Prescribing Drugs in Kidney Disease - Brenner and Rector's The Kidney, 8th ed

Brenner and Rector's The Kidney, 8th ed.

CHAPTER 57. Prescribing Drugs in Kidney Disease ^[*]

Christopher W. McIntyre Paul J. Owen

		Pharmacokinetics, 1930
		Effects of Uremia on Drug Disposition, 1931
		Bioavailability, 1931
		Distribution, 1932
		Metabolism, 1932
		Renal Excretion, 1933
		Initial Patient Assessment for Drug Dosing, 1934
		Calculating Drug Doses in Renal Impairment, 1935
		Drug Removal by Dialysis, 1936
		Factors Affecting Clearance, 1936
		Dosing Considerations for Specific Drug Categories, 1937
		Drug Level Monitoring, 1951

The number of patients with chronic kidney disease (CKD) and reduced renal function has been inexorably increasing. This has been related both to an increase in multisystem diseases commonly associated with CKD (predominantly type 2 diabetes and vascular disease) and increased awareness concerning the detection of CKD within the community. Population-based studies both within the United States and Europe have estimated about 5% of prevalent individuals have an estimated glomerular filtration rate (e GFR) of less than 60 ml/min.^[1] This percentage is considerably higher in the elderly and patients from African or South Asian backgrounds.^[2] Advances in the management of chronic diseases have permitted patients to live longer. Many of them develop decreased renal function over time.

The past decade has seen a similarly inexorable increase in the number of patients receiving chronic renal replacement therapy. This has been associated with the acceptance of an increasingly aged and co-morbidity-burdened population onto dialysis, as well as some modest increases in survival. The development of new dialysis membranes, the wide acceptance of chronic peritoneal dialysis, and the popularity of continuous renal replacement therapies add to the need for detailed understanding of drug transport across biologic and synthetic membranes. Furthermore an increasing number of patients being treated with a wider range of extracorporeal therapies (convective and sorbent assisted dialysis) as well as the emergence of quotidian dialysis regimes have combined to create a large patient group for which special understanding of drug disposition is important.

The kidney is the major regulator of the internal fluid environment, and uremia affects every organ system in the body. The physiologic changes associated with kidney disease have pronounced effects on the pharmacology of many drugs. Clinicians must take into account changes in the absorption, distribution, metabolism, and excretion of drugs and their active or toxic metabolites when dosing patients with decreased excretory ability or those receiving renal replacement therapy. The problems of kidney disease are often superimposed on underlying hypertension, diabetes mellitus, and heart disease within a group of patients who characteristically are receiving multiple drug treatment regimes.

At the same time that the number of patients with impaired renal function has grown, the number and complexity of new medications available continues to increase. The rapid development of complex, effective new drugs has added to the challenge of rational drug therapy in patients with impaired kidney function. Furthermore the extrapolation of clinical benefits from emerging drug regimes in the general population to those with CKD are handicapped not only by the differing pathophysiology of many disease process in CKD patients, but also ensuring that that dosing is equivalent between the two groups. Highly selective agonists or antagonists of cell receptors and specific enzyme inhibitors are routinely administered. Particularly in the realm of cardiovascular protection, multiple drugs of multiple classes are now being routinely administered in combination, potentially even in fixed dose “polypill” format.^[3]

Biosynthetic peptide hormones are available. More than 70% of all drugs currently under development fall into this category, and are directed to a huge number of specific therapeutic targets. The cost of these agents often precludes accruing above the minimum number of patient treatment years prior to successfully acquiring regulatory approval. Data on the use of these and many other newer drugs in CKD and the impact of dialysis is often limited. Many drugs by their very nature are difficult or impossible to monitor therapeutic plasma levels further increasing the complexity of their use in this challenging patient population. Even the use of currently available agents is an evolving issue with increasing awareness that tighter control of biological factors such as plasma glucose in diabetic patients is associated with improved outcomes.^[4] By escalating the doses of current agents there is a further erosion of the effective/toxic dose relationship in patients already with a reduced “safety margin”.

Physicians caring for patients with kidney disease must possess a basic understanding of the biochemical and physiologic effects of uremia on drug disposition and the effects of decreased kidney function and renal replacement therapies on drug and metabolite removal. This chapter considers these problems and offers suggestions on how to deal effectively with pharmacotherapy in patients with chronic kidney disease.

* The authors acknowledge the contributions of Drs. George R. Aronoff and Michael E. Brier to this chapter in the 7th edition of this book.
PHARMACOKINETICS

The ability to quantify drug bioavailability, distribution throughout the body, biotransformation to metabolites, and the elimination of drugs and metabolites from the body enhances practical therapeutics. Pharmacokinetics describes the time course of these events. However, pharmacologic effects are more than the sum of these processes. Pharmacodynamics involves the complex interaction of other pharmacologic factors, including drug concentrations, receptor-drug interactions, mechanism of action, and effect on body chemistry, as well as clinical factors, such as concurrent diseases and level of organ dysfunction. Knowledge of these aspects of drug disposition allows clinicians to predict drug behavior and clinical response, leading to rational dosimetry.

After a drug is given, it appears in the central circulation and distributes throughout the body. As shown in Figure 57-1 , when given intravenously, a rapid decrease in the plasma level follows an initial high drug concentration. This fall occurs as the drug distributes from the plasma into the extravascular space. Concurrent with and after the distribution phase, the processes of metabolism and excretion eliminate the drug at a slower rate. During the elimination phase, drug concentrations in plasma are in equilibrium with concentrations in body tissues.



FIGURE 57-1 Distribution and elimination of a drug after intravenous administration.

From graphical plots of plasma drug concentrations at different times after a dose is given, useful pharmacokinetic parameters may be determined. The rate and amount of drug absorption, the extent of drug distribution, and the rate of drug elimination may be measured. The elimination half-life of a drug is the time required for the plasma concentration to be decreased by one half and can also be determined from the plot of plasma drug concentration versus time after the dose. It is calculated from the slope of the elimination phase and is a reflection of the drug's elimination rate from plasma. By comparing pharmacokinetic data obtained from patients with normal kidney function with data from patients with renal insufficiency, rational drug dosimetry may be determined for patients with impaired kidney function. It is important to realize though that the functional half-life of a drug may be considerably longer. Agents that bind avidly to target receptors may modulate biological activity persisting long after clearance from plasma.

EFFECTS OF UREMIA ON DRUG DISPOSITION

Bioavailability

The relative amount of a drug that appears in the general circulation and the rate at which it appears are called bioavailability. The rate of absorption is reflected by a measure of time it takes to reach the maximum concentration, and the extent of drug absorption is often depicted as the area under the curve of the time after the dose and the plasma drug concentration.

Drugs given intravenously enter the central circulation directly and generally have a rapid onset of action. Drugs given by other routes must first traverse a series of membranes and may need to pass through important organs of elimination before entering the systemic circulation. Only a fraction of the administered dose may reach the circulation and become available at the site of drug action. Even drugs given intravenously and by inhalation must pass though the lungs before reaching arterial blood flow. Like other organs, the lungs remove substantial amounts of the agents. For example, Marik showed in the meta-analysis of 122 articles describing the effects of low-dose, intravenous dopamine in 970 subjects that the therapy has no renal protective effect.^[5] Juste and colleagues^[6] previously demonstrated an explanation for the inefficacy of low-dose dopamine in improving renal function. They found it impossible to predict the plasma dopamine level from the infusion rate, probably because the compound is highly metabolized by the lungs before it gets into the systemic circulation and the kidneys.^[6]

Most drugs are given orally. For these drugs, the rate and extent of gastrointestinal absorption are important considerations. After an orally administered drug is absorbed into the portal circulation, it must pass through the liver before reaching the systemic circulation. The bioavailability of a drug also depends on the extent of metabolism during its first pass through the liver.

First-pass biotransformation may also occur in the gut itself. For example, bioflavonoids in grapefruit juice can inhibit the isoenzyme cytochrome P-450 3A4 and noncompetitively inhibit the metabolism of drugs metabolized by this enzyme. This grapefruit juice-CYP 3A4 interaction was first noticed with the calcium channel blocker felodipine. Grapefruit juice increased felodipine bioavailability by 184% by inhibiting the enzyme present in gut mucosa.^[7] This interaction also increases the bioavailability of cyclosporine and may increase the absorption of cyclosporine by as much as 20%.^[8]

Generally, uremia decreases gastrointestinal absorption of drugs. Gastrointestinal symptoms are common in uremia, but little specific information about bowel function is available for patients with renal failure. When urea accumulates in the plasma, the salivary concentration of urea increases as well. Ammonia forms in the presence of gastric urease and buffers gastric acid, increasing gastric pH. The ammonia is absorbed and converted to urea again by the liver. The gastric alkalinizing effect of this internal urea-ammonia cycle decreases the absorption of drugs that are best absorbed in an acidic environment. For example, iron salts must be hydrolyzed by gastric acid for absorption. Uremic patients malabsorb these compounds if acid hydrolysis in the stomach is impaired. The dissolution of many tablet dosage forms requires the acid environment normally found in the stomach. Absorption of these products is incomplete and occurs more slowly in an alkaline environment.^[9]

The loss of gastric acidity also plays a role in determining the efficacy of oral phosphate binders. A large amount of dietary phosphate is realized from acid hydrolysis of protein within the stomach. The effectiveness of most phosphate binders is pH dependent. Furthermore, the ingestion of multivalent cations, frequently used in antacids or phosphate binders (or both), also diminishes drug absorption.^{[10] [11]} Chelation and the formation of nonabsorbable complexes reduce bioavailability of some drugs. This effect is particularly important on the absorption of some antibiotics and digoxin.

Craig and colleagues^[12] demonstrated impaired gastrointestinal absorptive function. They showed that the absorption of the simple sugar, d-xylose, is reduced by nearly 30% in patients with renal failure requiring dialysis.^[12]However, the processes of gastrointestinal drug absorption are complex, may be saturable and dose dependent, and are more variable in patients with renal failure than in those with normal renal function.^[13] Gastroparesis, commonly observed in diabetic patients with renal failure, prolongs gastric emptying and delays drug absorption. Similarly, diarrhea decreases gut transit time and diminishes drug absorption by the small bowel.

Uremia alters first-pass hepatic metabolism. Decreased biotransformation leads to the appearance of increased amounts of active drug in the systemic circulation and enhanced bioavailability of some drugs. Conversely, impaired protein binding allows more unbound drug to be available at the site of hepatic metabolism, thereby increasing the amount of drug removed during the hepatic first pass. With the complex interaction of absorption and first-pass hepatic metabolism, it is not surprising that drug bioavailability is more variable in patients with renal impairment than in patients with normal renal function.

Distribution

After a drug is administered, it is dispersed throughout the body at a given rate. At equilibrium, the apparent volume of distribution is calculated by dividing the amount of the drug in the body by its plasma concentration. This apparent volume of distribution does not correspond to a specific anatomic space. Rather, the volume of distribution is a mathematical construct used to estimate the dose of a drug to be given to achieve a therapeutic plasma concentration. Agents that are highly protein bound or those that are water soluble tend to be restricted to the extracellular fluid space and have small volumes of distribution. Highly lipid-soluble drugs penetrate body tissues and exhibit large volumes of distribution.

