drug dosing renal failure

ANALYTIC REVIEWS

Drug Dosing in Critically Ill Patients with RenalFailure: 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 Critically ill patients often have multiple medicalin critically ill patients with renal failure: a pharmacokinetic

problems and commonly receive complex medica-approach. J Intensive Care Med 2000;15:273313.tion regimens. These factors make critically ill pa-

Accurate pharmacotherapy management in the intensive tients highly susceptible to adverse drug events.care unit (ICU) patient is crucial to minimize adverse drug Adverse drug events have been shown occur inevents. Pharmacokinetic principles including absorption,

1012% of intensive care unit (ICU) patients anddistribution, metabolism, and excretion (ADME) all play anoccur approximately two times more frequentlyimportant role in determining the fate of medications used

in the critical care setting. Renal failure in this setting further when compared to patients on general medicinealters pharmacokinetic parameters, resulting in drug dosing units [1,2]. Patients who are critically ill are also atchanges. This article highlights and applies principles of drug increased risk for developing renal failure. Acutedosing in normal patients and in the pharmacokinetically

renal failure occurs in 725% of all patients admittedchallenging environment of critically ill patients with renalto ICUs and increases the average mortality fromfailure. Specific drug dosing tables serve as a guide for the

clinician to renally adjust medication doses in the critically approximately 15% to more than 60% [39]. Renalill patient with renal failure. failure is a risk factor for adverse drug events and

likely contributes to the high rate of adverse drugevents in critically ill patients. Up to 45% of patientswith an estimated creatinine clearance less than 40ml/min receive medications that are dosed 2.5 timeshigher than the maximum recommended dose [10].In addition, adverse drug reactions have beenshown to occur in 9% of patients with blood ureanitrogen (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 patientsat risk for morbidity and mortality, resulting in theutilization of tremendous financial resources. It hasbeen estimated that each adverse drug event in-creases hospital costs by $2,000$4,600 [1214]. Thecost of adverse drug events in patients admitted toan ICU have the potential to be higher due to theaugmented cost of an ICU bed. Accurate drugdosing in a pharmacokinetically challenging envi-ronment is essential to ensure optimal pharmaco-therapy in critically ill patients. This particularlyapplies to patients with renal failure. The followingreview will discuss some key concepts and theories

From the *Massachusetts College of Pharmacy and Health Sci- of drug dosing in critically ill patients. In addition,ences, University of Massachusetts School of Medicine, Univer-

practical guidelines for drug dosing in the criticallysity of Massachusetts Memorial Health Care, Worcester, MA,Regional Medical Center at Memphis, Memphis, TN, and Uni- ill patient with renal failure are delineated.versity of Maryland Medical Center, Baltimore, MD.

Received Jun 2, 2000, and in revised form Jul 17, 2000. Accepted Pharmacokinetics and Pharmacodynamicsfor publication Jul 18, 2000.

Address correspondence to Ronald J. DeBellis, Department ofIn order to comprehend the disposition of medica-Pharmacy, University Campus, 55 Lake Ave. N, Worcester, MA

01655, or e-mail: [email protected] tions in patients with renal failure, the clinician mustCopyright q 2000 Blackwell Science, Inc. 273

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

apply general pharmacokinetic and pharmacody- that will provide the practitioner with an under-standing of pharmacokinetics as it relates to drugnamic principles in order to construct an effective

and safe medication regimen. Pharmacokinetics de- dosing in the critically ill patient.Compartmental models are methods to mathe-scribes the processes influencing a drug's transport

through the body to its site of action. The processes matically describe and conceptualize pharmacoki-netic processes. A drug can be described in termsaffecting a drug's transport through the body are

absorption, distribution, metabolism, and elimina- of a one-, two-, or multicompartment model. One-compartment models do not precisely represent thetion (ADME). Clinical pharmacokinetics is the appli-

cation of these principles to individualize drug pharmacokinetics of most drugs, but the equationsused to describe one-compartment models are clin-therapy based on patient-specific information with

the goal of maximizing therapeutic outcomes while ically most useful. Two- and multicompartmentmodels more accurately describe the pharmacoki-minimizing the risk of toxicity. Pharmacodynamics

describes the relationship between a drug's con- netics of most drugs, but the equations needed todescribe these models are very complex and arecentration at the site of action and the ensuing phar-

macologic response. The relationship between not clinically practical. We will review the conceptsof a one-compartment model because the conceptspharmacokinetics and pharmacodynamics can be

described as the dose of a drug that provides a suffi- are clinically useful and they can be applied to two-and multicompartment models.cient drug concentration at the site of action in order

to elicit a biologic response (Fig 1). There are many In a one-compartment model, the drug entersthe central or vascular compartment either by directfactors in critically ill patients with renal failure that

will alter the pharmacokinetics and phar- intravenous injection or by other routes requiringabsorption. Drugs administered intravenously willmacodynamics of drugs and necessitate modifica-

tion of the drug therapy regimen. Before we discuss have 100% bioavailability or 100% of the adminis-tered dose reaches the systemic circulation. Bio-the changes that occur in critically ill patients with

renal failure,wewill briefly reviewpharmacokinetic availability refers to both the rate and extent ofabsorption and is defined as the relationship be-models and pharmacokinetic terminology.tween the total amount of drug and how fast thatdrug is absorbed from a nonintravenous route com-

Pharmacokinetic Models pared to the same dose administered intravenously.Drug absorption can occur through many differentmembranes including the gastrointestinal tract,Many mathematical models and equations have

been developed to describe pharmacokinetic pro- skin, subcutaneous or intramuscular tissue, lungs,or any other membrane. The bioavailability of drugscesses. The aim is to focus on concepts and ideas

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 Zero- and First-Order Kineticsbe highly variable. Once a drug is in the centralcompartment, it can bind to plasma proteins, pri-marily albumin or a1-glycoprotein, and may be pH Most drugs used in critically ill patients will follow

principles associated with first-order or linear phar-dependent. The drug will then achieve a state ofequilibrium between the unbound and bound state. macokinetics, however, some drugs demonstrate

zero-order or nonlinear kinetics. For example, phe-Only unbound or free drug is available to exert apharmacologic effect, and to be metabolized and/ nytoin follows zero-order pharmacokinetic princi-

ples or MichaelisMenten kinetics. Drugs areor eliminated. Unbound drug is primarily metabo-lized and eliminated from the central compartment described as exhibiting zero-order pharmacokinet-

ics when a constant quantity or amount of drug isvia the liver and kidneys, the major metabolic andelimination pathways (Fig 2). removed per unit of time. As the plasma concentra-

tion of the drug decreases or increases, the quantityIn two- and multicompartment models, all thesame processes of a one-compartment model or amount eliminated remains the same. Zero-order

kinetics is a result of metabolism by a saturatedoccur, but the drug will also distribute to peripheralcompartments such as adipose tissue, muscle tis- enzyme system eliminating drug at a constant rate

despite the serum concentration of the drug. Clini-sue, or the central nervous system. When theamount of unbound drug going into and coming cally this means small increases in the drug's dose

can lead to large increases in the plasma concentra-from various compartments is equal, a state of equi-librium is achieved. The phase where drug is tion, hence the term nonlinear pharmacokinetics

(Fig 3). Because there are few drugs that followachieving a state of equilibrium between compart-ments is called the distribution phase. Similar to zero-order pharmacokinetics, attention will be di-

rected toward drugs following principles of first-one-compartment models, unbound drug in thecentral compartment is often metabolized and elim- order or linear pharmacokinetics.

