]
Drug
Normal Dose
Carvedilol
(Coreg)
Notes
-Adrenergic receptor blockers

Doxazosin
(Cardura)
116 mg PO
every 24 hr
No change
No change
No change
No change
No change
A prolonged
effect may be
demonstrated in
renal failure
patients;
although not
specified a
reduced dose or
extended
interval may be
necessary [92]
Phenoxybenzamine
(Dibenzyline)
1040 mg PO
every 812 hr;
start low and
titrate for BP
response
Guidelines not
determined
Guidelines not
determined
Guidelines
not
determined
Guidelines
not
determined
Guidelines not
determined
Administration
is not
contraindicated
with renal
failure, caution
should be used
Appendix: Continued
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
515 mg IV
every 15 min in
hypertensive
crisis or pheochromocytoma
No change
No change
No change
No change
No change
Prazosin
(Minipress)
115 mg PO
every 12 hr
No change
No change
No change
No change
No change
Patients with
end-stage renal
disease may
respond to
lower dosages
[48]
Terazosin
(Hytrin)
120 mg/day
PO
No change
No change
No change
No change
No change
Doses >20 mg/

day do not
provide further
blood pressure
reduction [93]
Drug
Normal Dose
Phentolamine
(Regitine)
Notes
Sympatholytics for blood pressure control

Clonidine
(Catapres)
0.10.6 mg PO
every 12 hr for
hypertension;
0.10.2 mg can
be given every
hour for
malignant
hypertension to
a maximum of
0.7 mg
No change
No change
No change
No change
No change
Guanethidine
(Ismelin)
10100 mg PO
every 24 hr,
maximum dose
100 mg/day in
two divided
doses
No change
No change
10100 mg
PO every 36
hr
No data
10100 mg/day
PO every 24hr
Methyldopa
(Aldomet)
250500 mg PO
every 812 hr,
maximum dose
PO 3 g/day; or
250500 mg IV
every 6 hr,
maximum 1 g IV
every 6 hr
250500 mg
PO/IV every 12
hr
250500 mg
PO/IV every 12
hr
250500 mg
PO/IV every
24 hr
Administer
250 mg after
each HD
250500 mg
PO/IV every 12
hr
Trimethaphan
(Arofonad)
0.36 mg/min
No change
IV; titrate for BP
control
No change
No change
No change
No change
The half-life of
methyldopa is
significantly
prolonged in
patients with
ESRD
Calcium channel blockers

Amlodipine
(Norvasc)
2.510 mg PO
every 24 hr
No change
No change
No change
No change
No change
Bepridil (Vascor)
200400 mg PO
every 24 hr
No change
No change
No change
No change
No change
Diltiazem
(Dilacor,
Cardizem,
Tiazac)
3090 mg PO
No change
every 68 hr; for
atrial fibrillation,
administer IV at
20 mg 1 (0.25
mg/kg), if no
response in 15
min, give 25 mg
1 (0.35 mg/
kg) then begin
infusion at 515
mg/hr for rate
control
No change
No change
No change
No change
Bepridil does
not appear to be
effected by
renal
impairment,
however, trials
are ongoing
Appendix: Continued
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
515 mg PO
every 824 hr
No change
No change
No change
No change
No change
Dosing
parameters in
renal failure
may vary with
combination
products with
felodipine
Isradipine
(Dynacirc)
1.2510 mg/day
bid
No change
No change
No change
No change
No change
Patients with
CrCl of 3080
ml/min show a
significant
increase in area
under the curve
of isradipine,
however, this
effect returns to
normal as renal
function
deteriorates
Nicardipine
(Cardene)
2040 mg PO
No change
tid; or
continuous
infusion for
difficult to
control
hypertension at
515 mg/hr,
may increase
dose by 2.5 mg/
hr every 5 min
No change
No change
No change
No change
Manufacturer
recommends
starting with
lowest dose
possible in
patients with
renal failure
Nifedipine
(Adalat,
Procardia)
1030 mg/day
PO tid
No change
No change
No change
No change
No change
Nimodipine
(Nimotop)
60 mg PO every
4 hr
No change
No change
No change
No change
No change
Verapamil (Calan,
Isoptin, Verelan)
40120 mg PO
every 8 hr; IV
dose for atrial
arrhythmias is
510 mg, may
repeat until
maximum of 20
mg is reached;
constant IV
infusions run at
510 mg/hr
No change
No change
2060 mg PO
every 8 hr; IV
doses for
antiarrhythmic effect,
therefore no
change
No supplementation
necessary,
however,
observe
doses for CrCl
<10 ml/min
40120 mg PO
every 8 hr; IV
dose for atrial
arrhythmias is
510 mg, may
repeat until
maximum of 20
mg is reached
Abciximab
(ReoPro)
0.25 mg/kg IV
bolus, then
0.125 g/kg/
min 12 hr
No change
No change
No change
No change,
abciximab
may not be
cleared by
dialysis
No change,
abciximab may
not be cleared
by dialysis
Monitor
platelets 4 hr
into infusion
Aspirin
81325 mg PO
every 24 hr
No change
No change
Use if
benefits
outweigh
risks
Dose after
dialysis
No change
May increase
bleeding risk in
uremic patients
Drug
Normal Dose
Felodipine
(Plendil)
Notes
An increase in
elimination halflife as well as an
increase in area
under the curve
was noted in
patients with
renal failure,
however,
dosage
adjustments are
not necessary
[94]
Antiplatelet drugs
Appendix: Continued
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Loading doses
of 300 mg 1
may be given
followed by 75
mg PO every 24
hr
No change
No change
No change
No guidelines
determined,
administer if
benefits
outweigh
risks
Dipyradamole
(Persantine)
50100 mg PO
every 68 hr
No change
No change
No change
No guidelines No guidelines
determined
determined
Eptifibatide
(Integrilin)
Medical
management:
180 g/kg IV
bolus, then 2
g/kg/min.
Catheterization
lab: 180 g/kg
IV bolus, then 2
g/kg/min IV
bolus 10 min
into the
maintenance
infusion
SCr 2 mg/dl:
180 g/kg
bolus, then 2
g/kg/min
infusion. SCr
24 mg/dl: 135
g/kg bolus,
then 0.5 g/kg/
min infusion
SCr 2 mg/dl:
180 g/kg
bolus, then 2
g/kg/min
infusion. SCr
24 mg/dl: 135
g/kg bolus,
then 0.5 g/kg/
min infusion
SCr 2 mg/
dl: 180 g/kg
bolus, then 2
g/kg/min
infusion. SCr
24 mg/dl:
135 g/kg
bolus, then
0.5 g/kg/
min infusion
No data
available,
eptifibatide
may be
cleared by
dialysis
No data
available,
eptifibatide may
be cleared by
dialysis
If heparin is
used, maintain
aPTTs in the
range of 50 to 70
sec; continue
eptifibatide
1224 hr
postangioplasty
unless specified
otherwise
Ticlopidine
(Ticlid)
250 mg PO
every 12 hr
taken with food
No change,
reduce dose or
discontinue if
hemorrhagic
problems are
encountered
No change,
reduce dose or
discontinue if
hemorrhagic
problems are
encountered
No change,
reduce dose
or
discontinue if
hemorrhagic
problems are
encountered
200 mg/day
has been
used in
uremic
patients on
chronic
hemodialysis
[98];
administer if
benefits
outweigh
risks
No change,
reduce dose or
discontinue if
hemorrhagic
problems are
encountered
Monitor CBC
every 2 weeks
for the first 3
months, also
monitor for
signs and
symptoms of
TTP
Tirofiban
(Aggrastat)
0.4 g/kg/min
No change
IV bolus over 30
min followed by
0.1 g/kg/min
48108 hr
0.2 g/kg/min
IV bolus over 30
min followed
by 0.05 g/kg/
min 48108
hr
0.2 g/kg/
min IV bolus
over 30 min
followed by
0.05 g/kg/
min
48108 hr
No data
available,
tirofiban is
removed by
HD
No data
available,
tirofiban is
removed by HD
If heparin is
used, maintain
aPTTs in the 50to 70-sec range,
continue
tirofiban 1224
hr
postangioplasty
unless
otherwise
specified
Alteplase
(Activase)
>67 kg: 15 mg IV No change

