Dialysis patients routinely take an average of 10 different medications and experience adverse drug reactions at least three times more frequently than the general population (Jick, 1977; St. Peter et al., 1997). To optimize drug outcomes, health professionals must be prepared to recognize and manage problems associated with medication use. Table 17-1 lists several problematic reactions to medications that clinicians encounter in providing care to patients on dialysis and to other patients with renal impairment.
Table 17-1 Problem Areas Involving Drugs
|
Problem area |
Corresponding responsibility of dialysis personnel |
|
Drugs can damage kidneys, initiating or worsening renal failure. |
Monitor renal function of patients on drugs or drug combinations that can damage kidneys. Identify patients at high risk for renal damage from drugs. Avoid or use extreme caution with drugs that damage renal function in high-risk patients and in those with existing renal disease. Initiate hydration and other documented measures to minimize nephrotoxicity. |
|
Pharmacologic activity of drugs is altered by renal failure. |
Adjust dosages to compensate for altered pharmacokinetic and pharmacodynamic activity. Monitor for therapeutic failure, adverse effects, or toxicity of all drugs used. Anticipate more adverse effects in patients with renal impairment. |
|
The amount of medication removed from the body during dialysis varies, depending on the characteristics of the drug and dialysis conditions. |
Using references and formulas, estimate how much drug is removed by dialysis. Calculate dosage adjustments and/or postdialysis replacement dosage. Monitor clinical response to calculated doses and alter the dosage as indicated. |
|
Some poisons or drugs taken in overdose can be removed wholly or in part by dialysis. |
Know which poisons and overdosed drugs can be removed by various dialysis procedures. Implement dialysis to treat poisoning and overdose, providing appropriate supportive care and observation during the procedure. |
|
Medications may increase risks associated with the dialysis procedure. |
Know what medications the patient is taking. Monitor for excess effects of the medication. |
All of these problem areas are complex and require consideration of multiple factors unique to each situation, including patient characteristics (e.g., severity of renal impairment, acuity or chronicity of renal failure, comorbidities, age, nutritional status), drug properties (e.g., pharmacokinetics, pharmacodynamics, dose, route), and the dialysis procedures (e.g., treatment type, equipment, duration). The purpose of this chapter is to emphasize the pharmacologic principles common to managing these problem areas and to provide a brief overview of each problem area.
How do drugs cause renal impairment?
Approximately 20% of community- and hospital-acquired episodes of acute kidney injury are caused by drugs, with the incidence among older adults as high as 66%, (Naughton, 2008). There are several reasons why the kidneys are particularly vulnerable to damage by drugs. The kidneys constitute only 0.4% of body weight but receive 20% to 25% of total blood flow. This disproportionate blood flow exposes the kidneys excessively to drugs in the blood. In addition, drugs are concentrated as the tubular filtrate passes through the nephron and water is reabsorbed. Tubular transport systems further concentrate drugs in the filtrate. Enzymes in the kidney may metabolize drugs to metabolites that are nephrotoxic. In renal insufficiency, the remaining functional nephrons are even more susceptible to nephrotoxins.
Nephrotoxicity due to drugs contributes to 8% to 60% of AKI cases in hospitalized patients (Rosner & Okusa, 2008), The most commonly implicated pharmacologic nephrotoxins are antibiotics (aminoglycosides, cephalosporins, pentamidine, amphotericin B), radiocontrast agents used for radiologic studies, cyclosporine, cisplatin, angiotensin-converting enzyme (ACE) inhibitors, and nonsteroidal antiinflammatory drugs (NSAIDs). Because of the development of new agents (e.g., lower osmolar radiocontrast agents), changing drug use patterns (e.g., decreased use of aminoglycosides), and the shift of care from inpatient to outpatient settings, NSAIDs and ACE inhibitors are increasingly predominant causes of transient acute kidney injury. In chronic outpatient settings, chronic kidney disease (CKD) can occur due to combination analgesics, which consist of either aspirin or an NSAID combined with acetaminophen, caffeine, and/or codeine. Although the agents specifically cited here are the most frequent causes of renal damage, numerous other medications from diverse drug categories cause renal damage. The risk is greatest in individuals who already have poor kidney perfusion. Whenever a patient evidences renal impairment, a careful analysis of the drug profile for potential drug nephrotoxicity should be conducted. Nephrotoxins should be avoided in patients in any stage of CKD or used with appropriate dosage adjustments and meticulous monitoring.
How do these drugs usually cause renal damage?
Several mechanisms of renal damage by drug nephrotoxins have been identified (Rosner & Okusa, 2008), but most nephrotoxins damage the kidneys through more than one mechanism. Hemodynamic mechanisms involve inhibition of regulatory and compensatory processes, nonspecific renal vasoconstriction, or altered colloid oncotic pressure. A primary example of hemodynamic mechanisms for nephrotoxicity includes transient acute kidney injury from inhibition of the renin-angiotensin-aldosterone system by ACE inhibitors in patients with renal artery stenosis. A second example is the inhibition of prostaglandin-dependent renal blood flow by NSAIDs in patients with conditions associated with decreased renal blood flow (e.g., volume depletion and congestive heart failure). Renal vasoconstriction is a hypothesized mechanism of renal damage from propranolol, mannitol, a combination of triamterene and indomethacin, and the initial months of cyclosporine therapy. Dextran-40 can elevate oncotic pressure and impair glomerular filtration.
Another mechanism of damage is renal vascular alterations, such as thrombotic microangiopathy, that may result from oral contraceptives, cyclosporine, mitomycin C, cisplatin, and quinine. Glomerular alterations that result in nephrotic syndrome and glomerulonephritis are more often immune effects than toxic effects. The most common drug-induced glomerular alteration is membranous nephropathy that occurs with oral and parenteral gold therapy and penicillamine. Less common glomerular toxicities include the following: minimal change nephrotic syndrome associated with NSAIDs, ampicillin, rifampin, phenytoin, and lithium; focal segmental glomerulosclerosis secondary to heroin abuse; and membranoproliferative glomerulonephritis from hydralazine, interferon-alpha, and interleukin-2. Toxic drug effects resulting in acute tubular necrosis are most often caused by aminoglycosides, radiographic contrast media, cisplatin, amphotericin B, pentamidine, and foscarnet. Tubulointerstitial disease takes several forms and commonly manifests as one of the following conditions: acute allergic interstitial nephritis from antibiotics (e.g., penicillins, cephalosporins, tetracyclines, sulfonamides, fluoroquinolones), NSAIDs, diuretics, and anticonvulsants; chronic interstitial nephritis from lithium and cyclosporine; and papillary necrosis from analgesics (e.g., NSAIDs, aspirin, and acetaminophen used alone or in combination) or high-dose dapsone therapy.
Obstructive nephropathies from drugs include uric acid nephropathy during chemotherapy; rhabdomyolysis from phencyclidine, adrenergic drugs including terbutaline, cocaine, vasopressin infusion, erythromycin, and systemic cholesterol-lowering drugs, especially HMG-CoA reductase inhibitors (e.g., lovastatin, atorvastatin, simvastatin); and urinary tract outflow obstruction from anticholinergic drugs (e.g., tricyclic antidepressants, disopyramide), cyclophosphamide, and methysergide.
How can renal damage from such drugs be minimized or avoided?