Medications that demonstrate first-order or linearinated through the liver and kidney, though somedrugs can be metabolized and/or eliminated in pe- pharmacokinetics eliminate or dispose of a constant

percentage of drug from the plasma per unit ofripheral compartments as well.

Fig 2. Compartmental drug model.aDrugs administered intravenously enter the central compartment directly.bDrugs administered by any route other than intravenously must be absorbed before entering the central compartment.cDistribution to peripheral compartments only occurs in two or multicompartment models.dIn a one-compartment model, drug interacts with its receptor directly from the central compartment.


time required for a drug to reach equilibrium be-tween the central and peripheral compartments.Drug such as gentamicin demonstrate an alphaelimination phase. It is this phase that is importantin causing acute tubular necrosis. This is importantto keep in mind because most drugs take time todistribute. When drawing blood levels, it is im-portant to know the time required for the distribu-tion phase to complete. Obtaining plasma drugconcentrations prior to completion of distributionwill yield falsely elevated levels. This will ensureclinical decisions are not made on falsely elevateddrug levels that have not fully distributed to othertissues. Once distribution is complete, the slope

Fig 3. Effect of increasing daily dose on average steady- changes and is referred to as the beta or eliminationstate drug concentrations for drugs undergoing nonlinear

phase. The slope of the elimination phase is theor zero order pharmacokinetic modeling ( ). Effectelimination rate constant (Kel) and can be used toof increasing daily dose on average steady-state drugdetermine the drugs half-life (t1/2).concentrations for drugs undergoing linear or first order

pharmacokinetic modeling ( _____ ).

Half-Lifetime. As the plasma concentration increases, the

A drug's half-life (t1/2) is a constant value determinedamount of drug eliminated increases (a directly pro-by the function of the metabolizing and eliminatingportional relationship). As the plasma concentra-processes. The definition of a drug's half-life is thetion decreases, the amount of drug eliminatedamount of time required for the concentration ofdecreases. In a clinical sense, if the dose of a drugthe drug to decrease by 50%. Half-life is often ex-is increased, the plasma concentration increasespressed in minutes or hours. The half-life of a spe-proportionally as well as the amount eliminatedcific drug will remain the same as long as the(Fig 3). Regardless of the plasma concentration, thefunction of the metabolizing and eliminating pro-percentage that is eliminated remains constant. Ifcesses remains constant. For example, if it takes 8the logarithm of the plasma concentration versushours for the plasma concentration of a drug totime for a drug is plotted, one will see two differentdecline from 10 mg/L to 5 mg/L, the plasma half-slopes (Fig 4). The upper portion is referred to aslife is 8 hours. If, however, there is a change inthe alpha or distribution phase and represents therenal function, the half-life can be significantly pro-longed.

The half-life of a drug can be used to determinethe time required for a drug to be eliminated fromthe body, as well as the time required to reachsteady state. From a pharmacokinetic perspec-tive, it takes three to five half-lives to achieve87.596.875% of steady-state drug concentration(the point where the amount of drug going into thebody equals the amount being eliminated). Concur-rently it takes the same period of time for a drugto be 87.596.875% eliminated from the body. Thisis important since a clinician should generally waitfor steady state prior to drawing a blood level orincreasing the dose of a medication. Knowing howlong it will take before a drug is almost completelyremoved can help a clinician judge how long itshould take for a pharmacologic or toxic effect towear off [15]. It is important for a clinician to keep inFig 4. Logarithm of plasma concentration (Cp) versusmind that the pharmacodynamic behavior of sometime plot for a drug following rapid intravenous injectiondrugs may correlate with pharmacologic activitydelineating both the alpha distribution and beta elimina-

tion phase. regardless of pharmacokinetic drug behavior. Some


The volume of distribution is most commonlydrugs can stay at receptor sites and have pharmaco-logic activity long after the plasma concentration expressed in terms of liters (L) or liters per kilogram

(L/kg). It is important to remember that the volumehas decreased. For example, consider the extendedspectrum macrolide antibiotic azithromycin. A pa- of distribution is a theoretical volume, not a physio-

logical volume. For example, if a 700 mg dose oftient generally requires 5 days of therapy for mostinfections, however, administration of this drug for a drug administered intravenously to a 70 kg patient

results in a calculated maximum plasma concentra-5 days is the same as receiving 910 days of therapyfrom other antimicrobial agents. Understanding a tion of 7 mg/L, it appears as if the drug is dissolved

in 100 L of fluid. The volume of distribution woulddrug's pharmacokinetic and pharmacodynamicprofile is necessary to appropriately use it's half- be 100 L or 1.429 L/kg. Obviously under normal

physiologic conditions, a 70 kg adult does not havelife to dose and assess the response in critically illpatients with renal failure. 100 L of fluid in their body. A drug can have such

a high volume of distribution as a result of plasmaprotein binding and/or distribution to other com-Elimination Rate Constantpartments (intracellular space, lipid compartments,muscle). Protein binding or distribution to periph-

As mentioned earlier, most drugs follow first-ordereral compartments leads to a larger volume of distri-

models of elimination. The elimination rate con-bution by reducing the amount of measurable drug

stant (Kel) determines the rate of elimination from in the plasma. Drugs that are not highly bound tothe body. With first-order elimination, a constant

proteins and/or drugs that do not distribute out ofpercentage of drug is removed from the plasma per

the central (vascular) compartment will tend tounit of time and is often expressed as per minute

have lower volumes of distribution closer to theor per hour. The elimination rate constant for a

intravascular volume.drug can represent total body elimination (Kel) or In clinical situations it is difficult to calculate ait can be broken down into the specific organs

drug's volume of distribution. The equation aboveresponsible for elimination, such as renal (Kr) or assumes an intravenous bolus of a drug, instanta-metabolic (Km) [15]: neous distribution, and the maximum plasma con-

centration that immediately results. This cannot beKel 4 Kr Km. (1)accomplished in clinical situations. The maximum

The elimination rate constant for a drug can be plasma concentration (Cpmax) has to be calculateddetermined by plotting the logarithm of the drug or back-extrapolated from a measured peak plasmaplasma concentration (Cp) over time (t) and de- concentration (Cppeak). The following equation istermining the slope of the line after distribution has commonly used to calculate Cpmax [15]:occurred (Fig 4). The following equation describeslinear or first-order elimination [15]: Cpmax 4 measured Cp/e(Kel)(t). (5)