bolus, 50 mg
over 30 min,
then 35 mg over
the next 60 min.
67 kg: 15 mg
IV bolus, 0.75
mg/kg over 30
min (up to 50
mg), then 0.50
mg/kg over the
next 60 min (up
to 35 mg).
No change,
administer if
benefits
outweigh risks
No change,
administer if
benefits
outweigh
risks
No guidelines
determined,
administer if
benefits
outweigh
risks
No guidelines
determined,
administer if
benefits
outweigh risks
Maintain aPTT
with heparin at
1.52 times
control (5070
sec) for 48 hr
Anistreplase
(Eminase)
IV bolus of 30
units infused
over 25 min
No change
No change
No change
determined
determined
r-PA (Retaplase)
Two 10 U IV
boluses,
administered
over 2 min, 30
min apart
No change
No change,
administer if
benefits
outweigh risks
No change,
administer if
benefits
outweigh
risks
No guidelines
determined,
administer if
benefits
outweigh
risks
Drug
Normal Dose
Clopidogrel
(Plavix)
No guidelines
determined,
administer if
benefits
outweigh risks
Notes
Monitor for
signs and
symptoms of
TTP
Thrombolytic agents
No guidelines
determined,
administer if
benefits
outweigh risks
Maintain aPTT
with heparin at
1.52 times
control (5070
sec) for 48 hr
Appendix: Continued
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Arterial
thrombosis:
250,000 IU IV
load over 30
min, then
100,000 IU/hr
over 2472 hr.
Acute stroke/
MI: 1.5 MU IV
over 60 min
No change
No change
No change
determined
determined
TNK-tPA
(Tenectaplase)
<60 kg: 30 mg;

60 kg but <70
kg: 35 mg; 70
kg but <80 kg:
40 mg; 80 kg
but <90 kg: 45
mg; 90 kg: 50
mg
No change
No change
Benefits
should be
weighed
against risks
in patients
with
hemostatic
defects
secondary to
renal disease
Benefits
should be
weighed
against risks
in patients
with
hemostatic
defects
secondary to
renal disease
Urokinase
(Abbokinase)
4,400 U/kg IV
load over 10
min, then 4,400
U/kg/hr for 12
hr
No change
No change
No change
determined
determined
Ardeparin
(Normiflo)
50 U/kg SC
every 12 hr
No change
No guidelines
determined, no
dosage
adjustment is
necessary for
DVT
prophylaxis
No
guidelines
determined,
no dosage
adjustment is
necessary for
DVT
prophylaxis
No guidelines
determined,
ardeparin
does not
appear
dialyzable
No guidelines
determined,
ardeparin does
not appear
dialyzable
Not
recommended
for use in
patients with
CrCl <30 ml/min
unless
monitoring antiXa levels
Dalteparin
(Fragmin)
Prophylaxis:
2,5005,000 U
SC every 24 hr.
Treatment: 120
U/kg SC every
12 hr
No change
No guidelines
determined
No
guidelines
determined
5,000 U
before
dialysis
No guidelines
determined
Not
recommended
for use in
patients with
CrCl <30 ml/min
unless
Danaparoid
(Orgaran)
Prophylaxis:
750 U SC every
12 hr
No change
No guidelines
determined
No
guidelines
determined
determined
determined
Enoxaparin
(Lovenox)
DVT
No change
prophylaxis: 30
mg SC every 12
hr or 40 mg SC
every 24 hr.
DVT treatment
and acute
coronary
syndromes: 1
mg/kg SC every
12 hr or 1.5 mg/
kg SC every 24
hr
No guidelines
determined
No
guidelines
determined
determined
determined
Not
recommended
for use in
patients with
CrCl <30 ml/min
unless
Heparin
Pulmonary
No change
embolus: 80 U/
kg bolus IV, 18
U/kg/hr.
Prophylaxis:
5,000 U SC every
812 hr. Acute
coronary
syndromes: 60
No change
No change
No change
If using
subcutaneously,
may need larger
doses in uremic
patients;
maintain aPTT
in the range of
5070 sec for
patients
Drug
Normal Dose
Streptokinase
(Kabikinase,
Streptase)
Benefits should
be weighed
against risks in
patients with
hemostatic
defects
secondary to
renal disease
Notes
Maintain aPTT
with heparin at
1.52 times
control (5070
sec) for 48 hr
Anticoagulants
No change
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
U/kg
(maximum
4,000 U) IV
bolus followed
by 12 U/kg/hr
(maximum
1,000 U/hr) for
patients
receiving
fibrinolytics or
GP Iib/IIIa
receptor
antagonists
Notes
receiving
fibrinolytics or
GP Iib/IIIa
receptor
antagonists
Hirudin
(Hirulog)
Heparininduced
thrombocytopenia; 0.07 mg/
kg bolus, infuse
at 0.05 mg/kg/
hr
No guidelines
determined
No guidelines
determined
No
guidelines
determined
0.08 mg/kg
bolus prior to
dialysis
No guidelines
determined
Monitor aPTT
closely,
especially in
patients with
renal
impairment.
Therapeutic
range: aPTT
1.52.5
normal.
Lepirudin
(Refludan)
Heparininduced
thrombocytopenia; 0.4 mg/
kg bolus, infuse
at 0.15 mg/kg/
hr
0.2 mg/kg
bolus, infuse at
0.0750.045
mg/kg/hr
0.2 mg/kg
bolus, infuse at
0.0225 mg/kg/
hr
0.1 mg/kg
bolus,
monitor
aPTT and
rebolus
when aPTT
falls to 1.5
standard
0.1 mg/kg
bolus,
monitor aPTT
and rebolus
when aPTT
falls to 1.5
standard
0.1 mg/kg
bolus, monitor
aPTT and
redose when
aPTT falls to
1.5 standard
Monitor aPTT
closely,
especially in
patients with
renal
impairment.
Therapeutic
range: aPTT
1.52.5
normal.
Tinzaparin
(Innohep)
DVT treatment:
175 IU/kg SC
every 24 hr
No change
No guidelines
determined
No
guidelines
determined
determined
determined
Not
recommended
for use in
patients with
CrCl <30 ml/min
Warfarin
(Coumadin)
115 mg/day
PO, initiate at 5
mg PO every 24
hr, titrate slowly
based on INR
No change
No change
No change
No change
No change
Patients on HD
should be
monitored
closely due to
variable
response to
warfarin
Class IA antiarrhythmics
Disopyramide
(Norpace)
Load: 300 mg
100 mg PO
immediate
every 68 hr
release,
followed by
150300 mg PO
every 6 hr;
maximum:
1,2001,600 mg/
day
100 mg PO
every 12 hr
100 mg PO
every 24 hr
100 mg after
dialysis
No guidelines
determined
Therapeutic
range 24 g/
ml. Serum
levels >4 g/ml
may cause
toxicity, QRS
and QT interval
widening,
congestive heart
failure,
bradycardia,
and
hypotension [97]
Procainamide
(Procan,
Pronestyl)
50100 mg/min 500 mg PO

