Module 17 - Pharmacotherapy For Renal and Urological Disorders

Geriatric
Pharmacy Review Module 17: Pharmacotherapy for Renal and Urologic Disorders
Accreditation Information
ASCP is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education.
This home study web activity has been assigned 2 credit hours. ACPE UPN: 0203-0000-11-096-H01-P Release Date: 7/11/2011 Expiration Date: 7/11/2014
To receive continuing education credit for this course, participants must complete an on-line evaluation form and pass the online assessment with a score of 70% or better. If you do not receive a minimum score of 70% or better on the assessment, you are permitted 4 retakes. After passing the assessment, you can print and track your continuing education statements of credit online.
Geriatric Pharmacy Review courses have not yet been approved for Florida consultant pharmacy continuing education.
Copyright 2011 American Society of Consultant Pharmacists
Content Experts
Rowland J. Elwell, PharmD Assistant Professor of Pharmacy Practice Albany College of Pharmacy Michael R. Brodeur, PharmD, CGP Assistant Professor of Pharmacy Practice Albany College of Pharmacy
Faculty Disclosure: Rowland J. Elwell, PharmD has no relevant financial relationships to disclose. Michael R. Brodeur, PharmD, CGP has no relevant financial relationships to disclose.
Age-Related Changes in Renal Function & Chronic Kidney Disease in the Elderly
Content Expert Rowland J. Elwell, PharmD Assistant Professor of Pharmacy Practice Albany College of Pharmacy By the end of this Review Concept you should be able to: Understand the effects of aging on renal structure and function. Describe the pharmacotherapeutic implications of age-related changes in kidney function. Apply methods to assess kidney function in elderly patients. Identify common causes of acute renal failure and describe strategies to treat ARF and its complications. Describe the classification of the stages of chronic kidney disease (CKD) as defined by the National Kidney Foundation-Kidney Disease Outcomes Quality Initiative (K/DOQI). Compare therapeutic options for the management of anemia and renal bone disease in CKD patients.
The biologic process of aging leads to various changes within the kidney. These changes place elderly patients at an increased risk for developing a host of acute and chronic complications secondary to reduced kidney function. Age-related changes in kidney function must be considered by pharmacists caring for these patients in order to avoid drug toxicity and acute renal failure. In addition, the increasing prevalence of chronic kidney disease in the growing geriatric population necessitates an understanding of strategies for slowing the progression of chronic kidney disease, as well as managing the complications associated with chronic kidney disease.
Effects of Aging on Renal Function

Age-related changes in renal structure: Kidney mass, size and volume decreases. (normal kidney = 250 270 gm) 30 50 % decrease in the number of glomeruli. Sclerotic changes in renal vasculature. Age-related changes lead to decreased renal blood flow and glomerular filtration rate (GFR). Normal GFR @ age 30 = 120 130 mL/min. Alterations in renal tubular function which can affect drugs that are secreted into the renal tubules. Older individuals may have impaired homeostasis of: Fluid and electrolyte balance. Acid-base balance. Volume and water balance.
It is generally understood that aging is associated with a progressive decline in kidney function as well as changes in kidney structure. In addition, there is an increasing prevalence of renal diseases in the elderly population which amplify the changes in structure and function. When considering kidney structure - kidney mass, glomeruli, and renal vasculature are each adversely affected by aging. Kidney mass progressively declines with advancing age. For example, during young adulthood, normal kidney mass ranges from 250 to 270 grams; by age ninety, it declines to between 180 and 200 grams. This decline reflects a decrease in kidney size and volume and is proportional to the concurrent decrease in body surface area that occurs with aging. In addition, the number of glomeruli, the kidneys filtering apparatus, is diminished with age and may be reduced by 30% to 50% by age 70. Finally, the renal vasculature is also subject to age-related sclerotic changes. These vascular changes are worse when hypertension is present.
Age-related changes in the kidney lead to decreased renal blood flow and glomerular filtration rate, or GFR. Between age 20 to 30 years, the normal mean GFR ranges from 120 to 130 mL/min. GFR declines with age with a mean decrease of approximately 1 mL/min per year. Thus, by age 70, the normal mean value is approximately 70 mL/minute. It is important to note that the range of normal GFR is wide at all ages. Along with advancing age, risk factors such as hypertension, atherosclerosis, diabetes mellitus, and dyslipidemia may also contribute to a declining GFR in the elderly. Changes in renal anatomy and hemodynamics may impact renal tubular functions, which maintain homeostasis of fluids and electrolytes, acid-base balance, and volume and water balance. Although these functions are often adequate under normal conditions, aging kidneys may have a reduced functional reserve capacity. As a result they may not be able to maintain homeostasis under physiologic stress.
Pharmacotherapeutic Implications of Age-Related Changes in Renal Function

Pharmacokinetic changes: o Absorption o Distribution o Metabolism o Excretion / Elimination Drugs needing renal dose adjustments: o acetazolamide o amantadine o atenolol o captopril o lithium o vancomycin o digoxin o metformin o fluoroquinolones o cimetidine Drugs with renally eliminated metabolites: o Procainamide (N-acetylprocainamide) o Meperidine (normeperidine) o Morphine (morphine 6-glucuronide The physiologic effects of aging, particularly changes in kidney function, can have a significant impact on drug therapy. Aging is associated with alterations of nearly every pharmacokinetic parameter. In addition, the previously described alterations in kidney structure and function can also have profound effects on the excretion of drugs and their metabolites. This reduction in renal drug clearance may be the result of reduced glomerular filtration and / or active tubular secretion. Because kidney function declines with aging it is important to identify those drugs that are predominantly renally eliminated. These include medications such as acetazolamide, amantadine, atenolol, captopril, & lithium. Particularly caution is warranted for drugs with a narrow therapeutic index, such as digoxin & lithium. Other drugs, such as metformin, fluoroquinolones, and cimetidine, have well defined toxicities that can result due to drug accumulation in patients with diminished kidney function. Since older patients may have a reduced functional reserve capacity, they may be more susceptible to the nephrotoxic effects of agents such as aminoglycosides and antineoplastic agents. Furthermore they are less likely to recover their kidney function when an insult occurs.In addition, some hepatically metabolized drugs have active metabolites that are primarily renally excreted and can accumulate in geriatric patients with reduced kidney function. These include N-acetylprocainamide, normeperidine, and morphine 6-glucuronide. Given these factors, it is extremely important to monitor kidney function (GFR) in geriatric patients and make renal dosing adjustments as necessary to maximize efficacy and avoid toxicity. Finally when using potentially toxic, renally eliminated drugs, you should have a lower threshold for monitoring serum drug levels and understand how impaired renal function can alter the interpretation of these laboratory findings.
Assessing Renal Function in Geriatric Patients

Indicators of renal function Blood urea nitrogen (BUN) Serum creatinine Quantitative GFR measurement Inulin clearance Creatinine clearance 8 24 hour urine collection Estimating GFR (CrCL) Cockcroft-Gault Equation: GFR (mL/min) = (140 - Age) x IBW (SCr x 72) Multiple by 0.85 if female MDRD Study Equation*: GFR (mL/min/1.73 m2) = 170 x (Scr)-0.999 x (Age)-0.176 x (BUN)-0.170 x (Alb)+0.318 x (0.762 if female) x (1.180 if black)
* To access web-based calculators capable of calculating the MDRD equation go to: http://medcalc3000.com/GFREstimate.htm
Assessment of kidney function is essential in diagnosing and monitoring the progression of kidney disease, as well as for optimal dosing of renally eliminated drugs. The blood urea nitrogen (BUN) and serum creatinine concentrations are two common clinical laboratory measurements for assessing renal function. Urea and creatinine are eliminated from the body primarily by glomerular filtration and as such can be used as indicators of GFR. Other markers such as proteinuria may indicate the presence of kidney disease but do not necessarily estimate GFR.

BUN is not a specific marker for kidney function as it may be affected by protein intake, hemolysis, and hydration status. After glomerular filtration, up to 50% of filtered urea may be reabsorbed in the proximal tubules. In addition, urea is able to passively diffuse across cell membranes and its reabsorption rate is dependent on the reabsorption of water. As a result, urea excretion may be decreased under conditions of water conservation, such as dehydration. Although serum creatinine is the most commonly accepted marker of GFR, it should not be used alone to estimate GFR. Serum creatinine is a byproduct of muscle breakdown and therefore related to muscle mass. Older patients often have reduced muscle mass and produce less creatinine. As a result, an older patient with a normal serum creatinine may in fact have less than adequate kidney function. There are precise quantitative methods available to accurately assess GFR. These methods are performed by collecting urine over a specified time interval (usually 24 hours) and measuring the concentration of a substance that is predominantly cleared by glomerular filtration. The most commonly used markers are inulin and creatinine. Inulin clearance is considered the gold standard for measuring GFR. However, it is an exogenous substance and requires an intravenous infusion. As a result it is generally reserved for the research setting. Since creatinine is an endogenous substance and is easily measured in urine, it is the most commonly used clinical measure of GFR. This test requires the collection of urine over an 8 to 24 hour period. This can be difficult, particularly in elderly patients who may experience incontinence. However, a 24-hour urine collection should be performed if an accurate assessment of renal function is required, such as determining the need to start dialysis. In most clinical scenarios, GFR can be reliably estimated using creatinine clearance equations that take into account the impact of age, sex, and body mass on GFR. The most widely accepted equation is that proposed by Cockcroft and Gault. The Cockcroft-Gault equation will be discussed in detail later in this section.

Another equation that has gained popularity was derived from data gathered in the Modification of Diet in Renal Disease (MDRD) study. The MDRD equation provides estimates of GFR standardized for body surface area. It includes variables such as serum creatinine, age, BUN, serum albumin, sex and race. The calculation is complex but can be made easier using webbased calculators that can be downloaded at the indicated web link on your screen. There are several limitations to GFR estimating equations that must be considered. They require that serum creatinine be at steady state and are therefore are inaccurate in the presence of rapidly changing renal function. In addition, they may overestimate GFR in elderly patients with reduced muscle mass, who may have a low creatinine in spite of declining kidney function. For these types of patients, the results of creatinine clearance estimating equations should be interpreted cautiously. When using potentially toxic, renally eliminated drugs, appropriately timed drug levels and patient response should be monitored closely.
Assessing Renal Function in Geriatric Patients (continued)

Urinalysis (Normal) Specific gravity (1.001 1.030) pH (5.0 7.5) Protein (0 trace) Glucose (Negative) Ketones (Negative) Red blood cells (0 2/hpf) White blood cells (0 5/hpf)
In addition to assessing GFR, other kidney functions such as tubular function and glomerular permeability can be assessed by urinalysis. A urinalysis is a fairly simple test performed using a reagent strip often referred to as a dipstick. The urine dipstick contains several reagents that test for specific gravity, pH, protein, glucose, ketones, red blood cells, and leucocytes (white cells). A specific gravity greater that 1.025 indicates good urine concentrating ability; 1.010 to 1.012 indicates that the urine is isotonic with plasma. Glucosuria, iodinated contrast media, and massive proteinuria can also increase the specific gravity. The normal urine pH is 5.0 to 7.5 indicating a slightly acidic to neutral pH. An alkaline pH may be caused by urinary tract infections (UTI) with urea spitting organisms such as Proteus, Klebsiella, or E. coli. Protein in the urine, or proteinuria, suggests increased glomerular permeability or a renal tubular disorder. Proteinuria is a sensitive marker for many types of kidney disease including diabetes, glomerular disease, and hypertension. Ketones in the urine can result from starvation, poorly controlled diabetes, or alcoholism. The presence of red or white blood cells often signals a serious problem and may indicate parenchymal kidney disease, UTI, or urologic lesions, such as tumors.
Assessing Renal Function with the Cockcroft Gault Equation

Cockcroft Gault Equation1: CrCl= (140-Age) (Weight ) (SCr x 72)
Calculating Ideal Body Weight (IBW): Males= 50kg + (2.3kg for every inch over 5 feet) Females= 45.5kg +(2.3kg for every inch over 5 feet) Rules for use of IBW vs. Actual Body Weight (ABW) in the Cockcroft Gault equation If ABW < IBW, use ABW (e.g. underweight patients) If ABW > IBW, use IBW If ABW is greater than 120% of IBW use Adjusted Body Weight (Adjusted Body Weight= IBW + 0.4 (ABW-IBW)
1 Multiply
results by 0.85 if female patient
Salazar and Corcoran Equation (use if patient is obese) Men: (137-age)(0.28)(wt) + (12.1)(ht)2 (51)(Scr) Women: (146-age)(0.287)(wt) + (9.74)(ht)2 (60)(Scr) Weight: ABW in kg Height: meters Use 1.0 if serum creatinine value is less than 1.0
Assessing Renal Function with the Cockcroft Gault Equation

Using the Cockcroft Gault equation provides a quick bedside estimate of creatinine clearance in healthy elderly individuals. However wide individual variation between measured and calculated creatinine clearance can occur therefore it is important to consider these equations as estimates of GFR and not absolute calculations of renal function. It is common practice if the actual serum creatine value is less than 1.0 mg/dl in elderly patients with low muscle mass to round the serum creatinine up to 1.0 mg/dl. In most cases this is acceptable because the formula tends to overestimate renal function in patients with low muscle mass but this rounding may lead to underdosing of many drugs such as aminoglycosides. Therefore in situations in which underdosing may compromise a clinical response various formulas and clinical judgment should be used as an approximate guide to renal function. The second question that often comes up when using the Cockcroft Gault equation is about weight and which value to use. The first step is to ensure that you have an accurate actual body weight. The next step is to calculate the ideal body weight using the equations listed in the panel. Compare the actual body weight to the ideal body weight and use the actual body weight only if it is less than the ideal body weight. In most cases you will be using the ideal body weight in the Cockcroft Gault equation because this is thought to most closely approximate muscle mass, which produces creatinine. In obese patients who have an actual body weight greater than 120% of their ideal body weight you must use either an adjusted body weight or the Salazar and Corcoran formula.
Acute Renal Failure (ARF)

