Use of Drugs in Patients with Renal Failure

Ali J. Olyaei

Jessica L. Steffl

William M. Bennett

Chronic kidney disease (CKD) is associated with a great magnitude of morbidity and mortality in the United States. The recent data indicate that approximately 26 million Americans have CKD, including 350,000 patients with end-stage renal disease (ESRD) who require scheduled dialysis several times per week. Despite the advances in the field of dialysis and management of comorbid conditions in these patients, infections, cardiovascular complications, and adverse drug reactions are the most common cause of mortality in patients with CKD.¹,² A number of studies have documented the role of medication dosing errors in the overall increase in mortality of patients with renal failure.³,⁴,⁵ Although a number of algorithms and drug dosing recommendations have been proposed over the last two decades, most are not up-to-date, not adequately studied, and have not kept pace with new advances in the field of dialysis.⁶ Acute or chronic renal insufficiency alters the pharmacokinetic and pharmacodynamic properties of most commonly used drugs significantly. Kidneys play an important role in the excretion of active drugs and their pharmacologically active metabolites. Drug accumulation and adverse drug reactions can develop rapidly if drug dosages are not adjusted according to reduced renal function in patients with CKD. Most drugs should be adjusted as renal function improves to ensure efficacy and dosage should be reduced if renal function continues to deteriorate. Even in drugs that are mostly metabolized through the liver, patients with renal failure are at greater risk of adverse drug reactions and toxicity.⁷ Drug interactions are also a common problem in this population because most patients with renal insufficiency often have serious comorbid conditions requiring pharmacologic intervention.⁸,⁹,¹⁰,¹¹,¹²,¹³,¹⁴,¹⁵,¹⁶,¹⁷,¹⁸,¹⁹,²⁰

In addition, a large part of the difficulty in prescribing drugs for the rapidly growing numbers of older patients is due to age-related declines in renal function.³ Finally, renal replacement therapies including hemodialysis are considered the treatment of choice in patients with ESRD. The effects of dialysis on drug elimination and the need for supplemental dosing must also be considered in patients receiving renal replacement therapy.²¹,²²,²³,²⁴,²⁵,²⁶,²⁷

In this chapter, the basic principles of pharmacokinetic modeling and drug dosing in patients with CKD or dialysis are reviewed. The changes in drug pharmacokinetics and pharmacodynamics are highlighted, and practical guidelines for drug dosing in these patients are provided. However, dialysis patients also face the risk of drug-drug and drug-disease interactions, thus, no specific dosing guideline can be given confidently because individual patient factors such as age, gender, nutrition, body fluid volume, and disease states may influence pharmacokinetic and pharmacodynamic parameters significantly. To provide safe and effective pharmacotherapy, the clinician must utilize clinical judgments, knowledge of altered pharmacokinetic properties, and the patient’s specific physiologic status to administer drugs safely to a renal patient population. In order to optimize pharmacotherapy and avoid over- and undermedication, these factors should be taken into account and appropriate dosage adjustment should be considered.

PHARMACOKINETIC PRINCIPLES

The term pharmacokinetics refers to a mathematical model of the time course of drug concentration in a body compartment. Pharmacokinetic properties of a drug define or predict plasma concentrations and, therefore, drug activity or toxicity at the site of the action. Pharmacokinetics is the study of drug absorption, distribution, metabolism, and elimination. Pharmacokinetics can be thought of as the body’s effect on the drug over time. A simplified scheme of drug pharmacokinetics is illustrated in Figure 86.1. The pharmacologic effect of any drug depends on the concentration of the unbound active drug or an active metabolite at the receptor site of action. The blood and tissue levels of a drug are functions of the administered dose, rate of its absorption, concentration, rate of metabolism or biotransformation, and rate of elimination.⁹,¹⁰,¹¹,¹²,¹³

Drug Absorption

Following extravascular administration, drugs must be transported through a number of physiologic barriers
before reaching the systemic circulation. Drug absorption and bioavailability relate to the amount of drug that reaches the systemic circulation after oral administration. The fraction or percent of administrated drug that reaches systemic circulation is known as bioavailability (F). These parameters are often highly specific for a given compound and vary with the physical and chemical properties of the drug, its formulation, the integrity of the absorptive surface, and the presence of other agents and/or food in the gastrointestinal tract. Absorption rates of most therapeutic agents are slow and unpredictable. Uremia-induced vomiting or sluggish peristalsis secondary to enteropathy may further reduce the onset of action of most agents. In patients with diabetes mellitus, the drug absorption is more variable due to autonomic neuropathy. Both calcium- and aluminum-containing phosphate binders may form insoluble complexes with certain drugs such as antibiotics or ferrous sulfate, thereby impeding absorption. Acidic drugs prefer an acidic environment for optimal absorption whereas weak basic drugs are better absorbed in a more alkalinized small intestine. Use of proton pump inhibitors or phosphate binders presumably reduces the rate of absorption of a number of acidic agents.¹⁴,¹⁵,¹⁶,¹⁷,¹⁸ The gastrointestinal tract edema in patients with hypoalbuminemia may also diminish drug absorption.

FIGURE 86.1 Pharmacokinetic factors involved in drug distribution.

Propranolol, morphine, and verapamil are examples of drugs that undergo first pass metabolism.²⁸,²⁹ In first pass metabolism, a significant amount of the absorbed drug molecules are delivered to the liver via the portal vein. A drug is said to undergo significant first pass metabolism when it is metabolized in the liver so extensively upon absorption that only a small percentage of drug concentrations reaches the systemic circulation.³⁰,³¹ In addition many drugs may be metabolized via the cytochrome P-450 system in the gastrointestinal tract before reaching the systemic circulation. For example, it is well established that rifampin decreases and erythromycin increases the bioavailability of cyclosporine and calcium channel blockers by induction and inhibition of intestinal and hepatic cytochrome P-450 enzymes, respectively. Finally, patients with renal failure have a higher salivary urea concentration that increases the gastric ammonia levels and increases overall gastric pH. Drugs like iron and ketoconazole whose absorption is dependent on an acidic environment may have reduced bioavailability in renal failure.²⁹,³²

Volume of Distribution

The volume of distribution (Vd) for a specific drug is derived by dividing the fractional absorption of a dose by the plasma concentration.