IV until
every 6 hr
arrhythmia
suppressed or
reach 5001,000
mg, then infuse
at 26 mg/min.
Oral: 5001,000
mg PO every
46 hr
500 mg PO
every 12 hr
500 mg PO
every 1224
hr
500 mg PO
every 24 hr
after dialysis
No guidelines
determined
Monitor EKG,
procanamide,
and NAPA levels
closely in renal
dysfunction.
Procanamide:
412 g/ml.
NAPA: 515 g/
ml [97]
Appendix: Continued
Drug
Normal Dose
Quinidine
(Quinidex,
Quinaglute)
Sulfate: 200400
mg PO every
46 hr.
Gluconate:
324648 mg PO
every 812 hr.
Gluconate:
200300 mg IM
every 26 hr
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Notes
Sulfate:
150300 mg
PO every 46
hr
Sulfate:
100200 mg
given after
HD
No guidelines
determined
Monitor
quinidine levels
and EKG closely
in renal
dysfunction.
Quinidine: 28
g/ml [97]
Metabolite
accumulation
may occur in
renal
dysfunction,
resulting in
central nervous
system toxicity
[98]
Class IB antiarrhythmics
Lidocaine
(Xylocaine)
Bolus 50100
mg over 12
min, then infuse
14 mg/min.
May repeat
bolus one time.
No change
No change
No change
No change
No change
Mexilitine
(Mexitil)
200400 mg PO
every 8 hr
No change
No change
Guidelines
not
determined
Guidelines
not
determined
Guidelines not
determined
400600 mg PO
every 8 hr
No change
No change
200 mg PO
every 8 hr
200 mg PO
every 8 hr
No change
Monitor levels
closely in renal
failure.
Therapeutic
range: 310 g/
ml.
Phenytoin
(Dilantin)
See neurologic
agents section
Tocainide
(Tonocard)
Class IC antiarrhythmics
Encainide
(Enkaid)
2550 mg PO
every 8 hr
2550 mg PO
every 8 hr
25 mg PO every
8 hr
25 mg PO
every 1224
hr
Guidelines
not
determined
Guidelines not
determined
Dose should be
carefully titrated
based on patient
response
Flecainide
(Tambocor)
100200 mg PO
every 12 hr
No change
50100 mg PO
every 12 hr
50 mg PO
every 12 hr
No change
Guidelines not
determined
Monitor levels
closely in renal
failure.
Therapeutic
range: 0.21.0
g/ml.
Other antiarrhythmics
Moricizine
(Ethmozine)
200300 mg PO
every 8 hr
No change
No change
No change
No change
Guidelines not
determined
Propafenone
(Rythmol)
150300 mg PO
every 8 hr
No change
No change
No change
No change
Guidelines not
determined
No change
No change
No change
No change
Guidelines not
determined
Class II antiarrhythmics
-blockers
See section
labeled -blockers
Class III antiarrhythmics
Amiodarone
(Cordarone)
Oral loading
dose: 8001,600
mg/day in
divided doses
for 12 weeks.
Oral
maintenance
dose: 100600
mg/day
(300400 mg/
day for
Appendix: Continued
Drug
Normal Dose
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
No change
No change
No change
No change
Guidelines not
determined
Notes
ventricular
tachycardias;
100200 mg/
day for atrial
tachycardias).
IV treatment or
prevention of
refractory
ventricular
tachycardia or
fibrillation: 150
mg IV over 10
min, then 360
mg IV over the
next 6 hr,
followed by 540
mg over the
next 18 hr
Bretylium
(Bretyol)
5 mg/kg IV
bolus, may
repeat at 10 mg/
kg to a
maximum of 30
mg/kg
Class IV antiarrhythmics
Calcium channel
blockers
See section
labeled calcium
channel blockers
Other antiarrhythmics
Adenosine
(Adenocard)
6 mg IV push
over 12 sec,
may repeat
second dose at
12 mg IV, if
unsuccessful,
may repeat 12
mg dose 1
No change
No change
No change
No change
No change
Atropine
0.51.0 mg IV
push every 35
min, maximum
0.04 mg/kg
No change
No change
No change
No change
No change
Albuterol
(Proventil,
Ventolin)
MDI: 2 puffs
every 46 hr
prn. Nebulizer:
2.5 mg
nebulized every
46 hr prn. Oral:
24 mg PO
every 6 hr
No change
No change
No change
No change
No change
Aminophylline
Intravenous:
No change
56 mg/kg IV,
then 0.4 mg/kg/
hr infusion
No change
No change
Epinephrine
(Adrenaline)
0.20.5 mg (1:
No change
1,000 solution)
SC every 2 hr for
bronchodilation
No change
No change
No change
No change
Metoproterinol
(Alupent)
MDI: 23 puffs
every 46 hr prn
No change
No change
No change
No change
Administer
rapidly in most
proximal line
immediately
followed by a
saline flush;
half-life is 110
sec
Bronchodilators
No change
Guidelines not
determined
Monitor plasma
levels closely;
therapeutic
range: 515 g/
ml
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Terbutaline
(Brethine,
Brethaire)
MDI: 2 puffs
every 46 hr
prn; PO: 2.55
mg every 6 hr
MDI: no
change; PO:
1.252.5 mg
every 6 hr
MDI: 1 puff
every 46 hr
prn; PO:
1.252.5 mg
every 6 hr
Avoid use
No change
No change
Ipratropium
(Atrovent)
MDI: 2 puffs
every 46 hr
prn. Nebulizer:
500 g
nebulized every
46 hr prn
No change
No change
No change
No change
No change
Theophylline
(Theo-dur)
Load: 5 mg/kg
PO.
Maintenance:
100200 mg PO
every 68 hr
No change
No change
No change
Supplement
with 150%
normal dose
prior to
dialysis or
50%
postdialysis
Guidelines not
determined
Neuromuscular blockers
Atracurium
(Tracrium)
0.30.5 mg/kg
bolus, then
0.080.1 mg/kg
as needed to
maintain
paralysis
No change
No change
No change
No change
No change
Cisatracurium
(Nimbex)rm
0.10.2 mg/kg
load, then 23
g/kg/min IV
infusion or 0.03
mg/kg as
needed to
maintain
paralysis
No change
No change
No change
No change
No change
Doxacurium
(Nuromax)
0.0250.05 mg/
kg load, then
0.0050.01 mg/
kg as needed to
maintain
paralysis
0.01250.025
mg/kg, then
0.005 mg/kg as
needed to
maintain
paralysis
0.01250.025
mg/kg, then
0.005 mg/kg as
needed to
maintain
paralysis
0.01250.025
mg/kg, then
0.005 mg/kg
as needed to
maintain
paralysis
Guidelines
not
determined
Guidelines not
determined
Mivacurium
(Mivacron)
0.150.25 mg/
kg load, then 0.1
mg/kg as
needed to
maintain
paralysis
0.15 mg/kg,
then 0.1 mg/kg
as needed to
maintain
paralysis
0.15 mg/kg,
then 0.1 mg/kg
as needed to
maintain
paralysis
0.15 mg/kg,
Guidelines
then 0.1 mg/ not
kg as needed determined
to maintain
paralysis
Guidelines not
determined
Pancuronium
(Pavulon)
0.040.1 mg/kg
load, then
0.010.06 mg/
kg as needed to
maintain
paralysis
0.020.05 mg/
kg load, then
0.010.03 mg/
kg as needed to
maintain
paralysis
0.020.05 mg/
Avoid use
kg load, then
0.010.03 mg/
kg as needed to
maintain
paralysis
Guidelines
not
determined
Guidelines not
determined
Pipecuronium
(Arduan)
0.040.1 mg/kg
load, then
0.0050.025 mg/
kg as needed to
maintain
paralysis
0.020.05 mg/
kg load, then
0.0050.01 mg/
kg as needed to
maintain
paralysis
0.020.05 mg/
kg load, then
0.0050.01 mg/
kg as needed to
maintain
paralysis
0.010.025
mg/kg load,
then
0.0050.01
mg/kg as
needed to
maintain
paralysis
Guidelines
not
determined
0.020.05 mg/
kg load, then
0.0050.01 mg/
kg as needed to
maintain
paralysis
Rocuronium
(Zemuron)
0.61.0 mg/kg
No change
load, then
0.0750.15 mg/
kg as needed to
maintain
paralysis
No change
No change
No change
No change
Notes
Monitor plasma
levels closely;
therapeutic
range: 515 g/
ml
Appendix: Continued
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
0.31.1 mg/kg
No change
load, then
0.040.07 mg/
kg as needed to
maintain
paralysis
No change
No change
No change
No change
Tubocurarine
0.20.5 mg/kg
load, then
0.040.1 mg/kg
as needed to
maintain
paralysis
0.20.5 mg/kg
load, then
0.040.1 mg/kg
as needed to
maintain
paralysis
Avoid use
Guidelines
not
determined
Guidelines not
determined
Vecuronium
(Norcuron)
0.050.1 mg/kg No change