Definition and diagnosis ARF is abrupt loss of kidney function over a period of hours to days,resulting in an inability to excrete metabolic waste products and maintain fluid and electrolyte homeostasis. Serum creatinine Scr 0.5 mg/dL if baseline Scr < 3.0 mg/dL Scr 1.0 mg/dL if baseline Scr 3.0 mg/dL Scr 50 % of baseline Urine output Anuria (< 50 mL/day) Oliguria (< 400 mL/day) Non-oliguria (> 400 mL/day) Other factors to consider in ARF Acid-base balance Body fluid volume Nitrogenous waste products (BUN) Electrolytes Acute renal failure (ARF) is a common clinical syndrome characterized by an abrupt loss of kidney function over a period of hours to days resulting in an inability to excrete metabolic waste products and maintain fluid and electrolyte homeostasis. Because ARF often results in the accumulation of nitrogenous wastes, such as creatinine and urea, it is often referred to azotemia. ARF accounts for only 1% of hospital admissions, but affects 5 to 7% of hospitalized patients, and up to 30% of ICU patients. ARF causes significant morbidity and carries a 20 to 70% mortality rate.
Acute Renal Failure (ARF)

There is no commonly accepted definition for ARF therefore there is much confusion and disparity among accepted diagnostic criteria. One commonly used definition is an increase in the serum creatinine of at least 0.5 mg/dL in a patient whose baseline serum creatinine is less than 3.0 mg/dL or an increase of 1.0 mg/dL when the baseline serum creatinine is greater than, or equal to, 3.0 mg/dL. Alternatively, ARF may be defined as an increase in the serum creatinine of 50% or more over the base-line value. In addition to serum creatinine its important to assess other factors associated with ARF. Urine output is often reduced dramatically with ARF, although this is not always the case. ARF can result in anuria (urine output less than 50 mL per day), oliguria (urine output less than 400 mL per day), or non-oliguria (urine output greater than 400 mL per day). Finally, patients who are unable to maintain adequate control of body fluid volume, acid-base balance, and the levels of BUN and electrolytes may have ARF, regardless of whether the serum creatinine has increased significantly.
Classification of ARF
1.Pre-renal ARF 2.Renal / Intrinsic ARF Glomerular nephritis Acute tubular necrosis (ATN) Vasculitis Interstitial nephritis 3.Post-renal ARF (obstruction) 4.Functional ARF Drug-induced reductions in intraglomerular pressure and GFR NSAIDs affect afferent vasoconstriction ACEIs / ARBs affect efferent vasodilation
The etiology of ARF is classified into three main categories: prerenal, renal or intrinsic, and post-renal. In addition, a fourth category called functional ARF is sometimes used. Prerenal ARF occurs during conditions that lead to decreased renal perfusion, including intravascular volume depletion, hypotension, or compromised cardiac output. Intrinsic ARF results from diseases that affect the various internal kidney tissues such as the glomeruli, renal tubules, vasculature or interstitium. The most common of these is acute tubular necrosis or ATN, which is death of the tubular cells that usually results from nephrotoxins or prolonged renal hypoperfusion and ischemia. Its important to point out that prerenal ARF and ATN can result from the same pathophysiologic process which begins as prerenal azotemia and can progress to ATN if left untreated. Postrenal ARF results from urinary tract obstruction by calculi or kidney stones, tumors, urethral stricture, or obstructed urinary catheters. As one would expect, there is typically a reduced urinary output associated with postrenal azotemia.
Functional ARF is similar to pre-renal ARF in that it results in a decrease in intraglomerular hydrostatic pressure and GFR. However, functional ARF is generally drug-induced and results from changes in the circumference of glomerular afferent and/ or efferent arterioles. These arteriolar changes alter intrarenal hemodynamics and most often result from the use of medications such as NSAIDs, and ACEIs / ARBs. For example, NSAIDs inhibit prostaglandin synthesis. Thromboxane A2 is prostaglandin that causes dilation of the afferent arteriole. When this is inhibited by NSAID use, there is relative vasoconstriction of the afferent arterioles, which reduces intraglomerular pressure. Angiotensin 2 causes constriction of the efferent arteriole as a means of maintaining intraglomerular pressure. When angiotensin 2 is blocked by the use of ACEIs or ARBs, there is relative vasodilation of the efferent arterioles and again a reduction of intraglomerular pressure. Although most individuals can compensate for these hemodynamic changes, patients with conditions that lead to decreased renal perfusion, such as hypovolemia (e.g. Dehydration or blood loss) or CHF, may rely heavily on these mechanisms to maintain glomerular pressure. In this setting, the addition of these drugs causes a decompensation and ARF ensues.
Risk Factors
Preexisting Disease CKD Liver disease CHF Diabetes Nephrotoxins IV contrast dye Aminoglycosides Amphotericin B Advanced Age Decreased functional reserve Preexisting age-related reductions in kidney function Risk factors for ARF are usually multifactorial and ARF most often occurs in the presence of a chronic condition such as preexisting chronic kidney disease, liver disease, CHF or diabetes with the addition of a nephrotoxic insult. Examples of potential nephrotoxic insults include cardiovascular surgery or the administration of intravenous contrast dye, or the use of aminoglycosides, or amphotericin B. Decreased functional reserve capacity and preexisting age-related reductions in kidney function place the elderly patient at an increased risk for ARF. As mentioned previously, NSAIDs and ACEIs are a common cause of ARF in the elderly. Although most individuals can compensate for the hemodynamic changes induced by these drugs, the elderly often have other concommitant risk factors for ARF.
Treatment of ARF
Prevention 1. Avoidance of nephrotoxins or use of less nephrotoxic agents/regimens: Once-daily aminoglycoside dosing Lipid-based amphotericin B formulations Low-osmolality contrast media 2. Hydration (fluid and sodium loading) Minimize kidney damage There is little data to suggest that low-dose dopamine, fenoldopam, loop diuretics, mannitol,and calcium channel blockers are effective at minimizing kidney damage or hastening recovery of kidney function. Manage complications of ARF Infection Fluid overload / hyponatremia Hyperkalemia Hyperphosphatemia Acidosis Uremia
Treatment of ARF
Indications for dialysis (A,E,I,O,U) A- acidosis E- electrolytes (Hyperkalemia) I- intoxication (poisoning, overdose) O- overload (hypervolemia, hypertension) U- uremia (confusion, pericarditis, nausea, vomiting, BUN > 100 mg/dL) Treating Complications of ARF* Table 1 Extracellular volume overload Restriction of sodium and water intake. Diuretics, if responsive (usually loop diuretic thiazide). Consider dialysis. Restriction of water intake. Restriction of dietary K+ intake. Remove K+ with K+ binding ion-exchange resin (sodium polystyrene sulfonate) Consider: Calcium gluconate 10% (10 mL IV) Glucose (50 mL D50) and insulin (10 units regular) Sodium bicarbonate Albuterol (10 mg via nebulizer) Loop diuretic, if responsive Dialysis
Hyponatremia Hyperkalemia
17.01.09 Treatment of ARF
Hyperphosphatemia
Restriction of dietary phosphate intake. Phosphate binding agents (aluminum hydroxide, calcium carbonate, calcium acetate, sevelamer HCl)
Metabolic acidosis
Sodium bicarbonate (maintain serum bicarb > 15 mEq/L)Dialysis
*These are general guidelines and must be tailored to the needs of individual patients. Adapted from: Lancet 1995; 346: 1537.
Treatment of ARF
Table 2. Pharmacolgic Treatment of Hyperkalemia
HYPERKALEMIA TREATMENT Calcium gluconate 10%
DOSE 10 mL IVPB Monitor ECG Caution if patient on digoxin 5 Units IV q 30 min. Must give dextrose: 2-5 gm glucose / 1 U insulin Monitor BS (FS Q 15 min.) 50 mEq (1 amp)
MECHANISM OF ACTION Stabilizes myocardium, antagonizes the membrane actions of potassium Redistribute K+ (intracellular potassium uptake)
Insulin (Regular)
Sodium Bicarbonate (if acidosis) Albuterol
Redistribute K+ (intracellular potassium uptake)
10 mg via nebulizer Redistribute K+ (intracellular Monitor HR potassium uptake) B- blockers may prevent K+ effect Furosemide 40 - 120 mg IV q 6 8 hrs Dont use if patient is anuric 50 gm PO up to QID Caution in fluid overloaded patient Slow onset Increase urinary excretion of K+
Loop Diuretic
Sodium Polystyrene Sulfonate (Kayexalate)
Potassium binding ion exchange resin: exchanges Na+ for K+
17.01.09 Treatment of ARF

The treatment goals in ARF are focused on three primary objectives; prevention, minimizing damage to the kidney, and managing complications. Preventive measures are most commonly attempted for patients at risk for ARF who require treatment with nephrotoxic agents. These strategies include the avoidance of nephrotoxic agents when possible, aggressive fluid and sodium loading to maintain renal perfusion and substituting known nephrotoxins with potentially less nephrotoxic therapeutic alternatives. Examples of this include the use of once-daily aminoglycoside dosing as opposed to conventional thrice-daily dosing. Similarly, lipid-based amphotericin B formulations may be less nephrotoxic than conventional amphotericin B. The substitution of low-osmolality contrast media in place of higher osmolality dyes may also lower the risk for ARF. In patients with established ARF, the goals are to minimize damage to the kidney and to hasten recovery of kidney function. Although many therapies have been studied, there is little data to suggest that they are effective at accomplishing these goals. Examples include the use of low-dose dopamine, fenoldopam, loop diuretics, mannitol,and calcium channel blockers. Although these treatments have theoretical benefits, their efficacy has not been well demonstrated in well-designed clinical studies. As a result, the treatment of ARF focuses on measures to prevent and manage ARF complications with the hope that the patient will spontaneously recover renal function. ARF is associated with a host of complications. Infections are serious and the most common cause of death in ARF. Other complications result from the inability of the kidneys to excrete water, sodium, potassium, phosphorus, and acids. As a result, hypervolemia, hyponatremia, hyperkalemia, hyperphosphtemia, and metabolic acidosis often occur. In addition, patients cannot excrete the nitrogenous waste products of protein catabolism and can develop uremia. The severity of complications generally correlates with the degree of renal injury. These complications should be anticipated and preventive measures be taken when possible. Unfortunately, these complications are often inevitable and require aggressive management. General guidelines for managing complications of ARF are shown in Table 1.
Treatment of ARF
Hyperkalemia is the most common and potentially most serious complication that can arise in ARF. Because it can lead to life threatening arrhythmias, strategies to prevent hyperkalemia are of utmost importance. These include potassium restrictions and frequent monitoring of potassium levels. In the event that hyperkalemia occurs, there are many treatment options available. Severe hyperkalemia (K > 7 mEq/L) or moderate hyperkalemia (K > 6 mEq/L), when associated with EKG changes or clinical symptoms requires immediate treatment. Treatment options for hyperkalemia and their associated mechanisms are shown in Table 2. Renal replacement therapy, or dialysis, is not indicated for all cases of ARF. Similar to the treatments for ARF mentioned previously, there is little data to suggest that dialysis is effective at minimizing kidney damage or hastening the recovery of kidney function. Absolute indications for dialysis in ARF include symptoms or signs of uremia, and management of acidosis, hyperkalemia, or fluid overload that is refractory to medical treatment.
Chronic Kidney Disease (CKD)

National Kidney Foundataion (NKF) / Kidney Disease Outcomes Quality Initiative (K-DOQI): Evaluation, Classification, and Stratification of CKD Definition of CKD: Kidney damage for 3 months, as defined by structural or functional abnormalities of the kidney, with or without decreased GFR, manifest by either: Pathologic abnormalities; or Markers of kidney damage (proteinuria) Estimated GFR < 60 mL/min/1.73 m2 for 3 months, with or without kidney damage The Cockcroft-Gault or MDRD Study equations should be used. Serum creatinine alone should NOT be used to assess kidney function. 24-hour urine collection should be evaluated when a precise measure of GFR is critical, such as determining the need to start dialysis.

CKD Stages (Table 3) Stage 1 2 3 4 5 Description Kidney damage with normal or GFR Kidney damage with mild GFR Moderate GFR Severe GFR Kidney failure GFR (mL/min/1.73m2) 90 60 - 89 30 - 59 15 - 29 < 15 or dialysis
Chronic kidney disease (CKD) has traditionally been defined as a progressive and irreversible loss of kidney function, resulting in the inability to concentrate urine, conserve electrolytes and excrete wastes. In 2002, the National Kidney Foundations Kidney Disease Outcomes Quality Initiative published clinical practice guidelines for the evaluation, classification, and stratification of CKD. These guidelines not only provide precise definitions of what constitutes CKD, they also provide a method for stratifying CKD patients into one of five discreet CKD stages. Based on these guidelines, CKD is defined as either the presence of kidney damage, or a GFR less than 60 mL/ min. Either of these conditions must be present for at least 3 months. All patients with kidney damage are classified as having CKD, irrespective of the level of GFR. Kidney damage is defined as a structural or functional abnormality of the kidney, initially without decreased GFR, which over time can lead to a decreased GFR. Kidney damage is identified by observing pathologic abnormalities, which might be seen in a kidney biopsy, or markers of kidney damage, including abnormalities in the composition of blood or urine. Proteinuria, defined as greater than 300 mg of protein in the urine per day, is perhaps the most clinically useful marker, as it is an early and sensitive marker of kidney damage in many types of CKD.