Naturally, drugs with potential to cause renal damage should be avoided or used cautiously in patients with high risk for renal impairment. Conditions that predispose to renal damage by drugs include use of multiple nephrotoxins, sodium or fluid depletion, preexisting renal disease, and low renal blood flow in patients with diseases like congestive heart failure and cirrhosis, advanced age, and diabetes mellitus (Rosner & Okusa, 2008 ). Often drug-induced renal damage is reversible if the drug is discontinued and supportive care is initiated before permanent effects occur. Giving saline intravenously may decrease damage by some nephrotoxins such as cyclosporine and cisplatin by diluting the concentration of the drug in the renal tubule. Misoprostol, a prostaglandin analog, may prevent NSAID nephropathy. Drugs with the least nephrotoxic potential should be selected. For example, acetaminophen, aspirin, nonacetylated salicylates, sulindac, or nabumetone may have less nephrotoxicity than other NSAIDs. Finally, drugs should be given in the lowest effective doses for the shortest possible duration.
How does chronic kidney disease itself alter response to medications?
The changes that accompany CKD can alter drug response through two major mechanisms: pharmacodynamics and pharmacokinetics. Medications chemically interact with receptors on cell membranes or on enzymes to cause their effects. This interaction is known as pharmacodynamics and can be thought of as what the drug does to the body. Adverse effects (also called side effects or toxic effects) occur when a drug or metabolite acts at receptors other than the target receptors or when excess drug is present at the target receptor. Uremic substances in the blood or altered electrolyte concentrations resulting from renal failure can modify the drug-receptor interaction, resulting in altered drug effect. Altered receptor sensitivity is thought to be responsible for increased central nervous system effects of narcotics, sedatives, and hypnotics, as well as for the resistance to effects of epinephrine and other catecholamines that occurs in uremic patients. Altered electrolyte and acid-base balance also affect the response to such medications as antiarrhythmics, digoxin, phenothiazines, and antidepressants.
The magnitude and persistence of drug action depend on the duration and concentration of the drug in proximity to the receptor. This relationship of time and drug concentration is known as pharmacokinetics and can be thought of as how the body acts on the drug through the processes of absorption, distribution, metabolism, and excretion. How CKD affects pharmacodynamics is not well understood. On the other hand, many of the effects of altered pharmacokinetics in patients on dialysis have been sufficiently studied to develop mathematical formulas for calculating drug dosage. Decreased renal excretion is the most obvious alteration in pharmacokinetics resulting from renal dysfunction, but each of the other pharmacokinetic processes may also be altered.
What are the pharmacokinetic parameters that reflect alterations caused by chronic kidney disease?
Several measurement parameters can be computed for each drug to represent its pharmacokinetic profile. These include bioavailability, volume of distribution, clearance, and elimination half-life. Bioavailability, which is abbreviated as F (for fraction), is the measure of drug absorption. Bioavailability is the percentage of the administered dose that is absorbed into the systemic circulation.
Each drug has a unique pattern of distribution throughout the body, represented as its apparent volume of distribution (Vd). Vd is the hypothetical volume that would be required to contain the dose of drug at its concentration in the plasma. For example, if 500 mg of a drug were administered to a patient and an hour later the concentration of the drug in a sample of that patient’s plasma was 0.001 mg/mL, the Vd would be 500 L. Stated another way, if each milliliter of plasma had 0.001 mg in it, 500 L would be required to contain 500 mg. Although Vd is an abstraction, it can be interpreted to reflect the distribution characteristics of a drug. If the Vd is 5 L (0.06 L/kg), it is likely that most of the drug stays in the intravascular space. If the Vd is more than 46 L (0.7 L/kg), the drug is sequestered in the peripheral tissues, usually dissolved in fatty tissues or bound to tissues. Drugs with large volumes of distribution are poorly dialyzable because most of the drug is outside the bloodstream and therefore not exposed to the dialysis membrane. Vd is used in the calculation of loading doses.
The two modes of elimination, metabolism and excretion, are measured as drug clearance (CL). Clearance is defined as the rate of removal of a drug in proportion to its concentration in the plasma. Clearance is reported as the volume of plasma cleared of the drug per unit of time. Therefore, if the plasma concentration of a drug is 0.002 mg/mL and the body eliminates 2 mg/h, the clearance is 1 L/h or about 17 mL/min. (This is because, in such cases, 1000 mL or 1 L of plasma is needed to contain 2 mg at a concentration of 0.002 mg/mL.) Like Vd, clearance is a useful abstraction rather than a concrete reality. CL is useful for calculating the maintenance dose of a drug. In the patient with renal impairment and lower clearance, lower maintenance doses are needed.
Elimination half-life (t1/2) is an indicator of how long a drug stays in the body. It is the time required for half of the drug to be eliminated and is manifested clinically as the time required for the concentration in the blood to decline 50%. Half-life is prolonged by large Vd or by slow CL, which are both pharmacokinetic changes common in renal failure. The relationship among half-life, volume of distribution, and drug clearance is:
What factors affect absorption of medications in patients with chronic kidney disease?
In uremia the breakdown of urea in the gastrointestinal tract may raise pH and slow absorption of acid drugs, such as aspirin, iron preparations, and diuretics. Gastroparesis and gastrointestinal responses to uremia (nausea, vomiting, and diarrhea) may significantly alter the absorption of oral medication. Antacids, commonly used to bind dietary phosphate in CKD, diminish absorption of drugs by forming unabsorbable compounds with drugs like digoxin, iron preparations, and some antibiotics (e.g., tetracyclines and fluoroquinolones). Drugs used to suppress gastric acid secretions, such as H2 blockers (e.g., cimetidine, ranitidine, famotidine), antacids, and proton pump inhibitors (omeprazole, lansoprazole) affect the absorption of some drugs. For example, ketoconazole, which requires an acid environment for absorption, decreases bioavailability in patients taking drugs that suppress gastric acidity, whereas oral penicillins, which are inactivated by gastric acid, improve absorption when patients take these agents.
Orally administered drugs pass through the liver before reaching the main circulation, and large portions of a dose of drugs like morphine, propranolol, and codeine are metabolized during this “first pass” through the liver. Because the first-past effect reduces the bioavailability (F) of orally administered morphine, the oral dose of morphine must be much larger than the injected dose to achieve the same amount of pain relief. In uremia, the fraction of drug metabolized by this first-pass effect may be decreased, unchanged, or increased because some metabolic by-products of uremia change the activity of liver enzymes. Thus bioavailability of drugs is highly variable in CKD.
Drugs are absorbed across the peritoneum when administered into the dialysate. Antibiotics are frequently given via this route, which results in high concentrations at the site of a peritoneal infection. Some patients have experienced improved diabetic control with intraperitoneal administration of insulin. Administration of drugs by the peritoneal route will result in a different plasma profile than oral or parenteral administration, usually with delayed onset, decreased peak plasma concentration, and prolonged duration of action. Presence of peritonitis will alter the bioavailability of drugs administered peritoneally.
What factors affect distribution of medications in patients with renal failure?
When a drug is absorbed into the blood, some molecules bind to proteins in the plasma. Drugs that are highly bound to plasma proteins in the blood usually have small Vd because most of the drug molecules are attached to plasma protein, which normally cannot exit the blood vessels. Drugs that predominantly exit from the blood and bind to muscles or dissolve in fatty tissue in the periphery have large Vd. In general, drugs with small Vd have short half-lives because they are mostly in the plasma, which frequently passes through the liver and kidney (and dialysis machine), where they are eliminated. Conversely, drugs with large Vd have longer half-lives and less susceptibility to removal by dialysis. Edema and ascites often increase Vd and will increase the half-life of drugs that normally have small distribution volumes.