It is important to emphasize that Vd does not signify the total body fluid. Rather, it is an apparent volume needed for equal distribution of drug throughout the body compartment. For example, the plasma volume of a normal 70 kg man is approximately 3 to 3.5 L, whereas the Vd of 0.25 mg of digoxin to obtain a 0.7 ng per dL plasma level is 350 L, which is 10 times greater than the plasma volume. Therefore, Vd does not refer to a specific anatomic compartment per se. Instead, it is the volume of fluid in which the drug would need to be dissolved to give the observed plasma concentration.³³,³⁴,³⁵ A drug distributes in the body in a characteristic manner based on physiochemical properties of the drug and individual patient variables. Volume of distribution is used mathematically to determine the dose of a drug necessary to achieve a desired plasma concentration. Although the Vd is relatively constant for a given drug, many factors such as obesity, extracellular fluid volume status, age, gender, thyroid function, renal function, and cardiac output influence drug distribution. Volume of distribution echoes the water solubility and protein and tissue-binding characteristics of an individual agent. Drugs with a small Vd (Vd less than ˜0.7 L per kg) are usually considered more water soluble. Highly lipid-soluble drugs have a large Vd with little retention of drug in the plasma because the drug tends to stay in the lipophilic tissue compartment. Drugs that are highly tissue bound, such as digoxin, will also have a large Vd. If
tissue binding of drugs is decreased by azotemia, a decrease in Vd results. Digoxin is highly bound to cardiac and other tissue Na⁺-K⁺-ATPase transporters, accounting for its large Vd of 300 to 500 L and very low plasma concentrations. Waste products that accumulate in the azotemic patient serve to displace digoxin from its tissue-binding sites and thus reduce its Vd. Further, such waste products cross-react with the antidigoxin antibody used in drug monitoring assays, producing “therapeutic” digoxin levels in patients not even taking the drug. Insulin and methotrexate similarly have diminished Vd in the uremic state. As a general rule, plasma concentrations of a drug correlate inversely with its Vd.³,²⁹,³⁶

Protein Binding

The third important pharmacokinetic concept is protein binding. Only unbound drug or unbound active drug metabolites are able to exert any pharmacologic effects. Disease states that affect total body proteins may significantly alter free drug concentration and increase the risk of drug toxicity. Quantity (binding site) and quality (affinity) of protein binding are substantially altered in patients with renal failure.³⁷,³⁸,³⁹ Specifically, uremic toxins may decrease the affinity of albumin for a variety of drugs. Organic acids that accumulate in renal failure compete with acidic drugs for protein binding sites. This results in a larger fraction of acidic compounds existing in the unbound or active state. Conversely, basic drugs bind more readily to nonalbumin serum proteins such as α₁-acid glycoprotein and may demonstrate increased protein binding because this acute phase reactant is often elevated in patients with acute disease states including renal impairment. Malnutrition and proteinuria lower serum protein levels, which may increase the free fraction of a compound as well. Alterations in a drug’s protein binding and subsequent effects on drug disposition may be difficult to predict. Drugs that are highly protein bound (>80%) are not removed very effectively during dialysis. In general, drugs that are highly protein bound are largely confined to the vascular space and thus have a Vd of 0.2 L per kg or less. Generally, the Vd for a given agent increases as its protein binding decreases and diminishes as its protein-bound fraction increases.³⁷,³⁸,³⁹

Drug Metabolism or Biotransformation

The total body clearance of a drug is equal to the sum of renal clearance plus nonrenal clearance. Obviously, in patients with renal insufficiency, the contribution of renal clearance to total body clearance will be reduced. Nonrenal clearance, however, may be increased, decreased, or unchanged in such patients. Specifically, hepatic pathways of drug metabolism or biotransformation including acetylation, oxidation, reduction, and hydrolysis may be slowed or accelerated depending on the drug under consideration.⁴⁰,⁴¹ Sulfisoxazole acetylation, propranolol oxidation, hydrocortisone reduction, and cephalosporin hydrolysis are all slowed in uremic patients. Most drugs undergo biotransformation to more polar but less pharmacologically active compounds that require intact renal function for elimination from the body.⁷,⁴²,⁴³ Active or toxic metabolites of parent compounds may accumulate in patients with renal failure. The antiarrhythmic agent procainamide is metabolized to N-acetylprocainamide, which is excreted by the kidney. Thus, the antiarrhythmic properties and toxicity of procainamide and its active metabolite are additive, particularly in patients with renal failure. Meperidine, a commonly used narcotic, is biotransformed to normeperidine, which undergoes renal excretion. Although normeperidine has little narcotic effect, it lowers the seizure threshold as it accumulates in uremic patients.⁴⁴,⁴⁵

Renal Elimination

The most important route of drug elimination is the kidney. Specific processes involved in the renal handling and elimination of drugs include glomerular filtration, tubular secretion and reabsorption, and renal epithelial cell metabolism.⁴⁶ All of these functions can be directly or indirectly influenced by renal impairment. Because plasma proteins are too large to pass through a normal glomerulus, only unbound compounds will be freely filtered across this barrier. When proteinuria exists, protein-bound molecules may move into the tubular fluid and be eliminated from the circulation. Changes in renal blood flow may affect both drug reabsorption and secretion. Drugs that are highly protein bound can be eliminated without exerting any pharmacologic effects. For example, binding of furosemide to intraluminal albumin in nephrotic states may contribute to the diuretic resistance characteristic of such conditions. When renal disease reduces nephron numbers, the kidneys’ ability to eliminate drugs declines in proportion to the decline in glomerular filtration rate (GFR). As patients progress toward dialysis dependency, drugs usually filtered and excreted begin to accumulate, leading to a high prevalence of adverse reactions unless dosage adjustments are instituted.⁴⁷,⁴⁸,⁴⁹,⁵⁰

Drugs that are extensively bound to protein either have a low renal clearance or enter the filtrate by tubular secretion. Tubular handling of a drug is an energy-requiring, active transport process and involves two separate and distinct pathways in the proximal tubule that are used for the secretion and reabsorption of organic acids and bases.⁵¹ These processes are dependent on renal blood flow but not GFR. Accumulation of organic acids in the setting of renal failure competes with acidic drugs for tubular transport and secretion into the urinary space. This, in turn, may lead to drug accumulation and adverse reactions as serum concentrations of agents such as methotrexate, sulfonylureas, penicillins, and cephalosporins rise. Diuretics gain access to their intraluminal sites of action via organic acid secretory pumps. Competition for these secretory
pathways by accumulated uremic wastes results in diuretic resistance and necessitates increased diuretic doses to elicit the desired natriuretic effect.