All patients with GFR < 60 mL/min/1.73 m2 for 3 months are classified as having CKD, irrespective of the presence or absence of kidney damage. Reduction in kidney function to this level represents loss of half or more of the normal adult level of kidney function. As stated earlier, a reduction in GFR is expected with advancing age and the mean normal GFR for a 70 year old is 70 mL/min. Patients older than 80 years are likely to have a GFR less than 60 mL/min, and as such would be considered to have CKD based on these guidelines. However, a mild reduction in GFR may be normal at the extremes of age and in the absence of kidney damage these patients should not be considered as having CKD. Regardless of age, individuals with chronically decreased GFR are at risk for adverse outcomes, such as toxicity from renally excreted drugs, and may be more susceptible to acute renal failure in a wide variety of circumstances. The Kidney Disease Outcomes Quality Initiative guidelines state that it is not necessary to routinely perform creatinine clearance measurements (i.e. 24 hour urine collection) as this does not improve the estimate of GFR over that provided by prediction equations. However, a 24-hour urine collection should be evaluated when a precise measure of GFR is critical, such as determining the need to start dialysis. In most clinical scenarios, the level of GFR should be estimated using prediction equations that take into account the serum creatinine concentration and other variables, such as age, gender, race, and body size. The guidelines recommend using either the Cockcroft-Gault or MDRD Study equations for estimating GFR in adults. GFR should be adjusted to a standard body size of 1.73 m2. The serum creatinine concentration alone should not be used to assess kidney function. Once the presence or absence of kidney damage is established and the level of GFR has been estimated, the patient can be classified has having Stage 1 through Stage 5 CKD. Using the table shown, Stage-1 represents the mildest form of CKD where kidney damage is present but the GFR is normal or perhaps above normal. The stages then progress as GFR declines. In Stage-3 all patients have a GFR < 60 mL/min regardless of the presence or absence of kidney damage. Finally, in Stage-5 CKD, formerly known as End-Stage Renal Disease (ESRD), we have patients with kidney failure who require renal replacement therapy, either with kidney transplantation or dialysis.
Treatment of Chronic Kidney Disease

Treatment Goals: Early detection Slow progression Control hypertension Control blood glucose Manage complications
CKD Complications Hypertension Anemia Nutritional Status Hyperphosphatemia Secondary hyperparathyroidism (Renal Bone Disease) Others (neuropathy, functioning and well-being)
Treatment of Chronic Kidney Disease

The goals of treatment for CKD focus on early detection, strategies to slow the progression of the disease, and management of complications that arise secondary to loss of kidney function. Strategies to slow the progression of CKD focus primarily on strict blood pressure control and qlycemic control in diabetic patients. There are a host of complications associated with CKD. Complications such as anemia, hyperphosphatemia, and secondary hyperparathyroidism are common and expected in patients with stage 5 CKD. However, many of these can be prevented or delayed by early treatment. The figure shown illustrates the estimated prevalence of these complications by category of estimated GFR. The GFR categories on the x-axis correlate with the pre-dialysis CKD stages one through four. Looking at this figure we see that the prevalence of each of these complications increases as kidney function declines. Most striking is the prevalence of hypertension, which develops early in the course of CKD and progresses dramatically with loss of GFR. In addition, anemia (as indicated by a hemoglobin less than 12 g/dl) begins to become prevalent as early as stage 3 with over 50% of stage 4 CKD patients classified as anemic.
Hypertension in CKD
Goals of antihypertensive therapy in CKD Lower blood pressure Slow progression of kidney disease Reduce risk of cardiovascular disease Drugs of Choice ACE Inhibitors Angiotensin receptor blockers Thiazide diuretics (GFR 30 mL/min/1.73 m2) Loop diuretics (GFR < 30 mL/min/1.73 m2) Other agents, for example beta-blockers, calcium-channel blockers, should be added as necessary to achieve target blood pressure. Target blood pressure CKD Stages 1 4: < 130/80 mm Hg CKD Stage 5 (on dialysis) Pre-dialysis: < 140/90 mm Hg Post-dialysis: < 130/80 mm Hg
Hypertension in CKD
Hypertension is both a cause and complication of CKD and tends to develop early in the course of CKD. Patients with CKD and hypertension have an increased risk for experiencing adverse outcomes. These include further loss of kidney function and progression to kidney failure, accelerated progression of cardiovascular disease, and death. In 2004, the National Kidney Foundations Kidney Disease Outcomes Quality Initiative (K/DOQI) published clinical practice guidelines on hypertension and antihypertensive agents in CKD. These guidelines provided recommendations for treating hypertension patients with CKD stages 1 thru 4. More recently, the Kidney Disease Outcomes Quality Initiative published clinical practice guidelines for cardiovascular disease in dialysis patients. These guidelines provide recommendations for treating hypertension patients with stage 5 CKD on dialysis therapy. The goals of antihypertensive therapy in patients with stages 1 thru 4 CKD are to lower blood pressure, slow the progression of kidney disease and to reduce the risk of cardiovascular disease. Many studies have shown that antihypertensive regimes including an ACE Inhibitor or ARB, usually in combination with a diuretic, are more effective in slowing the progression of CKD than other antihypertensive regimens. However, the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) did not confirm these earlier studies. ALLHAT was a randomized controlled trial that compared calcium channel blockers and ACE inhibitors to thiazide-type diuretics to reduce risk of CVD. ALLHAT concluded that thiazide-type diuretics are superior in preventing one or more major forms of CVD and are less expensive. The ALLHAT investigators recommended diuretics should be preferred for first-step antihypertensive therapy. In response to ALLHAT the NKF released a statement reminding clinicians that the ALLHAT findings do not invalidate results of prior studies showing the beneficial effects of ACEI and ARBs in slowing the progression of kidney disease. In addition they noted that most CKD patients require more than one antihypertensive agent to achieve adequate blood pressure control and therefore should receive ACEI and/or ARBs in combination with diuretics. Since patients with CKD stages 4 and 5 (GFR < 30 mL/min) are less likely to respond to thiazide-type diuretics, loop diuretics are the preferred diuretic agents in these patients.
Hypertension in CKD
The Kidney Disease Outcomes Quality Initiative recommendations for blood pressure management are in agreement with JNC 7, which also recommends ACEI and/or ARBs in combination with loop diuretics for CKD patients. Both Kidney Disease Outcomes Quality Initiative and JNC 7 recommend a target blood pressure of less than 130/80 mm/Hg for CKD stage 1 4 patients. The Kidney Disease Outcomes Quality Initiative clinical practice guidelines for cardiovascular disease in dialysis patients provide recommendations for treating hypertensive patients with stage 5 CKD on dialysis therapy. Because these patients have already progressed to end-stage renal disease, the primary goal of antihypertensive therapy in patients with stage 5 CKD is to reduce the risk of cardiovascular disease. CVD is the leading cause of death in dialysis patients. The Kidney Disease Outcomes Quality Initiative guidelines recommend pre-dialysis and post-dialysis blood pressure goals of 140/90 mm Hg and 130/80 mm Hg, respectively. Achieving and maintaining appropriate blood pressure levels in dialysis patients requires attention to both management of body fluid status and use of antihypertensive medications. As in stages 1 4 CKD, ACEI and/or ARBs are the preferred agents. The effective treatment of hypertension in CKD patients often necessitates use of multiple antihypertensive agents. In patients with previous myocardial infarction or established CAD, beta blockers should be used. Other agents, such as calcium-channel blockers and alpha-adrenergic drugs, should be added as necessary to achieve target blood pressures.
Anemia of CKD
Causes Suppression of red blood cell synthesis Shortened red blood cell survival Iron deficiency Blood loss Nutritional deficiency (Vit B12, folate) Erythropoietin deficiency Benefits of Treating Anemia in CKD Improved quality of life Exercise / work capacity Cognitive function Sexual function Improved cardiac function Increased cardiac output Decreased CHF symptoms Anemia is a well established complication of CKD that can develop early in the course of CKD and is nearly universal in stage 5 CKD, or ESRD. The anemia of CKD may result from suppression of red blood cell synthesis by uremic toxins, shortened red blood cell survival, iron deficiency, blood loss, and nutritional deficiency. However, the primary cause of anemia in CKD is erythropoietin deficiency, resulting from the progressive reduction of kidney function. Unfortunately many CKD patients are not effectively treated for anemia until they start dialysis. Clinicians should be aware that there are many benefits to treating anemia during all stages of CKD. Quality of life is negatively impacted by anemia and effective treatment has been shown to improve exercise and work capacity, and cognitive and sexual functioning. In addition, newer studies have found that anemia is an independent risk factor for left ventricular hypertrophy and treatment can improve cardiac output (LVEF) and decrease symptoms of congestive heart failure.
NKF-K/DOQI Clinical Practice Guidelines for Anemia of CKD
Anemia Work-up in CKD See algorithm Hgb < 11 g/dL in pre- menopausal females Hgb < 12 g/dL in adult males and post-menopausal females Goals of Treatment Hgb: 11.0 12.0 g/dL Hct: 33 36% Treatment with Epoetin Alfa (EPO) Starting Dose IV: 120-180 units/kg/week, (~9,000 units/wk) given thrice weekly SC: 80-120 units/kg/week, (~6,000 units/wk) given once weekly Converting IV to SC SC is the preferred route SC dose = IV dose (if at target Hgb) Use same dose (if Hgb < 11)
Strategies for successful SC EPO Use the smallest possible gauge needle for injection (e.g. 29 gauge) Use a multidose Epoetin preparation that contains benzyl alcohol Administer a single, weekly injection to patients receiving a small dose Divide larger doses (a smaller volume for injection may reduce discomfort) Rotate injection sites between upper arm, thigh and abdominal wall areas Dose Adjustments Titrate dose up or down in increments of 25% as needed to maintain target Hgb Absolute rise in Hgb should be ~ 0.3 g/ dL per week Monitoring Parameters Hgb / Hct every 1 to 2 weeks until stable, then every 2 to 4 weeks

The NKF- Kidney Disease Outcomes Quality Initiative published comprehensive clinical practice guidelines for managing anemia in CKD in 2001. The guidelines for anemia work-up in CKD are illustrated in the algorithm shown on your screen. An anemia work-up should be initiated in all patients with CKD (defined as a serum creatinine > 2) when the hemoglobin level is less than 11 g/dL in pre-menopausal females, or less 12 g/dL in adult males and post-menopausal females. These patients should have a CBC done as well as other tests to rule out other causes of anemia, such as occult bleeding and iron deficiency. Once other causes are ruled out and the patient has sufficient iron levels, treatment with erythropoietin should be initiated. The goal of treatment is to achieve a target hemoglobin in the range of 11 to 12 g/dL, or a hematocrit between 33 and 36 percent. These levels are considerably lower than what is considered normal in patients without CKD. Whether CKD patients would benefit from higher hemoglobin and hematocrit levels has been debated. In the early stages of CKD, some authors have proposed that it may be appropriate to maintain these levels closer to the individuals baseline levels. When initiating therapy with epoetin alfa (EPO), the starting dose is calculated based on the patients weight. The drug can be given either intravenously (IV) or as a subcutaneous (SC) injection. A typical IV starting dose for a 70 kg patient would be 9,000 units given in 3 divided doses per week. Alternatively, a typical SC starting dose for the same patient would be 6,000 units per week given as a once weekly injection. The preferred route of Epoetin administration is SC as SC dosing provides a pharmacokinetic advantage of a longer duration of action, allowing for less frequent dosing and better efficacy. The only real disadvantage to SC EPO is that there can be pain associated with the injection. This is more common when single dose EPO vials are used or in patients receiving very large EPO doses. The multi-dose vials contain benzyl alcohol as a preservative, which also acts as a local anesthetic and can reduce the pain of SC dosing. Several strategies to improve the tolerability of SC EPO are shown.

EPO dose adjustments are generally made by titrating the dose up or down in increments of 25% as needed to achieve and maintain the target H/H. In addition, doses should be lowered if the hemoglobin is rising too rapidly. The absolute rise in Hgb should be approximately 0.3 g/dL per week as a rapidly rising hemoglobin/hematocrit can cause EPO induced hypertension. The Kidney Disease Outcomes Quality Initiative guidelines recommend that the hemoglobin and/or hematocrit be monitored at least twice per month after initiating EPO. Once a target level is reached, the hemoglobin and/or hematocrit should continue to be monitored twice monthly until a stable dose is achieved.Thereafter monthly monitoring may be sufficient. In addition, the patients blood pressure should be closely monitored after starting EPO. Hypertension can occur with EPO use and it is usually associated with rapidly rising hematocrit. Although its important to monitor blood pressure, hypertension is not a contraindication to EPO. Initiation of antihypertensive therapy or an increase in antihypertensive medication, and reduction of the EPO dose if there has been a rapid rise in H/H, may be required if EPO induced increases in blood pressure occur.
Treatment with Darbepoetin alfa

An analog of human EPO with a threefold longer half-life, allowing less-frequent dosing Once per week or once every other week dosing Starting Dose IV or SC: 0.45 mcg/kg/week 25 micrograms once weekly or; 60 mcg every other week
Conver'ng to darbepoe'n from EPO

Previous EPO dose (units/week) <2,500 2,500 to 4,999 5,000 to 10,999 11,000 to 17,999 18,000 to 33,999 34,000 to 89,999 > 90,000 Darbepoe'n dose (mcg/week) 6.25 12.5 25 40 60 100 200
Treatment with Darbepoetin alfa