Plasma protein binding of acidic drugs to albumin may be decreased in renal failure as a result of either decreased concentration of albumin or decreased capacity of the albumin to bind to drugs. Changes in protein binding can alter Vd and the drug effect because only the free drug is pharmacologically active. Decreased albumin binding is thought to contribute to the central nervous system toxicity of acid drugs like theophylline, phenytoin, penicillin, phenobarbital, and salicylates in uremia. Some alkaline drugs (e.g., lidocaine, phenothiazines, propranolol, quinidine, and tricyclic antidepressants) that bind to glycoprotein also undergo increased or decreased binding in renal disease, but the clinical relevance of these changes is not as well studied as albumin binding. Although changes in Vd and plasma protein binding theoretically could have substantial effects on drug response, current research suggests that the effects of altered Vd in renal disease are usually minimal. There are a few exceptions, in which these changes require modification in the approach to patient care. An example is decreased protein binding of phenytoin during renal failure, which must be considered in clinical management. Measured serum concentrations of phenytoin that reflect total (bound + free) drug concentration in the plasma often are reported in the subtherapeutic range in patients with renal failure. This is because the amount of phenytoin bound to albumin is decreased, but the fraction of unbound drug is increased. Because the unbound drug is the active portion, lower drug concentrations of phenytoin are desirable for patients in renal failure to achieve the desired effect (Aweeka, 1995). In some centers both free and total phenytoin drug concentrations are measured to avoid toxicity. In patients without CKD, protein binding is about 90% of the total drug, whereas in patients with CKD binding of phenytoin ranges from 65% to 80%. Another approach to interpretation of phenytoin levels in CKD patients is to use a correction formula that adjusts the reported phenytoin plasma concentration for albumin level, renal function, and decreased affinity of phenytoin for albumin in CKD (Liponi et al., 1984).
What factors affect elimination of medications in patients with chronic kidney disease?
Some drugs are cleared almost exclusively in their original chemical form by renal excretion; these drugs are said to be excreted unchanged. Other drugs undergo alteration of chemical structure by enzymes, a process called biotransformation or metabolism. Most drugs are cleared by a combination of hepatic metabolism and renal excretion. Metabolites (the form drugs take after chemical alteration by metabolism) are usually more water soluble than the original drug and are usually eliminated by the kidneys. Active metabolites retain the ability to bind to a receptor and elicit the same effect as the original drug. Inactive metabolites are usually insignificant because they do not stimulate the target receptor. Toxic metabolites are those that cause an adverse effect at a site different from the target receptor.
When a drug that is normally cleared unchanged by the kidneys is repeatedly administered to a patient with renal insufficiency, it begins to accumulate in the blood and may cause adverse effects. Increased portions of the drug may be eliminated by alternate routes, such as hepatic metabolism or through the lungs, bile, or sweat glands. Metabolites of drugs accumulate in renal insufficiency, and active or toxic metabolites contribute to adverse effects. An example is normeperidine, a metabolite of meperidine, which causes stupor or seizures when it accumulates. Box 17-1 includes examples of drugs with active or toxic metabolites that may accumulate in renal failure. If viable alternatives exist, drugs with active or toxic metabolites are avoided in patients with renal failure. When drugs with active or toxic metabolites are used in patients with renal failure, decreased dosages may be required and clinical monitoring must be vigilant. For example, patients with renal impairment who take allopurinol for gout or cancer require lower dosages than those with normal renal function because an active metabolite of allopurinol can cause exfoliative dermatitis when it accumulates in the body. Although far less important than active metabolites, inactive metabolites may also have consequences. For example, the accumulation of inactive metabolites may cause interference with laboratory tests.
Box 17-1 Examples of Drugs with Active or Toxic Metabolites
Acetaminophen
Allopurinol
Amiodarone
Azathioprine
Buspirone
Cefotaxime
Cimetidine
Diazepam
Enalapril
Fluoxetine
Glyburide
Levodopa
Meperidine
Metronidazole
Methyldopa
Nitroprusside
Procainamide
Propoxyphene
Quinidine
Triamterene
Verapamil
Impaired renal function may also affect liver metabolism, decreasing elimination of some drugs (e.g., morphine, clonidine) and increasing metabolism for a few others (e.g., phenobarbital and phenytoin). Renal impairment alters metabolism through accumulation of uremic substances that can induce (speed up) or inhibit (slow down) drug-metabolizing enzymes in the liver. Insulin is metabolized by enzymes in the kidney, so it is more slowly cleared in severe renal disease. Liver metabolism is dependent upon genetic inheritance, diet, environmental pollution, and concurrent administration of other medications; thus the effects of renal dysfunction are likely to be highly variable from drug to drug and from person to person. Effects on renal elimination are more predictable: the greater the proportion of drug or its active metabolites eliminated by the kidneys, the more likely that altered dosing will be required for patients with renal impairment and those on dialysis.
How does dialysis affect pharmacokinetics of drugs and poisons?
The kidneys eliminate drugs through several processes. Although dialysis is not a substitute for all of these renal processes, some drugs are removed by dialysis. Dialysis may also affect other pharmacokinetic parameters. For example, changes in total body water from predialysis to postdialysis will affect the Vd of some drugs. Characteristics of drugs that promote removal by dialysis are as follows: (1) small molecular size, (2) small Vd, (3) water solubility, and (4) low protein binding. If protein binding exceeds 90%, the drug will be negligibly eliminated by dialysis. Drugs are more likely to be removed when the dialyzer membrane is highly permeable and its surface area is large and when the blood flow rate and dialysate flow rate are high. Peritoneal dialysis generally provides little drug removal because dialysate flow rate is slower than with other methods, although a greater amount of protein-bound drug can be removed due to large protein losses seen with this mode. Continuous therapy with hemofiltration or continuous hemodialysis for critically ill patients can remove substantial fractions of drugs. Removal of drugs by hemofiltration procedures is determined by the ultrafiltration rate and the degree of protein binding. Treatment of drug overdose and poisoning involves application of these principles to decrease serum concentration of the toxic drugs or substance (Winchester & Kriger, 1995). Similarly, poisons with high protein binding or large Vd are not dialyzable. Although many standard references classify a drug as dialyzable or not dialyzable, dialyzability is not an all-or-nothing characteristic. Some drugs are virtually entirely removed by dialysis; others have negligible removal. Many drugs fall somewhere in the middle. The type of dialysis equipment and the length of dialysis greatly influence whether a drug is removed. Classification of dialyzability as “yes” or “no” is based on an expert’s opinion of whether removal is clinically significant—that is, sufficient to remove an overdose—or whether the patient will require dosage replacement.
How should drugs and dosages be selected for the patient with renal impairment or chronic kidney disease?
