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Drug Removal by Dialysis

The effect of dialysis on the removal of a specific drug must be considered when

using medications in patients undergoing dialysis. Patients may need supplemental

doses of a medication after a dialysis session or alteration in their dosage to maintain

therapeutic drug concentrations. Dialysis also can be initiated to hasten drug removal

from the body in some cases of drug overdose.

When using dialysis to manage a drug overdose, patients may respond clinically to

factors unrelated to dialysis of the drug. For example, declining plasma

concentrations may be caused by concurrent drug elimination by hepatic metabolism

or renal excretion, which is independent of the dialysis procedure itself.

Furthermore, clinical improvement may result from removal of active metabolites by

dialysis rather than the parent compound.

The primary literature should be used to determine whether any information is

available about the ability of dialysis to remove the drug. The application of data

from the literature to a specific clinical situation often is difficult, however, and

information pertaining to the dialysis of a specific drug may be limited.

When applying information from the primary literature to a specific patient, the

specifics of the dialyzer (e.g., type of machine, membrane surface area, pore size,

and blood and dialysis flow rates) must be considered (see Chapter 30, Renal

Dialysis). Furthermore, patient-specific information (e.g., time of drug ingestion,

liver and renal function) from case reports in the literature also should be evaluated

appropriately. The method used to calculate dialysis clearance also should be

considered. In addition, clinical investigators often use predialysis and postdialysis

serum drug concentrations for estimating drug dialyzability without considering the

contributing effects of drug metabolism and excretion on drug elimination.

DRUG-SPECIFIC PROPERTIES

The physical and chemical characteristics of drugs can be used to predict the

effectiveness of dialysis on drug removal.

21–23 Low MW compounds are more readily

dialyzed by conventional hemodialysis procedures because they can pass with

greater ease across the dialysis membrane. Using cuprophane dialysis membranes,

compounds with an MW of 500 or less are more likely to be significantly dialyzed

than compounds with a high MW (e.g., vancomycin, MW approximately 1,400).

Newer high-flux dialyzers using polysulfone membranes more effectively remove

large chemical compounds (see High-Flux Hemodialysis Section, and Chapter 30,

Renal Dialysis). In addition, water-soluble drugs (e.g., aminoglycosides, lithium) are

removed more readily by dialysis than are lipid-soluble compounds (e.g., diazepam)

or those that partition into red blood cells (e.g., tacrolimus).

Pharmacokinetic characteristics (e.g., Vd, protein binding) also can affect drug

dialyzability. A drug with a large Vd that distributes widely into the peripheral

tissues resides minimally in the plasma and, therefore, is not substantially removed

by dialysis. This is particularly true for highly lipid-soluble drugs such as digoxin

(Vd = 300–500 L) and amiodarone (Vd = 60 L/kg). In addition, drugs that are highly

protein bound, such as warfarin (99%) and ceftriaxone (83%–96%), are not

significantly removed by dialysis because the large protein–drug complex is unable

to pass through the dialysis membrane.

Because clearance values are additive, the hepatic and other nonrenal plasma

clearance of a drug should be considered in relation to the dialysis clearance. Only

when dialysis clearance contributes a substantially additive effect to the patient’s

own clearance is drug elimination enhanced. For example, AZT has a large nonrenal

plasma clearance in patients with severe renal disease (approximately 1,200

mL/minute). Therefore, despite a hemodialysis clearance of 63 mL/minute, the

contribution of dialysis to total AZT removal is negligible.

HIGH-FLUX HEMODIALYSIS

High-flux hemodialysis uses higher blood and dialysate flow rates compared with

conventional methods. The enhanced efficiency of high-flux dialysis and the larger

pore size of the polysulfone membranes allow for small- and mid-MW compounds

(e.g., vancomycin) to be partially removed. Drugs such as gentamicin and foscarnet,

which are removed by conventional dialysis, are also efficiently removed by highflux hemodialysis.

24,25

In many cases, the net amount of drug removed during a highflux dialysis session is greater than the amount removed during conventional dialysis

because of the use of higher blood flow rates. The principal difference is the greater

efficiency and the ability to clear drugs of larger MW compared with conventional

dialysis.

CONTINUOUS AMBULATORY PERITONEAL DIALYSIS

Continuous ambulatory peritoneal dialysis (CAPD) uses the patient’s peritoneum as

the dialysis membrane. Patients maintained with CAPD undergo infusion of a

dialysate solution via a catheter inserted into the peritoneal cavity; the solution is

allowed to dwell in the cavity for several hours. The accumulated fluid

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and uremic by-products diffuse from the blood into the dialysate solution, which is

exchanged every 4 to 8 hours (see Chapter 30, Renal Dialysis).