Darbepoetin alfa is also an erythropoiesis stimulating protein that is an analog of the recombinant human EPO molecule. Darbepoetin contains five carbohydrate side chains compared to 3 for Epoetin. This results in an approximately threefold longer half-life for darbepoetin allowing for less-frequent dosing (once per week or once every other week). Despite the structural differences, darbepoetin alfa binds to the same receptor as endogenous erythropoietin and exerts the same receptor-mediated erythropoetic action. The recommended starting dose is 0.45 mcg/kg/week. Based on a 70 kg patient, the starting dose of darbepoetin is 25 micrograms once weekly or 60 mcg once every other week. Higher doses may be necessary for patients weighing more than 70 kg. The dose is titrated as necessary to achieve and maintain the target hemoglobin. Interestingly, darbepoetin alfa's half-life is approximately twofold longer when administered via the SC versus IV route, despite the bioavailability of SC darbepoetin alfa being approximately 37%. The result of the increased half-life and reduced bioavailability are a similar area under the curve for both routes of administration and the same dosing recommendations for IV and SC. Converting patients from epoetin to darbepoetin is not immediately intuitive because EPO is dosed in units while darbepoetin is dosed in micrograms. However, the manufacturer provides a table with the package insert that provides recommended darbepoetin dose conversion based on the patients weekly EPO requirement. Additionally, a dose conversion calculator can be accessed from the manufacturers website.
Iron Support
Assessment of Iron Levels Transferrin saturation (TSAT): reflects the amount of iron available for erythropioesis Target Level: 20 - 50 % Serum ferritin: reflects the amount of iron stored in the liver, spleen, and bone marrow Target Level: 100 800 ng/mL An acute phase reactant, it can increase in the presence inflammation. Iron supplementation Oral Iron Dose: 200mg elemental iron per day Ferrous sulfate is 20 % iron (324 mg FeSO4 = 65 mg Fe) Ferrous gluconate is 11 % iron (324 mg FeGluc = 36 mg Fe) Side effects: anorexia, N&V, constipation , and dark stools IV Iron Formulations Iron Dextran (INFeD, Dexferrum) Repletion: 100 mg x 10 doses Maintenance: 25 to 100 mg q week Iron Gluconate (Ferrlicit) Repletion: 125 mg x 8 doses
Iron Support
Maintenance: 31.25 to 125 mg q week Iron Sucrose (Venofer) 100 mg, 1 to 3 times per week
It is important to remember that effective erythropoiesis requires both erythropoietin and iron. Iron is essential for hemoglobin formation and therefore patients receiving erythropoietin therapy must be assessed for iron deficiency. The Kidney Disease Outcomes Quality Initiative guidelines state that all CKD patients should have sufficient iron to maintain a hemoglobin in the target range of 11 to 12 g/dL. To achieve and maintain this target, patients must be administered sufficient iron to maintain a transferrin saturation (TSAT) between 20 and 50 percent and a serum ferritin level between 100 and 800 ng/ mL. The TSAT and ferritin are the best tests for iron status. TSAT reflects the amount of iron that is available for erythropoiesis and a level less than 20 % generally indicates iron deficiency. The serum ferritin reflects the amount of iron stored in the liver, spleen, and bone marrow reticuloendothelial cells. In addition to reflecting body iron stores, ferritin is an acute phase reactant and can increase in the presence of acute or chronic inflammation.
Iron Support
To achieve the goals for hemoglobin, TSAT, and ferritin levels, the administration of supplemental iron is often necessary. Iron can be administered either orally or intravenously. If oral iron is given, a daily dose of at least 200 mg of elemental iron is recommended. Oral iron is associated with gastrointestinal side effects and adherence may be poor. In addition, oral iron is poorly absorbed and CKD patients may not be able to maintain adequate iron levels with oral iron. As a result, many patients will require IV iron on a regular basis. Additionally, absorption of oral preparations of iron and many medications are decreased when used together. For example, iron can significantly decrease the absorption of levodopa, quinolones and tetracycline. Food and achlorhydria will also decrease iron absorption as will antacids, and H2 antagonists. The three IV iron formulations available in the US include iron dextran, iron gluconate, and iron sucrose. Dialysis or stage 5 CKD patients generally have the greatest requirements for EPO and iron to maintain adequate hemoglobin levels. A number of studies have documented the failure of oral iron to maintain adequate iron stores in EPO treated hemodialysis patients. As a result, the Kidney Disease Outcomes Quality Initiative Anemia work group developed IV iron dosing protocols to provide repletion and maintenance iron therapy to hemodialyisis patients. In iron deficient dialysis patients, the work group recommends 100 mg of iron dextran or 125 mg of iron gluconate during each dialysis for 10 or 8 doses respectively. For maintenance therapy, the recommendation is 25 to 100 mg of iron dextran every week for 10 weeks, or 31.25 to 125 mg of iron gluconate every week for 8 weeks. These protocols were developed prior to the US release of iron sucrose, however a similar protocol can be used for iron sucrose. Although these protocols are fairly easy to administer in hemodialysis patients who receive in-center hemodialysis three times weekly, they may not be convenient for peritoneal dialysis or pre-dialysis CKD patients. The most common approach to overcome this inconvenience is the administration of larger IV iron doses to non-hemodialysis patients. However, there is some controversy as to how much IV iron can be safely administered and these strategies are limited by the adverse effects associated with various IV iron formulations.
Safety of IV Iron
Adverse reactions Idiosynchratic / Immediate Anaphylaxis Hypotension Urticaria/pruritis Flushing Dose-Related / Delayed Arthralgia Myalgia Fever Other Adverse Effects Abdominal pain Diarrhea Cramps Test doses 25 mg given 15 to 60 min prior to iron dextran and gluconate. Test doses should be administered by trained personnel and there should be immediate access to medications needed to treat an anaphylactic reaction (epinephrine, diphenhydramine, etc.). Test dose not required with iron sucrose, but may be prudent.
Safety of IV Iron
There are two main categories of adverse effects associated with IV iron. Idiosynchratic reactions occur immediately and include anaphylaxis, hypotension, and pruritis. Dose-related effects are usually delayed and result from larger doses (> 100 mg) or rapid rates of infusion and include arthralgia, myalgia, and fever. Other reactions include abdominal pain, diarrhea, and muscle cramping. Because of the risk for acute adverse reactions, a 25 mg test dose is recommended 15 to 60 minutes prior to initiating IV iron dextran or iron gluconate. It is recommended that the test dose be administered by personnel trained to provide emergency treatment and there should be immediate access to medications needed to treat an anaphylactic reaction. If no allergic reactions occur, subsequent doses can be given without a test dose. The risk for anaphylactic reactions appears to be greatest with iron dextran. The two newer compounds, iron guconate and iron sucrose, appear to have a far lower risk for anaphylaxis. The package insert for iron sucrose states that a test dose is not required. However, some clinicians may still prefer to administer a test dose with this agent. It is important to note that an uneventful response to a test dose does not preclude a future reaction and caution is warranted with every dose of IV iron, particularly iron dextran. In addition, there is no evidence that anaphylactic reactions to these agents are less severe after a test dose than after the usual 100 to 125mg dose. In fact, most patients that have acute reactions with iron dextran have previously tolerated a test dose and previous therapeutic doses. As such, the clinical value of test doses is limited.
Hyperphosphatemia and Secondary Hyperparathyroidism in CKD (Renal Bone Disease)
Pathophysiology Decreased renal phosphorus excretion Hyperphosphatemia (serum P > 5.5 mg/dL) Decreased metabolic conversion of vitamin D to its active metabolite (1,25-(OH)2D3) leads to a decreased calcium absorption Hypocalcemia ( serum Ca++ < 9.2 mg/dL) Secondary hyperparathyroidism results from: Hyperphosphatemia Decreased 1,25-(OH)2D3 levels Hypocalcemia Renal Bone Disease (Renal Osteodystrophy) Hyperparathyroidism (iPTH > 300 pg/mL) Increased osteoclast activity Bone resorption Hyperphosphatemia and/or hypercalcemia Bone pain and/or fractures Metastatic Calcification Elevated calcium-phosphorus product (Ca++ x PO4 = CxP) > 70 mg/dL Corrected Ca++ = [(4.0 albumin) x 0.8] + serum Ca++

Therapeutic Goals: Serum Phosphorus (3.5 5.5 mg/dL) CxP Product (<55 mg/dL) Serum corrected calcium (8.4 9.5 mg/dL) Intact Plasma Parathyroid Hormone (iPTH) Stage 3 CKD (35 - 70 pg/mL) Stage 4 CKD (70 - 110 pg/mL) Stage 5 CKD (150 - 300 pg/mL)
The NKF-K/DOQI published comprehensive clinical practice guidelines for managing bone metabolism and disease in CKD in 2003. The treatment of renal bone disease focuses on maintaining the serum, phosphorus, calcium, and PTH levels within the ranges indicated. Hyperphosphatemia and secondary hyperparathyroidism are common complications of stage 5 CKD or kidney failure, but may also be seen in earlier stages of CKD. These complications are inter-related and usually develop in concert as renal function declines. Because they can eventually lead to altered bone metabolism and bone disease, they are often referred to as renal osteodystrophy, or renal bone disease. The pathophysiology of renal bone disease is best summarized as follows. The loss of excretory function results in decreased phosphorus excretion and Hyperphosphatemia. The loss of metabolic kidney function leads to decreased conversion of vitamin D to its active metabolite, 1,25 dihydroxy vitamin D3. Reduced levels of 1,25 dihydroxy vitamin D3 lead to decreased absorption of calcium from the GI tract and hypocalcemia. Each of these effects, hyperphosphatemia, low 1,25 dihydroxy vitamin D3 levels, and hypocalcemia, all lead to increased production of parathyroid hormone. Hyperparathyroidism leads to increased osteoclast activity and bone resorption. Bone resorption increases the patients risk for bone pain and fractures. Bone resorption also liberates phosphorus and calcium from the bone worsening hyperphosphatemia and possibly causing hypercalcemia.

Just as excessive PTH levels can adversely affect bone, so can over-suppression of PTH. Excessively low PTH levels can occur as a result of pharmacologic treatment (Vitamin D), hypercalcemia, or parathyroidectomy. Excessively low PTH levels cause less than optimal osteoclast activity, which can result in brittle, poor quality bone tissue, a condition referred to as adynamic bone disease. In addition to bone disease, elevations in the serum phosphorus and or calcium can result in precipitation of insoluble calciumphosphate into various tissues. This is referred to as Metastatic calcification. The greatest risk for calcification occurs when the calcium-phosphorus product exceeds 70. However, it is believed that calcification may occur even in CKD patients with a normal calcium-phosphorus product. The calcium-phosphorus product is calculated by multiplying the serum phosphorus times the serum calcium, which must be corrected for the serum albumin level. Calcification can occur in nearly all tissues including the skin, joints, lungs, and cardiovascular system. Calcification of these tissues leads to significant morbidity.
Treatment of Hyperphosphatemia and Secondary Hyperparathyroidism

Control of Serum Phosphorus Dietary restriction of high phosphorus foods Cola Cheese Peanut butter Chocolate Milk Phosphate binders Calcium carbonate (Tums ) Calcium acetate (Phoslo ) Aluminum hydroxide Sevelamer HCl (Renagel ) Lanthanum carbonate (Fosrenol ) Dosage: Usually 1 to 3 tablets taken with meals (you want to bind phosphate in the gut to prevent absorption) Adverse effects GI upset Hypercalcemia with calcium salts, especially with concomitant vitamin D Aluminum toxicity

Vitamin D Therapy(with usual starting doses) Calcitriol (Calcijex) 1-2 mcg IV 3 times per week Calcitriol (Rocaltrol) 25 mcg PO QD Paricalcitol (Zemplar) 3-7 mcg IV 3 times per week Doxercalciferol (Hectoral) 2.5 4 mcg IV 3 times per week 5 - 10 mcg PO 3 times per week Adverse Effects: Hypercalcemia Hyperphosphatemia Adynamic bone disease Calcimimetics Cinacalcet (Sensipar ) 30 180 mg PO QD The treatment goals for renal bone disease are achieved by efforts to control serum phosphorus, calcium, and PTH levels within the K/DOQI target ranges. These goals are achieved by dietary restrictions and the use of drugs such as phosphate binders, vitamin D sterols, and calcimimetics. Phosphorus levels are managed by limiting the dietary intake of foods known to be high in phosphorus. Dietary restriction alone is often ineffective and patients require treatment with phosphate binding agents. These drugs are taken with meals and bind dietary phosphorus in the GI tract, preventing it from being systemically absorbed. The commonly used phosphate binding agents include calcium salts, such as calcium carbonate and acetate, aluminum hydroxide, sevelamer HCl, and lanthanum carbonate. Up until a few years ago, the calcium salts were the most commonly used phosphate binding agents. Recently their use has decreased because of concerns regarding the onset of hypercalcemia and metastatic calcification. Hypercalcemia may be compounded in patients receiving concomitant treatment with vitamin D. The K/DOQI guidelines recommend that when calcium containing phosphate binders are used, the total daily dose of elemental calcium should not exceed 1500 mg per day. Calcium based phosphate binders should not be used in patients who are hypercalcemic (corrected Ca > 10.2 mg/dL) or whose plasma intact PTH levels are below the target range.

Aluminum is a very effective phosphate binder. However, systemic absorption and accumulation of aluminum can lead to toxicity. The K/DOQI guidelines recommend that aluminum based phosphate binders be reserved for patients with serum phosphorus greater than 7.0 mg/dL and should only be used as short-term therapy for up to 4 weeks. Sevelamer is a polymeric binding resin, which is not systemically absorbed. It does not contain calcium or aluminum, and therefore may be a safer alternative. Sevelamer not only binds to dietary phosphorus, but also binds to bile acids and results in lowering of LDL and total cholesterol levels. However, use of sevelamer is often limited by the drugs cost. As a result it is often reserved for patients with or at risk for hypercalcemia. Lanthanum, the newest phosphate binder, is a trivalent cation (La3+) classified as a rare earth element. Like sevelamer it results in a significant reduction in the incidence of hypercalcemia. Biliary excretion appears to be the predominant route of elimination for circulating lanthanum. While the oral bioavailability of lanthanum in normal human subjects is very low (<0.002%), animal data suggests the potential for accumulation over prolonged periods. This product comes as a chewable tablet, which should aid adherence in patients with a large pill burden. Because it received FDA approval following the release of the K/DOQI guidelines, its place in the treatment of renal bone disease has not yet been fully elucidated. Vitamin D therapy includes the administration of 1,25 dihydroxy vitamin D3, or calcitriol, which is the active metabolite of vitamin D. Calcitriol is available in both IV and oral formulations. Calcitriol effectively reduces PTH levels, however it also increases the absorption of dietary calcium and its use is often limited by the onset of hypercalcemia, particularly in patients taking calcium containing phosphate binders. The high incidence of calcitriol-induced hypercalcemia has lead to the development of two newer vitamin D options. Paricalcitol is a synthetic vitamin D analog, which is currently only available in an IV formulation. Doxercalciferol is also a vitamin D analog, but it is hepatically activated to the active form of vitamin D. It has both IV and oral formulations available. These agents effectively suppress PTH production and although they may have a lower incidence of hypercalcemia than calcitriol, hypercalcemia does occur with their use. In addition to hypercalcemia, these agents can increase the GI absorption of phosphorus and exacerbate hyperphosphatemia.