Drug selection for the patient with renal impairment requires consideration of the effect of the drug on kidney function, electrolyte balance, and uremia. Agents that will worsen the disease state or increase metabolic load (Box 17-2) are avoided or used with caution. A drug that increases metabolic load burdens the failing kidney with chemicals that accumulate in renal disease, such as urea, sodium, potassium, or acids. For the patient with CKD these substances must be removed by dialysis and may affect well-being or cause serious adverse effects, such as cardiac arrhythmia from hyperkalemia. Drugs with nephrotoxic properties are also used with caution in patients with renal impairment. Meticulous monitoring should be incorporated into the patient care plan for patients with renal impairment who take medications that are nephrotoxic or increase metabolic load. Medications should be avoided for self-limiting conditions and those that can be managed by nonpharmacologic methods. Whenever possible, a single agent that can manage several conditions should be selected. For example, in the absence of contraindications such as renal stenosis, an ACE inhibitor would be a prudent choice for the patient with both hypertension and congestive heart failure. Well-studied established agents are usually preferred over newly marketed drugs. All other therapeutic considerations being equal, drugs with reliable laboratory assays for drug level are advantageous because the drug level data can enhance clinical monitoring.
Box 17-2 Examples of Drugs Producing Metabolic Loads
Sodium load
Ampicillin (IV)
Azlocillin (IV)
Antacids
Carbenicillin (IV)
Cephalothin (IV)
Moxalactam (IV)
Sodium polystyrene sulfonate (Kayexalate)
Ticarcillin (IV)
Potassium load
Blood transfusion
Neuromuscular-blocking drugs
Penicillin G potassium (IV)
Salt substitutes
Spironolactone
Triamterene
Magnesium
Laxatives
Antacids
Urea
Dexamethasone
Prednisone
Tetracycline
Acid
Acetazolamide
Aspirin
Methenamine mandelate
Alkali
Antacids
Carbenicillin
The need for and extent of dosage modification in renal impairment depend on the pathophysiology of the disease process and its severity, as well as the pharmacology of the drug. Guidelines for dosage reduction of many drugs can be found in standard drug references such as the Physicians’ Desk Reference, drug handbooks, and package inserts. Many nephrology textbooks and other sources provide summary tables that include pharmacokinetic parameters in CKD (e.g., Vd, CL, t1/2), recommended dosage adjustments for various levels of renal function, and guidelines for postdialysis replacement doses. An example of a reference table format is shown in Table 17-2. Most of these data and guidelines are based on studies of patients with stable chronic renal failure on maintenance dialysis and may not apply to the patient with unstable acute kidney injury. You should reference a medication handbook to determine dosage modifications in CKD. Each of the following five steps of dosage selection is defined and discussed in subsequent sections:
1. Assessment of relevant patient variables
2. Determination of loading dose
3. Determination of maintenance dose
4. Determination of postdialysis replacement dose
5. Monitoring of drug levels and clinical response
Table 17-2 Sample Reference Chart for Pharmacokinetic Parameters, Dosage Adjustment, and Dialyzability
What are the unique assessment requirements related to drug dosing in chronic kidney disease?
In addition to the standard assessment of drug allergies, previous drug history, comorbidities, concurrent medications, and baseline laboratory and clinical findings that precede initiation of a new drug in any patient, patients in renal failure require estimation of residual renal function and determination of ideal body weight. Because weight may fluctuate between dialysis procedures and because daily dosage requirements usually correspond to lean body weight rather than actual weight in obese or edematous patients, ideal weight is calculated for men as 50 kg plus 2.3 kg for each inch in height over 5 feet. For women, ideal body weight is 45.5 kg plus 2.3 kg for each inch over 5 feet (Aronoff & Erbeck, 1994). Renal function can be determined in the stable patient by laboratory determination of creatinine clearance or estimation of creatinine clearance (CLcr) using the Cockroft-Gault formula:
For women the estimate of CLcr is 85% of the calculated value, so the results of the equation above are multiplied by 0.85 to estimate CLcr in women. The Cockroft-Gault formula yields artifactual results for patients on dialysis, so it is not a reliable estimate for these patients.
In addition to assessing residual renal function, the efficiency of extrarenal mechanisms for drug elimination, especially liver function, should be evaluated because concurrent hepatic impairment may necessitate more stringent dose reduction.
What is a loading dose and when is it indicated?
Loading doses are indicated when it is necessary to attain therapeutic plasma concentrations rapidly. Even in patients with normal renal function, loading doses can be dangerous, so this approach should be reserved for serious or life-threatening situations. This technique is most commonly employed in critical care settings. Loading doses are listed in references for some drugs or can be calculated as the product of the desired plasma concentration or “blood level” (Cp) and the Vd of the drug (Swan & Bennett, 1997).
The computed dose in mg/kg is then multiplied by the patient’s ideal weight.
What is a maintenance dose and how is it determined?
Maintenance doses are given regularly, usually once or more daily, but possibly less often in renal failure. Maintenance doses replace the drug eliminated since the previous dose and sustain therapeutic plasma concentrations. If no loading dose is given, plasma concentrations take four half-lives of repeated maintenance dosing to reach steady state. Steady state occurs when the amount of a drug absorbed and the amount eliminated per unit of time are equal. Before steady state, peak plasma concentrations increase with each subsequent dose. At steady state, the mean Cp levels off after four half-lives; peak and trough concentrations are effectively equal from dose to dose at steady state. Generally, dosages should not be adjusted upward until steady state. Because of prolonged half-life for many drugs in patients with renal failure, it may take days to weeks for drugs to reach steady state in these patients. Because the purpose of a maintenance dose is to replace the eliminated drug, the decreased CL in renal impairment requires reduced maintenance doses for agents eliminated unchanged by the kidneys and for agents with active metabolites eliminated by the kidneys. There are three main approaches to dosage reduction: (1) decreased amount of drug given at usual intervals, (2) usual dose of drug with extended time between doses, and (3) a combination of decreased amount and interval extension (Swan & Bennett, 1997). Extension of the time interval between doses causes wide fluctuations between peak and trough levels and is not indicated for drugs with a narrow therapeutic range or where a low serum concentration at the end of the dosing interval may be dangerous. The dosage reduction or combined approach is indicated when more constant serum concentrations are desirable. On dialysis days the recommended dose, as well as replacement doses, should be administered after the procedure is completed. For drugs removed by peritoneal dialysis, the additional dose is added to the usual daily maintenance dose.
Recommended maintenance doses are included in standard references, usually by level of CLcr (or glomerular filtration rate), as illustrated in Table 17-2. This table offers little individualization of dosage for the patient in renal failure because wide ranges of CLcr are grouped together and the dosage recommendations may be the same for patients with tenfold differences in CLcr. The variety of formulas used to calculate individualized maintenance doses include the following:
• Ratio method. Ratio methods involve the derivation of a dosage adjustment factor based on the ratio of some parameter in the patient with renal impairment compared with that of a person with normal renal function. One approach uses the ratio between the half-life in normal renal function and the half-life in renal impairment. For a drug with a half-life of 3 hours with normal renal function and 6 hours with renal failure, the ratio would be 3:6, or 1:2. Multiplying the usual dose by this ratio or dividing the usual interval by this ratio derives the therapy for renal failure: a drug usually given 300 mg every 12 hours would be given 150 mg every 12 hours or 300 mg once per day in renal failure. The ratio of the patient’s CLcr to normal CLcr can also be used to determine dosage (Brater, 1995). The dosage adjustment factor (Q) can be computed as follows (Matzke & Frye, 1997):
where fe is the fraction of the drug eliminated unchanged by the kidneys and KF is the ratio of the patient’s CLcr to normal CLcr. The usual dose is multiplied by Q to derive an individualized dose for a particular patient with renal impairment. It is also possible to derive the dosage adjustment factors from nomograms. Nomograms are graphs showing relationships among variables. Standardized nomograms have been developed and published for determining dosage in renal failure.