Cp(0) 4 Cp(t)e(Kel)(t). (2) The time (t) is the time difference between whenthe dose was administered and when the peakCp(0) is the plasma concentration of the drug atplasma concentration (measured Cp) was drawn.time zero, Cp(t) is the plasma concentration of the

drug at time (t), and (Kel) is the elimination rateconstant. The elimination rate constant is also in-

Clearanceversely proportional the drug's half-life (t1/2) [15]:

Clearance (Cl) is the term describing the volumet1/2 4 0.693/Kel. (3)of fluid cleared of drug over time, usually in millili-

The rate of elimination and half-life are constants ters per minute. Total body clearance (ClTB) repre-and do not change unless the function of the metab- sents all the processes involved in removing a drugolizing and/or eliminating processes change. from the body. Clearance can be broken down into

the individual organs or processes that are responsi-ble for the elimination of drug from the body, suchVolume of Distributionas renal clearance (ClR), metabolic clearance (ClM),or any other process that eliminates drug (ClX) fromThe volume of distribution (Vd) is a parameter relat-the body. Total body clearance is the sum of all theing the dose of a drug to the maximum plasmaclearance processes in the body [15]:concentration (Cpmax) [15]:

ClTB 4 ClR ClM ClX. (6)Cpmax 4 dose/Vd or Vd 4 dose/Cpmax. (4)


Clearance through an organ is determined by the Glomerular Filtrationblood flow to the organ (Q) and the extractionratio (ER) for the organ. Blood flow to the organ Plasma flow to the kidney is approximately 650700is expressed as a unit of volume per time, often ml/min in a healthy adult. Of this amount, aboutmilliliters per minute. The extraction ratio is the 20% is filtered at the glomerulus. Glomerular filtra-percentage or fraction of drug removed from the tion is the most common means of drug excretionblood as a result of passing through the organ and by the kidneys [1618]. Drug excretion via glomeru-has no units. The extraction ratio depends on the lar filtration is a passive, first-order process. Drugfraction of free drug presenting to the organ, the rate excretion is a function of the glomerular filtrationof blood flow through the organ, and the intrinsic rate (GFR) and the percentage of free unboundability of the organ to eliminate drug [15]: drug. The unbound drug is filtered through pores

in the glomerular capillaries called fenestrae. TheCl 4 (Q)(ER). (7) pores in the glomerular capillaries are much larger

than pores found in other capillaries, making themChanges in blood flow to the organ responsible much more permeable to solutes. The GFR for an

for clearing the drug or any factor altering the ex- average healthy adult is 100125 ml/min [1618].traction ratio of a drug will alter a drug's clearance. The GFR depends on the hydrostatic pressure orFor example, a patient experiencing septic or car- renal plasma flow and osmotic pressure gradientsdiogenic shock may have impaired blood flow to between the glomerulus and Bowman's capsule.the liver or kidneys impairing the clearance of a There are many factors influencing the amount ofparticular drug. In addition, if a pharmacologic va- drug filtered at the glomerulus. Table 1 lists thesesopressor is added to the therapy, blood flow to factors and how they influence drug filtration.the gastrointestinal tract may be compromised, re-sulting in a decreased transport of drug to targetsite. Clearance is also equal to the product of theelimination rate constant (Kel) and the volume of

Effects of Impaired Glomerular Filtrationdistribution (Vd) [15]:on Drug Elimination

Cl 4 (Kel)(Vd). (8)Impairment of glomerular filtration can lead to aclinically significant accumulation of drug and/orUsing pharmacokinetics to calculate Kel and Vd, itits metabolites. To assess the likely impact of de-is possible to calculate a drugs clearance from thecreased glomerular filtration, it is important to knowbody.Again, it is easy to see that changes in theelimi-what fraction of a drug is renally eliminated, as wellnation rate constant and/or volume of distributionas the excretion method for any active or toxicwill affect a drug's clearance from the body.metabolites [16,17]. Drugs excreted primarily byglomerular filtration will be filtered at a rate that is

Renal Drug Excretion proportional to the patients GFR (first order) andthe percentage of free drug in the plasma, since

The kidney is the primary organ responsible for the only free, unbound drug can be filtered:excretion of drugs and their metabolites. The threemain processes by which the kidney excretes drugs

Rate ofinclude glomerular filtration, tubular secretion, and4 (GFR) (free drug in plasma) (9)

drug filtrationtubular reabsorption.

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

Factor Effect on Glomerular Filtration

Hydrostatic pressure Drug filtration decreases as hydrostatic pressure decreasesPlasma protein binding Drug filtration decreases as plasma protein binding increasesVolume of distribution High volume of distribution decreases the amount of drug available to be filteredMolecular size Drug filtration decreases as molecular size increases (MW less than 5 kDa and

radii less than 15 A )Glomerular integrity Drug filtration increases as membrane integrity decreasesNumber of functioning nephrons Drug filtration decreases as the number of functioning nephrons decreases


For example, if a drug is excreted solely by filtra- free or unbound drug. There are two main transportsystems for drugs in the proximal tubule. One trans-tion and the GFR decreases by 50%, drug excretion

will also decrease by 50%. There are many mecha- port system is for anions and the other transportsystem is for cations [16,2227]. These secretorynisms by which GFR is altered. Table 2 summarizes

the major factors and mechanisms. transport systems are not fully understood and theremay be more than one transport subtype for eachsystem responsible for eliminating different sub-

Tubular Secretion stances. Drugs can compete for secretion with otherdrugs and endogenous substances secreted by thesame transporter, since they are saturable [2427].As mentioned before, 20% of the plasma flow is

filtered at the level of the glomerulus. The re- An example of competition for secretion via ananionic transporter is probenecid with penicillinsmaining 425600 ml/min of renal plasma flow not

filtered at the glomerulus is directed to the peritubu- or cephalosporins [28]. This combination has beenused to prolong the half-life of penicillin. Table 3lar capillaries, where drugs may be secreted. Tubu-

lar secretion is an active process where drugs are is a list of drugs actively secreted by the kidney.It is difficult to study drug secretion interactionstransported by membrane proteins from the intersti-

tial fluid surrounding the proximal tubule and se- because most drugs are metabolized and eliminatedby multiple processes. This makes it difficult tocreted into the lumen. Tubular secretion rate

depends on the intrinsic activity of the transporter, study the effects of secretion alone with all theseother processes occurring simultaneously. Studiesproximal tubule blood flow, and the percentage of

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 attemptto maintain blood flow to the heart, brain, and muscle at the expense of thekidney.

Renal plasma flow Decreased plasma flow to the kidney resulting in proportional decrease in GFR.Glomerular basement Increased permeability results in increased clearance rate of protein bound-drugs.

For example, with membrane permeability in nephrotic syndrome the glomerularbasement membrane loses negative charge, allowing albumin and other largemolecules to cross the barrier.

Renal tubule obstruction Tubular blockage with casts, cellular debris, or cellular swelling leading to decreasedGFR.

Reabsorption via back-leak Decreased GFR with luminal fluid back-leak into the interstitium and renal venousblood; caused by damaged epithelium in moderate to severe acute renal failure.