The calcimimetics are the newest class of drugs used to treat secondary hyperparathyroidism. Cinacalcet, currently the only agent in this class, is indicated for the treatment of secondary hyperparathyroidism in CKD patients on dialysis. It effectively lowers PTH levels by increasing the sensitivity of the calcium-sensing receptor to extracellular calcium. The calcium-sensing receptor is located on the surface of the chief cell of the parathyroid gland and is the principal regulator of PTH secretion. In a randomized controlled study, cinacalcet when added to standard therapy, effectively lowered PTH levels by 43% in hemodialysis patients. In addition to lowering PTH, serum calcium and phosphorus levels were reduced by 6.8% and 8.4%, respectively. Because cinacalcet lowers serum calcium levels, it is important to monitor patients for the occurrence of hypocalcemia. Serum calcium levels should be measured within 1 week after starting treatment. In addition the drug should not be used in patients with serum calcium less than 8.4 mg/dL. The most frequently reported adverse events are nausea and vomiting. The phase 3 clinical trials for cinacalcet included 1136 patients, of whom 26% were 65 years old, and 9% were 75 years old. No differences in safety or efficacy were observed in these geriatric patients. Because medical therapy is not always successful in achieving adequate control of secondary hyperparathyroidism, some patients require surgical parathyroidectomy to correct the problem. Parathyroidectomy is recommended for patients with severe hyperparathyroidism (persistent serum levels of intact PTH >800 pg/mL), associated with hypercalcemia and/or hyperphosphatemia that are refractory to therapy with pharmacologic agents.
Kidney Disease and Quality of Life Issues

Many CKD patients report reduced quality of life. Some of the factors contributing to this reduction in QoL include: Restricted dietary intake and tight regulation of potassium, sodium, proteins, glucose. Adverse drug reactions and effects of long term therapies. Loss of control due to urologic and neurologic symptoms and their management. Restrictions due to overall fatigue, dietary needs, dialysis and possible kidney transplant. Ethical and economic considerations for the use of limited medical resources.
The treatment of kidney disorders in the elderly must include the impact upon lifestyle and the overall quality of life. While some changes may be acceptable, others may not. Dietary changes in the elderly can be difficult but are usually effective. Drug therapies should be closely monitored for adverse reactions. Changes in urinary habits can usually be accommodated. As kidney disease progresses however, factors of fatigue, constant monitoring and lifestyle restrictions can be overwhelming to the older adult. Treatment options of dialysis and surgical intervention should be fully explained to patients before they reach stage 5 CKD, or kidney failure. If a kidney transplant is an option, all pharmacotherapy, including immunosuppressive drugs, must be discussed prior to any surgery. Once the ethical and economic issues are examined, the elderly patient can make more informed decisions.
Resources
Acknowledgment: Michael R. Brodeur, PharmD, CGP contributed to this section in a previous edition. For additional information, see: Choudry D, Palmer B, Levi M. Renal Function and Dysfunction in Aging. In: Seldin DW, ed. The Kidney: Physiology and Pathophysiology, 3rd Edition. Philadelphia, Lippincott Williams & Wilkins, 2000: 2671-2595. Vestal RE. Aging and pharmacology. Cancer 1997;80:1302-1310. OConnell MB, et al. Predictive performance of equations to estimate clearance in hospitalized elderly patients. Ann Pharmacother 1992; 26:627-35 Levey AS, Bosch JP, Lewis JB, et al. A more acurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 1999;130:461-470. Mueller B. Acute Renal Failure. In: DiPiro JT, ed. Pharmacotherapy: A Pathophysiologic Approach, 5th Edition. New York, McGraw Hill, 2002: 771 795. Brady HR, Singer GG. Acute renal failure. Lancet 1995; 346:1533-40. Dishart MK, Kellum JA. An evaluation of pharmacological strategies for the prevention and treatment of acute renal failure. Drugs 2000; 59(1): 79-91. NKF. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J Kidney Dis 2002;39(suppl 1): S1-S266.
Resources
NKF. K/DOQI Clinical Practice Guidelines for Anemia of Chronic Kidney Disease: Update 2000. Am J Kidney Dis 2001 37 (suppl 1): S182-S238. NKF. K/DOQI Clinical Practice Guidelines for Bone Metabolism and Disease in Chronic Kidney Disease. Am J Kidney Dis 2003; 42(suppl 3): S1-S201. NKF. K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 2004; 43(Suppl 1):S1-290. NKF. K/DOQI Clinical Practice Guidelines for Cardiovascular Disease in Dialysis Patients. Am J Kidney Dis 2005;45(3 Pt 2): 16-153. Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: A consensus approach. Am J Kidney Dis 2000;36: 646-661. Bailie GR, Johnson CA, Mason NA. Parenteral iron use in the management of anemia in end-stage renal disease patients. Am J Kidney Dis 2000;35(1):1-12. Van Wyck, D., G. Bailie, and G. Aronoff, Just the FAQs: Frequently asked questions about iron and anemia in patients with chronic kidney disease. Am J Kidney Dis 2002; 39(2): 426-432. Block G, Port F. Re-evaluation of risks associated with hyperphosphatemia and hyperparathyroidism in dialysis patients: Recommendations for a change in management. Am J Kidney Dis 2000; 35(6):1226-1237.
Urinary Incontinence
Learning Objectives: By the end of this Review Concept you should be able to: Define urinary incontinence (UI). Describe the main types and symptoms of urinary incontinence found in the elderly. Discuss the causes of each type of UI including medications that contribute to the condition. Recognize established pharmacotherapy for UI and list the effects of each medication. Discuss treatment plans and monitoring. List any adverse effects of treatments for UI. Describe non drug approaches to UI and how these are integrated into a treatment plan. Reflect on lifestyle adjustments and supportive therapy for the elderly patient.
Overview of Urinary Incontinence in the Elderly

Definition: the involuntary loss of urine on a consistent basis as a result of a disturbance in the control of urinary tract functions Prevalence: 3-11% of elderly with severe UI Etiology: Localized or systemic diseases that effect the lower urinary tract or surrounding structures including: Congential malformations Constipation Diabetes Neurologic diseases (cerebrovascular accident, Parkinsons disease, multiple sclerosis, spinal cord injury) Postmenopausal atrophic urethritis or vaginitis Urinary tract infections Medications Social embarrassment, financial constraints Activities curtailed due to fear of public accidents Embarrassed to use and purchase incontinent products Incontinent pads and diapers, which make up a $541 million dollar per year market, are expensive especially for seniors on a fixed budget. Declining cognitive skills
Overview of Urinary Incontinence in the Elderly
Broadly defined, urinary incontinence is the involuntary loss of urine on a consistent basis as a result of a disturbance in the control of urinary tract functions. Even though urinary incontinence is most often associated with the elderly, it is not a normal consequence of the aging process. Various physiological thresholds for maintaining continence may be lowered in the elderly as a result of infections, anatomical changes and other co-morbid conditions. Medications often cause or worsen UI. Therefore as a senior care pharmacist it is important that you understand the normal urinary tract function and recognize the medications that can worsen bladder control. Because UI is embarrassing to patients and their care-givers, many often dont seek help. The lack of treatment contributes to the high incidence of incontinence in this population. Lack of financial means to obtain treatment and declining cognitive skills also contribute to the problem.
Basic Anatomy and Pharmacology
From: http://education.adam.com/ http://training.seer.cancer.gov/module_anatomy/unit11_2_uri_comp3_bladder.html
Lower Urinary Tract Bladder Detrusor muscle ( surrounds bladder) Urethra Urinary or urethral sphincter Surrounding musculofascial structures Urinary Continence Urethra sphincter must maintain adequate resistance Patency of bladder for storage of urine Detrusor muscle contractility suppressed Intact neurologic system
Normal Emptying Decrease in urethral resistance Volitional bladder contraction Functional urinary sphincters Pharmacology Acetylcholine is the primary neurotransmitter at the neuromuscular junction in the lower urinary tract Voluntary and involuntary contraction of the detrusor muscle are mediated by activation of muscarinic receptor by acetylcholine
The physiologic process of urinary continence is complex and dependent on a number of systems working in unison. Starting from the kidneys, urine travels to the bladder through the ureters. Urine is stored in the bladder and when voiding occurs, the detrusor muscle contracts and the urine drains into the urethra. In normal emptying the detrusor muscle contracts at the same time there is a decrease in urethral resistance. If however there is abnormal contractions or inadequate urethral resistance urinary incontinences can occur. Urinary sphincters which regulate the follow of urine are located at the bladder neck and within the urethra. The structures surrounding the lower urinary tract are rich in blood vessels, nerves, and connective tissue. As illustrated in the diagram, acetylcholine is the primary neurotransmitter in the lower urinary tract and is responsible for contraction of the detrusor muscle. Alpha receptors are found in the bladder and urethra and are important to maintain the proper pressure.
From: http://www.spinalnet.co.uk
Risk Factors for Incontinence in the Elderly

Immobility/chronic degenerative disease Impaired cognition / Delirium Environmental barriers Medications Morbid obesity High-impact physical activities Estrogen depletion Pelvic muscle weakness Diuretics Smoking Fecal impaction Low fluid intake Diabetes Stroke Childhood nocturnal enuresis
Delirium and dementia Infections Atrophic vaginitis, atrophic urethritis, atonic bladder Psychological causes, depression Pharmacologic agents Endocrine (diabetes, hypothyroidism) Restricted mobility Stool impaction
Resnick NM.Principles and prac2ce of urodynamics and neuro- urology: New York MacMillan: 1986 p 180
Risk factors for urinary incontinence are shown on your screen. These risk factors range from pre-existing medical conditions, to pharmacological agents, to lifestyle choices. A helpful way to remember risk factors for urinary incontinences is with the pneumonic DIAPPERS. Some of these risk factors result from the persons inability to reach a bathroom in time or recognize that they need to use the bathroom. This may include someone who is in a wheelchair, or has dementia or cant access a second floor bathroom fast enough due to trouble climbing stairs. All of these are examples of functional incontinence.
Risk Factors for Incontinence in the Elderly

When intra-abdominal pressure exceeds the closing pressure of the urinary sphincters incontinence can occur. This may occur when the patient is morbidly obese, has excessive volume in the bladder, has weakened pelvic floor muscles or in physical activities that dramatically increase pressure such as weight-lifting. While many of our elderly patients may not be weight-lifters, they frequently suffer from this type of incontinence known as stress incontinence. Other types of incontinence can result when the bladder fails to empty properly causing it to overflow the sphincters. Finally some people suffer from abnormal bladder contractions whereby impaired signals to the bladder tell it to contract at inappropriate times. These two types of incontinence are referred to as overflow and urge.
Diagnosing Incontinence in the Elderly
Thorough medical history Assessment of lifestyle and mobility issues Physical examination Laboratory screening tests
Urinalysis Cystoscopy 24 hour urine collecAons for specic substances and volume X-rays Pad test with exercise
Biopsies Ultrasound Urine culture & sensiAviAes Urinary stress test Post void residual test
Diagnosing Incontinence in the Elderly

Patient risk factors related to incontinence are found by taking a thorough medical history. As mentioned on the last slide, lifestyle and mobility issues must also be considered as well as cognitive abilities. Laboratory screening tests which may help to determine causation or rule out other problems include urinalysis & urine culture to rule out infections. A twenty-four-hour urine collection for quantifying substances and volumes could isolate the source of the problem. Additional tests may include biopsies for suspected carcinoma, ultrasound, and a K-U-B X-ray which stands for Kidneys/Ureters and Bladder. This X-ray will show potential stones and if contrast is used can also show blockages. Cystoscopy is used when a visualization of the bladder is needed. A thorough urinary stress test will also involve measuring bladder volumes, sphincter closing pressures, & muscle tone. Stress incontinence can be evaluated by placing a sanitary pad beneath the urethra to determine the loss of urine during exercise or any activity that increase intraabdominal pressure. Finally, the volume of urinary that remains in the bladder after complete voiding should be measured to determine urinary retention.
Types of Urinary Incontinence

1. Transient or Acute UI 2. Established or Chronic UI Overflow or outflow obstruction Non-overflow Stress (elevated intra-abdominal pressure) Urge (involuntary bladder muscle contractions) Functional (physical or cognitive impairment) Mixed
Identification of underlying medical conditions and analysis of presenting signs and symptoms will provide clues to the type of urinary incontinence involved. Transient or acute urinary incontinence presents suddenly and is usually associated with a current illness or adverse effects of medications. Established or chronic urinary incontinence may take the form of overflow or outflow obstruction related to urinary retention. Or it may involve non-overflow incontinence caused by increased intra-abdominal pressure, involuntary bladder muscle contractions, or physical or cognitive impairment. There are also combinations of these types of urinary incontinence, presenting with mixed signs and symptoms often making the exact diagnosis very difficult to establish.
Transient Urinary Incontinence

Symptoms resul'ng from iatrogenic urinary incon'nence Reten?on and hesitancy (obstruc?ve symptoms) Non-Pharmacological Causes: Surgical procedures and inadequate follow-up during convalescence Acute illness with loss of urinary function Delirium, clinical depression Atrophic urethritis or vaginitis Excess urine production Stool impaction Urinary tract infections Restricted mobility or living conditions An2cholinergics Alpha agonists Calcium channel blockers Opioid analgesics Psychotropics Func?onal Psychotropics Diure2cs Frequency, urgency, polyuria Diure2cs Lithium Muscle relaxants Stress ACE inhibitors Alpha blockers Pharmacological Causes: Anticholinergics Antihistamines Antidepressants Opiates Antipsychotics Antispasmodics Benzodiazepines Sleeping aids Alcohol Diuretics Alpha-adrenergics Calcium channel blockers Muscle relaxants
Transient urinary incontinence is commonly triggered by a change in health status or living conditions and the use of certain medications. While prescription drugs may be implicated, over-the-counter medications such as antihistamines and decongestants can be the source of many acute episodes. Once the underlying cause is determined and treated, transient urinary incontinence is usually reversible.
Treatment of Transient Urinary Incontinence

Goals: Identify and treat underlying cause(s). Attend to symptoms and patient needs while treatment is sought and given.
Strategies: Removal, reduction or substitution of offending medications. Attendance to surgical complications, stool impaction and mobility restrictions where relevant. Improvement in mental status or mood; including self help measures. Specific therapy such as antibiotics for infections and vaginitis.
The cause of transient UI can almost always be identified. These causes often result from a deviation in the patients usual state of health. Whether the UI is caused by a urinary tract infection or results from post-operative complications, once the cause is identified the UI can be addressed and resolved. If the cause is iatrogenic, remove, reduce or substitute the offending medications. Post-operative UI can arise from restricted mobility, pain, stool impaction, impaired cognition or delirium and secondary to urinary catheter removal. Attending to surgical complications can have immediate effects and potentially reduce the patients hospital stay.
Overflow Incontinence or Outflow Obstruction
From: http://education.adam.com/ Definition: urine loss occurring when bladder pressure due to urinary retention exceeds urethral sphincter pressure. Prevalence: Urethral overactivity: 6.4% Bladder underactivity: 8.5%
Causes: Either can be caused by inability to remove urine due to obstruction or improper neurologic control over bladder contractions.
Causes: Either can be caused by inability to remove urine due to obstruction or improper neurologic control over bladder contractions. Obstruction Prostatic hypertrophy Fecal impaction Urethral stricture Kidney stones. Neurogenic Bladder Diabetic neuropathy Multiple sclerosis Post-surgical conditions Spinal cord injuries Parkinsons disease Anticholinergic medications Clinical Presentation: Elderly patients complain of frequent small losses of urine at any time. Urinary Stress test results show evidence of weak bladder muscles, or improper bladder contractions with large post-void residual volume.