• Pharmacokinetic method. The pharmacokinetic method involves measurement of pharmacokinetic parameters for a particular patient. After the patient receives one or more doses, blood samples are taken from which the Vd, t1/2, and CL are derived. These parameters are individualized to the patient and provide the most accurate indications of that patient’s drug disposition. From these parameters the maintenance dose can be computed using the following formula (Brater, 1995):
where CL is the patient’s drug clearance, Cp is the desired plasma concentration, and t is the dosing interval. The pharmacokinetic method is often paired with therapeutic drug monitoring, which involves determination of the Cp of the drug at steady state to validate the dosage selected, and at regular intervals thereafter. Therapeutic drug monitoring can also be used with the other dose calculation methods. Although the pharmacokinetic method yields the most accurate and individualized results, it is useful only when a reliable assay is available for the drug. It is commonly used with drugs with narrow therapeutic margins, such as gentamicin, digoxin, and antiarrhythmic drugs.
• Drug-specific method. Another method to determine maintenance dose is based on studies on individual drugs published in the literature. The studies establish the relationship between pharmacokinetic parameters (e.g., Vd, total body clearance) and some continuous index of renal function, such as CLcr. For example, the relationship for total clearance and clearance for ganciclovir has been reported as follows (Sommadossi et al., 1988):
Using the CLcr for the patient, the total clearance of ganciclovir can be estimated using this formula. The result of this calculation is then used to calculate the maintenance dose of ganciclovir, using the formula listed above in the pharmacokinetic method.
How is postdialysis replacement dosage determined?
Standard references and texts include recommendations for average postdialysis replacement for drugs that are substantially removed during dialysis. These recommendations vary by procedure because peritoneal dialysis and hemodialysis remove different amounts of drug. For example, for the β-blocker nadolol, which is renally excreted, a 40-mg dose is recommended following hemodialysis, but no supplementation is needed for peritoneal dialysis. Much of the data on which these reference tables were based was collected before recent advances in dialysis equipment affecting membrane function and blood flow rates, so it is likely that standard references underestimate the amount of drug removal during dialysis. Hemofiltration also removes different amounts of drug compared with other dialysis procedures, but research on dosage replacement after this procedure is limited. For drugs with long half-lives, regular maintenance doses may not be needed if the postdialysis replacement dose includes the drug eliminated between dialysis treatments, as well as that removed during the procedure.
For some drugs, the dialysis clearance values have been studied and published in the literature. These drug-specific values can be used to compute the replacement dose. Differences in dialysis equipment (type of membrane, surface area, blood flow rate, length of procedure) must be considered in determining replacement doses from these published values. For patients who have authorized reuse of dialysis filters, dialysis drug clearance may be lower when the filter has had multiple uses (Matzke & Frye, 1997). For increased accuracy, dialysis clearance rates can also be individually calculated based on laboratory measurement of dialysate and serial plasma concentrations. Other procedures base calculations of dialysis clearance on measures of drug concentration in the blood going into the filter and blood leaving the filter.
What are considerations for monitoring drug levels?
All of the methods for determining dosages include physiologic and mathematic assumptions that may not reflect an individual patient’s unique and changing physiologic status, so the formulas and guidelines should be considered beginning estimates of dosage requirements to be followed by dosage titration based on patient response. For drugs with valid and reliable laboratory assays, determination of plasma concentration (i.e., therapeutic drug monitoring) can be a useful tool for dosage adjustment. This is often called blood levels, which is an inaccurate term because the test is not run on whole blood but rather on plasma or serum, and the concentration of the drug is not level but fluctuates throughout each dosing cycle. Therefore it is very important that blood samples for drug levels be collected at the correct time. For peak concentrations, blood is usually drawn 1 to 2 hours after an oral dose or 30 to 60 minutes after a parenteral dose, although timing may vary depending upon the characteristics of the drug and route of administration. Trough concentrations are based on blood drawn immediately before the next dose. For some drugs, such as aminoglycosides, both peak and trough values may be collected because the peak value corresponds to therapeutic effect and the trough value may reflect risk of adverse effects with these agents.
Plasma concentrations are interpreted by comparing the patient’s measured value to the published therapeutic range for a drug. However, there are several pitfalls in interpreting plasma concentrations. Not all patients get therapeutic or toxic response at the same concentration. It has been estimated that up to 50% of older adults with digoxin concentrations in the therapeutic range are actually experiencing toxic effects and that many older adults are adequately treated with concentrations in the subtherapeutic range. In addition, decreased serum protein binding common in renal disease may also complicate the interpretation of laboratory reports of drug concentration. Laboratories generally report concentrations of total drug, including both bound and free fractions. A change in the ratio of bound to free drug can result in a reported normal serum concentration, when the concentration of free (active) drug is actually at toxic levels. Conversely, a patient may be adequately treated even though the reported serum concentration is subtherapeutic, because the portion of unbound active drug is increased. Some physicians order both total and free drug concentrations and compare the published reports of the normal percentage of drug binding to that reported for an individual patient.
Therefore, even when data on serum concentration are available, clinical data (such as the patient’s subjective information, physical examination findings, and laboratory results) should be used to regulate dosage. Interference with laboratory results by drugs and drug metabolites can be enhanced when drugs accumulate in renal insufficiency. Drug interaction with the laboratory test should be considered when reported laboratory values are inconsistent with the clinical presentation. Box 17-3 lists examples of drug test interactions relevant to dialysis patients. The mechanism of these interactions is interference by the drug or its metabolites with one of the reagents used in the laboratory test. When an abnormal value for one of these common tests is reported, intervention based on the laboratory result should not be initiated until the patient’s drug therapy is reviewed for interacting drugs. The laboratory director should be consulted about the resolution of the drug test interaction because an alternate assay methodology could circumvent the interaction.
Box 17-3 Example of Drugs That Interfere with Laboratory Tests
Serum creatinine
Ascorbic acid
Aspirin
Cefoxitin
Cimetidine
Levodopa
Methyldopa
Trimethoprim
Serum uric acid
Ascorbic acid
Acetaminophen
Aminophylline
Levodopa
Methyldopa
Salicylates
Urinary protein (dipstick method)
Acetazolamide
Aspirin
Cephalosporins
Contrast media
Penicillins
Sulfonamide antibiotics
Tolbutamide
The importance of clinical monitoring and observation cannot be overstated. Knowledge of the usual pattern of responses of the patient enables the clinician to recognize at an early stage deviations that suggest the need to evaluate the drug regimen.
Can drugs affect the dialysis procedure?
Several drug groups can affect the dialysis procedure. Many patients on dialysis take antihypertensive medications, which can contribute to hypotension during the dialysis procedure. Epoetin therapy is associated with a decrease in the prolonged bleeding time seen in some patients with CKD and may increase heparin requirement during dialysis in some patients. Vascular access thrombosis may be more frequent in those on epoetin, but there is no evidence of increased thrombosis with native arteriovenous fistula (St. Peter et al., 1997).
Antianemics
People with CKD or on maintenance dialysis are anemic and have considerably lower hematocrit values. Causes include (1) failure of production, or inhibition of action, of erythropoietin, a hormone produced by the kidney that stimulates the bone marrow to produce red blood cells; (2) a shortened life span of the red blood cells; (3) impaired intake of iron; (4) blood loss, including a tendency to bleed from the nose, gums, gastrointestinal tract, uterus, or skin, caused by platelet abnormalities; and (5) blood loss related to the dialysis procedure itself.
How does dialysis influence the anemia?