Decreased glomerular filtration Decreased GFR due to either afferent arteriolar vasoconstriction or efferent arteriolarcapillary hydraulic pressure vasodilation.

Drug induced Decreased GFR by drug-mediated prostaglandin inhibition.

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

Organic Anion TransportAcyclovir Acetazolamide Ampicillin Ascorbic acid BenzylpenicillinCaptopril Cephalosporins Cisplatin Clofibrate Ethacrynic acidFolic acid Furosemide Ibuprofen Indomethacin MethotrexateMoxalactam Nafcillin Naproxen Nitrofurantion OxalatePenicillin G Phenobarbital Probenecid Quinolones SalicylatesSulfonamides Thiazides Uric acid ZidovudineOrganic Cation TransportAcetylcholine Amantadine Amiloride Amphetamines Atropineb-blockers Cimetidine Creatinine Digoxin DisopyramideEphedrine Epinephrine Ethambutol Famotidine MetforminMethadone Morphine Nicotine Norepinephrine PindololProcainamide Pseudoephedrine Quinidine Quinine RanitidineSerotonin


evaluating changes in drug elimination in renal fail- Pharmacokinetic Changes in Critically Illure look at changes in total body clearance and/or Patients with Renal Failureincreases in blood concentration rather than excre-tion changes via secretion alone [2426].

There are many physiological changes that canoccur in a critically ill patient that will alter thepharmacokinetics of drugs. Overall, studies looking

Effects of Impaired Tubular Secretion on at specific pharmacokinetic changes in drugs inDrug Elimination critically ill patients are limited. Most pharmacoki-

netic studies are performed in healthy volunteersTubular secretion is an extremely efficient process or in patients with a specific disease state who arethat is capable of eliminating relatively large not critically ill. Critically ill patients are very dy-amounts of drug substances from the blood in a namic and often have multiple organ dysfunctionshort period of time [27]. When drugs are excreted or age-specific parameters potentially altering allfrom the body via tubular secretion, the rate of drug aspects of drug therapy. Some ADME changes thatclearance is greater than drug clearance via filtration can occur in critically ill patients, specifically those[26]. A decline in renal function impacts tubular with renal failure, will be addressed.secretion, as both endogenous and exogenous or-ganic acids and bases accumulate and compete fortransporters. This competition for the transporters Absorptionrequired for active secretion may lead to either drugtoxicity or lack of efficacy, however, it is not possi- There is a lack of abundant discussion concerningble to predict which is most likely to occur or the drug absorption in patients with renal failure [30].extent of the interaction [19]. Drug absorption in patients with renal failure may

be altered secondary to gastrointestinal edema,nausea and vomiting due to uremia, and delayed

Tubular Reabsorption gastric emptying [31,32]. Comorbid illnesses or con-ditions that commonly occur with renal diseasesuch as diabetic gastroparesis may also have aTubular reabsorption of drugs can occur by active

and/or passive processes. When ultrafiltrate passes significant effect on drug absorption. Patients re-ceiving peritoneal dialysis may experience compli-through the nephron, up to 99% of the filtered vol-

ume is reabsorbed. This can lead to a dramatic cations leading to peritonitis, which has beenshown to decrease gastrointestinal peristalsis, thusincrease in a drug's concentration in the tubule

as the volume decreases. This high concentration impairing the absorption process [19].In general, the average number of medicationsgradient of drug between the renal tubule and

plasma promotes passive diffusion from inside the taken by a patient in renal failure is eight [33,34].This setting provides the framework for multipletubule into the plasma. The properties that effect

passive tubular reabsorption are listed in Table 4. drug interactions. Specific drug interactions involv-ing decreased absorption secondary to chelationAltering urine pH has long been used to decrease

the amount of drug reabsorbed and enhance excre- manifest in patients taking phosphate binding ant-acids containing aluminum or calcium. Other enter-tion. Alkalinizing the urine can be used to enhance

the elimination of barbiturates (weak acids) by in- ally administered medications need to be spacedaround the antacid by at least 2 hours to minimizecreasing the fraction of ionized drug, which de-

creases the amount available for reabsorption [29]. chelation. Although these antacids are administeredfor the sole purpose of phosphate binding in renalTable 5 lists some drugs with pH-dependent elimi-

nation. failure patients, a subsequent increase in gastric pH

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

Factor Effect on Tubular Reabsorption

Lipid solubility of the drug Increased reabsorption with increased lipid solubilityDegree of ionization of the drug Decreased reabsorption with increased ionizationUrine pH Variable depending on if drug is acidic or basicUrine flow Decreased reabsorption as urine flow increasesConcentration gradient Increased reabsorption as concentration gradient increases


basic drugs tend to bind to a1-glycoprotein. DrugsTable 5. Drugs with pH-Dependent Elimination [16]like warfarin, phenytoin, valproic acid, and salicy-

Weak Acids Weak Bases lates are highly bound to albumin and can lead todisplacement-mediated drug interactions if admin-Phenobarbital Amphetaminesistered together [4345]. Even though drug displace-Salicylates Ephedrine

Sulfonamides N-acetylprocaninamide ment interactions occur, their clinical significanceProcanamide tends to be low. Drug-drug interactions do notPseudoephedrine occur primarily due to alteration in plasma proteinQuinidine binding, but they also occur in patients with poorTocanide renal function due to changes in the configurationTricyclic antidepressants of albumin [4648]. For example, the pharmacody-

namic effects of phenytoin and warfarin are in-creased in patients with renal failure. The decreasedbinding of drugs to albumin in patients with renaloccurs [19]. The elevated gastric pH may impair thefailure is thought to be due to the accumulation ofdissolution process of other enterally administeredsmall acidic molecules displacing these drugs frommedications, leading to incomplete drug absorp-binding sites or alterations in binding sites on thetion, particularly with acidic drugs. In addition, thealbumin molecules [49,50]. Critically ill patientsonset of drug action may be delayed secondary tooften have low albumin due to malnutrition and/decreased gastric emptying. The effects of enterallyor acute illness [52]. This can lead to higher freeadministered analgesics are often impaired in thisfractions of drugs and potentially increase the risksituation. Caution must be exercised in renal failureof toxicity. Drugs binding to a1-glycoprotein ap-patients with concomitant diabetic gastroparesis.pear to be less affected in critically ill patients withMetoclopramide or erythromycin are frequently ad-renal failure, even though it is an acute-phase re-ministered to enhance the motility of the gastroin-actant that increases with trauma, surgery, or acutetestinal tract. When these agents are administered,illness [49]. Any of these protein binding changesenteral absorption of medications is often de-may alter a drug's volume of distribution. For exam-creased due to an increase in gastrointestinal transitple, if plasma protein concentrations experience a[35].sudden decrease, and a patient is taking warfarin,Bioavailability studies, for the most part, are lack-the volume of distribution for that medication be-ing in critically ill patients. Most bioavailability stud-comes significantly smaller since warfarin is boundies are conducted in healthy adults versus criticallyto plasma proteins more than 90%. This occurrenceill patients, however, it is known that in a majoritybecomes significant by having warfarin exert moreof medications, the bioavailability in patients withof a pharmacodynamic effect by having less drugrenal failure is either unchanged or increasedbound to proteins that may result in an adverse(Table 6).event such as bleeding.