Renal insufficiency frequently alters drug distribution volume. Edema and ascites increase the apparent volume of distribution of highly water-soluble or protein-bound drugs. Usual doses of such drugs given to edematous patients result in inadequate, low plasma levels. Conversely, dehydration or muscle wasting tends to decrease the volume of distribution. In these cases, usual doses result in unexpectedly high plasma concentrations. The distribution of drugs may be altered by fluid removal during dialysis.^[14] Changes in lean body mass also commonly occur over time within dialysis patients.^[15] If this is not detected this often results in an inappropriate maintenance of the same dry weight with an increase in total body water, modifying drug distribution even within a patient.

The alteration of plasma protein binding in patients with renal insufficiency is an important factor affecting eventual drug action. The volume of distribution of a drug, the quantity of unbound drug available for action, and the degree to which the agent can be eliminated by hepatic or renal excretion are all influenced by protein binding. Drugs that are protein bound attach reversibly to albumin or glycoprotein in plasma. Organic acids are thought to bind to a single binding site, whereas organic bases probably have multiple sites of attachment.^{[16] [17]}

Protein-bound organic acids such as hippuric acid, indoxyl sulfate, and 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF) accumulate in renal failure and decrease protein binding of many acidic drugs.^{[18] [19] [20]} Altered protein binding affects organic bases less than organic acids. A combination of decreased serum albumin concentration and a reduction in albumin affinity for the drug reduces protein binding in patients with uremia. Even when the plasma albumin concentration is normal, the protein-binding defect of some drugs correlates with the level of azotemia and may be corrected with dialysis.^{[21] [22] [23] [24]} As illustrated in Figure 57-2 , affinity is influenced by uremia-induced changes in the structural orientation of the albumin molecule or by the accumulation of endogenous inhibitors of protein binding that compete with drugs for their binding sites.



FIGURE 57-2 Protein binding defect in uremia. Displacement of the drug from its binding site by an accumulation of undefined uremic toxin or a uremia-induced conformational change in the binding site geometry results in more free drug in the plasma.

The consequences of impaired plasma protein binding in uremia are important, because the unbound fraction of several acidic drugs is substantially increased. Serious toxicity can occur if the total plasma concentration of these drugs is pushed into the therapeutic range by increasing the dose. For such drugs, total and unbound plasma concentrations should be measured. Hemodiafiltration with highly porous membranes can result in considerable intradialytic plasma protein losses into the waste dialysate and in some patients both a short-term and longer-term reduction in serum albumin.^[25] The use of albumin dialysis (either as with a regenerating albumin circuit or as single pass albumin dialysis) largely utilized in the management of hepatic dysfunction markedly increases the removal of protein bound drugs. This is a property that allows such techniques to very effectively manage self poisoning with such agents.^[26] The addition of sorbent components to further clear uremic toxins introduces further complexities when predicting the effects of a dialysis therapy on drug clearance.

Predicting the clinical consequences of altered protein binding in uremia is difficult. Although decreased binding results in more unbound drug being available at the site of drug action or toxicity, the distribution volume is increased, resulting in lower plasma concentrations after a given dose. More unbound drug is available for metabolism and excretion, which decreases the half-life of the drug in the body. Drugs with decreased protein binding in dialysis patients are listed in Table 57-1 .

TABLE 57-1 -- Drugs with Decreased Protein Binding in Dialysis Patients

Barbiturates
Cardiac glycosides
Dicloxacillin
Cephalosporins
Clofibrate
Doxepin
Loop diuretics
Oxazepam
Penicillins
Pentobarbital
Phenobarbital
Phenytoin
Sulfonamides
Salicylate
Temazepam
Theophylline
Valproic acid
Warfarin

Metabolism

Biotransformation is an important mechanism for drug elimination. Many compounds are highly lipid soluble, cross cell membranes easily, and may have large volumes of distribution. Even when filtered by the glomerulus, these nonpolar molecules may diffuse from the tubule lumen and be reabsorbed into the circulation. Drug metabolism generally converts lipid-soluble compounds into more polar, water-soluble metabolites that have smaller distribution volumes and diffuse less readily across renal tubule cells. These are more easily excreted in the urine.

Although renal insufficiency is thought to affect primarily the renal elimination of drugs or metabolites, renal failure substantially affects drug biotransformation. Uremia slows the rate of reduction and hydrolysis reactions. For example, peptide and ester hydrolysis are substantially reduced. Microsomal oxidation may also be affected. In a model of uremic rats, Leblond and colleagues demonstrated up to a 50% decrease in the protein expression of several CYP450 isoforms and their mRNAs.^[27]

Even glucuronidation to polar, water-soluble metabolites, once thought to occur normally in renal failure, is impaired in patients with decreased renal function. Formation of acyl-glucuronides is under the control of a feedback cycle in which plasma drug clearance is a function of the formation, hydrolysis, and renal clearance of the glucuronide conjugate. Impaired kidney function in rabbits decreased glucuronide formation by more than 20%, largely because of the decreased clearance of glucuronide from plasma.^[28]

Uremia may also alter the disposition of drugs metabolized by the liver through changes in plasma protein binding. The systemic clearance of a highly protein-bound drug with a low hepatic extraction ratio depends on the simultaneous effects of renal disease on protein binding and intrinsic metabolic drug clearance. Protein binding of such a drug is related to creatinine clearance in an inverse hyperbolic relationship, whereas the unbound intrinsic metabolic clearance declines linearly with creatinine clearance. Because the effects of renal failure on these two factors offset each other in terms of total systemic clearance, the lowest total systemic clearance is not seen in dialysis patients but rather occurs in those with moderate renal impairment. The systemic clearance of drugs with a high hepatic extraction ratio is not thought to be as susceptible to the effect of renal disease as that of drugs with a low extraction ratio.^[29]

The production of active or toxic metabolites is an important aspect of drug metabolism in patients with renal failure. Many of these metabolites depend on the kidneys for their removal from the body. The accumulation of active metabolites can explain in part the high incidence of adverse drug reactions seen in renal failure. For example, propoxyphene is subject to extensive first-pass biotransformation after oral administration to its pharmacologically active metabolite norpropoxyphene, which is normally excreted in the urine. Norpropoxyphene substantially accumulates in renal failure and may result in oversedation.^[30] Similarly, although the liver usually rapidly metabolizes morphine, it is excreted mainly in the urine as its active metabolites, morphine-3-glucuronide (M-3G) and morphine-6-glucuronide (M-6G). M-3G and M-6G readily cross the blood-brain barrier and bind with strong affinity to opiate receptors, exerting strong analgesic effects. In patients with renal failure, morphine itself is metabolized more slowly, and these active metabolites increase, making prolonged narcosis and respiratory depression more likely.^[31]

The biotransformation of meperidine results in the production of normeperidine, a more polar metabolite that is rapidly excreted in the urine. Normeperidine has little narcotic effect, but it may lower the seizure threshold. In patients with renal impairment, frequently repeated doses of meperidine may result in the accumulation of this potentially toxic metabolite, with resultant seizures.^[32] Table 57-2 lists some drugs that form active or toxic metabolites in patients with reduced kidney function.

TABLE 57-2 -- Drugs That Have Active or Toxic Metabolites in Dialysis Patients

Acetaminophen
Angiotensin-converting enzyme inhibitors
Angiotensin receptor blockers
Adriamycin
Allopurinol
Amiodarone
Amoxapine
Azathioprine
Benzodiazepines
β-Blockers
Bupropion
Buspirone
Cardiac glycosides
Clorazepate
Cephalosporins
Chloral hydrate
Clofibrate
Desipramine
Diltiazem
Encainide
Esmolol
H₂-blockers
Hydroxyzine
Imipramine
Isosorbide
Levodopa
Lorcainide
Meperidine
Metronidazole
Methyldopa
Miglitol
Minoxidil
Morphine
Nitrofurantoin
Nitroprusside
Procainamide
Primidone
Propoxyphene
Pyrimethamine
Quinidine
Serotonin reuptake inhibitors
Spironolactone
Sulfonylureas
Sulindac
Thiazolidinediones
Triamterene
Trimethadione
Verapamil
Vidarabine

Drug dosing guidelines for dialysis patients are usually derived from studies of patients with stable, chronic renal failure. However, these recommendations are often extrapolated to seriously ill patients with acutely decreased renal function. The preservation of nonrenal metabolic clearance has been demonstrated in patients with acute renal failure.^[33] The preservation of metabolic clearance observed early in the course of acute renal failure suggests that drug dosing schemes extrapolated from individuals with stable chronic renal failure could result in potentially ineffectively low drug concentrations in patients with acute renal dysfunction. Furthermore failure to appreciate that changes in serum creatinine is not an accurate marker of GFR early on in acute kidney injury can lead to further dosing errors.

Renal Excretion

The renal handling of drugs depends on the glomerular process of filtration and on the tubular processes of secretion and reabsorption. However, the rate of drug and metabolite elimination by the kidneys is proportional to GFR. In addition to the GFR, the glomerular elimination of drugs depends on the molecular size and protein binding of the agent. Although protein binding decreases the filtration of drugs, it may increase the amount secreted by the renal tubule. When glomerular filtration is impaired by renal disease, the clearance of drugs eliminated primarily by this mechanism is decreased, and the plasma half-life of the drugs prolonged.

Although we do not clinically measure the tubule function of organic acid secretion, the excretion of drugs eliminated by active organic ion transport systems in the renal tubule is prolonged in patients with renal disease. As patients' creatinine clearance decreases, their ability to eliminate many drugs is adversely affected. Because the proximal tubule secretion of some agents is carrier mediated and capacity limited, multiple drugs eliminated by tubule secretion may saturate the transport system if they are administered concurrently.

The rate of elimination of drugs excreted by the kidneys is proportional to the GFR. The serum creatinine or creatinine clearance is needed to determine renal function before prescribing any drug. The Cockroft and Gault^[34]equation is useful for the purpose of calculating an estimated creatinine clearance. However, there are a number of significant limitations in relying on this measure. Intrinsically it is an estimation of creatinine clearance, which is in itself an approximation to GFR, thereby introducing another tier of error. The accurate measurement of height is often difficult, particularly in the acute setting. Weight is more regularly obtained, however again in the acute setting (with for instance congestive cardiac failure) this may be significantly influenced by changes in body composition and correlate poorly with lean body mass.

The use of estimated GFR is now more widely used, routinely calculated using one of the MDRD formulae from serum creatinine concentration, age, and sex alone. This also has limitations concerning adequately adjusting for reduced muscle mass in the debilitated or amputated patient. Estimated GFR correlates less well with actual GFR more than 60 ml/min. Furthermore it is less reliable in the extremes of the patient population as well as failing to fully compensate for racial differences.^[35] Reliance on what is a marker of GFR in the setting of CKD is also unwise in the acute setting. With rapidly changing renal function a timed urine collection utilizing the midpoint serum creatinine to measure creatinine clearance may still have a role.