Drug metabolism occurs in the kidney due to a high parenchymal concentration of cytochrome P-450 enzymes. Endogenous vitamin D metabolism and insulin catabolism are examples of processes that decline as renal failure progresses.³⁵,³⁹,⁴⁰,⁴¹

First-order pharmacokinetics describes the manner in which most drugs and their metabolites are eliminated from the body. Specifically, the amount of drug eliminated over time is a fixed proportion of the body stores. The half-life (t_1/2) of a given agent is most commonly used to express its elimination rate from the body and equals the time required for the drug’s plasma concentration to fall by 50%. Half-life can be expressed mathematically as follows:

where Kr represents the renal elimination rate constant and Knr represents the nonrenal elimination rate constant. As renal elimination declines with renal function, t_1/2 is prolonged.

DOSAGE ADJUSTMENT FOR THE PATIENT WITH CHRONIC KIDNEY DISEASE

The following outline provides a stepwise approach to prescribing drug therapy for patients with renal failure. Again, it must be emphasized that these steps simply provide a framework for dosage adjustments in patients with renal impairment and must be modified on a caseby-case basis.

Initial Assessment

A history and physical examination constitute the first step in assessing dosimetry in any patient but particularly in those with renal impairment. Kidney injury should be defined as acute or chronic and the cause ascertained if possible. In addition, a history of previous drug intolerance or toxicity should be determined. The patient’s current medication list must be reviewed, including both prescription as well as nonprescription and herbal formulations to identify potential drug interactions and nephrotoxins. Calculation of ideal body weight will be based on physical examination findings. For men, the ideal body weight is 50 kg plus 2.3 kg for each 2.54 cm (1 inch) over 152 cm (5 feet). For women, the formula is 45.5 kg plus 2.3 kg per 2.54 cm over 152 cm. An assessment of extracellular fluid volume is also key because significant shifts can affect the Vd of many pharmacologic agents. The presence of hepatic dysfunction may also require additional dosage adjustments.

Calculating Creatinine Clearance

The rate of drug excretion by the kidney is proportional to the GFR. Therefore, it is important to accurately assess renal function and GFR. Serum creatinine alone is an unreliable marker of renal function. Although it overestimates GFR, calculated creatinine clearance (Ccr) more accurately approximates the GFR than serum creatinine and can be estimated conveniently by the Cockcroft and Gault (CG) equation:

For women, the calculated value is multiplied by 0.85. The use of this formula implies that the patient is in a steady-state with respect to serum creatinine. There is no accurate method to quantify GFR when renal function is rapidly changing, and as such, it is best to assume a GFR value of less than 10 mL per minute in acute renal failure to avoid drug accumulation and toxicity.⁵²

Measured GFR is another method of renal assessment. Inulin is an ideal agent for measuring GFR. Following administration, inulin is filtered by the glomerulus and, in contrast to creatinine, inulin is not secreted, reabsorbed, or metabolized by the kidney. Like other exogenous substances, the inulin test is costly and time consuming and is not available for routine clinical use. Today, isotope tests (51Cr-EDTA, 99Tc-DTPA) have replaced the inulin clearance test for measuring GFR.⁵³

Other methods have been suggested to estimate GFR to improve accuracy and reduce estimation errors.⁵⁴ However, all newer methods are serum creatinine-based equations and are subject to the same systemic errors as CG method. The Modification of Diet in Renal Disease (MDRD) equation was derived from the 1,628 patients involved in the MDRD study group.⁵⁵ In this study, subjects underwent GFR measurement using 125 I-iothalamate, 24-hour creatinine clearance urine collection, and a single measurement of serum creatinine. Multiple variables (i.e., weight, height, sex, ethnicity, diabetes, etc.) were used to determine the most accurate assessment of GFR. Initially, a six-variable equation was determined by the study group. Upon further study, the four-variable equation was found to be as accurate as the six-variable equation. Adding albumin and urea as variables did not improve accuracy or reduces errors.

MDRD6 Equation^*

GFR = 170 × [Pcr]^-0.999 × [Age]^-0.176 × [0.762 if patient is female] × [1.180 if patient is black] × [SUN]^-0.170 × [Alb]^0.318

MDRD4 Equation

GFR = 186 × Scr^-1.154 × age^-0.203 × 0.742 [if female] × 1.21 [if black]

The U.S. Food and Drug Administration (FDA) released “Guidance for Industry: Pharmacokinetics in Patients with Impaired Renal Function-Study Design, Data Analysis and Impact on Dosing and Labeling” in 2010, recommending the CG or MDRD4 equations as the method for assessing renal function in pharmacokinetic studies.⁵⁶ It is important to emphasize that all different methods of GFR estimation and equations for drug dosing in CKD have small biases when comparing CG to other methods.⁵⁷

Choosing a Loading Dose

Loading doses are intended to achieve a therapeutic steady-state drug level within a short period of time. As such, the loading dose generally is not reduced in the setting of renal failure. Loading doses can be calculated if the Vd and desired peak level are known, as is discussed later. If extracellular volume depletion exists, the Vd may be reduced for certain pharmacologic agents, and slight reductions in the loading dose would be prudent. Specifically, drugs with narrow therapeutic-toxic profiles such as digoxin and ototoxic aminoglycosides should be administered with a 10% to 25% reduction in their loading dose when volume contraction is present in patients with renal failure.

Choosing a Maintenance Dose

Maintenance doses of a drug ensure steady-state blood concentrations and lessen the likelihood of subtherapeutic regimens or overdosage. In the absence of a loading dose, maintenance doses will achieve 90% of their steady-state level in three to four half-lives. One of two methods can be used to adjust maintenance doses for patients with renal insufficiency. The “dosage reduction” method involves reducing the absolute amount of drug administered at each dosing interval proportional to the patient’s degree of renal failure. The dosing interval remains unchanged, and more constant drug concentrations are achieved. The “interval extension” method involves lengthening the time period between individual doses of a drug, reflecting the extent of renal insufficiency. This method is particularly useful for drugs with a wide therapeutic range and long half-life.