In addition, fluid status can be highly variable inDistribution a critically ill patient with renal failure, leading to

changes in a drug's volume of distribution. Accumu-lation of fluid in renal failure patients can result inAltered plasma protein binding in critically ill pa-

tients with renal failure can significantly change lower drug concentrations [52]. The clearance ofdrugs can be affected by changes in the volumedrug distribution. Drugs that bind to plasma pro-

teins exist in a state of equilibrium betweenunbound (free) and bound drug (not free), andsince the unbound drug exerts a pharmacologic Table 6. Bioavailability of Drugs in Patients with Renal

Disease [19,2932,3642]effect, decreased binding increases the amount ofdrug available to exert a pharmacologic effect and

Decreased Unchanged Increasedtherefore increases the risk of toxicity. Drug-drug

D-Xylose Cimetidine Bufuralolinteractions can occur when two highly plasma pro-Furosemide Ciprofloxacin Dextropropoxyphenetein-bound drugs compete for binding with thePindolol Codeine Dihydrocodeinesame plasma protein. A drug is considered to be

Digoxin Oxprenololhighly plasma protein bound when more than 90%Labetalol Propranololis bound to plasma proteins. Drugs that are boundTrimethoprim Tolamolol

to plasma proteins less than 90% are not consideredSulfamethoxazole

to be clinically significant binders. Anionic or acidicdrugs tend to bind to albumin, while cationic or Adopted from [23].


of distribution and protein binding by altering the Acute renal failure is often accompanied by meta-bolic acidosis and respiratory alkalosis. Dependingamount of unbound drug available to be metabo-

lized and/or eliminated. Despite the potential for on the pKa value of drugs, the pH difference be-tween plasma and tissue compartments may altermany changes in the distribution of drugs in criti-

cally ill patients with renal failure, it is often difficult the ionization of drug molecules and therefore af-fect tissue redistribution versus clearance [64]. Renalor impossible to predict these interactions. It is im-

portant for the clinician to be aware of the potential failure also impacts total body water and thereforedrug volume of distribution. Patients who have afor interaction and monitor for the signs of efficacy

and toxicity so interactions are recognized and cor- low level of serum albumin via decreased hepaticsynthesis, protein loss through increased vascularrected.permeability, or malnutrition will have a corres-ponding decrease in plasma protein binding of

Metabolism drugs [65]. This can lead to an increase in clearanceof drugs that are normally highly plasma proteinbound. Plasma protein binding can also be reducedMost drug dosage changes in patients with renal

failure are necessary due to reduced renal elimina- in conditions such as the nephrotic syndrome, pro-teinuria, conditions that alter the molecular struc-tion, however, some drugs can have altered meta-

bolic elimination due to renal failure. The kidneys ture of albumin, and with accumulation of uremictoxins that compete with drugs for protein bindinghave been found to have many drug metabolizing

systems, and it is likely that renal disease alters sites [64,66].Cardiovascular failure contributes to the reduc-renal drug metabolism as well as hepatic metabo-

lism [5356]. The exact mechanisms are not com- tion in renal drug clearance by two mechanisms:reduction in cardiac output and therefore reductionpletely defined, but one study suggested drugs

oxidized by the cytochrome P-450 2D6 isozyme are in renal plasma flow and increased hepatic conges-tion, and increased sympathetic drive leading tomore likely to be affected [57]. The clinical signifi-

cance of these effects in critically ill patients with shunting of blood away from the kidney in orderto protect blood flow to the heart, brain, and mus-renal disease remains to be further explored. Criti-

cally ill patients often have impaired metabolic cle. This reduction in the supply of oxygenatedblood may further affect drug clearance if anaerobicfunction from nonrenal causes; either from direct

damage to the liver (cirrhosis), decreased blood metabolism and metabolic acidosis ensue, poten-tially causing changes in the ionization of drugs.flow to the liver (shock, elderly), or as a result

of other medications that are enzyme inhibitors or Retention of fluid may then increase the drug vol-ume of distribution, further reducing drug clearanceinducers [5860]. Clearance 4 flow 2 extraction

ratio (Equation 7) mathematically delineates this [64,66]. Other conditions with profound vasodila-tion such as sepsis, systemic inflammatory responseconcept. Careful drug dosing and monitoring is es-

sential to ensure drug therapy is achieving the syndrome (SIRS), multiple organ dysfunction syn-drome (MODS), pancreatitis, and liver failure willdesired pharmacologic effects without causing ad-

verse events. also cause a decrease in renal drug elimination dueto decreased GFR and renal plasma flow [65]. Pa-tients with respiratory failure who are placed on

Elimination mechanical ventilation may have reduced cardiacoutput (due to increased mean intrathoracic pres-sure) and volume of distribution changes, in addi-Studies to determine drug pharmacology and clear-

ance in critically ill patients are usually performed tion to possible alkalosis or acidosis which canaffect drug disposition if clearance is pH sensitiveon patients undergoing anesthesia. Occasionally

the study population includes patients with chronic [65,66].disease to one organ that is stable. It is thereforedifficult to apply these study results to critically

Principles of Drug Elimination Via Dialysisill patients with unstable, multiple organ disease.Critically ill patients each have a unique combina-tion of factors that can affect renal drug clearance Drug elimination via dialysis deserves specific at-

tention since there are many variables unique to[61]. In addition to renal failure, which is relativelycommon in this patient population, the impact of dialysis that can affect drug clearance. Dialysis pa-

tients, on average, take more than eight differentother organ dysfunction such as liver, cardiovascu-lar, or respiratory failure, as well as malnutrition, medications [33,34]. It is therefore extremely im-

portant to adjust the drug dosing schedules cor-must be assessed [62,63].


rectly according to the degree, if any, of residual side of the membrane, a negative pressure on thedialysate side, or a combination of the two [68]. Inrenal function, together with the dialyzability of

the drugs. The way in which drug dosing should our drug tables we provide dosing information forhemodialysis (HD) and continuos arteriovenous/optimally be adjusted depends on the particular

drug characteristics and the type of dialysis to be venovenous hemodialysis (CAVHD/CVVHD). In-formation on drug dosing in peritoneal dialysis isused.not included since this is not a common dialysismodality in the critically ill patient population.