Anemia can be a complex problem with CKD and it progresses as the disease progresses, most notably in stages 3 to 5. Incomplete blood recovery after dialysis, dialyzer leaks, and frequent blood sampling contribute to anemia. The patient who is receiving adequate dialysis, is in a good nutritional state, and has adequate iron stores and intake will usually stabilize with a hematocrit between 20% and 30%. It is unusual for the hematocrit to go much higher except in persons with polycystic kidney disease, in whom there may be greater than normal production of erythropoietin.
As the hematocrit improves on dialysis, the patient begins to feel better. These people still have considerably fewer red blood cells than normal and become dyspneic and tire easily. Other symptoms attributable to anemia include poor exercise tolerance, weakness, sexual dysfunction, anorexia, and inability to think clearly.
What is an erythropoiesis-stimulating agent?
Erythropoiesis-stimulating agent (ESA) is a broad term capturing the drugs that assist in stimulating the production of erythropoietin in the body. Examples of ESAs are epoetin alfa (Epogen, Procrit) and darbepoetin alfa (Aranesp).
Epoetin alfa (EPO) is a recombinant form of the hormone erythropoietin, which is produced by the normal, healthy kidney. It was introduced in 1989 and had a profound effect on the CKD patient. Darbepoetin alfa also is an erythropoiesis-stimulating protein.
How is epoetin alfa given?
EPO is given either intravenously or subcutaneously, usually three times per week at the end of a regular dialysis treatment.
What are some causes of suboptimal response to epoetin alfa therapy?
The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) Clinical Practice Guidelines for Anemia of Chronic Kidney Disease identify the most common cause of inadequate response to EPO therapy as iron deficiency. Nine conditions are cited as potential reasons for a patient’s nonresponse. The four most common conditions are infection and inflammation, chronic blood loss, osteitis fibrosa, and aluminum toxicity. The remaining five causes are less common and should only be considered after the first four have been ruled out as causes. They are hemoglobinopathies (such as sickle cell anemia), folate and vitamin B12 deficiency, multiple myeloma, malnutrition, and hemolysis.
Hemoglobin levels in the KDOQI target range of 11 to 12 g/dL are associated with improved outcomes, including increased energy and activity levels and quality of life, along with decreased risk of hospitalization and mortality.
What are the complications of epoetin alfa?
The major complication of EPO is an elevation in blood pressure due to the increased blood viscosity secondary to the increased red blood cell mass. This usually occurs during the initial 12 weeks of therapy, while the hematocrit is rising, and is treated with antihypertensive medications and fluid removal with dialysis. Blood pressure should be closely monitored and controlled.
As the hematocrit rises, the efficiency of dialysis falls somewhat because the red blood cells do not release their toxins (e.g., creatinine, potassium) very readily as they pass through the dialyzer. Close attention to blood chemistries is essential in patients receiving EPO, and some adjustment of the dialysis prescription may be necessary.
When should transfusions be given?
The routine administration of blood at a certain hematocrit value is not done. If the patient suffers a large blood loss from a dialyzer leak or from hemorrhage, the blood should be replaced. If the patient becomes short of breath or excessively fatigued or has angina, a transfusion will often relieve the symptoms. In general, increasing the dose of EPO to improve the anemia is more desirable than transfusion.
What are some of the complications of transfusions?
The most common complications of transfusions include the following:
• Incompatibility reactions caused by major or minor blood group incompatibility may occur. Chest or back pain, chills, and fever occur soon after blood is started. If this occurs, the transfusion should be stopped immediately. A blood specimen should be drawn from the patient for evidence of hemolysis and for recheck of type and crossmatch. Chills or fever should be treated symptomatically. Intravenous (IV) steroids may be used if symptoms are severe.
• Allergic reactions to leukocytes, platelets, or protein of the donor blood may occur. Manifestations include chilling, fever, or skin eruption developing about 30 to 60 minutes after the start of the transfusion. These are treated by slowing the rate of infusion. An antihistamine, such as diphenhydramine (Benadryl), 20 to 50 mg, or steroids should be given intravenously if symptoms are severe.
• Infections—whether caused by hepatitis A, B, or C; cytomegalovirus; Epstein-Barr virus; or human immunodeficiency virus (HIV)—may be transmitted by blood. The onset is from one to four months after the transfusion.
• Preformed antibodies may result from minor incompatibility or allergic reactions. These are particularly important to the patient awaiting a renal transplant. Some dialysis units with transplantation affiliation give a limited number of transfusions on a regular basis. This has an enhancing effect on graft survival.
What can be done to minimize the anemia?
A good dietary intake of protein is important. Adequate iron intake is essential if the patient’s iron stores are depleted before starting EPO. Maintenance iron therapy is needed in most patients to ensure adequate iron stores and an optimal response to EPO. Oral iron supplements are rarely adequate. They often cause gastrointestinal upset, nausea, gas, vomiting, or anorexia. IV iron, such as iron dextran, can be given in 100-mg doses, usually for a total course of 1 g, depending on the adequacy of iron stores. In patients on EPO, iron deficiency is almost inevitable because iron is used rapidly under EPO stimulation of red blood cell production and is continually lost from the patient. Patients on EPO may benefit from regular administration of small doses of parenteral iron. Folic acid and vitamin B12, both of which are important in red blood cell formation, are water soluble and theoretically could be depleted by dialysis. Although there is little evidence that these vitamins are seriously deficient, it is the usual practice to give a supplement, particularly of folic acid.
When is epoetin alfa administered?
EPO is administered intravenously during hemodialysis to stimulate red blood cell production. A predialysis hematocrit is used to monitor anemia and determine EPO administration. Each dialysis unit should follow its own protocol. The amount of EPO required is determined by hematocrit, hemoglobin, and individual patient response. Adequate iron stores and folic acid are required for erythropoietin to be effective. (A serum ferritin of 200 to 500 ng/mL is considered optimal per KDOQI guidelines.) Although EPO is given mostly intravenously during hemodialysis, KDOQI suggests that the subcutaneous route of administration is as effective as or more effective than the IV route. The Anemia Work Group recommends that subcutaneous EPO be the preferred route of administration. When given subcutaneously, the site of injection should be rotated. Most hemodialysis patients prefer the IV route because of the discomfort generated by subcutaneous administration.
When is iron therapy required?
The need for iron therapy is determined by two things: First, the serum iron value is divided by the total iron binding capacity, times 100. This is called the transferrin saturation, or TSAT, and it correlates with the amount of iron available for erythropoiesis. (Optimal TSAT is greater than 20%. A TSAT of less than 20% indicates absolute iron deficiency, and a TSAT of more than 50% indicates risk of iron overload, according to KDOQI guidelines published by the NKF.) Second, if the serum ferritin level is less than 100 ng/mL, iron therapy is prescribed, usually by the IV route.
How is iron administered?