Monitoring Drug Levels

Blood, serum, and plasma drug concentrations may not be equivalent. As a result, drug levels can only be interpreted if the dosage schedule is known, including the dose administered, timing, and route of administration. A peak level is usually obtained 30 minutes following intravenous administration and 60 to 120 minutes after oral ingestion. It reflects the maximum level achieved after the rapid distribution phase and before significant elimination has occurred. A trough level is obtained just prior to the next dose, reflects total body clearance, and may be a marker of drug toxicity. If the concentration of a drug and its Vd are known, the dose required to achieve a desired therapeutic level can be calculated by the following formula where Vd in L per kilogram is multiplied by ideal body weight (IBW) in kilograms and the desired plasma concentration in milligrams per L (Cp):

Drug level monitoring is a clinically useful tool when used appropriately. Clinical judgment is paramount because drug failure or toxicity can occur within “therapeutic concentrations.” For example, digitalis intoxication can occur in the presence of therapeutic serum levels if hypokalemia or metabolic alkalosis coexists. Phenytoin toxicity is a common problem in patients with renal failure and hypoalbuminemia because of an increase in the unbound or biologically active fraction of phenytoin despite a low total phenytoin plasma concentration. In this setting phenytoin levels should be adjusted for reduced protein binding and the effect of renal failure on phenytoin distributions (Table 86.1).

DIALYSIS AND DRUG DOSING

Patients undergoing renal replacement therapy (dialysis therapy) require special attention in terms of dosage adjustment because dialysis membranes significantly remove many therapeutic agents. An array of modalities including high efficiency, high flux, continuous, and conventional hemodialysis exist and differ from one another based on membrane porosity, surface area, and blood as well as dialysate flow rates. These differences, in turn, affect drug removal. In Table 86.2 are summarized drug properties and dialysis parameters that determine dialytic clearance of pharmacologic agents. In general, in thrice weekly intermittent hemodialysis (IHD), the drug removal is affected by blood and dialysate flow rate, molecular weight (MW) of the drug, fraction of protein binding, and dialyzer surface area. Drugs with MW greater than 500 D and that are highly protein bound (80%), highly tissue bound, and lipophilic are poorly dialyzed by conventional IHD. However, drugs with small MW, low protein binding, small volume of distribution, and of a hydrophilic character are effectively removed by IHD.⁵⁸,⁵⁹,⁶⁰,⁶¹

Drug Properties Affecting Dialytic Clearance

A drug’s molecular weight is a major determinant of its dialyzability. Specifically, drugs larger than 500 D are primarily cleared by convection as opposed to diffusion. If too large to pass through a given membrane, the drug will not

be cleared from the circulation. An inverse semilogarithmic relationship exists between molecular weight and dialysis clearance.

TABLE 86.1 Therapeutic Drug Monitoring

@@	Drug Name	Therapeutic Range	When to Draw Sample	When to Check Levels	Time to Reach Steady State	Other Considerations
Antibiotics	Aminoglycosides (conventional dosing) Gentamicin Tobramycin Amikacin	Gentamicin and tobramycin: Peak: 5 to 8 mg/L Trough: <2 mg/L (for moderate to severe non-UTI infections, or CF, peaks should be between 10 to 12) Amikacin	Trough: Immediately prior to dose Peak: 30 minutes after a 30 minute infusion or 30 minutes after a 60 minute infusion	With third dose for initial therapy or after dose change. For therapy less than 72 hours, levels not necessary. Repeat drug levels if renal function changes.	Steady state is reached in 4 to 5 elimination half-lives; generally by the third dose	Special considerations for renal patients and dialysis: 2 mg/kg then 1 mg/kg, redose if level less than 2 mg/L
		Peak: 20 to 30 mg/L Trough: <10 mg/L	CF patients: 15 minutes after 30 minute infusion
	Gentamicin Tobramycin Amikacin	0.5 to 3 mg/L	Obtain random drug level 12 hours after dose	After initial dose. Repeat drug level in 1 week or if renal function changes.	Steady state is not reached in most cases due to insufficient drug accumulation between dosing intervals	24-hour dosing not to be used for patients with burns, CrCl <20, CF, dialysis, endocarditis, neutropenia, pediatrics, pregnancy
	Vancomycin	Peak: 20 to 50 mg/L Trough: 5 to 20 mg/L	Trough: Immediately prior to dose Peak: 60 minutes after a 60-minute infusion	With third dose for initial therapy or after dose change. For therapy less than 72 hours, levels not necessary. Repeat drug levels if renal function changes.	Steady state is reached in 4 to 5 elimination half-lives; generally by the third dose	Special considerations for renal patients—goal trough <15 mg/L
Anticonvulsants	Carbamazepine	4 to 12 µg/mL	Trough: Immediately prior to dosing	2 to 4 days after first dose or change in dose	2 to 5 days	Monitor baseline LFTs, then 2 to 3 months after starting drug
	Phenobarbital	15 to 40 µg/mL	Trough: Immediately prior to next dose	2 weeks after first dose or change in dose. Follow-up level in 1 to 2 months.	14 to 21 days
	Phenytoin Free phenytoin	10 to 20 µg/mL 1 to 2 µg/mL	Trough: Immediately prior to dosing	5 to 7 days after first dose or change in dose	10 to 14 days	Adjustments necessary for albumin <3.5 g/dL or patients with renal impairment. For acutely ill patients, earlier levels should be considered.
	Valproic acid (includes divalproex sodium)	50 to 100 µg/mL	Trough: Immediately prior to next dose	2 to 4 days after first dose or change in dose.	2 to 4 days	Monitor baseline LFTs, then 2 to 3 months after starting drug
UTI, urinary tract infection; CF, cystic fibrosis; CrCl, creatinine clearance; LFTs, liver function tests.