Serum cystatin C measurement has also been put forward as a more reliable measure of renal function than serum creatinine. However, cystatin C levels can be effected by factors other than changes in renal function,^[36] the measurement is not widely available, and there is a paucity of data on adjusting drug doses based on this measurement.

Some dialysis patients have residual renal function that substantially contributes to the elimination of drugs and their metabolites. Estimating residual renal function in dialysis patients still making urine is difficult, because the serum creatinine level reflects the adequacy of dialysis and muscle mass as well as residual GFR. Creatinine clearance measurements less accurately reflect the GFR in patients with such severe renal failure as to require dialysis because this is a poor marker of GFR at very low levels, and the volume of urine output is heavily influenced by changing hydration status during the dialysis week. Changing serum creatinine levels over the duration of the clearance measurement, the contribution of tubule creatinine secretion, and the accumulation of chromogens contribute to the difficulty in measuring residual renal function. Serum creatinine measurements alone should not be used to estimate intrinsic renal function in dialysis patients. The plasma clearance rate of certain radioisotopes more accurately estimates residual renal function in these patients, although the use of radioisotopes is complicated by the need to dispose of radioactive materials.

Conventional quantification of residual renal function in hemodialysis patients is performed by measuring urea clearance, creatinine clearance, or a combination of both. This approach requires a 24-hour urine collection, which is often difficult to perform and inaccurate. It requires that serum urea and creatinine levels be measured before and after the urine collection to estimate the average values during the collection. Measuring the elimination of iohexol after an intravenous dose with a single blood measurement of iohexol has been reported to be an accurate and safe measure of residual renal function in dialysis patients and can potentially simplify drug dosing.^[37] This is conventionally performed with serial blood sampling but can also be performed on capillary blood collected on a blotting paper medium, with extraction and subsequent analysis when the patient returns from home.^[38] Residual renal function decreases over time and is usually less than 5 mL/min after 1 year on hemodialysis.^[39]

In addition to the process of filtration and secretion of drugs and metabolites into the urine, the kidney possesses enzymes capable of metabolizing drugs.^[40] The kidney plays an important role in the metabolism of many proteins and small peptides. Clinically, the most important aspect of renal drug metabolism is the peptide hydrolysis of insulin. The kidney clears insulin by glomerular filtration and subsequent luminal reabsorption of insulin by proximal tubule cells. The second involves diffusion of insulin from peritubule capillaries and subsequent binding of insulin to the contraluminal membranes of tubule cells.^[41] Impairment of the renal clearance of insulin prolongs the half-life of circulating insulin and often results in a decrease in the insulin requirement of diabetic patients with decreased renal function.^[42]

INITIAL PATIENT ASSESSMENT FOR DRUG DOSING

Clinical evaluation always begins with a careful history and physical examination. Knowledge of previous medication history, drug-related allergy or toxicity, and concurrent medicines are important in the initial evaluation of patients on dialysis. Reviewing the possibility of drug interactions before choosing a drug regimen reduces potentially adverse drug effects. On average, dialysis patients routinely receive 11 different medications and have three times the incidence of adverse drug events as patients with normal renal func-tion.^{[43] [44] [45]} Focusing therapy on specific diagnoses allows the clinician to limit the number of drugs the patient is taking and lessens the chances of untoward drug interactions. When possible, drug therapy should be individualized to take advantage of the fact that one drug can be used to manage several conditions. For example, a calcium channel antagonist can be used to manage hypertension and angina.

Estimating extracellular fluid volume is necessary to determine the distribution volume of drugs. Edema or ascites increases the distribution volume of many drugs. Dehydration contracts this volume. Individualization of the drug regimen requires measurements of body height and weight. Many clinicians use the average of the measured body weight and the ideal body weight as the value on which to base drug doses.^[46] An appreciation of total body water either measured (usually by bioimpedance) or calculated from regression equation can also help to refine dosing choices particularly for drugs with high volumes of distribution.

Evaluating functional impairment of other excretory organs is also important. The failure of other organs limits the possibilities for alternate pathways of drug and metabolite elimination. For instance, the stigmata of liver disease suggest the potential need to alter drug dosages further in patients with renal failure.

CALCULATING DRUG DOSES IN RENAL IMPAIRMENT

The goal of the initial drug dose is to achieve therapeutic drug concentrations rapidly. If no loading dose is prescribed, three to four half-lives of the drug must pass before the plasma levels are at steady state. The amount of the drug given affects how rapidly certain plasma levels are achieved and the magnitude of the steady-state plasma concentration. A loading dose equivalent to the dose given to a patient with normal renal function should always be given to patients with renal impairment if the drug's half-life is particularly long and if the physical examination suggests normal extracellular fluid volume. If the loading dose of a drug is not known, it can be calculated from the following expression:

Loading dose = V_d × IBW × Cp

In this equation, V_d is the drug's volume of distribution in L/kg, IBW is the patient's ideal body weight (kg), and Cp is the desired steady-state plasma drug concentration.

Several methods can be used to determine subsequent drug doses. The fraction of the normal dose recommended for a patient with renal failure can be calculated as follows:

Df = t1/2 normal/t1/2 renal failure

In this equation, Df is the fraction of the normal dose to be given, t½ normal is the elimination half-life of the drug in a patient with normal renal function, and t½ renal failure is the elimination half-life of the drug in a patient with renal failure. To maintain the normal dose interval in patients with renal impairment, the amount of each dose after the loading dose can be determined from the following relationship:

Dose in renal impairment = Normal dose × Df

The resulting dose is usually given at the same dose interval as that for patients with normal renal function. This method is effective for drugs with a narrow therapeutic range and short plasma half-life. Figure 57-3 illustrates plasma concentrations after an initial loading dose and reduction of the individual doses.



FIGURE 57-3 Plasma concentrations after a normal loading dose and reduced maintenance doses. This approach avoids high peak and low trough concentrations and is best for drugs with a narrow range between the therapeutic and toxic concentrations.

Prolonging the dose interval in dialysis patients is frequently a convenient method to reduce drug dosage. This method is particularly useful for drugs with a broad therapeutic range and long plasma half-life. If prolonging the dose interval, rather than decreasing the individual doses, is desirable, the dose interval in renal impairment can be estimated from the following expression, in which Df is the dose fraction:

Dose interval in renal impairment = Normal dose × interval/Df

If the range between therapeutic and toxic levels is too narrow, potentially toxic or sub therapeutic plasma concentrations result. The resulting plasma concentrations from prolonging the dose interval in an individual with impaired renal function are shown in Figure 57-4 .



FIGURE 57-4 Plasma concentrations after a normal loading dose and repeated normal doses at a prolonged dose interval. Higher peak and lower trough concentrations result.

A combined approach using the dose-reduction and interval-prolongation methods is often practical. Multiplying the usual daily maintenance dose by the dose fraction modifies the dosage. After the average daily dose is calculated, it can be divided into convenient dosing intervals. The decision to extend the dosing interval beyond a 24-hour period should be based on the need to maintain therapeutic peak or trough levels. The dosing interval may be prolonged if the peak level is most important. When the minimum trough level must be maintained, it is preferable to modify the individual dose or use a combination of dose and interval methods to determine the correct dosing strategy. Drugs removed by dialysis given once daily should be given after the dialysis treatment.

DRUG REMOVAL BY DIALYSIS

Factors Affecting Clearance

Drug removal by conventional hemodialysis occurs primarily by the process of drug diffusion across the dialysis membrane. Diffusion proceeds down a concentration gradient from the plasma to the dialysate. Drug removal by conventional hemodialysis is most effective for drugs that are less than 500 daltons (D) and are less than 90% protein bound. Drugs that have small volumes of distribution are more effectively removed by dialysis than compounds that are distributed in adipose tissue or have extensive tissue binding. Removal of low-molecular-weight drugs is enhanced by increasing the blood and dialysate flow rates and by using large-surface-area dialyzers. Larger molecules require more porous membranes for increased removal. The hemodialysis clearance of a drug can be estimated from the following relationship:

Cl_HD = Cl_urea × (60/MW_drug)

In this equation, Cl_HD is the drug's clearance by hemodialysis, Cl_urea is the clearance of urea by the dialyzer, and MW_drug is the molecular weight of the drug.^[47] The urea clearance for most standard dialyzers varies between 150 and 200 mL/minute.^[48]

However, such calculations only provide an estimate of clearance. Within clinical practice there are many further potential factors further modifying drug handling on dialysis. The use of porous dialysis membranes to perform high-flux dialysis decreases the importance of drug molecular mass in determining drug removal during extracorporeal circulation. During high-flux dialysis, the volume of distribution and percent of protein binding of the drug are more important determinants of drug clearance. Study results suggest that, for drugs that are not highly protein bound and have relatively small volumes of distribution, drug removal occurs by diffusion and parallels urea clearance, despite a very large molecular mass.^{[49] [50]} The removal of drugs during high-flux dialysis depends more on treatment time, blood and dialysate flow rates, distribution volume, and binding of the drug to serum proteins. As a consequence, much more drug is removed during high-flux dialysis than previously estimated for conventional hemodialysis. Substantial amounts of drug may be removed if the agent is given during high-flux dialysis treatments.^[51] Small solute removal over a dialysis week is far more efficient if an increasing frequency is employed.^[52] Certainly daily dialysis in the acute setting can result in significant under dosing with a variety of important drugs.^[53] Slow nocturnal dialysis requires a significant increase in gentamicin dosage to achieve adequate therapeutic levels as compared to conventional three times a week hemodialysis.^[54] However, the full impact of quotidian dialysis regimes on drug prescribing in the chronic context has not been evaluated enough.

Membrane type can also be an important factor. This does not only relate to the clearance characteristics of the dialyzer, but to charge upon the membrane resulting in differential removal of drugs dependent on their charge or degree of binding to heavily positively charged proteins. For instance very large differences in the removal of recombinant hirudin by differing membranes was noted, the main differences being charge related,^[55] clearly with significant consequences for safe anticoagulation with this agent. Reuse of dialyzers also results in some change of their functional characteristics.^[56] The reused dialyzer also coats with donor protein; the effects on drug elimination are inadequately studied.

Peritoneal dialysis is much less efficient at removing drugs than hemodialysis.^[57] As with conventional hemodialysis, drug removal by peritoneal dialysis is most effective for lower-molecular-weight drugs that are not extensively bound to serum proteins. Higher-molecular-weight drugs may be somewhat more removed by peritoneal dialysis because of secretion into peritoneal lymphatic fluid. Similarly, drugs that have small volumes of distribution are more effectively removed than those that are distributed in adipose tissue or have extensive tissue binding. Removal of low-molecular-weight drugs depends on the number of peritoneal dialysis exchanges done daily.

Although peritoneal dialysis does not rapidly remove drugs, many are well absorbed when placed in peritoneal dialysate. It should be noted that the low removal of many antibiotics by peritoneal dialysate requires them to be administered intraperitonealy to reach the necessary concentrations to adequately manage peritonitis.^[58] Table 57-3 includes some commonly used antibiotics for patients on chronic ambulatory peritoneal dialysis and suggestions for dosages used to manage ambulatory peritonitis and systemic infections. The additional effects of other peritoneal dialysis regimes such as nocturnal automated dialysis (with day dwell) or tidal regimes on drug removal are inadequately studied to allow any robust recommendations. The degree of residual renal function is an important factor in drug handling and it should be noted that peritoneal dialysis patients characteristically retain residual renal function to a greater (though variable) degree than hemodialysis patients.