Iron is administered orally and/or intravenously. Oral iron should not be taken with phosphate binders, which diminish its effect. When oral iron is prescribed, the patient should be instructed to always take the medication with food to avoid gastrointestinal distress. Patients will usually need to supplement oral iron with the IV form at intervals to maintain adequate stores for erythropoiesis. IV iron is given during hemodialysis. The dosage is determined by the patient’s starting hematocrit and TSAT. If TSAT is less than 20% and serum ferritin is less than 100 ng/mL, KDOQI guidelines recommend 50 to 100 mg of iron IV once per week for 10 hemodialysis treatments. However, each facility should follow its own policy. IV iron should be held if the TSAT is greater than 50% or serum ferritin is greater than 800 ng/mL in accordance with KDOQI guidelines. Iron dextran (Infed) was used most commonly before the newer iron products—Ferrlecit (sodium ferric gluconate) and Venofer (iron sucrose injection)—became available. Today the newer forms of IV iron have been shown to cause a lower incidence of anaphylaxis than previous generations of IV iron. A test dose is recommended before administering iron dextran products, whereas the other irons do not require a test dose. Various side effects may occur from the administration of IV iron, ranging from hypotension (which is usually related to the rate of administration) to cramping, nausea, headaches, and hypersensitivity reactions. IV iron should always be administered according to the manufacturer’s instructions.
Can a patient receive too much iron?
Iron overload or hematochromatosis may occur from multiple transfusions, excessive iron intake via diet or medications, receiving iron therapy for anemia not related to iron deficiency, or in those patients with certain genetic markers predisposing them to iron overload. Nausea and vomiting, diarrhea, and elevated liver enzymes may be present.
Antihypertensives
What is hypertension?
A blood pressure greater than 140/90 mm Hg is classified as hypertension. Hypertension is commonly seen in the CKD patient and can be a cause or result of the disease. Hypertension can be attributed to volume overload, increased renin secretion, uremic toxins, dietary sodium, and secondary hyperparathyroidism. Hypertension can cause left ventricular hypertrophy and other cardiac complications. Both nonpharmacologic and pharmacologic treatment options must be employed to manage the hypertension associated with CKD. A variety of antihypertensive medications are available to treat the patient. It is not unusual for the patient to be prescribed more than one antihypertensive for treatment.
The National Heart Lung and Blood Institute classifies two levels of high blood pressure: stage 1 and stage 2 (Table 17-3).
Table 17-3 Categories for Blood Pressure Levels in Adults* (in mm Hg)
|
Category |
Systolic (top number) |
Diastolic (bottom number) |
|
Normal |
Less than 120 |
Less than 80 |
|
Prehypertension |
120–139 |
80–89 |
|
High Blood Pressure |
||
|
Stage 1 |
140–159 |
90–99 |
|
Stage 2 |
160 or higher |
100 or higher |
Note: When systolic and diastolic blood pressures fall into different categories, the higher category should be used to classify blood pressure level. For example, 160/80 mm Hg would be stage 2 high blood pressure. There is an exception to the above definition of high blood pressure: A blood pressure of 130/80 mm Hg or higher is considered high blood pressure in persons with diabetes and chronic kidney disease.
* For adults 18 and older who are not on medicine for high blood pressure, are not having a short-term serious illness, and do not have other conditions (such as diabetes and kidney disease).
From National Heart Lung and Blood Institute, Diseases and conditions index, high blood pressure (website): www.nhlbi.nih.gov/health/dci/Diseases/Hbp/HBP_WhatIs.html. Accessed October 12, 2010.
Antihypertensive medications are divided into different categories because their mechanisms of action vary by drug. Most of these medications are used for the control of high blood pressure; however, some of the medications are used in the treatment of heart failure, angina, and cardiac dysrhythmias.
What are the different types of antihypertensive medications?
Ace inhibitors.
ACE inhibitors work by blocking an enzyme in the body that is responsible for causing the blood vessels to narrow. When the blood vessels are relaxed, blood pressure is lowered. ACE inhibitors also lower the amount of salt in the body, which assists in decreasing the blood pressure. ACE inhibitors have renoprotective effects and are thought to prevent the progression of renal disease in the compromised patient.
ACE inhibitors do cause a number of side effects, including dry persistent cough, increased serum creatinine, rash, increased serum potassium, and angioedema. Examples of ACE inhibitors are quinapril (Accupril), ramipril (Altace), captopril (Capoten), benazepril (Lotensin), trandolapril (Mavik), fosinopril (Monopril), lisinopril (Prinivil, Zestril), and enalapril (Vasotec).
Angiotensin-receptor blockers (arbs).
ARBs are an alternative medication to ACE inhibitors. ARBs block the enzyme angiotensin II, which causes vasoconstriction. ARBs are as effective as, but do not cause the cough sometimes associated with, the ACE inhibitors. Some potential side effects of this medication are headaches, angioedema, and hyperkalemia. Examples of ARBs are losartan (Cozaar), valsartan (Diovan), irbesartan (Avapro), and candesartan (Atacand).
B-blockers.
β-blockers work by slowing the nerve impulses that travel through the heart. When this happens, the heart has less demand for blood and oxygen, which makes it work less hard, thereby decreasing blood pressure. Bradycardia, fatigue, cold hands and feet, weakness, dizziness, dry mouth, wheezing, and swelling of the hands and feet are side effects that might occur from taking a β-blocker.
β-blockers include timolol (Blocadren), esmolol (Brevibloc), carteolol (Cartrol), nadolol (Corgard), propranolol (Inderal), metoprolol (Lopressor, Toprol-XL), labetalol (Normodyne, Trandate), acebutolol (Sectral), atenolol (Tenormin), and pindolol (Visken).
Calcium channel blockers.
Calcium channel blockers slow the rate at which calcium passes into the heart muscle and into the vessel walls. This relaxes the vessels and allows blood to flow more easily through them, thereby lowering blood pressure. Side effects of calcium channel blockers are headaches, lower leg and ankle edema, fatigue, and stomach discomfort. Examples of calcium channel blockers are amlodipine (Norvasc), bepridil (Vascor), diltiazem (Cardizem, Cardizem CD, Cardizem SR, Dilacor XR, Tiamate, Tiazac), felodipine (Plendil), isradipine (DynaCirc, DynaCirc CR), nicardipine hyd rochloride (Cardene, Cardene SR), nifedipine (Procardia, Procardia XL, Adalat, Adalat CC), nisoldipine (Sular), and verapamil (Calan SR, Covera-HS, Isoptin, Isoptin SR).
Diuretics.
Diuretics are recommended as the first line of treatment for high blood pressure. They are usually recommended as one of at least two medications to control hypertension. Diuretics work by restricting the reabsorption of water, promoting diuresis, and removing excess sodium and water from the body. This reduction in total body water reduces blood pressure. Several different types of diuretics work on different areas of the kidneys.
Side effects include frequent urination, weakness, increased thirst, and reduced levels of some electrolytes in the blood (potassium, sodium, and magnesium). Examples of diuretics include chlorthalidone (Hygroton), chlorothiazide (Aldoclor, Diupres, Diuril), hydrochlorothiazide(Hydrodiuril, Ezide, Hydro-Par, Microzide), hydrochlorothiazide combinations (Aldoril, Capozide, Dyazide), bumetanide (Bumex), furosemide (Lasix), and torsemide (Demadex).
Cation exchange resin
What medication is used to treat hyperkalemia?
Sodium polystyrene sulfonate (Kayexalate) is used in the treatment of hyperkalemia. Kayexalate is a cation exchange resin that replaces potassium ions for sodium ions, mostly in the large intestine. This exchange or lowering of the serum potassium may take hours to days, so this is not an effective method of treating severe hyperkalemia. Kayexalate is administered either orally or by retention enema. Some CKD patients take Kayexalate regularly to control hyperkalemia. Side effects of this medication may include constipation, diarrhea, nausea, vomiting, hypokalemia, hypomagnesemia, or hypocalcemia, because it is not selective to just potassium.