Some drugs, such as antibiotics, can be administered intraperitoneally (IP) in

patients on CAPD by directly adding them to the dialysate solution. This is

particularly useful for patients with peritonitis who require high intraperitoneal

concentrations of antimicrobial agents to treat this infection. After intraperitoneal

administration of drugs, such as the aminoglycosides, plasma and intraperitoneal drug

concentrations will eventually reach equilibrium. Despite systemic absorption of

these drugs from the peritoneal fluid, peritoneal dialysis (PD) usually is inefficient at

removing drugs from the plasma.

26 Because CAPD contributes little to the overall

elimination of most drugs, dosage modifications are not always necessary in patients

having this procedure.

Continuous venovenous hemofiltration (CVVH) is a form of continuous renal

replacement therapy (CRRT) used in the critically ill patient with renal failure.

CRRT is typically reserved for patients who are unable to tolerate hemodialysis

because of hemodynamic instability. As with hemodialysis, this procedure removes

fluid, electrolytes, and low- and mid-MW molecules from the blood. Using a hollow

fiber that is made of a semipermeable membrane, water and solutes are filtered by

hydrostatic pressure. A countercurrent dialysate can be added to the circuit to

improve solute removal (continuous venovenous hemodialysis with filtration).

Limited data are available on the effect of CVVH on the removal of drugs. Drugs

that have a high sieving coefficient (permeability of a drug through a semipermeable

membrane), such as the aminoglycosides, ceftazidime, vancomycin, and

procainamide, are readily removed by CVVH.

27–29 Data concerning the removal of

drugs by hemodialysis cannot be extrapolated to CVVH because of differences in the

membranes used, blood flow rates, ultrafiltration rate, dialysate flow rate, and the

continuous nature of the procedure compared with intermittent hemodialysis. CVVH

clearance can be estimated to determine the appropriate dosage regimen based on the

pharmacologic characteristics of a specific drug (see Case 31-1, Question 8).

HEMOPERFUSION

Hemoperfusion is another method of drug removal that may be used to facilitate the

elimination of a drug in the setting of an overdose.

30,31 During the hemoperfusion

procedure, blood is passed through a column of adsorbent material (e.g., activated

charcoal or resin) to bind toxins and drugs. Hemoperfusion can be particularly useful

for removing large MW compounds or highly protein-bound drugs that are not

removed efficiently by hemodialysis. Large compounds and drug–protein complexes

are adsorbed onto the high-surface-area resin as blood passes through the adsorbent

column. Hemoperfusion can also be used to remove lipid-soluble drugs not easily

removed by hemodialysis. Lipid-soluble drugs often have a large Vd. Removal of

drugs by hemoperfusion is of limited value because a significant amount of these

lipophilic compounds resides in peripheral tissues.

Pharmacodynamics and Renal Disease

Few studies have investigated the pharmacodynamics of drugs in patients with renal

disease. Clinical observations report that patients with renal disease are more

sensitive to various drugs. For example, morphine has been associated with

increased neurologic depression in patients with renal failure.

32,33 The ability of

morphine to potentiate the CNS-depressant effects of uremia may result from an

alteration in the permeability of the blood–brain barrier that results in higher CNS

levels of morphine and morphine-6-glucuronide.

Another example of altered drug response in uremia is that of nifedipine, which at

similar unbound plasma concentrations has an increased antihypertensive effect in

patients with renal disease.

34 The mean maximal effect change in diastolic blood

pressure values in the control group and in patients with severe renal failure were

12% and 29%, respectively. Therefore, the dose of nifedipine may need to be

adjusted in patients with renal disease because of changes in drug effects rather than

pharmacokinetic alterations.

The pharmacokinetics of warfarin is not significantly altered in renal failure.

However, patients with renal failure who are prescribed warfarin have a higher

incidence of hemorrhagic complications, likely because of platelet dysfunction from

uremia, and drug–drug interactions from concomitant medications.

35,36

PHARMACOKINETICS AND

PHARMACODYNAMICS OF SPECIFIC DRUGS IN

RENAL FAILURE

Ceftazidime

DOSAGE MODIFICATION: FACTORS TO CONSIDER

CASE 31-1

QUESTION 1: G.G., a 31-year-old, 70-kg woman with a 3-year history of systemic lupus erythematosus,

presents to the emergency department (ED) with a 5-day history of fatigue, weakness, and nausea as well, as

worsening of her facial rash and a fever of 40°C. Her systemic lupus erythematosus had been moderately

controlled until this acute flare. Her admission laboratory workup now reveals the following pertinent values:

Potassium (K), 6.0 mEq/L

Sodium (Na), 142 mEq/L

Serum creatinine (SCr), 3.4 mg/dL

Blood urea nitrogen (BUN), 38 mg/dL

Complete blood count reveals a hematocrit of 32% and a hemoglobin of 9.2 g/dL. The platelet count is

50,000/μL, and her erythrocyte sedimentation rate is 35 mm/hour. Physical examination is significant for a blood

pressure of 136/92 mm Hg and 2+ pedal edema. Prednisone is started at a dose of 1.5 mg/kg/day.