TABLE 57-3 -- Antibiotic Dosages for Patients on Chronic Ambulatory Peritoneal Dialysis

Drug	Loading Dose	Maintenance Dose
Amikacin	7.5 mg/kg	25 mg/L
Ampicillin	1 g	60 mg/L
Aztreonam	15 mg/kg	250 mg/L
Carbenicillin	5 g	250 mg/L
Cefazolin	1 g	125 mg/L
Cefoperazone	—	2 g every other bag
Ceftazidime	1 g	125 mg/L
Ceftriaxone	—	1 g in one bag/day
Clindamycin	—	150 mg/L
Gentamicin	2 mg/kg	4 mg/L
Imipenem/cilastatin	500 mg	250 mg every other bag
Moxalactam	1 g	125 mg/L
Penicillin	500,000 U	100,000 U/L
Piperacillin	—	4 g every other bag
Ticarcillin/clavulanate	1.2 g	120 mg/L
Tobramycin	2 mg/kg	4 mg/L
Vancomycin	30 mg/kg	20 mg/L

Molecular weight, membrane characteristics, blood flow rate, and the addition of dialysate determine the rate and extent of drug removal during continuous renal replacement therapies (CRRT). Molecular weight affects drug removal by diffusion during dialysis more than during convection during CRRT because of the large pore size of membranes used for CRRT. Because most drugs are less than 1500 D, drug removal by CRRT does not depend greatly on molecular weight.

The volume of distribution of a drug is the most important factor determining removal by CRRT. Drugs with a large volume of distribution are highly tissue bound and not accessible to extracorporeal circuit in quantities sufficient to result in substantial removal by CRRT. Even if the extraction across the artificial membrane is 100%, only a small amount of a drug with a large volume of distribution is removed. A volume of distribution greater than 0.7 L/kg substantially decreases CRRT drug removal. The volume of fluid exchanged may also be important, particularly given the wider spread application of “high dose” CRRT in the intensive care setting.^[59] Actual drug handling may be significantly different to be predicted in high-efficiency CRRT, especially for drugs with narrow therapeutic indicies. This may result in under dosing with such agents as vancomycin during such therapies.^[60]

Drug protein binding also determines how much is removed during CRRT. Only unbound drug is available for elimination by CRRT. Protein binding of more than 80% provides a substantial barrier to drug removal by convection or diffusion. During continuous hemofiltration, an ultrafiltration rate of 10 mL/min to 30 mL/min is achieved. The addition of diffusion by continuous dialysis increases drug clearance, depending on blood and dialysate flow rates. As during high flux dialysis, drug removal parallels the removal of urea and creatinine. The simplest method for estimating drug removal during CRRT is to estimate urea or creatinine clearance during the procedure.^[61]

Recommendations for dosing selected drugs in patients with impaired renal function are given in Table 57-4 . These recommendations are meant only as a guide and do not imply efficacy or safety of a recommended dose in an individual patient. A loading dose equivalent to the usual dose in patients with normal renal function should be considered for drugs with a particularly long half-life. The table indicates potential methods for adjusting the dose by decreasing the individual doses or increasing the dose interval. In the table, when the dose method (D) is suggested, the percentage of the dose for normal renal function is given. When the interval method (I) is suggested, the actual dose interval is provided.