load, then
0.010.015 mg/
kg as needed to
maintain
paralysis
No change
No change
No change
No change
Dexamethasone
(Decadron)
0.759 mg/day
PO
No change
No change
No change
No change
No change
Hydrocortisone
(Solu-cortef)
25125 mg IV
every 6 hr;
20240 mg/day
PO
No change
No change
No change
No change
No change
Methylprednisolone (Solumedrol)
20125 mg IV
No change
every 6 hr; 448
mg/day PO
No change
No change
No change
No change
Prednisone
(Deltasone)
560 mg/day
PO
No change
No change
No change
No change
No change
Fludricortisone
(Florinef)
0.10.3 mg/day
PO
No change
No change
No change
No change
No change
Acetazolomide
(Diamox)
Epilepsy: 830
mg/kg/day PO
divided every
68 hr
Epilepsy: 830
mg/kg/day PO
divided every
812 hr
Epilepsy: 830
mg/kg/day PO
divided every
12 hr
Not effective, Guidelines

avoid use
not
determined
Guidelines not
determined
Dexamethasone
(Decadron)
4 mg IM every 6 No change
hr
No change
No change
No change
No change
Diazepam
(Valium)
210 mg IV/IM
every 24 hr
prn; 210 mg
PO every 612
hr prn
No change
No change
No change
No change
No change
Active
metabolites may
accumulate in
renal failure;
doses should be
titrated to
patient
response
Lorazepam
(Ativan)
110 mg IV/IM No change

every 24 hr
prn; 0.510 mg
PO every 46 hr
prn
No change
No change
No change
No change
Lorazepam may
accumulate in
renal failure;
doses should be
titrated to
patient
response
Guidelines not
determined
Guidelines
not
determined
Guidelines
not
determined
Guidelines not
determined
Magnesium can
accumulate in
patients with
renal failure,
serum levels
should be
monitored
Drug
Normal Dose
Succinylcholine
(Anectine)
CrCl
(3050 ml/min)
0.20.5 mg/kg
load, then
0.040.1 mg/kg
as needed to
maintain
paralysis
Notes
Steroids
Neurologic agents
Magnesium sulfate Hypomagnesemic seizures/

arrhythmias: 12
g IV every 46 hr
Guidelines not
determined
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Mannitol
(Osmitrol)
0.252 g/kg IV
every 46 hr
0.25 g/kg IV
every 612 hr
0.25 g/kg IV
every 812 hr
Avoid use
Avoid use
Avoid use
Methohexital
(Brevital)
Induction
anesthesia:
11.5 mg/kg IV,
then 6 mg/min
infusion or
2040 mg IV
every 510 min
No change
No change
No change
Guidelines
not
determined
Guidelines not
determined
Midazolam
(Versed)
0.54 mg/kg
No change
load over 25
min, then
0.020.1 mg/kg/
hr titrated to
response
No change
0.54 mg/kg
load over 25
min, then
0.010.05
mg/kg/hr
titrated to
response
Guidelines
not
determined
Guidelines not
determined
Pentobarbital
(Nembutal)
Barbiturate
No change
coma: 510 mg/
kg load, 35
mg/kg IV every
3 hr to maintain
blood levels
3040 g/ml.
Hypnotic:
100200 mg PO
every 24 hr
No change
No change
No change
Guidelines not
determined
Phenobarbital
(Luminal,
Solfoton)
Status
No change
epilepticus:
1020 mg/kg IV;
60250 mg PO
every 24 hr
No change
60100 mg
PO every 24
hr
No change,
dose after
dialysis
Guidelines not
determined
Monitor levels
closely;
therapeutic
range: 1040
g/ml
Phenytoin
(Dilantin)
15 mg/kg IV
load, then
200400 mg/
day PO/IV
divided every
812 hr
No change
No change
No change
No change
No change
Monitor levels
closely.
Phenytoin
binding is
altered in
uremic patients
and patients
with low
albumin serum
levels and
perhaps dose
should be
adjusted
accordingly
Secobarbital
(Seconal)
Preoperative
sedation: 12
mg/kg IM or
100300 mg PO
1 hr prior to
procedure
No change
No change
No change
No change
Guidelines not
determined
Notes
Maintain serum
osmolarity of
290310
Prolonged
infusions,
especially in
patients with
renal failure,
may result in
prolonged
sedation due to
the
accumulation of
metabolites;
doses should be
titrated to
patient
response
Appendix: Continued
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Barbiturate
coma: 20 mg/kg
IV over 1 hr,
then 10 mg/kg/
hr IV for 6 hr,
then 3 mg/kg/hr
continuous
infusion.
Induction
anesthesia:
50100 mg IV as
needed
No change
No change
Induction
anesthesia:
50 mg IV as
needed
Guidelines
not
determined
Guidelines not
determined
Chlorpromazine
(Thorazine)
50400 mg IM
every 46 hr prn
No change
No change
No change
No change
No change
Monitor QTc
interval; stop
therapy if QTc >
450 msec
Droperidol
(Inapsine)
1.2510 mg IM/
IV every 46 hr
prn
1.255 mg IM/
IV every 46 hr
prn
1.255 mg IM/
IV every 46 hr
prn
Guidelines
not
determined
Guidelines
not
determined
Guidelines not
determined
Monitor QTc
interval, stop
therapy if QTc >
450 msec
Fluphenazine
(Prolixin,
Permitil)
2.510 mg IM
every 68 hr prn
No change
No change
No change
No change
No change
Monitor QTc
interval, stop
therapy if QTc >
450 msec
Haloperidol
(Haldol)
110 mg IM/IV
every 46 hr
prn, maximum
80 mg/day
No change
No change
No change
No change
No change
Monitor QTc
interval, stop
therapy if QTc >
450 msec
14 MU IV
every 812 hr
Drug
Normal Dose
Thiopental
(Pentothal)
Notes
Neuroleptics
Penicillins used for primarily gram-positive infections