TABLE 86.2 Antimicrobal Agents in Renal Failure

Drugs	Normal Dosage	% of Renal Excretion	Dosage Adjustment in Renal Failure			Comments	HD	CAPD	CVVH
Drugs	Normal Dosage	% of Renal Excretion	GFR>50	GFR 10 to 50	GFR <10	Comments	HD	CAPD	CVVH
Aminoglycoside Antibiotics						Nephrotoxic, ototoxic Toxicity worse when hyperbilirubinemic Measure serum levels for efficacy and toxicity Peritoneal absorption increases with presence of inflammation Vd increases with edema, obesity, and ascites
Streptomycin	7.5 mg/kg q12h (1.0 g q24h for TB)	60%	q24h	q24 to 72h	q72 to 96h	For the treatment of TB May be less nephrotoxic than other members of class	1/2 normal dose after dialysis	20 to 40 mg/L/d	Dose for GFR 10 to 50 and measure levels
Kanamycin	7.5 mg/kg q8h	50% to 90%	60% to 90% q12h or 100% q12 to 24h	30% to 70% q12 to 18h or 100% q24 to 48h	20% to 30% q24 to 48h or 100% q48 to 72h	Do not use once-daily dosing in patients with creatinine clearance less than 30 to 40 mL/minutes or in patients with acute renal failure or uncertain level of kidney function	1/2 full dose after dialysis	15 to 20 mg/L/d	Dose for GFR 10 to 50 and measure levels
Gentamicin	1.7 mg/kg q8h	95%	60% to 90% q8 to 12h or 100% q12 to 24h	30% to 70% q12h or 100% q24 to 48h	20% to 30% q24 to 48h or 100% q48 to 72h		1/2 full dose after dialysis	3 to 4 mg/L/d	Dose for GFR 10 to 50 and measure levels
Tobramicin	1.7 mg/kg q8h	95%	60% to 90% q8 to 12h or 100% q12 to 24h	30% to 70% q12h or 100% q24 to 48h	20% to 30% q24 to 48h or 100% q48 to 72h		1/2 full dose after dialysis	3 to 4 mg/L/d	Dose for GFR 10 to 50 and measure levels
Netilmicin	2 mg/kg q8h	95%	50% to 90% q8 to 12h or 100% q12 to 24h	20% to 60% q12h or 100% q24 to 48h	10% to 20% q24 to 48h or 100% q48 to 72	May be less ototoxic than other members of class Peak 6 to 8, trough <2	1/2 full dose after dialysis	3 to 4 mg/L/d	Dose for GFR 10 to 50 and measure levels
Amikacin	7.5 mg/kg q12h	95%	60% to 90% q12h or 100% q12 to 24h	30% to 70% q12 to 18h or 100% q24 to 48h	20% to 30% q24 to 48h or 100% q48 to 72h	Monitor levels Peak 20 to 30, trough <5	1/2 full dose after dialysis	15 to 20 mg/L/d	Dose for GFR 10 to 50 and measure levels
Cephalosporin						Coagulation abnormalities, transitory elevation of BUN, rash, and serum sickness-like syndrome
Oral Cephalosporin
Cefaclor	250 to 500 mg tid	70%	100%	100%	50%		250 mg bid after dialysis	250 mg q8 to 12h	N/A
Cefadroxil	500 to 1 g bid	80%	100%	100%	50%		0.5 to 1.0 g after dialysis	0.5 g/d	N/A
Cefixime	200 to 400 mg q12h	85%	100%	100%	50%		300 mg after dialysis	200 mg/d	Not recommended
Ceftibuten	400 mg q24h	70%	100%	100%	50%		300 mg after dialysis	No data: Dose for GFR <10	Dose for GFR 10 to 50
Cefuroxime axetil	250 to 500 mg tid	90%	100%	100%	100%	Malabsorbed in presence of H2 blockers. Absorbed better with food.	Dose after dialysis	Dose for GFR <10	N/A
Cephalexin	250 to 500 mg tid	95%	100%	100%	100%	Rare allergic interstitial nephritis. Absorbed well when given intraperitoneally. May cause bleeding from impaired prothrombin biosynthesis.	Dose after dialysis	Dose for GFR <10	N/A
Cephradine	250 to 500 mg tid	100%	100%	100%	50%		Dose after dialysis	Dose for GFR <10	N/A
IV Cephalosporin
Cefazolin	1 to 2 g IV q8h	80%	q8h	q12h	q12 to 24h		0.5 to 1.0 g after dialysis	0.5 g q12h	Dose for GFR 10 to 50
Cefepime	1 to 2 g IV q8h	85%	q8 to 12h	q12h	q24h		1 g after dialysis	Dose for GFR <10	Not recommended
Cefmetazole	1 to 2 g IV q8h	85%	q8h	q12h	q24h		Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Cefoperazone	1 to 2 g IV q12h	20%	No renal adjustment is required			Displaced from protein by bilirubin. Reduce dose by 50% for jaundice. May prolong prothrombin time.	1 g after dialysis	None	None
Cefotaxime	1 to 2 g IV q6 to 8h	60%	q8h	q12h	q12 to 24h		1 g after dialysis	1 g/d	1g q12h
Cefotetan	1 to 2 g IV q12h	75%	q12h	q12 to 24h	q24h		1 g after dialysis	1 g/d	750 mg q12h
Cefoxitin	1 to 2 g IV q6h	80%	q6h	q8 to 12h	q12h	May produce false increase in serum creatinine by interference with assay	1 g after dialysis	1 g/d	Dose for GFR 10 to 50
Ceftazidime	1 to 2 g IV q8h	70%	q8h	q12h	q24h		1 g after dialysis	0.5 g/d	Dose for GFR 10 to 50
Ceftriaxone	1 to 2 g IV q24h	50%	No renal adjustment is required				Dose after dialysis	750 mg q12h	Dose for GFR 10 to 50
Cefuroxime sodium	0.75 to 1.5 g IV q8h	90%	q8h	q8 to 12h	q12 to 24h		Dose after dialysis	Dose for GFR <10	1.0 g q12h
Penicillin						Bleeding abnormalities, hypersensitivity. Seizures.
Oral Penicillin
Amoxicillin	500 mg po tid	60%	100%	100%	50% to 75%		Dose after dialysis	250 mg q12h	N/A
Ampicillin	500 mg po q6h	60%	100%	100%	50% to 75%		Dose after dialysis	250 mg q12h	Dose for GFR 10 to 50
Dicloxacillin	250 to 500 mg po q6h	50%	100%	100%	50% to 75%		None	None	N/A
Penicillin V	250 to 500 mg po q6h	70%	100%	100%	50% to 75%		Dose after dialysis	Dose for GFR 10	N/A
IV Penicillin
Ampicillin	1 to 2 g IV q6h	60%	q6h	q8h	q12h		Dose after dialysis	250 mg q12h	Dose for GFR 10 to 50
Nafcillin	1 to 2 g IV q4h	35%	No renal adjustment is required				None	None	Dose for GFR 10 to 50