TABLE 57-4 -- Drug Doses in Renal Failure

Drug	Dose Method	GFR > 50 (mL/min)	GFR 10–50 (mL/min)	GFR < 10 (mL/min)	HD	CAPD	CRRT
Acarbose	D	100%	Avoid	Avoid	Unknown	Unknown	Avoid
Acebutolol	D	100%	50%	30–50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Acetaminophen	I	q4h	q6h	q8h	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Acetazolamide	I	q6h	q12h	Avoid	No data	No data	Avoid
Acetohexamide	I	Avoid	Avoid	Avoid	Avoid	Avoid	Avoid
Acetohydroxamic Acid	D	100%	100%	Avoid	Unknown	Unknown	Unknown
Acetylsalicyclic Acid	I	q4h	q4–6h	Avoid	As normal GFR	As normal GFR	As normal GFR
					Dose post HD
Acrivastine	D	8 mg q12h	8 mg q12–24h	8 mg q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Aciclovir	D, I	5 mg/kg q8h	5 mg/kg q12–24h	2.5 mg/kg q24h	Dose as GFR < 10	Dose as GFR < 10	3.5 mg/kg/day
					Dose post HD
Adenosine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Albuterol	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Alfentanil	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Allopurinol	D	75%	50%	33%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Alprazolam	D	100%	100%	100%	Unknown	Unknown	NA
Alteplase (t-PA)		100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Altretamine	D	Unknown	Unknown	Unknown	No data	No data	Unknown
Amantadine	I	q24–48h	q48–72h	q7d	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Amikacin	D, I	60–90% q12h	30–70% q12–18h	20–30% q24–48h	5 mg/kg post HD	15–20 mg/L/day	Dose as GFR 10–50
Amiloride	D	100%	50%	Avoid	NA	NA	NA
Aminophylline	D	100%	200–400 mg q12h	200–300 mg q12h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Amiodarone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Amitriptyline	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Amlodipine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Amoxapine	D	100%	100%	100%	Unknown	Unknown	NA
Amoxicillin	I	q8h	q8–12h	q24h	Dose as GFR < 10	250 mg q8h	As normal GFR
					Dose post HD
Amphotericin	I	q24h	q24h	q24–36h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Amphotericin B Colloidal	I	q24h	q24h	q24–36h	Dose as GFR < 10	Dose as GFR < 10	Dose for GFR 10–50
Amphotericin B lipid	I	q24h	q24h	q24–36h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ampicillin	I	q6h	q6–12h	q12–24h	Dose as GFR < 10	Dose as GFR < 10	Dose as G FR 10–50
					Dose post HD
Amrinone	D	100%	100%	50–75%	No data	No data	Dose as GFR 10–50
Anistreplase	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Astemizole	D	100%	100%	100%	Unknown	Unknown	NA
Atenolol	D, I	100% q24h	100% q24h	50% q24h	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Atovaquone		100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Atracurium	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Auranofin	D	3–6 mg q24h	3 mg q24h	Avoid	Avoid	Avoid	Dose as GFR 10–50
Azathioprine	D	100%	75%	50%	As normal GFR	Dose as GFR < 10	Dose as GFR 10–50
Azithromycin	D	100%	100%	100%	No data	No data	No data
Azlocillin	I	q4–6h	q6–8h	q8h	Dose as GFR < 10	Dose for GFR < 10	Dose as GFR 10–50
					Dose post HD
Aztreonam	D	100%	50–75%	25%	Dose as GFR < 10	Dose for GFR < 10	Dose as GFR 10–50
					Dose post HD
Basiliximab		100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Benazepril	D	100%	50–75%	25–50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Betamethasone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Betaxolol	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Bezafibrate	D	70%	50% q24–48h	Avoid	200 mg q72h	200 mg q72h	Dose as GFR 10–50
Bisoprolol	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Bleomycin	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Bopindolol	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Bretylium	D	100%	25–50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Bromocriptine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Brompheniramine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Budesonide	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Bumetanide	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Bupropion	D	100% q24h	100% q24h	100% q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Buspirone	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
					50% if anuric	50% if anuric
Busulfan	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Butorphanol	D	100%	75%	50%	Unknown	Unknown	NA
Capreomycin	I	q24h	q24h	q48h	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Captopril	D, I	100% q8–12h	75% q12–18h	50% q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Carbamazepine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Carbidopa	D	100%	100%	100%	Unknown	Unknown	Unknown
Carboplatin	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Carmustine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Carteolol	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Carvedilol	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Cefaclor	D	100%	50–100%	50%	250–500 mg q8h	250 mg q8–12h	As normal GFR
Cefadroxil	I	q12h	q12–24h	q24–48h	0.5–1.0 g post HD	0.5 g/day	As normal GFR
Cefamandole	I	q6h	q6–8h	q12h	0.5–1.0 g q12h	0.5–1.0 g q12h	Dose as GFR 10–50
					Dose post HD
Cefazolin	I	q8h	q12h	q24–48h	0.5–1.0 g post HD	0.5 g q12h	Dose as GFR 10–50
Cefepime	I	q12h	q16–24h	q24–48h	1.0 g post HD	Dose for GFR < 10	Not recommended
Cefixime	D	100%	75%	50%	200 mg q24h	200 mg q24h	Dose as GFR 10–50
					Dose post HD
Cefmenoxime	D, I	1.0 g q8h	0.75 g q8h	0.75 g q12h	0.75 g q12h	0.75 g q12h	Dose as GFR 10–50
					Dose post HD
Cefmetazole	I	q16h	q24h	q48h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Cefonicid	D, I	0.5 g/d	0.1 g–0.5 g/day	0.1 g/day	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ceforanide	I	q12h	q12–24h	q24–48h	0.5–1.0 g post HD	None	1.0 g/day
Cefotaxime	I	100% q8h	100% q8h	50% q8–12h	Dose as GFR < 10	1 g q24h	1 g q12h
					Dose post HD
Cefotetan	D	100%	50%	25%	250–500 mg q24h	1 g q24h	750 mg q12h
					+500 mg post HD
Cefoxitin	I	100%	1–2 g q8–24h	0.5–1 g q12–24h	0.5–1 g q24–48h	1 g q24h	Dose as GFR 10–50
					+1 g post HD
Cefpodoxime	I	100%	100%	100–200 mg	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
				q24–48h
Cefprozil	D, I	100%	50% q24h	50% q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR < 10
					Dose post HD
Ceftazidime	I	100%	0.5–1 g q12–24h	0.5–1 g q48h	1 g post HD	0.5–1 g q24h	0.5–1 g q12h
Ceftibuten	D	100%	50%	25%	400 mg post HD	Dose as GFR < 10	Dose as GFR 10–50
Ceftizoxime	I	0.5–1.5 g q8h	0.25–1 g q12h	0.25–0.5 g q24h	0.25–0.5 g q24h	0.5–1.0 g q24h	Dose as GFR 10–50
					Dose post HD
Ceftriaxone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
					Dose post HD
Cefuroxime axetil (oral)	D	100%	100%	250 mg q24h	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
					Dose post HD
Cefuroxime (iv)		100%	0.75–1.5 g q8–12h	750 mg q12h	750 mg q24h	750 mg q24h	Dose as GFR 10–50
				Dose post HD
Celiprolol	D	100%	100%	75%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Cephalexin	I	250–500 mg q6h	250–500 mg q8–12h	250–500 mg	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
				q12–24h	Dose post HD
Cephalothin	I	q6h	q6–8h	q12h	Dose as GFR < 10	Dose as GFR < 10	1 g q8h
					Dose post HD
Cephapirin	I	q6h	q6–8h	q12h	Dose as GFR < 10	Dose as GFR < 10	1 g q8h
					Dose post HD
Cephradine	D	100%	50%	25%	Dose as GFR < 10	Dose for GFR < 10	As normal GFR
					Dose post dialysis
Cetirizine	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Chloralhydrate	D	100%	Avoid	Avoid	Avoid	Avoid	Avoid
Chlorambucil	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Chloramphenicol	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Chlorazepate	D	100%	100%	100%	Unknown	Unknown	NA
Chlordiazepoxide	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Chloroquine	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Chlorpheniramine	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Chlorpromazine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Chlorpropamide	D	50%	Avoid	Avoid	Avoid	Avoid	Avoid
Chlorthalidone	I	100%	100%	Avoid	Avoid	Avoid	NA
Cholestyramine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Cibenzoline	D, I	100% q12h	100% q12h	66% q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Cidofovir	D	50–100%	Avoid	Avoid	No data	No data	Avoid
Cilastin	D	100%	50%	Avoid	Avoid	Avoid	Avoid
Cilazapril	D, I	75% q24h	50% q24–48h	10–25% q72h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Cimetidine	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Cinoxacin	D	100%	50%	Avoid	Avoid	Avoid	Avoid
Ciprofloxacin	D	100%	50–75%	50%	250 mg q12h	250 mg q8h	200 mg IV q12h
Cisapride	D	100%	50%	50%	Dose as GFR < 10	Dose as GFR < 10	50–100%
Cisplatin	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Cladribine	D	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
Clarithromycin	D	100%	75%	50–75%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Clavulanic acid	D	100%	100%	50–75%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Clindamycin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Clodronate	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Clofazimine		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	No data
Clofibrate	I	q6–12h	q12–18h	Avoid	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Clomipramine	D	100%	Start at lower dose and monitor effect		Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Clonazepam	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Clonidine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Codeine	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Colchicine	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Colestipol	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Cortisone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Cyclophosphamide	D	100%	75–100%	50–75%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Cycloserine	I	q12h	q12–24h	q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Cyclosporine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Cytarabine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Dapsone		100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Daunorubicin	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Delavirdine		100%	100%	100%	Dose as GFR < 10	No data	Dose as GFR 10–50
Desferrioxamine	D	100%	100%	50%	Unknown	Unknown	Dose as GFR 10–50
Desipramine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Dexamethasone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Diazepam	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Diazoxide	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Diclofenac	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Dicloxacillin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Didanosine	I	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Diflunisal	D	100%	50%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Digitoxin	D	100%	100%	50–75%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Digoxin	D, I	100% q24h	25–75% q36h	10–25% q48h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Dilevalol	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Unknown
Diltiazem	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Diphenhydramine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Dipyridamole	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Dirithromycin		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Disopyramide	I	q8h	q12h	q24–40h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Dobutamine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Doxacurium	D	100%	50%	50%	Unknown	Unknown	Dose as GFR 10–50
Doxazosin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Doxepin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Doxorubicin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Doxycycline	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Dyphylline	D	75%	50%	25%	⅓ dose	Unknown	Dose as GFR 10–50
Ebastine	D	100%	50%	50%	Unknown	Unknown	Dose as GFR 10–50
Enalapril	D	100%	75–100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Epirubicin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Erythromycin	D	100%	100%	50–75%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Estazolam	D	100%	100%	100%	Unknown	Unknown	NA
Etanercept		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ethambutol	I	q24h	q24–36h	q48h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Ethchlorvynol	D	100%	Avoid	Avoid	Dose as GFR < 10	Dose as GFR < 10	NA
Ethionamide	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ethosuximide	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Etodolac	D	100%	100%	100%	As normal GFR	As normal GFR	Dose as GFR 10–50
Etomidate	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Etoposide	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Famciclovir	I	100%	q12–48h	50% q48h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Famotidine	D	100%	50%	20 mg q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Fazadinium	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Felodipine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Fenoprofen	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Fentanyl	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Fexofenadine	I	q12h	q12–24h	q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Flecainide	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Fleroxacin	D	100%	50%	50%	400 mg post HD	400 mg/24h	Dose as GFR 10–50
Fluconazole	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
					Dose post HD
Flucytosine	I	q12h	q16h	q24h	Dose as GFR < 10	0.5/24h	Dose as GFR 10–50
					Dose post HD
Fludarabine	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Flumazenil	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Flunarizine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Fluorouracil	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Fluoxetine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Flurazepam	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Flurbiprofen	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Flutamide	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Fluvastatin	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Fluvoxamine	D	100%	100%	100%	Dose as GFR < 10	Unknown	NA
Foscarnet	D	28 mg/kg/q8h	15 mg/kg/q8h	6 mg/kg/q8h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Fosinopril	D	100%	100%	75–100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Furosemide	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Gabapentin	D, I	400 mg q8h	300 mg q12–24h	300 mg q48h	300 mg load then	Dose as GFR < 10	Dose as GFR 10–50
					200 mg post HD
Gallamine	D	75%	Avoid	Avoid	NA	NA	Dose as GFR 10–50
Ganciclovir	I	2.5–5 mg/kg q12h	1.25–2.5 mg/kg q24h	1.25 mg/kg q24h	Dose as GFR < 10	Dose as GFR < 10	2.5 mg/kg q24h
					Dose post HD
Gemfibrozil	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Gentamicin	D, I	60–90% q8–12h	30–70% q12h	20–30% q24–72h	Dose as GFR < 10	3–4 mg/L/day	Dose as GFR 10–50
					Dose post HD
Glibornuride	D	Unknown	Unknown	Unknown	Unknown	Unknown	Avoid
Gliclazide	D	100%	20–40 mg/day	20–40 mg/day	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Glipizide	D	100%	100%	Contraindicated	Dose as GFR < 10	Dose as GFR < 10	Avoid
Glyburide	D	Unknown	Avoid	Avoid	Avoid	Avoid	Avoid
Gold Sodium Thiomalate	D	50%	Avoid	Avoid	Dose as GFR < 10	Dose as GFR < 10	Avoid
Griseofulvin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Guanabenz	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Guanadrel	I	q12h	q12–24h	q24–48h	Unknown	Unknown	Dose as GFR 10–50
Guanethidine	I	q24h	q24h	q24–36h	Unknown	Unknown	Avoid
Guanfacine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Haloperidol	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Heparin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Hexobarbital	D	100%	100%	100%	Dose as GFR < 10	Unknown	NA
Hydralazine	I	q8h	q8h	q8–16h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Hydrocortisone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Hydroxyurea	D	100%	50%	20%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Hydroxyzine	D	100%	Unknown	Unknown	100%	100%	100%
Ibuprofen	D	100%	100%	100%	As normal GFR	As normal GFR	Dose as GFR 10–50
Idarubicin		Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
Ifosfamide	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Iloprost	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Imipenem	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Imipramine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Indapamide	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	NA
Indinavir		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Indobufen	D	100%	50%	25%	Unknown	Unknown	NA
Indomethacin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Infliximab		100%	No data	No data	No data	No data	No data
Insulin (soluble)	D	Variable	Variable	Variable	Variable	Variable	Variable
Ipratropium	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Isoniazid	D	100%	100%	75%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
					Dose post HD
Isosorbide	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
					Dose post HD
Isradipine	D	100%	100%	100	As normal GFR	As normal GFR	As normal GFR
Itraconazole	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Kanamycin	D, I	60–90% q8–12h	30–70% q12h	20–30% q24–48h	⅔ normal dose	15–20 mg/L/day	Dose as GFR 10–50
Ketamine	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Ketanserin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ketoconazole	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ketoprofen	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ketorolac	D	100%	50%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Labetolol	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Lamivudine	D, I	100%	50–150 mg qd	25 mg qd	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Lamotrigine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Lansoprazole	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Lepirudin		0.4 mg/kg bolus	50% bolus	Avoid	Dose as GFR < 10	Dose as GFR < 10	50% bolus
		0.15 mg/kg/h	15–30%				15%
Levodopa	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Levofloxacin	D	100%	50%	25–50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Lidocaine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Lincomycin	I	q6h	q6–12h	q12–24h	Dose as GFR < 10	Dose as GFR < 10	NA
Linezolid	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
				Caution
Lisinopril	D	100%	50–75%	25–50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Lispro Insulin	D	Variable	Variable	Variable	Variable	Variable	Variable
Lithium carbonate	D	100%	50–75%	25–50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Lomefloxacin	D	100%	50–75%	50%	Dose as GFR < 10	Dose as GFR < 10	NA
Loracarbef	I	q12h	q24h	q3–5d	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Lorazepam	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Losartan	D	100%	100%	100%	25 mg/24h and titrate	25 mg/24h and titrate	Dose as GFR 10–50
Lovastatin	D	100%	100%	100%	Unknown	Unknown	Dose for GFR
Low-molecular-weight heparin	D	100%	Prophylactic dose only	Prophylactic dose only	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Maprotiline	D	100%	100%	100%	Unknown	Unknown	NA
Meclofenamic acid	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Mefenamic acid	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Mefloquine		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Melphalan	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Meperidine	D	100%	75%	50%	Avoid	Avoid	Avoid
Meprobamate	I	q6h	q9–12h	q12–18h	Dose as GFR < 10	Dose as GFR < 10	NA
Meropenem	D, I	500 mg q6h	250–500 mg q12h	250–500 mg q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Metaproterenol	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Metformin	D	50%	Avoid	Avoid	Avoid	Avoid	Avoid
Methadone	D	100%	100%	50–75%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Methenamine Mandelate	D	100%	Avoid	Avoid	NA	NA	NA
Methicillin	I	q4–6h	q6–8h	q8–12h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Methimazole	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Methotrexate	D	100%	50%	Contraindicated	Contraindicated	Contraindicated	Dose as GFR 10–50
Methyldopa	I	q8h	q8–12h	q12–24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Methylprednisolone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
					Dose post HD
Metoclopramide	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	50–75%
Metocurine	D	75%	50%	50%	Unknown	Unknown	Dose as GFR 10–50
Metolazone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Metoprolol	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Metronidazole	D	100% q8–12h	100% q8–12h	100% q12h	As normal GFR	Dose as GFR < 10	As normal GFR
					Dose post HD
Mexiletine	D	100%	100%	50–75%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Mezlocillin	I	q4–6h	q6–8h	q8h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Miconazole	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Midazolam	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Midodrine		5–10 mg q8h	5–10 mg q8h	2.5–10 mg q8h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Miglitol	D	50%	Avoid	Avoid	Unknown	Unknown	Avoid
Milrinone	D	100%	100%	50 to 75%	No data	No data	Dose as GFR 10–50
Minocycline	D	100%	100%	100%	None	None	Dose as GFR 10–50
Minoxidil	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Mitomycin C	D	100%	100%	75%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Mitoxantrone	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Mivacurium	D	100%	50%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Moricizine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Morphine	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Moxalactam	I	q8–12h	q12–24h	q24–48h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Mycophenolate mofetil	D	100%	50–100%	50–100%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Nabumetone	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
N-Acetylcysteine	D	100%	100%	75%	Dose as GFR < 10	Dose as GFR < 10	100%
Nadolol	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Nafcillin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nalidixic acid	D	100%	Avoid	Avoid	Avoid	Avoid	Avoid
Naloxone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Naproxen	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nefazodone	D	100%	100%	100%	Unknown	Unknown	NA
Nefopam	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nelfinavir		No data	No data	No data	No data	No data	No data
Neostigmine	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Netilmicin	D, I	50–90% q8–12h	20–60% q24h	10% q24h	2 mg/kg post each	IV: 2 mg/kg q48h	Dose as GFR 10–50
					HD session	IP: 7.5–10 mg/LPE
Nevirapine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nicardipine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nicotinic acid	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nifedipine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nimodipine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nisoldipine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Nitrazepam	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Nitrofurantoin	D	Avoid	Contraindicated	Contraindicated	Contraindicated	Contraindicated	Contraindicated
Nitroglycerine	D	100%	100%	100%	No data	No data	Dose as GFR 10–50
Nitroprusside	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Nitrosoureas	D	100%	75%	25–50%	Dose as GFR < 10	Unknown	Unknown
Nizatidine	D	75%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Norfloxacin	I	q12h	q12–24h	Avoid	NA	NA	NA
Nortriptyline	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Ofloxacin	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Omeprazole	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Ondansetron	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Orphenadrine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Oxaprozin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Oxatomide	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Oxazepam	D	100%	100%	75%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Oxcarbazepine	D	100%	100%	100%	Unknown	Unknown	Unknown
Paclitaxel	D	100%	100%	100%	As normal GFR	As normal GFR	Dose as GFR 10–50
Pancuronium	D	100%	50%	Avoid	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Paroxetine	D	100%	50–75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Paraamino salicylic acid (PAS)	D	100%	50–75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose after dialysis
Penbutolol	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Penicillamine	D	100%	Avoid	Avoid	125–250 mg thrice weekly post HD	Avoid	Avoid
Penicillin G	D	100%	75%	20–50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Penicillin VK	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
					Dose post HD
Pentamidine	I	q24h	q24–36h	q48h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Pentazocine	D	100%	75%	50%	Dose as GFR < 10	Unknown	Dose as GFR 10–50
Pentobarbital	D	100%	100%	100%	Dose as GFR < 10	Unknown	Dose as GFR 10–50
Pentopril	D	100%	50–75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Pentoxifylline	D	100%	100%	100%	Unknown	Unknown	100%
Pefloxacin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Perindopril	D	100%	75%	50%	25–50%	Unknown	Dose as GFR 10–50
Phenelzine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Phenobarbital	I	q8–12h	q8–12h	q12–16h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Phenylbutazone	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Phenytoin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Pindolol	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Pioglitazone	D	100%	100%	100% with caution	As normal GFR with caution	As normal GFR with caution	As normal GFR with caution
Pipecuronium	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Piperacillin	I	q4–6h	q6–8h	q8h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Piretanide	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Piroxicam	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Plicamycin	D	100%	75%	50%	Unknown	Unknown	Unknown
Pravastatin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Prazepam	D	100%	100%	100%	Unknown	Unknown	NA
Prazosin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Prednisolone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
					Dose post HD
Prednisone	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Pregabalin	D	100% q8–12h	50% q8–12h	25% q24h	Dose as GFR < 10	Dose as GFR < 10	No data
				Extra dose post HD
Primaquine		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Primidone	I	q8h	q8–12h	q12–24h	⅓ dose	Unknown	Unknown
Probenecid	D	100%	Avoid	Avoid	Avoid	Avoid	Avoid
Probucol	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Procainamide	I	q4h	q6–12h	Avoid	Avoid	Avoid	Avoid
Promethazine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Propafenone	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Propofol	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Propoxyphene	D	100%	100%	Avoid	Avoid	Avoid	NA
Propranolol	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Propylthiouracil	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Protryptyline	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Pyrazinimide	D	100%	As normal GFR	As normal GFR	As normal GFR	As normal GFR	As normal GFR
Pyridostigmine	D	50%	35%	20%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Pyrimethamine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Quazepam	D	Unknown	Unknown	Unknown	Unknown	Unknown	NA
Quinapril	D	100%	75–100%	50%	Dose as GFR 10–50	Dose as GFR < 10	Dose as GFR 10–50
Quinidine	D	100%	100%	100%	Dose as GFR < 10	As normal GFR	As normal GFR
Quinine	I	q8h	q8–12h	q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Ramipril	D	100%	50–75%	25–50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ranitidine	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Ribavirin	D	100%	100%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Rifabutin		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Rifampin	D	100%	50–100%	50–100%	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Ritonavir		100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Rituximab		100%	100% Use with caution	100% Use with caution	100% Use with caution	100% Use with caution	100% Use with caution
Rosiglitazone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Saquinavir		100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Secobarbital	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Sertraline	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Simvastatin	D	100%	100%	10 mg q24h	Dose as GFR < 10	Dose as GFR < 10	As normal GFR
Sodium valproate	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Sotalol	D	100%	25–50%	Avoid	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Sparfloxacin	D, I	100%	50–75%	50% q48h	Dose as GFR < 10	No data	Dose as GFR 10–50
Spectinomycin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Spironolactone	I	q6–12h	q12–24h	Avoid	Dose as GFR < 10	Dose as GFR < 10	Avoid
Stavudine	D, I	100%	50% q12–24h	50% q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Streptokinase	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Streptomycin	I	q24h	q24–72h	q72–96h	750 mg 2–3/week	20–40 mg/L/day	Dose as GFR 10–50
Streptozotocin	D	100%	75%	50%	Unknown	Unknown	Unknown
Succinylcholine	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Sufentanil	D	100%	100%	100%	Unknown	Unknown	Dose as GFR 10–50
Sulbactam	I	q6–8h	q12–24h	q24–48h	Dose as GFR < 10	0.75–1.5 g/day	750 mg q12h
					Dose post HD
Sulfamethoxazole	I	q12h	q18h	q24h	1 g after dialysis	1 g/day	Dose as GFR 10–50
Sulfinpyrazone	D	100%	100%	Avoid	None	None	Dose as GFR 10–50
Sulfisoxazole	I	q6h	q8–12h	q12–24h	2 g after dialysis	3 g/day	NA
Sulindac	D	100%	50–100%	50–100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Sulotroban	D	50%	30%	10%	Unknown	Unknown	Unknown
Tacrolimus		100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Tamoxifen	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Tazobactam	D	100%	75%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Teicoplanin	I	q24h	q48–72h	q72h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Temazepam	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Teniposide	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Terazosin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Terbutaline	D	100%	50%	Avoid	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Terfenadine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Tetracycline	I	q8–12h	q12–24h	q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Thiazides	D	100%	100%	Avoid	Dose as GFR < 10	Dose as GFR < 10	NA
Thiopental	D	100%	100%	75%	NA	NA	NA
Ticarcillin	D, I	1–2 g q4h	1–2 g q8h	1–2 g q12h	3 g after dialysis	Dose as GFR < 10	Dose as GFR 10–50
Ticlopidine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Tigecycline		100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Timolol	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Tobramycin	D, I	60–90% q8–12h	30–70% q12h	20–30% q24–48h	⅔ normal dose	3–4 mg/L/day	Dose as GFR 10–50
Tolazamide	D	100%	100%	100%	Unknown	Unknown	Avoid
Tolbutamide	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Avoid
Tolmetin	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Topiramate	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Topotecan	D	75%	50%	25%	No data	No data	No data
Torsemide	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Tramadol	D	100%	50–100 mg q6–12h	50 mg q12h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Tranexamic acid	D	50%	25%	10%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Tranylcypromine	D	Unknown	Unknown	Unknown	Unknown	Unknown	NA
Trazodone	D	100%	100%	Avoid/50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Triamcinolone	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Triamterene	I	q12h	q12h	Avoid	Avoid	Avoid	Avoid
Triazolam	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Trihexyphenidyl	D	Unknown	Unknown	Unknown	Unknown	Unknown	Unknown
Trimethadione	I	q8h	q8–12h	q12–24h	Unknown	Unknown	Dose as GFR 10–50
Trimethoprim	I	q12h	50% q18h	50% q24h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Dose post HD
Trimetrexate	D	100%	50–100%	Avoid	No data	No data	No data
Trimipramine	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	NA
Tripelennamine	D	Unknown	Unknown	Unknown	Unknown	Unknown	NA
Triprolidine	D	Unknown	Unknown	Unknown	Unknown	Unknown	NA
Tubocurarine	D	75%	50%	Avoid	Unknown	Unknown	Dose as GFR 10–50
Urokinase	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Valganciclovir	D	50–100%	450 mg q24–48h	450 mg BiW	Avoid	Avoid	450 mg q48h
Vancomycin	D, I	500 mg q6–12h	500 mg q12–48h	500 mg q48–96h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Vecuronium	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Venlafaxine	D	100%	50%	50%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Verapamil	D	100%	100%	100%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Vidarabine	D	100%	100%	75%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
					Infuse post HD
Vigabatrin	D	100%	50%	25%	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Vinblastine	D	100%	100%	100%	100% 2–3/week	As normal GFR	As normal GFR
					Dose post HD
Vincristine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Vinorelbine	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Warfarin	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Zafirlukast	D	100%	100%	100%	As normal GFR	As normal GFR	As normal GFR
Zalcitabine	I	100%	q12h	q24h	Dose as GFR < 10	No data	Dose as GFR 10–50
					Dose post HD
Zidovudine (AZT)	D, I	100% q8h	100% q8h	50% q12h	Dose as GFR < 10	Dose as GFR < 10	Dose as GFR 10–50
Zileuton		100%	100%	100%	Dose as GFR < 10	Unknown	Dose as GFR 10–50