Overflow incontinence is defined by urinary retention and the involuntary loss of urine resulting from the pressure created by the distended bladder. As the bladder becomes distended the pressure generated by the increased urinary volume will overcome the closing pressure of the urinary sphincters. The result is frequent small losses of urine and the sensation of incomplete voiding. Patients will also complain of urinary frequency. Overflow incontinence can result when the signals to the bladder controlling micturition are impaired resulting in a loss of the sensation to void. Anticholinergic medications reduce acetylcholine transmission to the bladder and result in either acute urinary retention or overflow incontinence. Additionally, overflow incontinence also results when there is bladder outlet obstruction (BOO). This can be caused by BPH, stones, infection with resulting tissue inflammation or trauma. Urethral strictures indicate a narrowing of the urethra and can be caused by scar tissue resulting from frequent catheterizations. In the setting of fecal impaction, the colon is distended to the point that it presses against the urethra causing obstruction. If an obstruction was left untreated the patient is placed at risk of developing hydronephrosis and can suffer permanent kidney damage.
Treatment of Overflow Incontinence

Surgery: when appropriate for removal of obstruction. See Module 17, review concept 3 for more information on surgery for BPH. Non-Pharmacologic: instruct the patient to void on a regular schedule to avoid increased volume and bladder distention. For example, place patient on an every two hour toileting schedule. Bethanechol (Urecholine): for relief of post-surgical symptoms. Works by increasing levels of acetylcholine causing bladder contractions. Most appropriate for short-term use. Effect: increases tonicity and contractility of bladder Dosing: 10-50 mg qid ADRs: Related to increased levels of acetylcholine (SLUD: Salivation/Lacrimation/Urination/Defecation) Nausea Vomiting Bradycardia Hypotension Bronchoconstriction Increased gastric secretion

Terazosin (Hytrin), Doxazosin (Cardura): for relief of BPH. Works by blocking alpha1-adrenergic smooth muscle receptors in the prostate and urethra. Effect: relaxes smooth muscle tone, improving urine flow Dosing: Terazosin 1 mg hs initially, titrated slowly up to 2 mg, 5 mg, or 10 mg qd. Doxazosin 1 4 mg, titrated slowly, maximum daily dose 12mg.
ADRs: syncope, first-dose effect, orthostasis, dizziness, palpitations, drowsiness. Afluzosin (Uroxatral): Is reported to be selective for alpha-1 receptors in the bladder. Available in Europe since 1987 it was only approved in the US in late 2003. A European meta-analysis on the efficacy and tolerability of all alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction concluded that all agents were equally effective. However, there are concerns about afluzosins potential for drug interactions. Afluzosin is extensively metabolized through the CYP-3A4 and is contraindicated in patients taking potent 3A4 inhibitors such as itraconazole or ritonavir. Effect: relaxes smooth muscle tone, improving urine flow Dosing: 10 mg once daily immediately after eating. There is no need for dose titration and no need for dose reduction in the elderly or those with renal impairment. The drug is contraindicated in patients with moderate to severe liver impairment. ADRs: dizziness (5%), less retrograde ejaculations reported than tamsulosin. QT prolongation reported in doses > 40 mg daily.

Tamsulosin (Flomax): Is a selective for the alpha-1a receptors, located mainly in the prostate and responsible for contraction of smooth muscle. Overall effect similar to alpha1-adrenergic antagonists. Effect: believed to open or release the internal urethral sphincter ADRs: fewer cardiovascular side effects than non selective alpha blockers. Can cause retrograde or diminished ejaculations. Also can cause rhinitis. Dosing: 0.4mg qd, 30 minutes after same meal each day. Titration to 0.8 mg qd has not shown additional benefit. Finasteride (Proscar): Lowers hormone levels of dihydrotestosterone (DHT) by inhibiting the enzyme, 5-alpha-reductase. DHT plays a pivotal role in enlargement of the prostate gland. Finasteride inhibits type 2 alpha-reductase found in the reproductive tissues. Dosing: 5 mg qd Success Rate: 30-40% show a better urine flow rate and decreased symptoms after 6-12 months. More effective in men with larger prostates (>40grams). Adverse Drug Reactions: decreased libido, impotence, ejaculatory dysfunction Dutasteride (Avodart): Similar to finasteride, dutasteride is also a 5-alpha-reductase inhibitor. However, dustateride inhibits both type 1 alpha reductase found in the skin and liver and also type 2 found in the reproductive tissues. Dosing: 0.5mg qd Adverse Drug Reactions: Dutasteride can decrease the volume of ejaculate 4.7% compared to 1.7% with placebo, and of decrease libido 3%, compared to 1.4% with placebo. Gynecomastia occurred in 0.5-1% of patients taking dutasteride compared to 0.1-0.3% with placebo.

Like finasteride, dutasteride may inhibit development of the external genitalia of a male fetus; pregnant women should not handle the drug, which can be absorbed through the skin. Men taking the drug should not donate blood until at least 6 months after they have stopped to avoid potential transmission to a pregnant woman. When treating a patient with suspected overflow incontinence it is important to identify the likely cause of their incontinence. While sources of the obstruction may vary so to will your treatment options. Please review module 17, review concept 3 for a detailed discussion on the management of BPH. A concern with all alpha-blockers is the potential for additive hypotensive effects when combined with PDE5 inhibitors such as sildenafil, vardenafil and tadalafil. In the US package inserts, vardenafil is contraindicated for use with any alpha1-blocker, and tadalafil is contraindicated with any alpha1-blocker except a 0.4 mg dose of Tamsulosin. Sildenafil is not contraindicated for use with these drugs in general, but doses higher than 25 mg should not be taken within 4 hours of alpha1-blocker administration. If a 5 alpha-reductase inhibitor is selected then clinicians must obtain baseline PSA levels prior to initiating therapy as both agents decrease prostate specific antigen levels by 50%.
Stress Incontinence
Definition: involuntary loss of urine associated with an increase in intra-abdominal pressure. Incidence: 20% of females over age 75 years have daily incontinence. Possible in men following prostate surgery. Causes: Weakened pelvic muscles supporting the bladder. Malfunction of the urethral sphincter. Trauma and neurological damage to urethral area. Prostate surgery for men or pelvic surgery for women. Low estrogen levels. Pelvic prolapse.
Triggers: exercising, coughing, jumping, lifting, laughing, pulling, climbing stairs, or sneezing.
Stress Incontinence
Stress incontinence is defined as an involuntary loss of urine associated with an increased intra-abdominal pressure. The condition is common among older women with nearly 20% of females over 75 years of age experiencing daily incontinence. Whereas overflow incontinence results from increased urine volume leading to bladder distention and increased bladder pressure which eventually overcomes the closing pressure of the urinary sphincters, stress incontinence occurs when the urinary sphincters are weakened. This may result from low estrogen levels, pelvic prolapse and other disorders resulting in muscle weakness. Weakened muscles are overcome by intra-abdominal pressure triggered by any number of routine physical activities. This in turn produces a sensation of a full bladder, and results in increased urinary frequency. Men also have this type of incontinence following prostate transurethral resection and related surgeries. Testing for stress incontinence may be objectively demonstrated in women by asking the patient to cough vigorously while the examiner watches for the leakage of urine. If the patient losses only a small amount of urine a pad or a piece of toilet paper placed below the urethra may aid in making the diagnosis.
Non-Pharmacological Treatment of Stress Incontinence

Surgical inventions attempt to restore proper muscle tone, or provide bladder support. These include: Sling procedure Collagen injection Artificial urinary sphincter Needle bladder neck suspension Retropubic suspension Anterior vaginal repair Other non-pharmacological interventions are designed to teach the individual exercises they can do to improve muscle tone. Bladder and muscle retraining therapy Kegel exercises Vaginal weight training Biofeedback Electrical stimulation
Surgery and other non-pharmacological interventions are effective in treating stress incontinence when underlying causes are identified. Surgery can help to support the bladder or tighten urethral sphincter. Bladder and muscle retraining therapy may help to delay voiding and inhibit the urge to void. Medications can also improve symptoms but must be matched to the diagnostic cause to prevent adverse reactions. Examples include avoiding the use of alpha-adrenergic agonists, cases involving obstruction or to avoid prescribing estrogen if breast or uterine cancer is suspected.
Pharmacological Treatment of Stress Incontinence

Goal: to increase contraction and tone of urethral sphincter muscle. Alpha-adrenergic Agents (pseudoephedrine*): Effects: increase in striated and/or smooth muscle tone, increasing urethral resistance. Dosing: pseudoephedrine 15-30 mg tid. ADRs: anxiety, insomnia, agitation, respiratory difficulty, sweating, arrhythmia, hypertension. Contraindications: cases of obstruction, hypertensive disease. Estrogen: Effect: stimulation of squamous epithelium Oral preparations (not preferred as it may worsen UI) 0.3-1.25 mg/d, women with an intact uterus require the addition of medroxyprogesterone. Vaginal preparations Conjugated estrogen cream 0.5gm three times a week. Estrace Cream 2-4 gms QD for 1-2 weeks then dose for 1-2 weeks. E-String 2mg intravaginally change every 90 days. Vagifem tablets one tab intravaginally qhs x 2 weeks, then 2 times a week. Local treatment is given for 6-8 weeks then the patient should be reassessed Contraindications: cases of breast or uterine cancer, history of DVT or other thromboembolic complications.
Pharmacological Treatment of Stress Incontinence

* Pseudoephedrine is one of the products that some states want kept behind pharmacists' counters and subject to sales limitations for fear it may be made into methylamphetamine. At the time of this update legislation was pending to restrict sales of pseudoephedrine. Pfizer has recently reformulated Sudafed with phenylephrine.
The goal of pharmacotherapy in stress incontinence management is to increase contraction and tone of urethral sphincter muscles. Before any therapy is initiated it is important to rule-out overflow incontinence which can present very similarly to stress incontinence. Any agent that increases contraction and sphincter tone would worsen overflow incontinence and could put the patient in acute urinary retention. Alpha-adrenergic agonists such as pseudoephedrine may provide relief by increasing sympathetic tone in the urinary tract. However alpha-adrenergic agonists should be avoided in cases involving obstruction or hypertensive disease. In women, estrogen use should be limited to topical administration in patient with vaginal atrophy. Epidemiologic studies have shown that systemic estrogen has no positive effect on incontinence symptoms and in some cases may actually worsen urinary incontinence. The tricyclic antidepressant imipramine has both an agonist activity and ACH effects. Imipramine is therefore useful in selected cases where patients have both stress and urge symptoms.
Urge Incontinence
Definition: a large involuntary loss of urine linked to involuntary bladder muscle contractions and a strong desire to urinate; also known as detrusor or bladder muscle instability. Overactive Bladder is a term adopted by the Food and Drug Administration to describe the clinical syndrome that includes not only urge incontinence, but urgency, frequency, dysuria and nocturia as well. Incidence: most common form of incontinence in elderly Causes: Neurological disorders such as multiple sclerosis. Parkinsons disease Stroke Infection Inflammation Clinical Presentation: Signs and symptoms: urgent need to urinate, frequent urination, abdominal discomfort and the inability to control the loss of urine. Clinical Indicators: volume (large for urge incontinence, small for stress incontinence); circumstances surrounding urine loss (cough, sneeze, urinary tract infections, etc.). Urge incontinence is the most common form of incontinence seen in the geriatric population. The sudden and frequent loss of urine has a great impact on the lifestyle and care of the elderly patient. Known as detrusor or bladder muscle instability, patients experience inappropriate contractions often leading to complete emptying of the bladder. Symptoms also include an urgent need to urinate, frequent urination, abdominal discomfort and the inability to control the loss of urine. The patients presenting symptoms and the amount of urine lost are important when differentially diagnosing urge and stress incontinence.
Non-pharmacological Treatment of Urge Incontinence

Surgical Interventions: augmentation cystoplasty is the most common procedure. In augmentation cystoplasty, a segment of intestine, either small or large bowel, is used to form a "patch" on the bladder. This patch expands over time and often eliminates the need for anticholinergic agents. Most patients must perform intermittent self-catheterization in order to fully empty their augmented bladders. Diet Modifications: attempt to regulate fluid intake and eliminate substances irritating the bladder. Bladder Retraining: Toileting schedule Episode awareness Occasional use of biofeedback and electrical stimulation Ongoing Kegel exercises and weighted vaginal cone training have also shown improvements. While surgical and dietary modifications are helpful in some urge incontinence patients, the majority benefit from scheduled toileting. If the patient is successful with a toileting schedule they can gradually increase the intervals between urinations. This process of bladder training allows the bladder to gradually expand in capacity without triggering bladder spasms and an urge incontinence episode. In addition to a toileting schedule, exercises designed to strengthen the pelvic floor muscles should also be employed. One type of exercise is known as Kegel exercises. If you have ever tried to stop yourself from urinating in mid-stream you have used the muscles necessary for a Kegel maneuver. For people who have difficulty identifying which muscles to use, biofeedback can be used to teach them which muscle groups to activate. Patients who perform Kegel exercises and vaginal weight training have also shown a reduction in incontinence episodes.
From: http://www.sportstek.net/qlc4.html
Pharmacological Treatment of Urge Incontinence