Types of Dialysis

Dialysis Drug ClearanceThere are two main types of dialysisdiffusive andconvectivewith many variations or combinations

Drug clearance via hemodialysis can be estimatedof these principles (Table 7). Diffusive dialysis in-as follows:volves the system of dialysate and blood separated

by a semipermeable membrane, with selectiveClHD 4 (Clurea)(60/MWdrug) (10)movement of substances down a concentration gra-

dient. In this way drugs that are capable of beingwhere ClHD is the drug's clearance by hemodialysis,dialyzed can be cleared from the blood, and electro-Clurea is the clearance of urea by the dialyzer (typi-lytes can be simultaneously replaced from the dialy-cally about 150 ml/min for standard dialyzers), andsate if needed. In convective dialysis, however,MWdrug is the molecular weight of the drug [33]. Ifsolutes are removed from blood via solvent draga drug has negligible clearance via dialysis, thenthat is independent of concentration gradients anda postdialysis replacement dose is not necessary;is not limited by drug molecule size. Conventionalhowever, if clearance is more efficient, then thehemodialysis describes a process that is primarilypercentage of the drug removed is usually calcu-diffusive with minimal convective losses, whereaslated and a replacement dose provided. In additionhemofiltration describes primarily convective sol-to taking into account the amount of drug removal,ute clearance. The terms ``high efficiency'' andit is also important to consider the degree of residual``high flux'' are used to indicate large membranerenal function of the patient, since additional dos-surface area and pore size, respectively [67]. Hemo-age may need to be administered to take this intodiafiltration indicates one-third convection andaccount.two-thirds high-flux diffusion [34]. Ultrafiltration re-

fers to removal of fluid volume from the patient[68]. In arteriovenous dialysis the driving force is

Components of Dialysis System andthe mean arterial pressure of the patient, whereasFactors That Affect Drug Removalfor venovenous dialysis the system relies on the

use of a mechanical blood pump. The driving pres-There are three main components to the dialysis sys-sure for ultrafiltration is established by one of threetem: blood, dialysate, and membrane. Changes toways: a positive pressure gradient on the bloodeach of these will affect drug removal. Table 8 sum-marizes how drug removal is affected by changes to

Table 7. Types of Dialysis the respective components [33,34,67,68]. Since in-formation pertaining to drug dosing in patients re-

Dialysis Typesceiving different types of dialysis is not always

Hemodialysis Conventional hemodialysis (HD) available, assessing the patient-specific dialysisContinuous arteriovenous method together with an analysis of the variables

hemodialysis (CAVHD) discussed above should provide a basis from whichContinuous venovenous to make clinical decisions on drug dosing regimens.

hemodialysis (CVVHD)Hemofiltration Continuous arteriovenous

hemofiltration (CAVH)Serum Drug Monitoring with DialysisContinuous venovenous

hemofiltration (CVVH)Hemodiafiltration Continuous arteriovenous If there is a known relationship between serum

hemodiafiltration (CAVHD) drug level and efficacy/toxicity, serum drug moni-Continuous venovenous toring can be a useful tool in drug dosing for dialysis

hemodiafiltration (CVVHD)patients. If a replacement dose of drug is provided

Ultrafiltration Slow continuous ultrafiltration (UF)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 adrug's dialyzability. Generally if MW > 1,000 Da, then convection is required rather thandiffusion to clear the drug.

Plasma protein binding Increased PPB results in a decreased amount of free drug available for dialysis. Note thatwith dialysis heparinization, lipoprotein lipase is induced which increases levels of freefatty acids (FFA). These FFA compete with certain drugs for protein binding sites.

Volume of distribution 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 willbe marginally dialyzable, and > 2 L/kg is unlikely to be dialyzable.

MembraneMembrane type Synthetic membranes tend to have higher ultrafiltration coefficients than those produced

from biologic materials. Modified biologic materials include cellulose and cupranederivatives. Synthetic materials include polysulfone, polycarbonate,polymethylmethacrylate, and polyacrylonitile-based materials.

Surface area Increased surface area leads to increased efficiency of drug clearance. However, as theMW increases drug clearance becomes more reliant on convection techniques ratherthan diffusion.

Dialyzer systemFlow rate 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.Duration of dialysis Longer duration of dialysis increases the likelihood of clearance; however, reequilibration

of high Vd drugs must be considered.

MW 4 molecular weight, PPB 4 plasma protein binding, Vd 4 volume of distribution.

must be established before measuring the drug centrations may only decrease by 12% afterdialysis, with intercompartmental reequilibrationlevel to allow adequate tissue distribution. A peak

level is typically drawn 12 hours after oral drug taking place after dialysis completion. This meansthat if serum drug levels are monitored, it is im-administration, and about 30 minutes after paren-

teral administration. A trough level is drawn at the portant to allow sufficient time for reequilibrationbefore measuring the drug level, generally 4 hoursend of a dosing interval. For example, if a drug is

to be administered every 12 hours, a trough level after hemodialysis is complete [69]. High ultrafiltra-tion can increase the level of reequilibration re-should be drawn after 11.5 hours from the time that

the dose was administered, or just prior to the next bound.dosage administration. In most instances, if a main-tenance dose has been given, then care must be

Measuring Renal Functiontaken to ensure that three to four doses are givenbefore checking the drug level to ensure a steady-state level is established [33]. However, by defini- Assessing the degree of renal function in a critically

ill patient is a crucial step toward being able totion, steady state is based on the half-life of thedrug and the dosing schedule is partially based on select appropriate medication dosages for drugs

that are renally eliminated. Since it is not possiblethe half-life. Given this, steady state can occur wellbefore the third or fourth doses or well after. For to directly measure the GFR, indirect measurements

to estimate GFR utilizing either exogenous or en-example, digoxin can be administered on a oncea day dosing interval. It takes 57 days to achieve dogenous marker substances can be used. The

``gold standard'' for estimating GFR is the measure-steady state with this drug, drawing a level afterthe third dose will in fact not truly reflect steady ment of clearance of an exogenous substance called

inulin. This sugar is considered to provide the moststate. It is important to note that the drug's volumeof distribution must also be taken into account accurate GFR estimation because it is filtered freely

through the glomerulus and is not subject to renalwhen considering serum drug monitoring. Drugswith a high volume of distribution (e.g., digoxin) metabolism, reabsorption, or secretion. Clinically

inulin is not commonly used because the adminis-will be extensively distributed into tissues andtherefore are not available in the circulation for tration technique is cumbersome and impractical.

An intravenous bolus followed by a maintenanceclearance via dialysis. Thus intracellular drug con-


infusion is provided to maintain a certain plasma collection is complete is to compare the amount ofcreatinine collected to the usual rate of productionconcentration, and then serial venous blood and

urine collections are taken at specific time intervals of about 20 mg/kg/day to see how these two valuescompare. Perhaps a more reliable method of mea-[69].

The alternative to using inulin in estimating GFR suring urine creatinine is to collect consecutivecarefully timed urine samples over time periods ofis to utilize the endogenous substance, creatinine.

Creatinine is a product of muscle creatine decom- a couple of hours instead of 24 hours. However, ashortened collection period may serve to increaseposition. Daily, a constant rate of approximately

1.62.0% of the total amount of creatine (or approxi- the inaccuracy in measuring urine volume if thebladder is not completely emptied [70].mately 20 mg/kg/day depending on age, gender,

diet, and physical condition) in the body is con- Since the early 1970s many researchers have de-veloped nomograms or formulas to more easilyverted spontaneously to creatinine [70]. This con-

stant production means that urinary excretion rate estimate GFR using serum creatinine without theneed to perform urine collections. There are manyvaries by only a small amount in a healthy person.