CAPD, chronic ambulatory peritoneal dialysis; CRRT, continuous renal replacement therapies; HD, hemodialysis; GFR, glomerular filtration rate; D, decreasing individual doses; I, increasing individual doses; NA, not applicable.

No controlled clinical trials have established the efficacy of these two methods of dose reduction. Prolonging the dose interval is often more convenient and less expensive. When the dose interval can safely be lengthened beyond 24 hours, extended parenteral therapy may be completed without prolonging hospitalization. In patients requiring chronic hemodialysis, many drugs must be given only at the end of the dialysis treatment. Compliance with any drug regimen may be better when fewer doses can be taken at convenient times. In practice, a combination interval prolongation and dose-size reduction is often effective and convenient.

The effect of the standard clinical treatment on drug removal is shown for hemodialysis chronic ambulatory peritoneal dialysis, and continuous renal replacement therapy. Most of these recommendations were established before very high-efficiency hemodialysis treatments were practical, continuous cycling nocturnal peritoneal dialysis was common, and diffusion was added to hemofiltration in continuous renal replacement therapies. Some drugs that have high dialysis clearance do not require supplemental doses after dialysis if the amount of the drug removed is not sufficient, as is the case if the volume of distribution is large. To ensure efficacy when information about dialysis loss is not available and to simplify dosimetry, maintenance doses of most drugs should be given after dialysis.