Penicillin G	2 to 3 million units IV q4h	70%	q4 to 6h	q6h	q8h		Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Piperacillin	3 to 4 g IV q4 to 6h	No renal adjustment is required			Sodium, 1.9 mEq/g	Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Ticarcillin/clavulanate	3.1 g IV q4 to 6h	85%	1 to 2 g q4h	1 to 2 g q8h	1 to 2 g q12h	Sodium, 5.2 mEq/g	3.0 g after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Piperacillin/tazobactam	3.375 g IV q6 to 8h	75% to 90%	q4 to 6h	q6 to 8h	q8h	Sodium, 1.9 mEq/g	Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Quinolones						Food, dairy products, tube feeding, and Al(OH)₃ may decrease the absorption of quinolones.
Ciprofloxacin	200 to 400 mg IV q24h	60%	q12h	q12 to 24h	q24h	Poorly absorbed with antacids, sucralfate, and phosphate binders. Intravenous dose 1/3 of oral dose. Decreases phenytoin levels.	250 mg q12h (200 mg if IV)	250 mg q8h (200 mg if IV)	200 mg IV q12h
Levofloxacin	500 mg po qd	70%	q12h	250 q12h	250 q12h	L-isomer of ofloxacin: appears to have similar pharmacokinetics and toxicities	Dose for GFR <10	Dose for GFR <10	Dose for GFR 10 to 50
Moxifloxacin	400 mg qd	20%	No renal adjustment is required				No data	No data	No data
Nalidixic acid	1.0 g q6h	High	100%	Avoid	Avoid	Agents in this group are malabsorbed in the presence of magnesium, calcium, aluminum, and iron. Theophylline metabolism is impaired. Higher oral doses may be needed to treat CAPD peritonitis.	Avoid	Avoid	N/A
Norfloxacin	400 mg po q12h	30%	q12h	q12 to 24h	q24h	See above.	Dose for GFR <10	Dose for GFR <10	N/A
Ofloxacin	200 to 400 mg po q12h	70%	q12h	q12 to 24h	q24h	See above.	100 to 200 mg after dialysis	Dose for GFR <10	300 mg/d
Miscellaneous Agents
Azithromycin	250 to 500 mg po qd	6%	No renal adjustment is required			No drug-drug interaction with CsA/FK	None	None	None
Clarithromycin	500 mg po bid		No renal adjustment is required				None	None	None
Clindamycin	150 to 450 mg po tid	10%	No renal adjustment is required			Increase CsA/FK level	None	None	None
Dirithromycin	500 mg po qd		No renal adjustment is required			Nonenzymatically hydrolyzed to active compound erythomycylamine	None	No data: None	Dose for GFR 10 to 50
Erythromycin	250 to 500 mg po qid	15%	No renal adjustment is required			Increase CsA/FK level, avoid in transplant patients	None	None	None
Ertapenem	1 gm IV q24h		1 gm IV q24h	0.5 gm IV q24h	0.5 gm IV q24h		Dose after dialysis	Dose for GFR <10	Dose for GFR <30
Imipenem/Cilastatin	250 to 500 mg IV q6h	50%	500 mg q8h	250 to 500 q8 to 12h	250 mg q12h	Seizures in ESRD. Nonrenal clearance in acute renal failure is less than in chronic renal failure. Administered with cilastin to prevent nephrotoxicity of renal metabolite.	Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Meropenem	1 g IV q8h	65%	1 g q8h	0.5 to 1g q12h	0.5 to 1g q24h	Fewer seizures compared to imipenem	Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Metronidazole	500 mg IV q6h	20%	No renal adjustment is required			Peripheral neuropathy, increase LFTs, disulfiram reaction with alcoholic beverages	Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Pentamidine	4 mg/kg/day	5%	q24h	q24h	q48h	Inhalation may cause bronchospasm, IV administration may cause hypotension, hypoglycemia, and nephrotoxicity	None	None	None
Trimethoprim/sulfamethoxazole	800/160 mg po bid	70%	q12h	q18h	q24h	Increase serum creatinine. Can cause hyperkalemia.	Dose after dialysis	q24h	q18h
Vancomycin	1 g IV q12h	90%	q12h	q24 to 36h	q48 to 72h	Nephrotoxic, ototoxic, may prolong the neuromuscular blockade effect of muscle relaxants Peak 30 to 40. Trough 5 to 10.	500 mg q12 to 24h (high FLX)	1.0 gm q24 to 96h	500 mg q12h
Vancomycin	125 to 250 mg po qid	0%	100%	100%	100%	Oral vancomycin is indicated only for the treatment of C. diff.	100%	100%	100%
Antituberculosis Antibiotics
Rifampin	300 to 600 mg po qd	20%	No renal adjustment is required			Decrease CsA/FK level. Many drug interactions.	None	Dose for GFR <10	Dose for GFR <10
Antifungal Agents
Amphotericin B	0.5 mg to 1.5 mg/kg/day	<1%	No renal adjustment is required			Nephrotoxic, infusion related reactions, give 250 mL NS before each dose	q24h	q24h	q24 to 36h
Amphotec	4 to 6 mg/kg/day	< 1%	No renal adjustment is required
Abelcet	5 mg/kg/day	< 1%	No renal adjustment is required
AmBisome	3 to 5 mg/kg/day	< 1%	No renal adjustment is required
Azoles and other Antifungals						Increase CsA/FK level
Fluconazole	200 to 800 mg IV qd/bid	70%	100%	100%	50%		200 mg after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Flucytosine	37.5 mg/kg	90%	q12h	q16h	q24h	Hepatic dysfunction. Marrow suppression more common in azotemic patients.	Dose after dialysis	0.5 to 1.0 g/d	Dose for GFR 10 to 50
Griseofulvin	125 to 250 mg q6h	1%	100%	100%	100%		None	None	None
Itraconazole	200 mg q12h	35%	100%	100%	50%	Poor oral absorption	100 mg q12 to 24h	100 mg q12 to 24h	100 mg q12 to 24h
Ketoconazole	200 to 400 mg po qd	15%	100%	100%	100%	Hepatotoxic	None	None	None
Miconazole	1,200 to 3,600 mg/day	1%	100%	100%	100%		None	None	None
Posaconazole	200 mg qid	1%	100%	100%	100%
Terbinafine	250 mg po qd	>1%	100%	100%	100%
Voriconazole	4-6 mg/kg q12h	1%	100%	100%	100%	Avoid IV formulation in CKD
Caspofungin	70 mg LD then 50 mg daily	1%	100%	100%	100%