Penicillin G
14 MU IV every
46 hr; 12 MU
for most uses, 4
MU in
meningitis
14 MU IV
every 68 hr
14 MU IV
every 812 hr
14 MU IV
every 1218
hr
14 MU IV
every 1218
hr;
supplemental
doses are not
needed if
maintenance
doses are
scheduled
after HD
Ampicillin
(Principen,
Omnipen)
12 g IV every
46 hr
12 g IV every
68 hr
12 g IV every
812 hr
12 g IV
every 12 hr
12 g IV every 12 g IV every
12 hr;
812 hr
supplemental
doses are not
needed if
maintenance
doses are
scheduled
after HD
Methicillin
(Staphcillin)
12 g IV every
46 hr
12 g IV every
68 hr
12 g IV every
68 hr
12 g IV
every 812 hr 812 hr; no
812 hr
specific
dosing
necessary for
HD
Nafcillin (Nafcil,
Unipen)
12 g IV every
46 hr
No change
No change
No change
No change
No change
Oxacillin
(Bactocil)
12 g IV every
46 hr
No change
No change
No change
No change
No change
Ampicillin is
useful in
treating UTIs in
RF patients,
serum levels of
drug are high
and
parenchymal
levels are about
half of serum
levels
Nafcillin is
eliminated by
nonrenal
mechanisms
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Notes
Penicillins used for mixed gram-positive and gram-negative infections with anaerobic
coverage
Amoxicillin/
Clavulonic acid
(Augmentin)
250500 mg PO
every 8 hr; or
875 mg bid
No change
250500 mg PO
every 12 hr; no
change on 875
mg dose
Ampicillin/
Sulbactam
(Unasyn)
1.53 g IV every 1.53 g IV every 1.53 g IV every 1.53 g IV

6 hr
8 hr
12 hr
every 24 hr
1.53 g IV
every 24 hr
administered
at the end of
HD
1.53 g IV every
12 hr
Piperacillin/
Tazobactam
(Zosyn)
3.375 g IV every 3.375 g IV every 3.375 g IV every 3.375 g IV

46 hr
6 hr
8 hr
every 12 hr
2.25 g IV
every 8 hr,
administer
after HD is
complete
3.375 g IV every
8 hr
Ticarcillin/
Clavulonic acid
(Timentin)
3.1 g IV every
46 hr
2 g IV every
12 hr,
administered
at the end of
HD
2 g IV every 12
hr
3 or 4 g IV every
68 hr
2 g IV every 4 hr 2 g IV every 12
hr
250500 mg
Administer
PO every 24 dose at the
hr; 875 mg
end of HD
dose every 24
hr
2 g IV every
12 hr
250500 mg PO
every 12 hr
Patients with
CrCl <10 ml/min
with hepatic
dysfunction
should receive 2
g IV every 24 hr
Penicillins used for gram-negative infections with Pseudomonas aeruginosa

Azlocillin (Azlin)
3 g IV every 4 hr 3 or 4 g IV every 3 or 4 g IV every 3 or 4 g IV

or 4 g IV every 68 hr
68 hr
every 8 hr
6 hr
3 g IV every
12 hr
administered
at the end of
HD
Mezlocillin
(Mezlin)
34 g IV every
46 hr
34 g IV every
68 hr
8 hr
68 hr
administered
at the end of
HD
Piperacillin
(Pipracil)
3 g IV every 46
hr
3 g IV every 6 hr 3 g IV every 8 hr 3 g IV every

12 hr
34 g IV every
68 hr
34 g IV
every 8 hr
2 g IV every 8
hr
administered
at the end of
HD
3 g IV every 8 hr
Cephalosporins used for gram-positive infections

Cefazolin (Ancef,
Kefzol)
12 g IV every 8
hr
12 g IV every 8
hr
12 g IV every
12 hr
12 g IV
every 24 hr
24 hr
12 hr
administered
at the end of
HD
Cephalosporins used for mixed gram-positive and gram-negative infections with anaerobic coverage
Cefotetan
(Cefotan)
12 g IV every
12 hr
12 g IV every
12 hr
12 g IV every
24 hr
12 g IV
every 48 hr
48 hr
24 hr
administered
at the end of
HD
Cefoxitin
(Mefoxin)
12 g IV every
68 hr
12 g IV every 8
hr
12 g IV every
12 hr
12 g IV
every 24 hr
24 hr
12 hr
administered
after HD
Cephalosporins used for mixed gram-positive and gram-negative infections

Cefuroxime
(Zinacef)
0.751.5 g IV
every 8 hr
0.751.5 g IV
every 8 hr
0.751.5 g IV
every 12 hr
0.751.5 g IV
every 24 hr
0.751.5 g IV
every 24 hr
administered
at the end of
HD
0.751.5 g IV
every 12 hr
No
supplemental
HD dose is
required
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
12 g IV every
24 hr
Notes
Cephalosporins used for primarily gram-negative infections

Cefepime
(Maxipime)
12 g IV every
812 hr
12 g IV every
1224 hr
12 g IV every
24 hr
0.51 g IV
every 24 hr
0.51 g IV
every 24 hr
administered
at the end of
HD
Cefotaxime
(Claforan)
12 g IV every 8
hr
12 g IV every 8
hr
12 g IV every
12 hr
12 g IV
every 24 hr
24 hr
12 hr
administered
at the end of
HD
Ceftazidime
(Fortaz, Tazidime,
Tazicef)
hr
Loading dose 2 Loading dose

g IV, then 0.51 2 g IV, then 1
g IV every 24 hr g IV every 48
hr
Loading dose Loading dose 2

2 g IV, then 1 g IV, then 0.51
g IV every 48 g IV every 24 hr
hr
administered
at the end of
HD
Ceftizoxime
(Cefizox)
12 g IV every 8
hr
12 g IV every
12 hr
12 g IV every
12 hr
12 g IV
every 24 hr
1 g IV every
48 hr
administered
at the end of
HD
12 g IV every
12 hr
Ceftriaxone
(Rocephin)
12 g IV every
24 hr
No change
No change
No change
No change
No change
Ciprofloxacin
(Cipro)
500750 mg PO
(or 400 mg IV)
every 12 hr
250500 mg PO
(or 400 mg IV)
every 12 hr
250500 mg PO
every 18 hr, or
400 mg IV every
24 hr
250500 mg
PO every 18
hr, or 400 mg
IV every 24 hr
250500 mg
PO every 24
hr, or 400 mg
IV every 24 hr
administered
at end of HD
250500 mg PO
every 18 hr, or
400 mg IV every
24 hr
Gatifloxacin
(Tequin)
400 mg PO/IV
every 24 hr
Loading dose
400 mg IV/PO
1, then 200
mg PO/IV every
24 hr
Loading dose
400 mg IV/PO
1, then 200
mg PO/IV every
24 hr
Loading dose
400 mg IV/
PO 1, then
200 mg PO/
IV every 24 hr
Loading dose
400 mg IV/
PO 1, then
200 mg PO/
IV every 24 hr
administered
at the end of
HD
Loading dose
400 mg IV/PO
1, then 200
mg PO/IV every
24 hr
Levofloxacin
(Levaquin)
250500 mg IV/
PO every 24 hr
Loading dose of
500 mg IV/PO
1, then 250
mg IV/PO every
24 hr
Loading dose of
500 mg IV/PO
1, then 250
mg IV/PO every
48 hr
Loading dose
of 500 mg IV/
PO 1, then
250 mg IV/
PO every 48
hr
Loading dose
of 500 mg IV/
PO 1, then
250 mg IV/
PO every 48
hr, administer
at end of HD
Loading dose of
500 mg IV/PO
1, then 250
mg IV/PO every
48 hr
Trovafloxacin
(Trovan)
200300 mg IV/
PO every 24 hr
No change
No change
No change
No change
No change
Covers
Pseudomonas
aeruginosa as
well as some
gram-positive
organisms
Covers
Pseudomonas
aeruginosa; has
limited if any
gram-positive
coverage
Dose
adjustments in
renal failure are
unnecessary
unless >2 g/day
is used and
concurrent
hepatic failure
exists [99]
Fluoroquinolones
Monitor LFTs
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Notes
Aminoglycosides
Gentamicin
(Garamycin)
Varies
depending on
traditional
versus highdose extendedinterval dosing
regimens;
consult
institutionspecific
guidelines
Tobramcyin
(Nebcin)
See Gentamicin
See Gentamicin
Amikacin
(Amikin)
7.5 mg/kg IV
every 12 hr
7.5 mg/kg IV
every 1824 hr
2 mg/kg
based on
lean body
weight,
monitor
levels once a
day and
redose when
trough level
is <2.0 g/ml
2 mg/kg
following
each HD
treatment
Dose based on
CrCl of 25 ml/
min
Trough
aminoglycoside
levels post-HD
should be
drawn 4 hr after
HD has stopped
to allow for
equilibrium
See Gentamicin
See
Gentamicin
See
Gentamicin
See Gentamicin
See Gentamicin
7.5 mg/kg IV
every 2448 hr
7.5 mg/kg IV
every 48 hr
7.5 mg/kg IV
based on
serum levels,
redose with
levels <5 g/
ml
7.5 mg/kg IV
every 2448 hr
Trough levels
should be <10
g/ml
No change
No change
Clindamycin is
the most
frequent cause
of Clostridium
difficile toxinmediated
diarrhea
Antibiotics used to treat anaerobic infections