Peritonitis is a major complication of peritoneal dialysis, and treatment usually involves intraperitoneal administration of antibiotics. For some drugs, sophisticated pharmacokinetic studies are available, whereas for others, use is still based on empirical dosage recommendations. In general, there is excellent drug absorption after intraperitoneal administration of common antibiotics. Factors favoring absorption include inflamed membranes and high-concentration gradients. For many drugs, peritoneal fluid levels after intravenous or oral administration are inconsistent.

Dosing Considerations for Specific Drug Categories

Analgesics

Analgesic agents are frequently used for the management of pain in patients with impaired renal function. Most analgesics are eliminated by hepatic biotransformation. However, important changes in their metabolism and protein binding occur. The accumulation of active metabolites results in prolonged oversedation. The formation of toxic metabolites can cause CNS toxicity and seizures. Specifically, the disposition of morphine, meperidine, and dextropropoxyphene in patients with impaired renal function is complicated by the accumulation of active or toxic metabolites with prolonged use. Prolonged narcosis is associated with codeine and dihydrocodeine, whereas the use of fentanyl may lead to prolonged sedation.^[62] Patient-controlled analgesia pumps should be used with caution by patients with decreased renal function.^[63]

Saturable, nonlinear excretion complicates salicylate elimination kinetics. Because of the hemorrhagic diathesis in patients with severe renal failure and the variability of salicylate elimination, large doses of aspirin in patients with severe renal failure should be avoided. Furthermore given the recognized importance of retained residual renal function in the outcomes for dialysis patients aspirin (at analgesic doses) and nonsteroidal agents should be avoided in patients with any significant retained urinary volume. Alternative weak opiod or non-opioid alternatives are often used as analgesics in dialysis patients (e.g., tramadol, buprenorphine, or nefopam); unfortunately these are often tolerated poorly in dialysis patients due to metabolite accumulation.

Anticonvulsants

Generalized major motor seizures occur in patients with uremia, and phenytoin is one of the most frequently used drugs for such seizures. Phenytoin absorption is slow and erratic, hepatic metabolism is concentration dependent and saturable, and distribution and elimination vary.^[64] Phenytoin protein binding is decreased and the distribution volume increased in renal failure.^[65] With any given total serum phenytoin level, the concentration of active, free drug is higher in uremic patients than in patients with normal renal function. Most clinical laboratories measure the total serum drug concentration, and a low total phenytoin level in a patient with renal failure should not be misinterpreted as subtherapeutic.

Physical findings such as nystagmus may be helpful in deciding not to increase the dose. Seizures are also a manifestation of phenytoin excess, and small dosage increases may result in disproportionately large increases in the serum drug level. Dose increments should be small, sufficient time should be allowed for the patient to reach steady-state drug levels, and measurement of free serum phenytoin concentration should be done frequently in uremic patients who are not responding to therapy. The wide variety of other newer agents as add-on therapy or monotherapy alternatives are less well studied in renal impairment. Marked dose reductions are usually required with significant renal impairment. This is particularly important as a number of anticonvulsants such as pregabalin are often used in the management of neuropathy in dialysis patients. Failure to adequately reduce the dose markedly increases the neurotoxic potential of such agents.^[66]

Antihypertensive and Cardiovascular Agents

Hypertension and cardiovascular disease are common in patients with renal insufficiency. Eighty percent of hemodialysis patients are hypertensive, and 75% have left ventricular hypertrophy.^{[67] [68]} Antihypertensive and cardiovascular agents are the most commonly prescribed drugs for patients with renal disease. Despite the fact that the kidneys excrete many antihypertensive and cardiovascular drugs or their metabolites, most of the drugs are given by titrating the dose based on the clinical response. Long-acting drugs are preferred because of improved compliance. However, steady-state drug levels are usually not achieved until after the drug has been given for at least three or four half-lives. Narrow therapeutic range and individual variability in drug response complicate the use of these drugs.

Many cardiovascular drugs or their metabolites accumulate in patients with renal insufficiency. Abnormalities of drug binding to plasma proteins increase free drug at receptor sites, enhancing drug efficacy and toxicity.

Each of the antihypertensive drugs can be toxic. In general, the adverse effects are related to their pharmacologic effect and can be avoided by careful dose titration. The development of newer, effective antihypertensive agents allows more individualized pharmacotherapy. Choosing an antihypertensive agent should include understanding the altered homeostatic mechanisms in patients with impaired renal function. Furthermore, the effect of the antihypertensive agents chosen on the dialysis session itself should be considered. An increased number of such agents enhance the propensity to intradialytic hypotension, which is associated with poorer long-term outcomes. Drugs that interfere with the normal peripheral pressor response to dialysis, or limit a compensatory increase in cardiac output are particularly undesirable. There is no robust evidence base to support the practice of omission of such agents on the day of dialysis.

The relation between renal drug elimination and the cardiovascular system is well established. Drugs may alter their own elimination rate or their effect on the kidneys by improving cardiac output and effective renal blood flow. For example, patients with decompensated congestive heart failure may be resistant to diuretics. If natriuresis can be initiated, subsequent improvement in cardiovascular function can increase response to the diuretic. The effect of cardiovascular drugs may also vary for individual patients as cardiac function changes.

The use of antiarrhythmic agents requires particular care. Because toxicity may appear as the arrhythmia the drug is intended to correct, recognition of toxicity may be delayed. Inappropriate increases in antiarrhythmic dose may be fatal. Monitoring other electrocardiographic evidence of toxicity such as a prolonged QT interval or widening of the QRS complex may be essential to proper diagnosis. ECG monitoring for arrhythmic risk is difficult in hemodialysis patients due to the wide range of variability that is characteristic, and the relatively low level of prediction afforded by repolarization changes in this patient group.^[69]

Diuretics may be helpful in patients with fluid overload and are commonly used as part of an antihypertensive regime in patients with CKD. However, the pharmacokinetics and pharmacodynamics of diuretics are altered in patients with proteinuria or renal impairment. Binding to proteins in tubule fluid decreases the diuretic efficacy of thiazide and loop diuretics. The natriuretic response to diuretics is limited by the counter-regulation of increased proximal tubule sodium reabsorption in response to hypovolemia and increased distal tubule sodium reabsorption in response to increased sodium load. Hypovolemia can result in a further decrease in renal function and should be carefully evaluated during diuretic therapy.

Diuretics can be grouped into two categories based on their clinical use. The potassium-sparing drugs (i.e., amiloride, spironolactone, and triamterene) may produce hyperkalemia in patients with creatinine clearances below 30 mL/min and should be avoided in these patients. The remaining diuretics are organic acids and must reach the tubule lumen to be active. In patients with impaired renal function, endogenous organic acids accumulate and compete with diuretics for secretion into the tubule lumen. Consequently, as renal function decreases, larger doses of diuretics are required. As glomerular filtration falls, the thiazides become ineffective. However, large doses of the loop diuretics (i.e., furosemide, bumetanide, torsemide, or ethacrynic acid) may still produce diuresis.

In patients with renal insufficiency, diuretic-induced dehydration may result in a further loss of renal function. Unless patients require diuresis for substantial peripheral edema or congestive heart failure, hypertension in patients with decreased renal function should be managed to avoid unnecessary volume contraction.

Thiazides lose their diuretic efficacy when the GFR falls below about 30 mL/min. Loop diuretics may remain effective at very low levels of renal function, although high doses may be required and a combination of loop diuretic with a thiazide may be required.^[70]

Potassium-sparing diuretics are contraindicated in patients with impaired renal function and the decreased ability to excrete potassium because of the risk of life-threatening hyperkalemia. Clinical situations that increase the risk of hyperkalemia include the concurrent administration of potassium supplements, ACE inhibitors, angiotension receptor antagonists and the use of nonsteroidal anti-inflammatory drugs (NSAIDs). Particular caution should be taken with the use of spirinolactone in patients with significant renal impairment. Such patients were excluded from the original studies confirming the reduction in mortality of patients with cardiac failure. Subsequent review of the introduction into wider clinical practise (often not utilizing the same exclusion criteria as rigidly adhered to in the original studies) was demonstrated to be associated with a large increment in hyperkalaemic hospital admissions and deaths in a large Canadian cohort.^[71]

Angiotensin-converting enzyme inhibitors and angio-tensin receptor antagonists decrease the rate of progression of diabetic renal disease.^{[72] [73]} However, these drugs must be given with caution in patients with decreased renal func-tion and those on dialysis. The hemodynamic effects of decreased angiotensin II can result in a sudden decrease in renal function in patients with renal artery occlusion or severe, diffuse microvascular renal disease. The initial doses of ACE inhibitors and angiotensin receptor antagonists should be low and carefully titrated, and renal function should be monitored; modest reductions in renal function should be tolerated, but if progressive reduction occurs after the initiation of such an agent the ACE inhibitor or angiotension receptor antagonist should be discontinued. Anaphylactoid reactions have been reported in hemodialysis patients taking ACE inhibitors during dialysis with polyacrylonitrile dialysis membranes.^[74] Despite reports of worsening anemia and erythropoietin resistance that has also been reported in ACE-treated hemodialysis patients,^[75] this association is far from universal in the literature as a whole and is of little practical importance in the general treatment of patients with renal impairment.

Management of hypertension in patients with renal dysfunction is particularly effective in patients presenting with malignant phase hypertension. Treatment, particularly with ACE inhibitors, should be continued with even in those patients who have become dialysis dependent. Functional and structural recovery of the characteristic histological lesions can occur with recovery of function. In the majority of patients, however good hypertensive control is more usually instituted to manage progression.

Antimicrobial Agents

The most important consideration in the use of antimicrobial drugs in patients with renal insufficiency is the early initiation of effective agents at doses that can achieve therapeutic drug concentrations quickly. Dose reduction that results in ineffectively low plasma concentration is the greatest danger in prescribing antimicrobial agents for patients with renal impairment. The initial drug choice may depend empirically on the source of the suspected infection. More specific treatment should follow an aggressive search for the pathogen. A single loading dose, equivalent to the usual maintenance dose for patients with normal renal function, should almost always be given to patients with impaired renal function. Although many antimicrobial drugs are excreted by the kidneys, the therapeutic range between efficacy and toxicity is generally wide, and the initial high doses used to achieve blood levels above the minimum inhibitory concentrations should be decreased, if necessary, in time to avoid toxicity from drug or metabolite accumulation. Therapeutic drug monitoring of drug levels and microbial sensitivities is the best guide to the use of many antimicrobial agents in patients with impaired drug excretion.

Antimicrobial therapy in patients with renal disease begins with an attempt to isolate the causative organism. Uremic patients with serious infections may not have elevated temperatures. Uremic symptoms or the effects of dialysis may mask nonspecific symptoms of infection. Because patients with renal insufficiency are more likely to have adverse effects from antimicrobial therapy than patients with normal renal function, culture documentation of bacterial infection is essential.

Adverse reactions to antimicrobial treatment in patients with impaired renal function are usually caused by the accumulation of drugs or their metabolites to toxic levels with repeated doses and may affect any organ system. Manian and colleagues divided the adverse effects of antibiotics due to drug or metabolite accumulation into six major categories, including neurologic toxicity, coagulopathy, nephrotoxicity, hypoglycemia, hematologic toxicity, and aminoglycoside inactivation by penicillins. They further considered neurologic toxicity according to central nervous system toxicity consisting primarily of encephalopathy and seizures, ototoxicity, peripheral neuropathy, or neuromuscular blockade with potential respiratory depression.^[76] Drug toxicity should be considered in antibiotic-treated patients with renal insufficiency who develop new symptoms.