Micofungin	100-150 mg IV daily	1%	100%	100%	100%
Anidulafungin	200 mg LD, then 100 mg daily	1%	100%	100%	100%
Antiviral Agents
Acyclovir	200 to 800 mg po 5×/day	50%	100%	100%	50%	Poor absorption. Neurotoxicity in ESRD. Intravenous preparation can cause renal failure if injected rapidly.	Dose after dialysis	Dose for GFR <10	3.5 mg/kg/d
Adefovir	10 mg q24h	45%	100%	10 mg q48h	10 mg q72 h	Renal toxicity	10 mg weekly after HD	No data	No data
Amantadine	100 to 200 mg q12h	90%	100%	50%	q96h to 7 days		None	None	Dose for GFR 10 to 50
Cidofovir	5 mg/kg weekly ×2 (induction); 5 mg/kg every 2 weeks	90%	Avoid in CKD	No data: Avoid	No data: Avoid	Dose-limiting nephrotoxicity with proteinuria, glycosuria, renal insufficiency; nephrotoxicity and renal clearance reduced with coadministration of probenecid	No data	No data	Avoid
Delavirdine	400 mg q8h	5%	No data: 100%	No data: 100%	No data: 100%		No data: None	No data	No data: Dose for GFR 10 to 50
Didanosine	200 mg q12h (125 mg if <60 kg)	40% to 69%	q12h	q24h	50% q24h	Pancreatitis	Dose after dialysis	Dose for GFR <10	Dose for GFR <10
Emtricitabine	200 mg q24h	86%	q24h	q48-72h	q 96 h			Dose after dialysis	No data
Entecavir	0.5 mg q24h	62%	q24h	q48-72h	q96 h			Dose after dialysis	No data
Famciclovir	250 to 500 mg po bid to tid	60%	q8h	q12h	q24h	VZV: 500 mg po tid HSV: 250 po bid. Metabolized to active compound penciclovir.	Dose after dialysis	No data	No data: Dose for GFR 10 to 50
Foscarnet	40 to 80 mg IV q8h	85%	20 to 40 mg	q8 to 24 h according to ClCr		Nephrotoxic, neurotoxic, hypocalcemia, hypophosphatemia, hypomagnesemia, and hypokalemia	Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Ganciclovir IV	5 mg/kg q12h	95%	q12h	q24h	2.5 mg/kg qd	Granulocytopenia and thrombocytopenia	Dose after dialysis	Dose for GFR <10	2.5 mg/kg q24h
Ganciclovir	1,000 mg po tid	95%	1,000 mg tid	1,000 mg bid	1,000 mg qd	Oral ganciclovir should be used ONLY for prevention of CMV infection. Always use IV ganciclovir for the treatment of CMV infection.	No data: Dose after dialysis	No data: Dose for GFR <10	N/A
Indinavir	800 mg q8h	10%	No data: 100%	No data: 100%	No data: 100%	Nephrolithiasis; acute renal failure due to crystalluria, tubulointerstitial nephritis	No data: None	No data: Dose for GFR <10	No data
Lamivudine	150 mg po bid	80%	q12h	q24h	50 mg q24h	For hepatitis B	Dose after dialysis	No data: Dose for GFR <10	Dose for GFR 10 to 50
Maraviroc	300 mg bid	20%	300 mg bid	No data	No data	Drug interaction with CYP III-A	No data	No data	No data
Nelfinavir	750 mg q8h	No data	No data	No data	No data		No data	No data	No data
Nevirapine	200 mg q24h × 14d	< 3	No data: 100%	No data: 100%	No data: 100%	May be partially cleared by hemodialysis and peritoneal dialysis	Dose after dialysis	No data: Dose for GFR <10	No data: Dose for GFR 10 to 50
Oseltamivir	75 mg bid	99%	75 bid	75 mg daily	75 mg q48h		Dose after dialysis
Ribavirin	500 to 600 mg q12h	30%	100%	100%	50%	Hemolytic uremic syndrome	Dose after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Rifabutin	300 mg q24h	5% to 10%	100%	100%	100%		None	None	No data: Dose for GFR 10 to 50
Rimantadine	100 mg po bid	25%	100%	100%	50%
Ritonavir	600 mg q12h	3.50%	No data: 100%	No data: 100%	No data: 100%	Many drug interactions	No data: None	No data: Dose for GFR <10	No data: Dose for GFR 10 to 50
Saquinavir	600 mg q8h	<4%	No data: 100%	No data: 100%	No data: 100%		No data: None	No data: Dose for GFR <10	No data: Dose for GFR 10 to 50
Stavudine	30 to 40 mg q12h	35% to 40%	100%	50% q12 to 24h	50% q24h		Dose for GFR <10 after dialysis	No data	No data: Dose for GFR 10 to 50
Telbivudine	600 mg po daily		100%	600 mg q48h	600 mg q96h		Dose for GFR <10 after dialysis	No data	No data: Dose for GFR 10 to 50
Tenofovir	300 mg q24h		100%	300 mg q48-72h	300 mg q96h	Nephrotoxic	Dose for GFR <10 after dialysis	No data	No data: Dose for GFR 10 to 50
Valacyclovir	500 to 1,000 mg q8h	50%	100%	50%	25%	Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome	Dose after dialysis	Dose for GFR <10	No data: Dose for GFR 10 to 50
Valganciclovir	900 mg po daily or bid		100%	50%	25%	Granulocytopenia and thrombocytopenia	Dose after dialysis	Dose for GFR <10	450 mg daily
Vidarabine	15 mg/kg infusion q24h	50%	100%	100%	75%		Infuse after dialysis	Dose for GFR <10	Dose for GFR 10 to 50
Zanamivir	2 puffs bid × 5 days	1%	100%	100%	100%	Bioavailability from inhalation and systemic exposure to drug is low	None	None	No data
Zalcitabine	0.75 mg q8h	75%	100%	q12h	q24h		No data: Dose after dialysis	No data	No data: Dose for GFR 10 to 50
Zidovudine	200 mg q8h, 300 mg q12h	8% to 25%	100%	100%	100 mg q8h	Enormous interpatient variation. Metabolite renally excreted.	Dose for GFR <10	Dose for GFR <10	100 mg q8h
HD, hemodialysis; CAPD, chronic peritoneal dialysis; CVVH, continuous venovenous hemofiltration; GFR, glomerular filtration rate; q, every; TB, tuberculosis; BUN, blood urea nitrogen; tid, three times a day; bid, twice a day; IV, intravenous; po, by mouth; ESRD, end-stage renal disease; C. diff, Clostridium difficile; CKD, chronic kidney disease; VZV, varicella zoster virus; HSV, herpes simplex virus; ClCr, creatinine clearance; CMV, cytomegalovirus.