During her hospital course, G.G.’s condition worsens and signs of sepsis develop. Pseudomonas aeruginosa is

cultured from her urine. Therapy with ceftazidime is initiated at a dose of 2 g every 8 hours, a dose commonly

used for patients with normal renal function. Considering that G.G.’s renal function has remained stable and that

she has an estimated CrCl of 27 mL/minute, what factors should be considered before modifying her dose?

What would be an appropriate dose of ceftazidime for G.G.?

Before modifying the dose of any drug, its route of elimination should be

established. As a general rule, the degree to which renal impairment affects

elimination depends on the percentage of unchanged drug that is excreted by the

kidney. Thus, the elimination of most drugs that are primarily cleared by the kidneys

will be decreased in the setting of renal impairment. For many drugs dependent on

the kidney for elimination, relationships between some measurement of renal function

(e.g., CrCl) and some parameter of drug elimination (e.g., plasma clearance or halflife) have been established to help clinicians determine the appropriate dosing

modifications in patients with renal disease.

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In contrast, the clearance of drugs that are eliminated primarily by nonrenal

mechanisms (e.g., hepatic metabolism) is not altered significantly in patients with

renal disease. However, some drugs have water-soluble metabolites that have either

pharmacologic activity or potential toxicity and that may accumulate with renal

dysfunction, warranting dosage adjustment or avoidance of the drug entirely (e.g.,

meperidine; see Case 31-8, Question 1).

Enzymes with metabolic capacity have also been found within renal tissue, which

can result in the kidneys playing a limited role in the metabolism of certain drugs (see

Case 31-3, Question 2). The clinical importance of this elimination pathway is

unclear.

Another important factor to consider is the “therapeutic window” for a given drug,

i.e., the range of drug concentrations thought to be most effective. Drug

concentrations below this range are usually subtherapeutic, whereas concentrations

above this range can lead to a greater incidence of adverse effects. For drugs with a

wide therapeutic window, the difference between toxic and therapeutic

concentrations is large. Although many drugs that are cleared primarily by the kidney

may require dosing modifications in patients with renal dysfunction, aggressive dose

reduction may not be necessary for drugs with a large therapeutic window,

particularly if the adverse effects of the drug (e.g., fluconazole) are relatively mild.

This is in contrast to drugs (e.g., aminoglycosides, vancomycin, or foscarnet) that are

eliminated primarily by the kidney and have narrow therapeutic windows. For these

drugs, the toxic plasma concentrations are very close to the therapeutic drug

concentrations, with little room for dosing error.

Ceftazidime is a cephalosporin that has excellent activity against most strains of

Pseudomonas species. As with most cephalosporins, ceftazidime primarily is cleared

by the kidneys, with little nonrenal or hepatic elimination. The correlation between

the clearance of ceftazidime and CrCl in mL/minute is represented by the following

equation

37

:

Using Equation 31-3, the clearance of ceftazidime in G.G. is estimated to be 32

mL/minute compared with an average normal clearance of approximately 100

mL/minute. Because her drug clearance is approximately one-third of normal, she

would require about one-third of the normal daily dose (i.e., 2 g every 24 hours). As

with other cephalosporins, ceftazidime has a large therapeutic window.

38 Failure to

reduce the dose from a normal dose of 2 g every 8 hours, although likely safe, might

lead to accumulation of ceftazidime, predisposing G.G. to seizures and other adverse

effects associated with toxic β-lactam antibiotic plasma levels.

39,40 This is in contrast

to the aminoglycosides, which must be dosed based on specific pharmacokinetic

calculations. Therefore, more generalized or empirical dosage modifications can be

made with ceftazidime.

Aminoglycosides

CASE 31-1, QUESTION 2: G.G.’s medical team decides that the addition of an aminoglycoside antibiotic is

necessary to treat her infection. Considering that her renal function has remained stable, how should gentamicin

be dosed in G.G.? Is it best to alter the dose or the dosing interval for this drug?

ALTERATION OF DOSE VERSUS DOSING INTERVAL

The aminoglycosides (e.g., tobramycin, gentamicin, amikacin) are effective in the

treatment of serious systemic infections caused by gram-negative organisms such as

Pseudomonas species. Unlike the cephalosporins and penicillins, however, the

aminoglycosides have a relatively narrow therapeutic window. Using

pharmacokinetic principles, a dose regimen can be designed to produce specific peak

and trough serum concentrations. Peak serum concentrations (Cppeak

) (e.g.,