The choice of antimicrobial agents includes consideration of these potential toxicities and the consequences of inadvertent drug or metabolite accumulation. Side effects rarely seen in patients with normal renal function occur more frequently in patients with renal failure. For example, seizures from β-lactam accumulation are rare in patients with sufficient kidney function to prevent drug accumulation but may occur in patients with renal impairment when large doses are given. Antiviral agents may also be problematic. Acyclovir, valacyclovir, and ganciclovir accumulate in renal failure, resulting in increased CSF levels of both parent compound and metabolites (such as 9-carboxymethoxymethylguanine) resulting in neuropsychiatric side effects.^[77]

Mild nephrotoxicity in patients with renal insufficiency may result in overt uremia. A decrease in renal function by as much as 50% from aminoglycoside nephrotoxicity may go unnoticed in patients with normal kidney function. A similar change in patients with creatinine clearances less than 20 mL/min could precipitate the need for dialysis. Although daily dosing with gentamicin based on a body weight nomogram is now widely used particular caution must be taken in obese or cachectic patients, patients with hypotension, inotrope usage, or those patients with changing or significantly reduced renal function.

The accumulation of metabolic waste products in patients with impaired excretory capacity may cause symptoms. The anti-anabolic effects of tetracycline can cause an increase in the blood urea nitrogen. Drugs that increase metabolic load should be avoided in patients with decreased kidney function.

Nephrotoxicity of antimicrobial agents may be the result of direct, cellular toxicity or allergic interstitial nephritis. Although decreasing renal function during antimicrobial treatment may be the result of drug toxicity or the underlying infection, the suspicion of an adverse drug event should prompt careful evaluation. Drug level monitoring is particularly important in patients with unstable renal function.

Hypoglycemic Drugs

Nearly 46% of new dialysis patients have diabetes mellitus.^[78] Careful consideration of hypoglycemic drug selection and dosage is important for patients with impaired renal function. The kidney accounts for almost 30% of the elimination of insulin from the body.^[79] As renal function decreases, insulin clearance decreases because of impaired insulin filtration and decreased insulin uptake from the tubule lumen and peri-tubule surface.^[80] As a result, insulin requirements often decrease in patients with decreasing renal function, and hypoglycemia is more common in diabetics with impaired renal function.

The longer half-life of insulin in patients with impaired renal function may affect the use of drugs that enhance endogenous insulin secretion. For example, although glyburide pharmacokinetics do not differ after initial or chronic administration in patients with end-stage renal disease treated with hemodialysis compared with controls, hemodialysis patients treated with this oral hypoglycemic agent have increased C-peptide and insulin levels with chronic dosing.^[81] Simply stated, patients with impaired renal function are at increased risk of hypoglycemia when they are treated with insulin or oral hypoglycemic drugs. Initial drug doses should be low and titrated carefully and long acting oral hypoglycaemic agents used with caution.

Lactic acidosis can result from metformin accumulation. Although a rare complication of the use of this drug, metformin plasma levels in excess of 5 mg/mL are generally found in patients with renal insufficiency, including intrinsic renal disease and renal hypoperfusion. The kidneys excrete metformin, and the risk of metformin accumulation and lactic acidosis increases with age and the degree of impairment of renal function. Consequently, metformin should not be used in patients with impaired renal function or in the elderly. Diabetic patients taking metformin should have their renal function measured frequently. Glitazones appear to be safe in patients with CKD. Patients with significant renal dysfunction should not monitor their glycaemic control and modulate therapy from measurement of urinary glucose. The reduction in the renal threshold of the kidney for glucose often results in a degree of glycosuria that is related to the usual level of hyperglycaemia. Repeated titration of hypoglycaemic agents in this setting can result in catastrophic clinical consequences.

Nonsteroidal Anti-Inflammatory Drugs

Adverse effects of NSAIDs can be the result of the pharmacologic action of prostaglandin synthesis inhibition or hypersensitivity. Prostaglandins are important in maintaining renal vasodilatation and ensuring adequate renal blood flow. NSAIDs are potent inhibitors of renal prostaglandin synthesis, resulting in renal arteriolar constriction, decreased renal blood flow, and a reduced GFR.

Prostaglandins are also important for maintaining fluid and electrolyte homeostasis. Reduction in glomerular filtration allows increased tubule reabsorption. Decreased prostaglandin production increases tubule chloride reabsorption in the loop of Henle and increases the effect of antidiuretic hormone on the distal tubule. These effects may lead to salt and water retention. Renin generation is also diminished. The resultant decrease in plasma aldosterone production can lead to potassium retention and hyperkalemia in patients with decreased renal function.

Nonsteroidal antiinflammatory drugs should be used cautiously in patients with decreased renal function. NSAIDs may cause a sudden decrease in renal function related to the hemodynamic effects of decreased renal prostaglandin production. Patients at greatest risk are those in whom renal vasoconstrictors are up-regulated and the renal vasodilatory properties of prostaglandins are the most important. Patients with congestive heart failure, volume contraction, and ascites or edema from liver failure are at greatest risk.^[82] Hyperkalemia and sodium retention may also occur in patients with impaired renal function treated with NSAIDs. These drugs should not be used in patients with renal impairment without a specific indication, and when they are required, renal function and other signs of toxicity should be monitored.

The selective inhibition of certain cyclooxygenase (COX) isoforms, such as COX-2, was hoped to decrease toxicity of NSAIDs. However, it is now recognized that, because COX-2 is constitutively expressed in the kidney, it plays an important role in renal function.^[83] The entire spectrum of NSAID effects on the kidney have also been observed with those NSAIDs that more specifically inhibit COX-2, and there appears to be no advantage in using these agents over less expensive, nonselective inhibitors of prostaglandin synthesis.^[84] In general the nephrotoxic potential of NSAIDs is determined by the potency, length of action, and period of administration. It is not clear if the recently reported increase in adverse cardiovascular effects seen associated with the long-term use of NSAIDs in the general population is also relevant to patients with CKD. In patients not characterized by renal dysfunction naproxen may be the NSAID with the least additional cardiovascular risk.^[85] The antithrombotic effects of aspirin can be antagonised by co administration of NSAIDs.^[86]

Acute renal failure characterized by proteinuria or the nephritic syndrome, hematuria, pyuria, and histologic evidence of immune glomerular injury or interstitial nephritis is consistent with a hypersensitivity reaction. Discontinuing treatment with the NSAID results in the gradual disappearance of proteinuria and a return toward normal renal function.^[87]

Antiplatelet and Anticoagulant Agents

Aspirin is commonly prescribed to reduce cardiovascular risk in patients with chronic kidney disease with hypertension or other vascular co-morbidities, despite there being no robust evidence base to justify the practice. There appears to be no significant effect of low-dose aspirin on renal function in patients with CKD. Antiplatelets are also often used to maintain the patency of vascular access in hemodialysis patients. Such interventions appear to be largely ineffec-tive,^[88] and indeed the combination of clopidogrel and aspirin is associated with an excess of significant haemhorragic complications in hemodialysis patients.^[89] The use of low-molecular-weight heparins as formal systemic anticoagulation (as opposed to anticoagulation of the extracorporeal circuit in dialysis) is also problematical in patients with significant renal dysfunction. In the absence of factor Xa monitoring dose adjustment using standard weight-based nomograms can lead to excessive anticoagulation in patients with GFRs of less than 50%. This is particularly evident with the use of twice daily administered enoxaparin. For this reason, and the difficulty of antagonizing inadvertent over anticoagulation associated with low-molecular-weight heparin usage, reliance on conventional unfractionated heparin is often prudent. Thromboprophylaxis with low-molecular-weight heparin appears not to carry the same risks as long as the dose is halved in patients with significantly reduced renal function.

Sedatives, Hypnotics, and Drugs used in Psychiatry

Psychotherapeutic drugs are commonly given to patients with renal disease to relieve anxiety and depression. Excessive sedation is the most frequent adverse effect in patients with renal insufficiency. Because malaise, somnolence, and encephalopathy are also common uremic symptoms, recognition of adverse drug reactions may be delayed.

Benzodiazepines are often used to manage emotional stress associated with decreasing renal function in patients on dialysis, although the efficacy of chronic benzodiazepine treatment has been questioned. Members of this class are generally safer than other anxiolytic agents, and short-term administration is effective. Active polar metabolites of these compounds normally excreted by the kidneys are likely to accumulate in patients with renal impairment and produce enhanced, prolonged sedation. Diazepam, chlordiazepoxide, and flurazepam are examples of such compounds. Because of the potential for drug or metabolite accumulation, the chronic use of these agents and others in this drug class should be discouraged in patients with decreased renal function.

Phenothiazines, used to manage major psychoses, and tricyclic antidepressants, used for severe depression in patients with renal disease, can also produce excessive sedation. Patients taking these drugs may also exhibit anticholinergic effects, orthostatic hypotension, confusion, and extrapyramidal symptoms.

Lithium carbonate has become an increasingly prescribed antidepressant. The drug is excreted by the kidney and has a narrow therapeutic range. Careful dose reduction and plasma lithium level monitoring is required in patients with impaired or unstable renal function. Hemodialysis has been used in cases of lithium overdose. Although lithium is effectively removed by dialysis, a rebound increase in plasma levels is common after hemodialysis, and repeated treatments may be required.

DRUG LEVEL MONITORING

Measurement of plasma drug concentrations is helpful in assessing a particular dosage regimen when the relationship between drug levels and efficacy or toxicity has been established. These measurements are most important for drugs with a narrow therapeutic range or difficult-to-measure pharmacologic effects.

Serum levels are determined after an appropriate loading dose has been given. In the absence of a loading dose, three or four doses of the drug should be administered before serum levels are measured. This ensures that a steady-state serum concentration has been established. For some drugs, maximum and minimum concentrations are relevant. Peak levels are most meaningful when measured after rapid drug distribution has occurred. Conversely, minimum concentrations are usually measured just before giving the next scheduled dose. A practical schema for drug prescribing in patients with renal impairment is shown in Figure 57-5 .



FIGURE 57-5 A practical scheme for drug dosing in dialysis patients.

Adverse drug events are common and costly. Johnson and Bootman estimated the annual cost of drug-related morbidity and mortality in the U.S. ambulatory care population to be between $30.9 billion and $76.6 billion.^[90] The heterogeneity of renal disease makes responses to drug therapy quite variable. Dosage nomograms, drug tables, and computer-assisted dosing recommendations provide guidelines for deriving an initial approach to drug administration in patients with decreased renal function. Continuing evaluation of the therapeutic response and modification of the regimen individualized for each patient and each clinical situation ensure effective clinical treatment of dialysis patients.

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Contents

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Brenner and Rector's The Kidney, 8th ed.

CHAPTER 57. Prescribing Drugs in Kidney Disease [*]

CHAPTER 57. Prescribing Drugs in Kidney Disease ^[*]