Clindamycin
(Cleocin)
600900 mg IV
every 8 hr
No change
No change
No change
Metronidazole
(Flagyl)
250500 mg IV/
PO every 8 hr
No change
No change
250 mg IV/
Administer
No change
PO every 8 hr dose after HD
Treatment for
Clostridium
difficile
diarrhea, causes
dark urine
Miscellaneous antibiotics
Aztreonam
(Azactam)
12 g IV every
68 hr
12 g IV every
68 hr
Loading dose
12 g; then 1 g
IV every 68 hr
Loading dose
12 g; then
0.5 g IV every
68 hr
Loading dose Loading dose

12 g; then
12 g; then 1 g
0.5 g IV every IV every 68 hr
68 hr;
administer
dose after HD
Note that the

dosing interval
remains
constant, and
there is a
reduction in
dose with
worsening renal
function [103]
Imipenem
(Primaxin)
500 mg IV every
6 hr
500 mg IV every
8 hr
500 mg IV every
12 hr
250 mg IV
every 12 hr
250 mg IV
500 mg IV every
every 12 hr;
12 hr
administer
dose after HD
Use cautiously
in patients with
renal
impairment,
adjusting dose
may not be
adequate to
prevent seizure
[104]; average
time to seizure is
7 days [105]
Linezolid
(Zyvox)
600 mg IV every
12 hr
No information
No information
No
information
Administer
No information
dose after HD
Meropenem
(Merrem)
hr
500 mg IV every
12 hr
500 mg IV
every 24 hr
500 mg IV
500 mg IV every
every 24 hr;
12 hr
administer
dose after HD
Quinupristin/
Dalfopristin
(Synercid)
7.5 mg/kg IV
every 8 hr
No change
No change
No change
No change
No change
Seizures have
only occurred in
patients with
preexisting
seizure disorder
Appendix: Continued
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
600 mg/day PO
300600 mg PO
every 2448 hr
300600 mg PO
every 2448 hr
300600 mg
PO every 48
hr
300600 mg
300600 mg PO
PO every 48
every 2448 hr
hr; administer
dose after HD
Trimethoprim/
Sulfamethoxazole
(Bactrim, Septra)
820 mg/kg/
day; when IV
divide into
every 6 hr; when
PO divide into
every 612 hr
410 mg/kg/
day; when IV or
PO divide into
every 12 hr
410 mg/kg/
day; when IV or
PO divide into
every 12 hr
25 mg/kg/
day; when IV
or PO divide
into every 24
hr
25 mg/kg/
day; when IV
or PO divide
into every 24
hr; administer
dose after HD
Vancomycin
(Vancocin)
Refer to
institutionspecific
guidelines
Drug
Normal Dose
Rifampin
(Rifadin)
410 mg/kg/
day; when IV or
PO divide into
every 12 hr
Notes
Dosing values
are based on the
trimethoprim
component
1 g IV every
week;
measure
random
vancomycin
level on the
fourth day
after dose to
ensure blood
levels, redose
when level
<10 g/ml
Antifungal agents
Amphoterecin B
(Fungizone)
nonlipid
0.41.0 mg/kg
IV every 24 hr
0.41.0 mg/kg
IV every 24 hr
0.41.0 mg/kg
IV every 24 hr
0.41.0 mg/
kg IV every
48 hr
0.41.0 mg/
kg IV every
48 hr
0.41.0 mg/kg
IV every 24 hr
Amphoterecin B
(Abelcet) lipid
complex
5 mg/kg IV
every 24 hr
5 mg/kg IV
every 24 hr
5 mg/kg IV
every 24 hr
5 mg/kg IV
every 48 hr
5 mg/kg IV
every 48 hr
5 mg/kg IV
every 24 hr
Amphoterecin B
(Amphotec)
cholesteryl sulfate
complex
36 mg/kg/day
IV every 24 hr
36 mg/kg/day
IV every 24 hr
36 mg/kg/day
IV every 24 hr
36 mg/kg/
day IV every
48 hr
36 mg/kg/
day IV every
48 hr
36 mg/kg/day
IV every 24 hr
Amphoterecin B
(Ambisome)
liposome
35 mg/kg IV
every 24 hr
35 mg/kg IV
every 24 hr
35 mg/kg IV
every 24 hr
35 mg/kg IV
every 48 hr
35 mg/kg IV
every 48 hr
35 mg/kg IV
every 24 hr
Fluconazole
(Diflucan)
100400 mg IV/
PO every 24 hr
Loading dose
100400 mg IV/
PO, then
50200 mg IV/
PO every 24 hr
Loading dose
100400 mg IV/
PO, then
50200 mg IV/
PO every 24 hr
Loading dose 100400 mg

Loading dose
100400 mg
IV/PO after
100400 mg IV/
IV/PO, then
each HD only PO, then
50200 mg
50200 mg IV/
IV/PO every
PO every 24 hr
24 hr
Itraconazole
(Sporanox)
200 mg IV every
12 hr
200 mg IV every
12 hr
200 mg IV every
12 hr
200 mg IV
every 24 hr
200 mg IV
every 24 hr;
administer
after HD
200 mg IV every
12 hr
Ketoconazole
(Nizoral)
200 mg PO
every 24 hr
No change
No change
No change
No change
No change
Must have low

gastric pH for
sufficient drug
absorption
510 mg/kg IV
every 8 hr
510 mg/kg IV
every 12 hr
510 mg/kg IV
every 24 hr
2.55 mg/kg 2.55 mg/kg