Goal: to reduce bladder contractions and frequency of urination. It is important to note that all of these drugs are only modestly better than placebo and are associated with significant adverse effects. Anti-cholinergic/Antispasmodic Agents (e.g., propantheline, dicyclomine, oxybutynin, tolterodine + Solifenacin and Darifenacin): MOA: muscarinic receptor antagonists which reduce cholinergic transmission to the bladder. Effects: inhibition of involuntary detrusor contraction and increase in bladder capacity. Dosing: Darifenacin 7.5-15 mg PO once/d Oxybutynin 2.5-5 mg tid-qid Oxybutynin XL 5-30 mg qd Oxytrol 39 cm2 patch 2x/week (3.9 mg/day) Propantheline 7.5-30mg tid Dicyclomine 10-20 mg tid Solifenacin 5 mg qd Tolterodine1-2 mg bid Tolterodine LA 2-4mg bid Trospium 20 mg po bid

ADRs: dry mouth, visual disturbances, constipation, dry skin. Contraindications: cases of obstruction. Drug interactions
Tolterodine: Reduce dose in patients receiving cytochrome P450 3A4 inhibitors (macrolide antibiotics and antifungals). Darifenacin/Solifenacin: CYP3A4 inhibitors may raise serum concentrations. When taken with potent 3A4 inhibitors, the dosage of darifenacin should not exceed 7.5 mg and of solifenacin should not exceed 5 mg. Darifenacin can increase serum concentrations of CYP2D6 substrates with a narrow therapeutic index such as thioridazine ( Mellaril, and others) and imipramine ( Tofranil, and others). It has slightly increased serum concentrations of midazolam (Versed) and digoxin ( Lanoxin, and others). Because of their mechanism of action, cholinesterase inhibitors such as donepezil (Aricept) used to treat Alzheimers disease and anticholinergic drugs may interfere with each other. Trospium: Absorbed trospium is excreted, mostly unchanged, by active renal tubular secretion, with a terminal half-life of 18 hours. Therefore drugs that undergo active renal tubular secretion may compete for elimination. This could result in higher levels of such drugs as digoxin, morphine and metformin. Also of note, only 10% of oral administration of trospium is absorbed from the GI tract. Taking with food can reduce this by an additional 70 80%.

Tricyclic Antidepressants (e.g., imipramine, doxepin, desipramine, nortriptyline): MOA: Anticholinergic. Effects: reduction or inhibition of involuntary detrusor contraction. Dosing: 25-100 mg/d. ADRs: dry mouth, visual disturbances, constipation, dry skin. Contraindications: cases of obstruction. Therapy for urge incontinence has never before experienced such tremendous publicity. With the release of several new agents added to those already being touted it is easy for clinicians to feel overwhelmed by the number of choices available. Regardless of the agent chosen, treatment must be based on achievable decreases in bladder muscle contractions and frequency of urination as well as increases in bladder capacity. While pharmacotherapy is central to most treatment plans, many medications have only limited success and may present too many adverse effects for the elderly patient. In fact, most medications are only modestly better than placebo. For example, anti-cholinergic agents such as propantheline, dicyclomine and tricyclic antidepressants can block contractions but causing dry mouth, visual disturbances, and constipation in about half of all elderly patients using these medications. Tricyclic antidepressants such as imipramine and doxepin also appear to inhibit contractions by producing anesthetic, anti-cholinergic type blocking and smooth muscle relaxant effects. Tolterodine is an anticholinergic agent with more selective actions on the bladder and a decreased incidence of adverse effects. Another often prescribed anticholinergic agent, oxybutynin, also has antispasmodic activity. Both the controlled release preparations of tolterodine and oxybutynin are better tolerated than the immediate release formulations. Oxybutynin is also available transdermally which may cause less dry mouth than when it is taken orally. Studies comparing the oral product with the transdermal patch indicate it may also be less effective for incontinence, and itching at the application site can be a problem.

None of these drugs are as effective as advertisements to the public have suggested. In a recent review that analyzed 2000 patients in prospective randomized placebo controlled trials, oxybutynin and tolterodine represented the treatments of choice for urge incontinence. A meta-analysis also published as a Cochrane review suggested that immediate release oxybutynin is more effective than immediate release tolterodine however many elderly patient may not tolerate the anticholinergic side effects of the immediate release products and may need sustained release preparations. Fortunately in the Cochrane Database review, 60% of patients receiving anticholinergics and 45% of patients receiving placebo for the treatment of urge incontinence reported symptom improvement. However, to date there has been no published placebo controlled trial comparing the sustained release preparations of tolterodine and oxybutynin. Therefore the senior care pharmacist should carefully consider the risk and benefits of these agents in frail elderly patients especially those suffering from dementia. It should be stressed that pharmacologic intervention should be utilized in conjunction with non-pharmacologic measures. Recent additions to the market include trospium, darifenacin and solefenacin. While the efficacy to date is similar to other agents already available, there are some important concerns specific to these agents. Notably, darifenacin is an inhibitor of CYP 2D6 and both darifenacin and solifenacin substrate for CYP 3A4. Therefore dose reductions are needed with potent 3A4 inhibitors. Regarding trospium, this agent should be taken on an empty stomach to enhance bioavailability.
Mixed Incontinence
Definition: a combination of stress and urge incontinence. Causes: varies with individual. Signs & Symptoms: varies with individual.
Treatment: combination therapy for stress and urge incontinence. Initial therapy should focus on the predominate symptom.
Mixed incontinence presents with a combination of stress and urge incontinence. This type of incontinence is common in older women. Overlapping symptoms and multiple causes can be a challenge when designing a successful treatment plan. Usually, treatments for both types of incontinence are given as long as obstructive causes can be eliminated.
Functional Incontinence
Definition: incontinence resulting from impairments of a physical or cognitive nature. Causes: cognitive difficulties, disabilities, mobility restrictions. Signs & Symptoms: similar to urge incontinence. Treatment: providing for scheduled or prompted toileting and removing physical barriers/obstacles.
Functional incontinence is defined as incontinence resulting from impairments of a physical or cognitive nature. This type of incontinence may be seen in patients having cognitive difficulties, disabilities, or restrictions in their mobility. The symptoms are similar to those of urge incontinence. Elderly patients with functional incontinence have healthy urinary tracts but do not reach the toilet before voiding. Treatment may simply focus on providing for scheduled or prompted toileting.
Incontinence and Geriatric Lifestyles

In the elderly, loss of urinary control can mean: A loss of self esteem. Restriction from outside activities. A decline in health and happiness. A restriction in fluid intake with resulting dehydration. Proper treatment can dramatically improve geriatric patients capabilities and their outlook!
The degree of continence shown in the elderly can be expressed in terms of three major groups. The independent group does not need assistance and is continent most of the time. The dependent group can remain continent with the help and support of caregivers. The incompetent group cannot maintain continence even with help and must be changed frequently. For these latter groups, loss of urinary control can mean restriction from outside activities and a loss of self esteem. In the nursing home, it can also contribute to a decline in the residents health and happiness. More insidious is the chronic dehydration that results when people limit their fluid intake to try and prevent incontinence. Treatment plans can allow for more independence and self esteem, which in turn translates into more personal control and a more positive outlook. As a senior care pharmacist you are in a unique position to understand the pharmacotherapy of urinary incontinence and positively impact your patients by assiduously monitoring for iatrogenic incontinence. Furthermore you can anticipate the adverse effect profile common to these agents and minimize their impact on your patients.
Resources
Acknowledgment Susan W. Miller, PharmD, CGP, FASCP contributed to this section in a previous edition. Updated 5/05 by: Sean M. Jeffery, PharmD, CGP, FASCP Assistant Clinical Professor University of Connecticut School of Pharmacy & Course Editor, Geriatric Pharmacy Review For additional information, see: AHCPR (1996), Publication No. 96-0682, March 1996, Clinical Practice Guideline Update: Urinary Incontinence in Adults: Acute and Chronic Management. May be downloaded from http://www.ahcpr.gov Buzelin JM, Fonteyne E, Kontturi M, et al. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction. European Tamsulosin Group. Br J Urol 1997; 80: 597605. Cardozo L et al. Randomized, double-blind placebo controlled trial of the once daily antimuscarinic agent solifenacin succinate in patients with overactive bladder. J Urol 2004; 172:1919. Chapple CR et al. Randomized, double-blind placebo- and tolterodine-controlled trial of the once-daily antimuscarinic agent solifenacin in patients with symptomatic overactive bladder. BJU Int 2004; 93:303. Culligan PJ, Heit M. (2000) Urinary incontinence in women: evaluation and management. Am Fam Physician, 62:2433-44, 2447, 2452. Available full text online at [http://www.aafp.org/afp/20001201/contents.html]
Resources
Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999; 36:1 Drug interactions. Med Lett Drugs Ther 2003; 45:46. Haab F et al. Darifenacin, an M3 selective receptor antagonist, is an effective and well-tolerated once-daily treatment for overactive bladder. Eur Urol 2004; 45:420. Lipton RB et al. Assessment of cognitive function of the elderly population: effects of darifenacin. J Urol 2005; 173:493. Miller S. W.(1997). Managing Urinary Incontinence to Geriatric Patients. Journal of the American Society of Consultant Pharmacists, 13:Suppl.9, (clinical consult) Ohtake A et al. In vitro and in vivo tissue selectivity profile of solifenacin succinate (YM905) for urinary bladder over salivary gland in rats. Eur J Pharmacol 2004; 492:243. Resnick N.M.(1996). Geriatric incontinence. Urologic Clin North Am,23(1):55-74 Rovner ES, Wyman J, Lackner T, Guay D. Urinary Incontinence In: Diprio JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, eds. Pharmacotherapy A Pathophysiologic Approach. 5th ed. New York: McGraw-Hill; 2002:1543-1556. Thakar R, Stanton S. (2000) Management of urinary incontinence in women. BMJ; 321:1326-31. The Medical Letter: Alfuzosin (Uroxatral) Another Alpha1-Blocker For Benign Prostatic Hyperplasia. Vol. 46 (Issue 1173) January 5, 2004 Yim, P. S. & Peterson, A. S. (1996). Urinary incontinence. basic types and their management in older patients. Postgrad Med; 99(5): 137-40, 143-4, 149-50. http://www.simonfoundation.org/
Benign Prostatic Hyperplasia

Learning Objectives
By the end of this Review Concept you should be able to: Define benign prostatic hyperplasia (BPH) and its incidence among the male population. Discuss the pathophysiology and main causes of BPH. Describe signs, symptoms and lifestyle effects of BPH on males and their families. Interpret basic laboratory findings related to the diagnosis and treatment of BPH. List treatment types and summarize surgical interventions. Discuss pharmacotherapy in BPH and criteria for selecting specific medications. List the adverse effects of medications prescribed for BPH and interactions with drugs to treat other disorders. Describe the role of the pharmacist in managing BPH.
Epidemiology of Benign Prostatic Hyperplasia (BPH)

Rare prior to age 40 years, but clinical symptoms arise by age 50 years Peak incidence of clinical BPH 63 to 65 years By age 80 years 78% of patients will develop clinical BPH
Benign prostatic hyperplasia is a disorder characterized by nonmalignant growth within the prostate gland. It is truly a disorder of aging, and is commonly found in elderly men and rare in individuals under forty. Clinical symptoms of urethral obstruction and blockage of the bladder neck can begin as early as age fifty. When asked about the possibility of developing BPH many clinicians reply that all men will have benign prostatic hyperplasia if they live long enough!
Pathogenesis of Benign Prostatic Hyperplasia

BPH develops in a specific area of the inner periurethral zone known as the transition zone. As the prostate continues to enlarge, the urethra is compressed, causing urinary obstruction and retention. Tissue growth appears correlates with aging and hormone changes within the prostate. Sufficient production of androgen hormones by the testicles is needed in order for BPH to develop. Testosterone is converted by the enzyme 2, 5-alpha-reductase into dihydrotestosterone (DHT). Some tissues in the prostate use DHT in a process of abnormal growth, while other tissues are unaffected. The affected tissue, with the help of DHT, continues to grow until obstructive symptoms occur.
Pathogenesis of Benign Prostatic Hyperplasia
Anatomically, benign prostatic hyperplasia develops in a specific area of the inner periurethral zone known as the transition zone. This differentiates B-P-H from carcinoma of the prostate, which usually arises in the outer peripheral zone. As the transitional zone cells enlarge, the urethra is compressed and symptoms of urinary obstruction and retention result. The process by which the transitional zone cells are stimulated to grow appears dependent on testosterone. Circulating testosterone is converted by the enzyme 2, 5-alpha-reductase into dihydrotestosterone which is then results in prostate growth Future genetic and metabolic research may determine the exact mechanisms of prostate enlargement and explain why benign prostatic hyperplasia develops.
Signs and Symptoms of Benign Prostatic Hyperplasia

Lower Urinary Tract Symptoms (LUTS) Obstructive - result from the narrowing of the prostatic urethra and bladder neck: Hesitancy Straining to void Weak urine stream Dribbling after urination Urinary retention Sensation of incomplete emptying
Irritative related to reduced bladder efficiency when obstruction is exhibited: Nocturia Dysuria Frequent urination Urgency and urge incontinence Note: Watch out for both prescription and over-the-counter medications which can worsen LUTS!
Signs and Symptoms of Benign Prostatic Hyperplasia