In addition, creatinine is freely filtered across the equations available to clinicians, and some are lesscumbersome and more practical to use than others.glomerulus. However, in contrast to inulin, creati-

nine undergoes a small degree of renal tubular se- Six of the main methods used clinically to estimateGFR, and therefore renal function in adults, arecretion, which means that the use of creatinine as

a GFR estimation marker is considered to be less outlined in Table 9, with the relative positive andnegative aspects of each of the formulas listed inaccurate than inulin. Clinically, however, creatinine

is commonly used to estimate GFR because mea- Table 10.Clinically the Cockcroft and Gault equation (orsurement of either serum or urine creatinine are

more practical. However, whether or not to mea- a variation of this equation) is the most commonlyused in both the clinical and research settings wheresure creatinine in the blood or urine is subject to

practitioner debate. Traditionally a 24-hour urine urine collection is not deemed practical or neces-sary. When utilizing the Cockcroft and Gault equa-collection is conducted to measure the amount of

creatinine collected over this time period and as- tion to determine creatinine clearance, the valueobtained is most likely an overestimation of thesessed with serum creatinine levels taken at the

beginning and end of the 24 hours. The most com- GFR, because between 10 and 60% of creatinineundergoes renal tubular secretion, and thereforemon problem with this method is that urine collec-

tions are often incomplete, and therefore the appropriate clinical judgment should be exercised[7072]. It is also important to note that the Jaffeamount of creatinine collected is inaccurate. One

possible method to assess whether or not a urine reaction used to measure serum creatinine is based

Table 9. Equations Used to Estimate Creatinine Clearance [16,73]

Equation Formula

CockcroftGault (males)a CrCl 4 [(140 - age) 2 IBW]/SCr 2 72CockcroftGault (females)a Male value 2 0.85Jelliffe (males)b CrCl 4 [98 - 16 2 (age - 20)/20]/SCrJelliffe (females)b Male value 2 0.90Walsera,c (GFR)(3/ht2) 4 a b(cr)11 c(age) d(wt)Mawer (males)a CrCl 4 TBW 2 [29.3 - (0.203 2 age)]Mawer (females)a CrCl 4 TBW 2 [25.3 - (0.175 2 age)]Mawer (males)a CrCl 4 IBW [29.3 - 0.203(age)][1 - 0.03(SCr)]/[14.4(SCr)]Mawer (females)a CrCl 4 IBW [25.3 - 0.175(age)][1 - 0.03(SCr)]/[14.4(SCr)]Wagner (males)a Log CrCl 4 2.008 - 1.19 log SCrWagner (females)a Log CrCl 4 1.888 - 1.20 log SCrHull (males)d CrCl 4 145 - age - 3/SCrHull (females)d Male value 2 0.85

CrCl 4 creatinine clearance; GFR 4 glomerlar filtration rate; SCr 4 serum creatinine; IBW 4 ideal body weight (in kilograms); TBW4 total body weight (in kilograms); IBW males 4 50 2.3(each inch > 60 inches); IBW females 4 45 2.3(each inch > 60 inches).aCrCl in ml/min.bCrCl in ml/min/1.73 m2.cFor the Walser equation: a 4 16.66 (males) or 14.81 (females); b 4 7.57 (males) or 6.05 (females); c 4 10.103 (males) or10.080 (females); d 4 0.096 (males) or 0.080 (females); cr 4 SCr in millimoles; wt 4 kilograms; ht 4 meters.dCrCl 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 Overestimates GFR; does not consider nonrenalGFR'' clearance

Jelliffe Not complicated, therefore rapid bedside No adjustment for body size, estimates CrCl,estimation of CrCl urinary creatinine is constant

Walser Attempts to measure GFR and not CrCl Number of variables and correlation factorsneeded for each gender

Wagner Does not consider age, IBW, nonrenal clearanceHull Does not consider IBW and nonrenal clearance

CrCl 4 creatinine clearance, IBW 4 ideal body weight.

on the red color that is produced when creatinine is of the currently available methods of GFR estima-tion and use of clinical judgment in order to assesscomplexed with alkaline picrate. Other substances

present in the blood sample such as glucose, pro- the level of renal function that will be assumed inorder to use the medication dosage tables in thetein, and ascorbic acid are also picked up by the

test and provide a reading that is approximately appendix.15% higher than it should be. This inaccuracy canserve to offset some of the overestimation of GFRthat is obtained when using the Cockcroft and Gault Referencesformula [73].

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Appendix: Creatinine Clearance Calculated According to Cockroft and GaultContinuousHemoperfusion

CrCl CrCl CrCl Hemodialysis (CAVHD/Drug Normal Dose (3050 ml/min) (1030 ml/min) (


Appendix: ContinuedContinuousHemoperfusion




CrCl CrCl CrCl Hemodialysis (CAVHD/Drug Normal Dose (3050 ml/min) (1030 ml/min) (2.5 mg/dldivided dosesfor edema

Isosorbide 1040 mg PO tid No change No change No change Administer 1040 mg PO tid Dose alterationdinitrate (Isordil)t dose after HD not necessary in

renal failure [84]

Metolazone 520 mg/day No change No change No change Not effective Not effective Although(Zaroxylyn)t PO thiazides may

not be effectivein renal failure,metolazone hasdemonstratedefficacy withGFRs at 20 ml/min

Nitroglycerin Many methods No change No change No change Guidelines No change(Nitro Bid, and routes of notNitrostat, Nitrol, dosing determinedNitrodur)t

Spironolactone 25200 mg/day 12.5100 mg PO 12.5100 mg PO Not effective Not effective Not effective Use should be(Aldactone)t PO in 24 every 24 hr every 24 hr avoided in

divided doses patients withfor edema; GFRs 2.5mg/dl; risk ofhyperkalemia

Angiotensin converting enzyme (ACE) inhibitors

Benazepril 1040 mg PO 520 mg PO 520 mg PO 520 mg PO 520 mg PO 520 mg PO Maximum dose(Lotensin)t every 24 hr every 24 hr every 24 hr every 24 hr every 24 hr every 24 hr should not

exceed 40 mg;fixed doses ofbenazepril andamlodipinetogether shouldnot be given topatients withSCr >3.0 mg/dl

Captopril 25100 mg PO 18.7575 mg PO 18.7575 mg PO 12.550 mg Supplement 18.7575 mg PO(Capoten)t every 8 hr every 1218 hr every 1218 hr PO every 24 2530% of every 1218 hr

hr dose after HD



CrCl CrCl CrCl Hemodialysis (CAVHD/Drug Normal Dose (3050 ml/min) (1030 ml/min) (20 mg/(Hytrin)t PO day do not

provide furtherblood pressurereduction [93]