IV every 24 hr IV every 24
hr; administer
after HD
510 mg/kg IV
every 24 hr
To help avoid
nephrotoxicity
following IV
acyclovir, it is
recommended
that the patient
have 1 ml of
urine for each
1.3 mg of
acyclovir
administered;
adequate
hydration is
essential [103]
Shake IV bag
every 2 hr to mix
contents
Antiviral agents
Acyclovir
(Zovirax)
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Amantadine
(Symmetrel)
100 mg PO
every 12 hr
100 mg PO
every 24 hr
100 mg PO
every 48 hr
200 mg every
7 days
200 mg every
7 days
100 mg PO
every 48 hr
Ganciclovir
(Cytovene)
Induction: 5
mg/kg IV every
12 hr;
maintenance: 5
mg/kg IV every
24 hr
Induction: 2.5
mg/kg IV every
24 hr;
maintenance:
1.25 mg/kg IV
every 24 hr
Induction: 1.25
mg/kg IV every
24 hr;
maintenance:
0.625 mg/kg IV
every 24 hr
Induction:
1.25 mg IV
three times a
week;
maintenance:
0.625 mg/kg
IV three times
a week
Induction:
1.25 mg IV
three times a
week;
maintenance:
0.625 mg/kg
IV three times
a week
Induction: 1.25
mg/kg IV every
24 hr;
maintenance:
0.625 mg/kg IV
every 24 hr
Rimantadine
(Flumadine)
100 mg PO
every 12 hr
100 mg PO
every 12 hr
100 mg PO
every 12 hr
100 mg PO
every 24 hr
100 mg PO
every 24 hr
100 mg PO
every 12 hr
Notes
Accumulation of
ganciclovir
occurs in renal
tissue [104]
Anesthetics used in supportive care

Etomidate
(Amidate)
Induction: 0.3
mg/kg IV over
1560 sec;
maintenance
infusion 1020
g/kg/min
No change
No change
No change
No change
No change
Ketamine
(Ketalar)
Induction:
0.54.5 mg/kg
IV over 60 sec;
maintenance:
0.10.5 mg/min
No change
No change
No change
No change
No change
Methohexital
(Brevital)
Induction: 11.5 No change

mg/kg IV
administered at
10 mg/ml every
5 sec;
maintenance:
2040 mg/ml IV
every 47 min or
via continuous
infusion
No change
No change
No change
No change
Propofol
(Diprivan)
ICU sedation:
No change
Induction: 5 g/
kg/min for 5
min, increments
increasing by
510 g/kg/min
may be
required;
maintenance
infusions range
from 550 g/
kg/min
No change
No change
No change
No change
Thiopental
(Pentothal)
Anesthesia
induction:
50100 mg IV
every 3040 sec
until desired
effect
Anesthesia
induction:
50100 mg IV
every 3040 sec
until desired
effect
Anesthesia
induction:
50100 mg IV
every 3040 sec
until desired
effect
Anesthesia
induction:
2575 mg IV
every 3040
sec until
desired effect
Anesthesia
induction:
2575 mg IV
every 3040
sec until
desired effect
Anesthesia
induction:
50100 mg IV
every 3040 sec
until desired
effect
Fentanyl
(Sublimaze)
For pain: 0.5 g/

kg IV every 12
hr; titrate for
pain control
No change
0.375 g/kg IV
every 12 hr
0.25 g/kg IV
every 12 hr
0.25 g/kg IV
every 12 hr
0.375 g/kg IV
every 12 hr
Doses for
anesthesia
induction
generally do not
vary in patients
with renal
failure because
of the one-time
dose
Hydromorphone
(Dilaudid)
12 mg IV every No change
46 hr; titrate for
pain control
No change
No change
No change
No change
Hepatically
metabolized
Opioids
Appendix: Continued
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Meperidine
(Demerol)
50100 mg IV
every 34 hr;
titrate for pain
control
37.575 mg IV
every 34 hr;
titrate for pain
control
37.575 mg IV
every 34 hr;
titrate for pain
control
2550 mg IV
every 34 hr;
titrate for
pain control
Avoid
37.575 mg IV
every 34 hr;
titrate for pain
control
Normeperidine,
a toxic
metabolite,
effects the CNS
and can lead to
seizure when
meperidine is
used in patients
with renal
failure [105]
Morphine
215 mg IV
every 24 hr;
titrate for pain
control
1.512 mg IV
every 24 hr;
titrate for pain
control
1.512 mg IV
every 24 hr;
titrate for pain
control
18 mg IV
every 24 hr;
titrate for
pain control
18 mg IV
every 24 hr;
titrate for pain
control
1.512 mg IV
every 24 hr;
titrate for pain
control
Although
morphine is
hepatically
metabolized,
dose adjustment
in renal
insufficiency is
recommended
to avoid
accumulation of
morphine-6glucuronide,
which may have
narcotic activity
[106]
Sufentanyl
(Sufenta)
15 g/kg IV for
anesthesia
induction
No change
No change
No change
No change
No change
No change
No change
No change
No change
Notes
Opioid agonists/antagonists and antagonists

Buprenorphine
(Buprenex)
0.30.6 mg IV
every 6 hr
No change
Butorphanol
(Stadol)
0.52 mg IV
every 34 hr
0.3751.5 mg IV 0.3751.5 mg IV 0.251 mg IV

every 34 hr
every 34 hr
every 34 hr
0.251 mg IV
every 34 hr
0.3751.5 mg IV Increased
every 34 hr
sensitivity to
butorphanol
exists in ESRD
Flumazenil
(Romazicon)
0.2 mg IV every
15 sec until
reversal occurs
or a total of 1 mg
total has been
administered
No change
No change
No change
No change
No change
Naloxone
(Narcan)
0.42 mg IV
No change
every 23 min to
desired
response or a
maximum dose
of 10 mg has
been
administered
No change
No change
No change
No change
Pentazocine
(Talwin)
30 mg IV every
34 hr for pain
20 mg IV every
34 hr for pain
15 mg IV
every 34 hr
for pain
15 mg IV
every 34 hr
for pain;
administer at
the end of HD
20 mg IV every
34 hr for pain
20 mg IV every
34 hr for pain
Nonsteroidal anti-inflammatory medications