Protein binding represents another major determinant of drug dialyzability. Compounds that are highly protein bound have a smaller fraction of unbound drug available for removal by dialysis. Because heparin stimulates lipoprotein lipase, free fatty acid levels may increase during dialysis. Free fatty acid levels may displace sulfonamides, salicylates, and phenytoin from their protein binding sites, resulting in increased free fractions of each drug. In contrast, free fatty acids can increase protein binding of certain cephalosporins. The free fraction of phenytoin is increased by free fatty acids.

As discussed previously, drugs with a large Vd (greater than 2 L per kg) tend to have low concentrations in the intravascular space and are thus not readily dialyzable. The lower the Vd (less than 1 L per kg), the greater the drug’s availability to the circulation and, similarly, to the dialyzer.

Larger molecular weight compounds do not equilibrate rapidly between the extracellular and intracellular compartments during dialysis—little change is detected in intracellular concentrations whereas extracellular levels may fall significantly. As such, postdialysis rebound may occur in which pharmacologic agents move down their concentration gradients into the extracellular space. Rebound can be sizable as well as highly unpredictable in its time course, as demonstrated by vancomycin. Ultrafiltration raises the hematocrit, which can influence the dialytic clearance of drugs that partition into red blood cells. Drugs such as ethambutol, procainamide, and acetaminophen partition into red blood cells and demonstrate decreased dialytic clearance due to hemoconcentration following dialysis ultrafiltration.

Thus, parent compounds and their metabolites will be eliminated by dialysis to a greater extent if they possess a low molecular weight, limited Vd, and are water soluble. An increase in drug clearance of 30% or greater by dialytic therapy is considered significant and may warrant supplemental dosing following dialysis.

Dialytic Factors Affecting Drug Clearance

Dialysis membranes, dialysate flow rates, and the dialytic technique used can significantly alter drug clearance (Table 86.3).⁶² A wide variety of membranes have been developed including cellulose, cellulose acetate, polysulfone, polyamide, polyacrylonitrile (PAN; AN69), and polymethylmethacrylate (PMMA) in an effort to improve membrane permeability for larger uremic toxins. Similarly, albumin can cross polysulfone membranes to a limited extent.⁶³ Vancomycin clearance is significantly increased when polysulfone or PAN membranes are used.⁵⁹,⁶⁰ Likewise, cuprammonia rayon membranes allow greater aminoglycoside removal compared to cellulose fibers.⁴⁴ Two endogenous compounds that are poorly dialyzed, phosphate and β₂-microglobulin, undergo enhanced clearance when PAN, PMMA, and polysulfone membranes are used due to the increased surface area of these membranes.⁶⁴ The electrical charge of a dialysis membrane as well as the drug may help or hinder clearance. Like charges will repel one another, whereas opposite charges between membrane and drug may lead to drug adsorption to the membrane, ultimately reducing clearance.⁶⁵,⁶⁶

TABLE 86.3 Factors Affecting Drug Removal During Dialysis

Drug Properties

Dialysis System Properties

Renal clearance

Volume of distribution

Water and lipid solubility

Protein binding

Drug charge

Molecular weight

Filter properties

Blood flow, dialysate flow, and ultrafiltration rates

Drug clearance is achieved primarily by two processes: diffusion and convection. Diffusion of a compound increases as its molecular weight decreases and is negligible when standard membranes are used for substances larger than 1,000 D.²¹,⁶⁷ Diffusion of a drug is enhanced when the concentration gradient between blood and dialysate is maximized by countercurrent flow and increased blood and dialysate flow rates. Flow rates have less impact on the diffusion of middlesized and large molecules, but the surface area and hydraulic permeability of the membrane assume greater significance. Diffusion can be hindered, however, when high ultrafiltration rates lead to the mixing of dialysate and ultrafiltrate. This results in a decreased concentration gradient between blood and dialysate, reducing diffusive clearance.⁶⁸ Convection refers to the movement of solute by way of ultrafiltration, which affects molecules of all sizes but particularly large molecular weight substances, which diffuse poorly. To be removed by dialysis, compounds greater than 1,000 D require ultrafiltration when cellulose membranes are used, whereas those greater than 2,000 D demonstrate limited clearance. Ultrafiltration, and thus convection, can be reduced by protein binding to membrane surfaces during the dialytic procedure, which ultimately diminishes drug removal.²¹,²²

Continuous Renal Replacement Therapies and Drug Removal

Critically ill patients may require continuous renal replacement therapies (CRRTs) such as hemofiltration or hemodialysis, and an awareness of drug handling by such procedures is crucial to the patient’s outcome. Continuous hemofiltration removes solute by convection. The degree to which a
solute can convectively cross a membrane can be quantitated by its sieving coefficient (S), the ratio of solute concentration in the ultrafiltrate to solute concentration in the retentate (returning to the patient’s circulation). This can be approximated by the formula:

where UF is ultrafiltrate and A is arterial concentrations of solute, which will remain relatively constant during hemofiltration because blood flow does not affect sieving. Clearance of a solute (drug) is determined by multiplying the ultrafiltration rate by the S for that substance. The sieving coefficient for a given molecule can change, however, when comparing different dialysis membranes and is likely due to drug-membrane binding. Sieving can also be reduced by negatively charged solutes, although exceptions to this exist.²³,²⁵ Because inulin (5,200 D) can readily cross polysulfone hemofiltration membranes, nearly all therapeutic agents would be expected to permeate such membranes given molecular weights less than that of inulin. The drug’s degree of protein binding will be the major limiting factor to drug removal during hemofiltration.

In contrast to hemofiltration, drug removal during continuous hemodialysis occurs primarily via diffusion rather than convection. Protein binding again plays a central role whereby unbound drug diffuses more readily than protein-bound drug and molecular weight correlates inversely with diffusion. It should be noted that during continuous hemodialysis with venovenous access and average blood flow rates of 200 mL per minute, a GFR of 20 to 30 mL per minute can be achieved, which may provide greater drug clearance than expected. As previously discussed, when supplemental dosing is indicated, the amount of drug required to achieve a desired blood level can be calculated by multiplying the drug’s Vd by the patient’s IBW and the difference between the desired drug concentration and the trough concentration.

Lastly, peritoneal dialysis generally provides minimal drug removal, as dialysate flow rates are significantly slower than other forms of dialytic therapy. Drugs that are dialyzable via peritoneal dialysis must be small in size and have a low Vd. Drugs that are highly protein bound, however, may undergo greater clearance with peritoneal dialysis versus hemodialysis given the large protein losses commonly seen with peritoneal therapy.

SPECIFIC CONSIDERATIONS FOR DRUG PRESCRIBING IN RENAL FAILURE

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