Intradialytic parenteral nutrition
Intradialytic parenteral nutrition is a form of nutritional support for the patient who has hypoalbuminemia and consists of an emulsion of amino acids, lipids, and dextrose. See Chapter 14 for more information.
Levocarnitine
What is the role of levocarnitine?
Levocarnitine, an amino acid derivative, is sometimes deficient in the patient with CKD who is undergoing dialysis therapy. Levocarnitine is similar in shape and size to creatinine, so it can be dialyzed out during the dialysis treatment. Another reason for the deficiency is that the dialysis patient’s diet is lacking in red meat and dairy products, which provides a good source for this amino acid. The patient who has been on dialysis for several years will experience a decrease in plasma and skeletal muscle carnitine. Levocarnitine is essential for fatty acid and energy metabolism. Many organs, including the heart, muscle, liver, and kidney, rely on levocarnitine as an energy source. Levocarnitine (Carnitor) is a medication used for carnitine deficiency. The benefits of levocarnitine supplementation in dialysis patients are decreased muscle cramps and weakness, decreased intradialytic hypotension, and increased cardiac output and exercise capacity. See Chapter 14 for additional information on carnitine.
Phosphate binders
Disturbances of calcium and phosphorus metabolism are common in patients who develop renal insufficiency gradually and are often apparent even before dialysis is required. During the progression of renal failure there is loss of ability to excrete phosphate. Phosphate ions accumulate in the body fluids and lead to a reciprocal decrease of serum calcium. The parathyroid glands seek to maintain a normal concentration of calcium in body fluid and respond by increasing production of parathyroid hormone (PTH). This causes calcium to be reabsorbed from the bones, resulting in loss of bone density and strength. In addition, the active form of vitamin D, needed for normal bone metabolism, is manufactured in the kidney and is deficient in CKD patients. Dialysis does not fully correct the disordered calcium-phosphorus metabolism, and progressive osteodystrophy (the term for several bony manifestations) is a serious problem for many CKD patients.
What is the function of oral calcium as a phosphate binder?
Oral calcium (usually as calcium carbonate), when taken immediately after a meal, binds phosphorus in the stomach so that it passes out with the stool, thereby not contributing to raising the serum phosphorus. This helps control the calcium-phosphorus product. If the oral calcium is taken too long after eating or on an empty stomach, it may contribute to making the patient hypercalcemic. If a high serum phosphorus with a low serum calcium is left untreated, the parathyroid glands become stimulated and result in loss of calcium from the patient’s bones.
How are phosphate binders taken?
Phosphate binders need to be taken with every meal and with snacks containing protein. It is best not to take phosphate binders when oral iron or antibiotics are taken because the efficacy of these medications becomes reduced. Patient compliance with the regular use of phosphate binders is problematic. A major factor contributing to noncompliance with phosphate binder therapy is the number of medications the CKD patient takes on a regular basis. The addition of phosphate binders, which need to be taken with every meal, to the already sizable number of pills the patient must take is cumbersome. Some of the phosphate binders leave a chalky taste in the mouth and may cause constipation, which becomes a deterrent to some patients taking the medication.
Are there different types of phosphate binders?
Several different types of phosphate binders are available to control excess phosphorus in the bloodstream. Aluminum-based phosphate binders (aluminum hydroxide [Alu-Cap]) were the first type of binders to be used in the CKD patient. Aluminum-based binders are extremely effective in keeping serum phosphorus levels low because of their high phosphorus-binding ability. These binders, however, have the capability to cause high serum aluminum levels or aluminum toxicity. Aluminum-based binders are therefore seldom used in the CKD patient today. Calcium-based binders (calcium acetate [PhosLo, Phosex] and calcium carbonate [Titralac, Calci-Chew]) are more commonly used and serve a dual role of decreasing serum phosphorus as well as supplementing calcium in the patient with hypocalcemia. Attention must be given to the patient’s monthly laboratory studies to ensure that he or she is not becoming hypercalcemic.
A new phosphate binder is available that is both calcium and aluminum free (sevelamer hydrochloride [Renagel]). Sevelamer works in the gastrointestinal tract, where positively charged hydrogel binds with negatively charged phosphate from the diet. The complex formed does not cross the gastrointestinal tract but is instead excreted in the feces. Because sevelamer contains no calcium, the patient will be able to have phosphorus control while keeping the calcium-phosphorus product at an acceptable level. Sevelamer must be taken with every meal and when eating between meals.
Vitamins and vitamin analogs
What are the indications for administering vitamin D analog 1,25-dihydroxyvitamin d3 (calcitriol)?
Calcitriol is used to treat hypocalcemia in patients receiving chronic dialysis. It is the active form of vitamin D3. It increases calcium levels and has been shown to reduce elevated PTH levels, preventing secondary hyperparathyroidism and improving renal osteodystrophy.
How and when is calcitriol administered?
Calcitriol in the intravenous form (Calcijex) is administered during a hemodialysis treatment as an intravenous bolus. An oral form of calcitriol (Rocaltrol) is available.
Are there any adverse effects of treatment with calcitriol?
Hypercalcemia can result from calcitriol treatment. Serum calcium and phosphorus must be evaluated on a regular basis to avoid hypercalcemia that could lead to generalized vascular calcification and soft tissue (eyes, skin, and heart) calcification.
When is calcitriol withheld?
Hold the calcitriol (Calcijex) when the serum calcium is between 10.5 and 12.5 mg/dL and the product (calcium mg/dL times phosphorus mg/dL) is greater than 70. Conversely, hold the calcitriol if the serum calcium is greater than 12.5 mg/dL, even if the product is less than 70.
What is paricalcitol injection?
Paricalcitol (Zemplar) is a recent synthetic analog of vitamin D for treatment of secondary hyperparathyroidism. Paricalcitol is given intravenously to CKD patients to decrease PTH levels with minimal effect on calcium and phosphorus; however, the calcium-phosphorus product should continue to be monitored for elevations. Hypercalcemia will promote digitalis toxicity, so laboratory studies should be monitored closely in the patient taking digitalis. Paricalcitol should never be used in patients with vitamin D toxicity, or hypercalcemia. It is an aggressive treatment of secondary hyperparathyroidism.
What is doxercalciferol?
Doxercalciferol (Hectorol) is a synthetic vitamin D analog used to suppress PTH and manage secondary hyperparathyroidism. Doxercalciferol is available in either IV or oral form. Hypercalcemia, hyperphosphatemia, and oversuppression of the parathyroid gland are possible adverse effects associated with the use of this medication. The dosing is based on PTH levels along with the monitoring of the serum calcium and phosphorus.
When is deferoxamine mesylate used?
Deferoxamine mesylate (Desferal) is a chelating agent used to remove excessive metals from the bloodstream. It was originally formulated to treat iron overload. Deferoxamine has been found to be useful as an aluminum chelating agent in dialysis patients, and acts to remove aluminum from the tissues so it can be dialyzed out or adsorbed by a special cartridge. The dosage of deferoxamine varies for different patients. The dosage is usually based on body weight and is ordered by the physician. Deferoxamine is usually mixed with 200 mL of normal saline infused during the last two hours of the dialysis treatment three times a week. Deferoxamine should be held for two weeks after infusion of IV iron. Deferoxamine administration may cause visual and auditory disturbances when administered over prolonged periods at high doses. Flushing, urticaria, hypotension, tachycardia, and shock may occur during IV administration, so the patient must be carefully observed during administration.