Ibuprofen
(Motrin)
200800 mg PO
every 6 hr
No change
No change
No change
No change
No change
Indomethacin
(Indocin)
2550 mg PO
every 812 hr
No change
No change
No change
No change
No change
Increased
sensitivity to
pentazocine
exists in ESRD
Appendix: Continued
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Drug
Normal Dose
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Ketorolac
(Toradol)
IM: 60 mg
loading dose,
then 1530 mg
every 6 hr; IV: 30
mg loading
dose, then 15
mg every 6 hr
IM: 60 mg
loading dose,
then 1530 mg
every 6 hr; IV:
30 mg loading
dose, then 15
mg every 6 hr
IM: 60 mg
loading dose,
then 1530 mg
every 6 hr; IV:
30 mg loading
dose, then 15
mg every 6 hr
IM/IV: 15 mg
every 6 hr
without
bolus dose
IM/IV: 15 mg
every 6 hr
without bolus
dose
IM: 60 mg
loading dose,
then 1530 mg
every 6 hr; IV:
30 mg loading
dose, then 15
mg IV every 6 hr
Pharmacokinetic
parameters
including
decreased
plasma
clearance,
prolonged halflife, and
decreased
protein binding
may warrant
adjustment in
renal failure
[107]
Naproxen
(Naprosyn)
250500 mg PO
every 812 hr
No change
No change
No change
No change
No change
In patients with
CrCl <20 ml/min
the
manufacturer
recommends
considering
dose adjustment
secondary to
metabolite
accumulation,
however,
guidelines have
not been
provided
Metoclopramide
(Reglan)
1020 mg IV
every 6 hr
7.515 mg IV
every 6 hr
7.515 mg IV
every 6 hr
510 mg IV
every 6 hr
510 mg IV
every 6 hr;
administer at
the end of HD
7.515 mg IV
every 6 hr
Erythromycin (Emycin)
250 mg PO
every 8 hr
No change
No change
No change
No change
No change
Notes
Prokinetic agents
Parenteral antiemetics
Dolasetron
(Anzemet)
Chemotherapy
induced N/V:
1.8 mg/kg or
100 mg IV
administered 30
min prior to
chemotherapy;
postoperative
N/V: 12.5 mg IV
15 min prior to
stopping
anesthesia
No change
No change
No change
No change
No change
Granisetron
(Kytril)
Chemotherapy
induced N/V: 10
g/kg IV
administered 30
min prior to
chemotherapy;
postoperative
N/V: 2040 g/
kg
No change
No change
No change
No change
No change
Study
performed in
patients with
diabetic
gastroparesis
[108]
Appendix: Continued
CrCl
(3050 ml/min)
CrCl
(1030 ml/min)
CrCl
Hemodialysis
(<10 ml/min) (HD)
Continuous
Hemoperfusion
(CAVHD/
CVVHD)
Treatment of
chemotherapyinduced N/V: 2
mg/kg IV every
24 hr 25
doses; delayed
N/V: 0.5 mg/kg
or 30 mg IV
every 46 hr
35 days
Treatment of
chemotherapyinduced N/V:
1.5 mg/kg IV
every 24 hr
25 doses;
delayed N/V:
0.375 mg/kg or
20 mg IV every
46 hr 35
days
Treatment of
1.5 mg/kg IV
every 24 hr
25 doses;
delayed N/V:
0.375 mg/kg or
20 mg IV every
46 hr 35
days
Treatment of
1 mg/kg IV
every 24 hr
25 doses;
delayed N/V:
0.25 mg/kg
or 15 mg IV
every 46 hr
35 days
Treatment of
1 mg/kg IV
every 24 hr
25 doses;
delayed N/V:
0.25 mg/kg or
15 mg IV
every 46 hr
35 days
Treatment of
1.5 mg/kg IV
every 24 hr
25 doses;
delayed N/V:
0.375 mg/kg or
20 mg IV every
46 hr 35
days
Ondansetron
(Zofran)
Treatment of
chemotherapyinduced N/V: 8
mg IV 30 min
prior to
chemotherapy;
postoperative
N/V: 4 mg IV at
the end of the
procedure
No change
No change
No change
No change
No change
Prochlorperazine
(Compazine)
510 mg IV
every 6 hr
No change
No change
No change
No change
No change
Trimethobenzamide (Tigan)
200 mg IM every
68 hr
No change
No change
No change
No change
No change
Drug
Normal Dose
Metoclopramide
(Reglan)
Notes
H2-receptor blockers
Cimetidine
(Tagamet)
300 mg IV every
6 hr or 37.550
mg/hr
continuous
infusion
300 mg IV every
8 hr or 2537.5
mg/hr
continuous
infusion
300 mg IV every
8 hr or 2537.5
mg/hr
continuous
infusion
300 mg IV
every 12 hr or
1825 mg/hr
continuous
infusion
300 mg IV
every 12 hr
administered
at the end of
HD
300 mg IV every
8 hr or 2537.5
mg/hr
continuous
infusion
Famotidine
(Pepcid)
2040 mg IV
every 12 hr
20 mg IV every
12 hr
20 mg IV every
12 hr
20 mg IV
every 24 hr or
40 mg IV
every 48 hr
20 mg IV
every 24 hr
administered
at the end of
HD
20 mg IV every
12 hr
150 mg PO
every 24 hr
150 mg PO
every 24 hr
150 mg PO
every 48 hr
150 mg PO
every 48 hr
150 mg PO
every 24 hr
50 mg IV every
12 hr
50 mg IV
every 24 hr
50 mg IV
every 24 hr
administered
at the end of
HD
50 mg IV every
12 hr
Nizatidine (Axid) 150 mg PO

every 12 hr or
300 mg PO at
bedtime
Ranitidine
(Zantac)
50 mg IV every 50 mg IV every
8 hr or 6.25 mg/ 12 hr
hr continuous
infusion
Proton pump inhibitors

Lansoprazole
(Prevacid)
1530 mg PO
every 1224 hr
No change
No change
No change
No change
No change
Omeprazole
(Prilosec)
2040 mg PO
every 1224 hr
No change
No change
No change
No change
No change
Pantoprazole
(Protonix)
2080 mg PO
every 24 hr; IV
dosing not yet
established
No change
No change
No change
Do not
exceed 40
mg/day
No change
Cytochrome P450 enzyme

inhibitor
For best acid

control results,
daily doses
should be
administered at
bedtime

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ANALYTIC REVIEWS

Drug Dosing in Critically Ill Patients with Renal

Accurate pharmacotherapy management in the intensive

Critically ill patients often have multiple medical

Pharmacokinetics and Pharmacodynamics

Address correspondence to Ronald J. DeBellis, Department of

274 Journal of Intensive Care Medicine Vol 15 No 6 November/December 2000

apply general pharmacokinetic and pharmacodynamic principles in order to construct an effective

Fig 1. The relationship between pharmacokinetics and pharmacodynamics.

DeBellis et al.: Drug Dosing in Renal Failure 275

administered by any route requiring absorption can

Zero- and First-Order Kinetics

Fig 2. Compartmental drug model.

276 Journal of Intensive Care Medicine Vol 15 No 6 November/December 2000

Fig 4. Logarithm of plasma concentration (Cp) versus

A drugs half-life (t1/2) is a constant value determined

DeBellis et al.: Drug Dosing in Renal Failure 277

Elimination Rate Constant

The elimination rate constant for a drug can be

Cp(0) is the plasma concentration of the drug at

The volume of distribution is most commonly

The time (t) is the time difference between when

Clearance (Cl) is the term describing the volume

Cpmax dose/Vd or Vd dose/Cpmax.

ClTB ClR ClM ClX.

The rate of elimination and half-life are constants

278 Journal of Intensive Care Medicine Vol 15 No 6 November/December 2000

Clearance through an organ is determined by the

Changes in blood flow to the organ responsible

Effects of Impaired Glomerular Filtration

Using pharmacokinetics to calculate Kel and Vd, it

Renal Drug Excretion

Impairment of glomerular filtration can lead to a

Table 1. Factors Influencing Glomerular Filtration of Drugs [1618]

Effect on Glomerular Filtration

Drug filtration decreases as hydrostatic pressure decreases

DeBellis et al.: Drug Dosing in Renal Failure 279

free or unbound drug. There are two main transport

Decreased cardiac output leads to decreased GFR. Homeostatic mechanisms attempt

Renal plasma flow

Renal tubule obstruction

Table 3. Drugs Secreted by Anionic and Cationic Transport Systems [2227]

280 Journal of Intensive Care Medicine Vol 15 No 6 November/December 2000

Pharmacokinetic Changes in Critically Ill

Effects of Impaired Tubular Secretion on

Table 4. Factors Influencing Tubular Reabsorption [16,22,26]

Effect on Tubular Reabsorption

Lipid solubility of the drug

Increased reabsorption with increased lipid solubility

DeBellis et al.: Drug Dosing in Renal Failure 281

Table 5. Drugs with pH-Dependent Elimination [16]

occurs [19]. The elevated gastric pH may impair the

basic drugs tend to bind to 1-glycoprotein. Drugs

Table 6. Bioavailability of Drugs in Patients with Renal

Adopted from [23].

282 Journal of Intensive Care Medicine Vol 15 No 6 November/December 2000

of distribution and protein binding by altering the

Principles of Drug Elimination Via Dialysis

DeBellis et al.: Drug Dosing in Renal Failure 283

rectly according to the degree, if any, of residual

side of the membrane, a negative pressure on the

Conventional hemodialysis (HD)

Dialysis Drug Clearance