Sympatholytics for blood pressure control

Clonidine 0.10.6 mg PO No change No change No change No change No change(Catapres)t every 12 hr for

hypertension;0.10.2 mg canbe given everyhour formalignanthypertension toa maximum of0.7 mg

Guanethidine 10100 mg PO No change No change 10100 mg No data 10100 mg/day(Ismelin)t every 24 hr, PO every 36 PO every 24hr

maximum dose hr100 mg/day intwo divideddoses

Methyldopa 250500 mg PO 250500 mg 250500 mg 250500 mg Administer 250500 mg The half-life of(Aldomet)t every 812 hr, PO/IV every 12 PO/IV every 12 PO/IV every 250 mg after PO/IV every 12 methyldopa is

maximum dose hr hr 24 hr each HD hr significantlyPO 3 g/day; or prolonged in250500 mg IV patients withevery 6 hr, ESRDmaximum 1 g IVevery 6 hr

Trimethaphan 0.36 mg/min No change No change No change No change No change(Arofonad)t IV; titrate for BP

control

Calcium channel blockers

Amlodipine 2.510 mg PO No change No change No change No change No change(Norvasc)t every 24 hr

Bepridil (Vascor)t 200400 mg PO No change No change No change No change No change Bepridil doesevery 24 hr not appear to be

effected byrenalimpairment,however, trialsare ongoing

Diltiazem 3090 mg PO No change No change No change No change No change(Dilacor, every 68 hr; forCardizem, atrial fibrillation,Tiazac)t administer IV at

20 mg 2 1 (0.25mg/kg), if noresponse in 15min, give 25 mg2 1 (0.35 mg/kg) then begininfusion at 515mg/hr for ratecontrol



CrCl CrCl CrCl Hemodialysis (CAVHD/Drug Normal Dose (3050 ml/min) (1030 ml/min) (67 kg: 15 mg IV No change No change, No change, No guidelines No guidelines Maintain aPTT(Activase)t bolus, 50 mg administer if administer if determined, determined, with heparin at

over 30 min, benefits benefits administer if administer if 1.52 timesthen 35 mg over outweigh risks outweigh benefits benefits control (5070the next 60 min. risks outweigh outweigh risks sec) for 48 hr#67 kg: 15 mg risksIV bolus, 0.75mg/kg over 30min (up to 50mg), then 0.50mg/kg over thenext 60 min (upto 35 mg).

Anistreplase IV bolus of 30 No change No change No change No guidelines No guidelines(Eminase)t units infused determined determined

over 25 min

r-PA (Retaplase)t Two 10 U IV No change No change, No change, No guidelines No guidelines Maintain aPTTboluses, administer if administer if determined, determined, with heparin atadministered benefits benefits administer if administer if 1.52 timesover 2 min, 30 outweigh risks outweigh benefits benefits control (5070min apart risks outweigh outweigh risks sec) for 48 hr

risks



CrCl CrCl CrCl Hemodialysis (CAVHD/Drug Normal Dose (3050 ml/min) (1030 ml/min) (450 msec

Droperidol 1.2510 mg IM/ 1.255 mg IM/ 1.255 mg IM/ Guidelines Guidelines Guidelines not Monitor QTc(Inapsine)t IV every 46 hr IV every 46 hr IV every 46 hr not not determined interval, stop

prn prn prn determined determined therapy if QTc >450 msec

Fluphenazine 2.510 mg IM No change No change No change No change No change Monitor QTc(Prolixin, every 68 hr prn interval, stopPermitil)t therapy if QTc >

450 msec

Haloperidol 110 mg IM/IV No change No change No change No change No change Monitor QTc(Haldol)t every 46 hr interval, stop

prn, maximum therapy if QTc >80 mg/day 450 msec

Penicillin's used for primarily gram-positive infections

Penicillin G 14 MU IV every 14 MU IV 14 MU IV 14 MU IV 14 MU IV 14 MU IV46 hr; 12 MU every 68 hr every 812 hr every 1218 every 1218 every 812 hrfor most uses, 4 hr hr;MU in supplementalmeningitis doses are not

needed ifmaintenancedoses arescheduledafter HD

Ampicillin 12 g IV every 12 g IV every 12 g IV every 12 g IV 12 g IV every 12 g IV every Ampicillin is(Principen, 46 hr 68 hr 812 hr every 12 hr 12 hr; 812 hr useful inOmnipen)t supplemental treating UTIs in

doses are not RF patients,needed if serum levels ofmaintenance drug are highdoses are andscheduled parenchymalafter HD levels are about

half of serumlevels

Methicillin 12 g IV every 12 g IV every 12 g IV every 12 g IV 12 g IV every 12 g IV every(Staphcillin)t 46 hr 68 hr 68 hr every 812 hr 812 hr; no 812 hr

specificdosingnecessary forHD

Nafcillin (Nafcil, 12 g IV every No change No change No change No change No change Nafcillin isUnipen)t 46 hr eliminated by

nonrenalmechanisms

Oxacillin 12 g IV every No change No change No change No change No change(Bactocil)t 46 hr



CrCl CrCl CrCl Hemodialysis (CAVHD/Drug Normal Dose (3050 ml/min) (1030 ml/min) (2 g/dayis used andconcurrenthepatic failureexists [99]

Fluoroquinolones

Ciprofloxacin 500750 mg PO 250500 mg PO 250500 mg PO 250500 mg 250500 mg 250500 mg PO(Cipro)t (or 400 mg IV) (or 400 mg IV) every 18 hr, or PO every 18 PO every 24 every 18 hr, or

every 12 hr every 12 hr 400 mg IV every hr, or 400 mg hr, or 400 mg 400 mg IV every24 hr IV every 24 hr IV every 24 hr 24 hr

administeredat end of HD

Gatifloxacin 400 mg PO/IV Loading dose Loading dose Loading dose Loading dose Loading dose(Tequin)t every 24 hr 400 mg IV/PO 400 mg IV/PO 400 mg IV/ 400 mg IV/ 400 mg IV/PO

2 1, then 200 2 1, then 200 PO 2 1, then PO 2 1, then 2 1, then 200mg PO/IV every mg PO/IV every 200 mg PO/ 200 mg PO/ mg PO/IV every24 hr 24 hr IV every 24 hr IV every 24 hr 24 hr

administeredat the end ofHD

Levofloxacin 250500 mg IV/ Loading dose of Loading dose of Loading dose Loading dose Loading dose of(Levaquin)t PO every 24 hr 500 mg IV/PO 500 mg IV/PO of 500 mg IV/ of 500 mg IV/ 500 mg IV/PO

2 1, then 250 2 1, then 250 PO 2 1, then PO 2 1, then 2 1, then 250mg IV/PO every mg IV/PO every 250 mg IV/ 250 mg IV/ mg IV/PO every24 hr 48 hr PO every 48 PO every 48 48 hr

hr hr, administerat end of HD

Trovafloxacin 200300 mg IV/ No change No change No change No change No change Monitor LFTs(Trovan)t PO every 24 hr

drug dosing renal failure

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