The signs and symptoms of benign prostatic hyperplasia may develop slowly but become more severe as the enlargement progresses. Lower Urinary Tract Symptoms are the clinical manifestation of B-P-H. The term L-U-T-S has been suggested by some clinicians to replace B-P-H because it more accurately reflects the clinical symptoms of the disease. L-U-T-S symptoms are broken down into obstructive and irritative symptoms. Obstructive signs and symptoms such as those listed on your screen are caused by the narrowing of the prostatic urethra and bladder neck. Irritative symptoms listed on your screen result from the bladders decreased ability to effectively empty after each void. This reduced bladder efficiency is a result of obstruction and while many men may try to tolerate obstructive symptoms they find it hard to ignore irritative symptoms. Once irritative symptoms are present they often trigger the search for treatment. It is important to remember that while irritative symptoms are usually resulting from BPH that they can also be caused by related conditions such as urinary tract infections, bladder carcinoma or nerve damage. Even more important to consider is the impact of both prescription and non-prescription medication on the LUT. Therefore a complete diagnostic workup is necessary when assessing new LUTS.
Diagnosis of Benign Prostatic Hyperplasia

The diagnosis of BPH is based on patient symptomatology, physical exam findings and other tests used to rule-out comorbid conditions. Physical Exam includes palpating the prostate through a digital rectal exam (DRE).This exam helps determine prostate size and texture. Prostates above 40 gm are considered enlarged. Tests used to rule-out other disorders include: Ultrasounds for stones and masses Urinalysis and cultures for infections and renal problems Prostate specific antigen blood test for potential carcinoma Intravenous Pyelogram (IVP) for various obstructions Cystoureterograms and cystoscopy For most patients the diagnosis of BPH is made based on their presenting signs and symptoms and the findings of a digital rectal exam. On PE the normal prostate is smooth and uniform in size. In the setting of BPH the prostate is enlarged, can be nodular and may be asymmetric. In addition, the tissue might be described as boggy. While the DRE is commonly used to help diagnose BPH it is also a subjective exam dependent on the providers experience and ability to palpate the prostate.
Diagnosis of Benign Prostatic Hyperplasia

Therefore other studies may be employed to aid in the diagnosis. These include measuring the patients urinary flow rate, which if less than ten milliliters per second is consistent with B-P-H. Post void residual volumes can be obtained either by catheterization or by using a bladder scanner which uses ultrasound to detect residual volume. Ultrasound can also identify stones and masses. Any patient with acute changes in urinary tract function should receive a urinalysis and cultures to rule out infections. Many men are concerned that changes in urinary tract function mean they have prostate cancer. The prostate specific antigen blood test for potential carcinoma in conjunction with the PE will help to discern the cause of the symptoms. For problems resulting from renal diseases, an I-V-P may indicate the location of various obstructions. Additional tests such as a cystoureterograms and give a more accurate picture and in the case of cystoscopy allow visulazation of the bladder and urethra. Dont forget that while diagnostic testing is being performed, a thorough check for drug induced LUTS should be conducted.
Treatment Priorities for Benign Prostatic Hyperplasia

One approach to assessing the severity of BPH is to use the American Urological Association (AUA) Symptom Index. The AUA Symptom Index is a patient self-screening form to determine symptoms and severity. For Patients with Less Severe Symptoms (AUA < 7): Monitor for behavioral changes Check lifestyle annually For Patients with More Severe Symptoms (AUA >= 8): Initiate a treatment plan Consider surgical methods to alleviate symptoms Consider pharmacotherapy to reduce symptoms and decrease the size of the prostate itself A useful tool in assessing the severity of symptoms and determining the course of treatment is the American Urological Association Symptom Index. The AUA Symptom Index which produces a score which can be tracked when evaluating treatment plans. The patient should be encouraged to complete a self screening form to help determine the types and severity of symptoms.
Treatment Priorities for Benign Prostatic Hyperplasia
Patients with less severe symptoms may be simply monitored through watchful waiting. Of these men who receive no treatment for B-P-H, 31 to 55% show an improvement and with five percent or less developing complications this approach is a useful strategy to minimize unnecessary drug exposure and control cost. Once a treatment strategy is initiated the AUA Index can be periodically re administered to assess the patients response and reassess the need for changes in therapy. As the symptoms of BPH increase in frequency and intensity, treatments including surgery and pharmacotherapy may become necessary. Indications for initiating a treatment plan for B-P-H include increased frequency of symptoms in addition to urinary retention, recurring urinary tract infections, obstruction related renal disorders, hematuria with no other source, & urge incontinence.
Surgical Treatment of Benign Prostatic Hyperplasia

Primary Techniques: Transurethral resection of the prostate (TURP) 88% success rate; 14% incidence of impotence Transurethral incision of the prostate (TUIP) 80% success rate, 12% incidence of impotence Open prostatectomy 98% success rate, 16-32% incidence of impotence Other Techniques: Electrosurgical ablation techniques to destroy prostate tissue Balloon dilation to compress tissues and open urethral channels Intraurethral stents to provide a rigid channel for urine flow through the prostate and elsewhere Transurethral laser prostatectomy
Surgical Treatment of Benign Prostatic Hyperplasia

Most patients will try pharmacotherapy before submitting to surgical treatment of BPH. In cases where pharmacotherapy is either not an option or has failed, surgical treatment options such as transurethral resection of the prostate improve symptoms in eighty-eight percent of cases. This procedure, which consists of inserting a scope through the urethra, produced impotence in nearly fourteen percent of patients. Transurethral incision of the prostate, which enlarges the urethral lumen and bladder outlet, has been shown to help in eighty percent of cases. In the hands of a skilled surgeon, an open prostatectomy which involves the removal of hyperplastic tissues can result in a success rate of up to ninety-eight percent. However depending on the specific approach, sixteeen to thirty-two percent of patients reported impotence. Other techniques are being refined to reduce adverse effects and recovery time.
Treatment of BPH with Alpha-adrenergic Blocking Agents

Terazosin (Hytrin), Doxazosin (Cardura), Prazosin (Minipress): for relief of BPH. Works by blocking alpha1-adrenergic smooth muscle receptors in the prostate and urethra. Effect: relaxes smooth muscle tone, improving urine flow Dosing: Terazosin 1 mg hs initially, titrated slowly up to 2 mg, 5 mg, or 10 mg qd. Doxazosin 1 4 mg, titrated slowly, maximum daily dose 12mg. Prazosin: 1 mg hs, initially titrate slowly to 4 mg/day (2 mg bid). Avoid due to a high incidence of adverse effects ADRs: syncope, first-dose effect, orthostasis, dizziness, palpitations, drowsiness. Afluzosin (Uroxatral): Is reported to be selective for alpha-1 receptors in the bladder. Available in Europe since 1987 it was only approved in the US in late 2003. A European meta-analysis on the efficacy and tolerability of all alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction concluded that all agents were equally effective. However, there are concerns about afluzosins potential for drug interactions. Afluzosin is extensively metabolized through the CYP-3A4 and is contraindicated in patients taking potent 3A4 inhibitors such as itraconazole or ritonavir. Effect: relaxes smooth muscle tone, improving urine flow Dosing: 10 mg once daily immediately after eating. There is no need for dose titration and no need for dose reduction in the elderly or those with renal impairment. The drug is contraindicated in patients with moderate to severe liver impairment. ADRs: dizziness (5%), less retrograde ejaculations reported than tamsulosin. QT prolongation reported in doses > 40 mg daily.

Tamsulosin (Flomax): Is a selective for the alpha-1a receptors, located mainly in the prostate and responsible for contraction of smooth muscle. Overall effect similar to alpha1-adrenergic antagonists. Effect: believed to open or release the internal urethral sphincter ADRs: fewer cardiovascular side effects than non selective alpha blockers. Can cause retrograde or diminished ejaculations. Also can cause rhinitis. Dosing: 0.4mg qd, 30 minutes after same meal each day. Titration to 0.8 mg qd has not shown additional benefit. Pharmacotherapy represents the mainstay of therapy for patients with BPH. With continued monitoring, medications may offer enough relief to avoid surgery. For example, alpha-adrenergic blocking agents may be used to relax the muscles of the bladder neck and prostate, allowing for easier urination. Sixty to 80% of men receiving alpha-blockers for BPH show improvement in four to six weeks. Since alpha blockers are also used to treat HTN, common adverse effects include orthostasis & syncope. Additionally they can also cause headache, asthenia and nasal congestion. Recent data has raised concerns regarding the use of non selective alpha blockers. In the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT) the data-safety monitoring board prematurely discontinued the doxazosin arm of the study. The arm was stopped because of increased incidences of congestive heart failure and combined cardiovascular disease in those patients receiving doxazosin compared to diuretics and ACE inhibitors. This has caused some clinicians to question whether non-selective alpha blockers should be used to treat BPH. Until more definitive research is available clinicians should use alpha-blockers with caution in CHF patients. The most recent addition to this group of agents is afluzosin, a selective alpha1 antagonist. Afluzosin appears similar in response to tamsulosin as it is more specific for prostatic tissue and may be useful in patients who do not respond to or tolerate standard alpha blockers. Additionally, both afluzosin and tamsulosin do not lower blood pressure to the same extent that non-selective alpha blocker and are therefore useful in patients at risk of hypotension.

A concern with all alpha-blockers is the potential for additive hypotensive effects when combined with PDE5 inhibitors such as sildenafil, vardenafil and tadalafil. In the US package inserts, vardenafil is contraindicated for use with any alpha1-blocker, and tadalafil is contraindicated with any alpha1-blocker except a 0.4 mg dose of Tamsulosin. Sildenafil is not contraindicated for use with these drugs in general, but doses higher than 25 mg should not be taken within 4 hours of alpha1-blocker administration.
Treatment of BPH with 5 alpha-reductase inhibitors

Finasteride (Proscar): Lowers hormone levels of dihydrotestosterone (DHT) by inhibiting the enzyme, 5-alpha-reductase. DHT plays a pivotal role in enlargement of the prostate gland. Finasteride inhibits type 2 alpha-reductase found in the reproductive tissues. Dosing: 5 mg qd Success Rate: 30-40% show a better urine flow rate and decreased symptoms after 6-12 months. More effective in men with larger prostates (>40grams). Adverse Drug Reactions: decreased libido, impotence, ejaculatory dysfunction
Dutasteride (Avodart): Similar to finasteride, dutasteride is also a 5-alpha-reductase inhibitor. However, dustateride inhibits both type 1 alpha reductase found in the skin and liver and also type 2 found in the reproductive tissues. Dosing: 0.5mg qd Adverse Drug Reactions: Dutasteride can decrease the volume of ejaculate 4.7% compared to 1.7% with placebo, and of decrease libido 3%, compared to 1.4% with placebo. Gynecomastia occurred in 0.5-1% of patients taking dutasteride compared to 0.1-0.3% with placebo. Like finasteride, dutasteride may inhibit development of the external genitalia of a male fetus; pregnant women should not handle the drug, which can be absorbed through the skin. Men taking the drug should not donate blood until at least 6 months after they have stopped to avoid potential transmission to a pregnant woman. Another class of agents used in the treatment of benign prostatic hyperplasia are the 5 alpha-reductase inhibitors finasteride and dutasteride. Finasteride lowers levels of DHT by inhibiting the enzyme 2,5-alpha-reductase. Dutasteride blocks both isoenzymes of 5 alpha reductase causing an almost complete blockade of DHT which is a theoretical advantage over finasteride, however no head to head trials have been conducted and efficacy is similar between the two compounds.
Treatment of BPH with 5 alpha-reductase inhibitors

Unlike alpha-blockers, 5-alpha-reductase inhibitors are slow in onset and dont reach their maximum efficacy until approximately one year of therapy at which point 30 40% of patients show improved urine flow rates and decreased B-P-H symptoms. Studies show that finasteride treatment for four years can reduce the probability of surgery and acute urinary retention. Additionally, research indicates that patients with larger prostates tend to benefit more from 5-alpha-reductase inhibitors than patients with smaller prostates. One reason for this may be the reduction in prostatic tissue that occurs with therapy. Adverse effects for both include decreased libido, impotence, and ejaculatory dysfunction in up to five percent of those treated. One important laboratory interaction that you should note is the ability of 5-alpha-reductase inhibitors to Prostate Specific Antigen levels by 50%. It is important to therefore obtain a baseline PSA prior to initiating therapy. Initial results from the Medical Treatment of Prostatic Symptoms (MTOPS) trial sponsored by the National Institute of Health suggests that combination therapy with finasteride and an alpha blocker works best in patients at high risk for progression of BPH. High risk patients are men over 50 with low urinary flow rates, high PSA levels or prostates greater than 40 grams which are considered larger. Combination therapy reduced the risk of BPH progression by 67% while treatment with doxazosin or finasteride reduced the risk by 39% and 34% respectively. These end points are clinical significant and include recurring urinary tract infections, incontinence, and need for invasive surgical therapy. Results from the Prostate Cancer Prevention Trial revealed that finasteride reduced the overall risk of prostate cancer by 25% in older men > 55 yers of age, but increased the risk of more aggressive high-grade tumors. The numbers needed to treat reveal that if 1000 men were treated with 5 mg/day finasteride for 7 years, 15 fewer men would develop prostate cancer, but four more men in the treatment group would be diagnosed with high grade cancers than in men who did not receive the drug. A small study conducted over 2 years showed that dutasteride reduced the overall risk of prostate cancer. However, the study lacked sufficient power to assess the risk of high-grade tumors with dutasteride. These results are concerning for many practitioners. It is important to realize that presence of BPH does not increase the risk of prostate cancer, but high-grade prostatic intraepithelial neoplasia is considered a precursor of the malignancy. Careful consideration is needed before initiating a therapy that was once thought relatively benign.
Phytotherapy
Saw Palmetto Inhibits 5a reductase Decrease epidermal growth factor Decrease DHT Anti-inflammatory properties Berry extract dosed up to 320 mg/d (doses of 160 mg) Crushed berry 1 to 2 grams orally daily. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10796790&dopt=Abstract
Phytotherapy
Many men will initially seek treatment for BPH by trying various over-the-counter agents. Frequently these agents contain an extract from Serenoa repens also known as Saw Palmetto. Saw Palmetto is a medicinal herb grown in the southeastern United States. Saw palmetto has become the fifth leading medicinal herb consumed in the U.S. and is considered first-line therapy for BPH in several Western European countries. The exact mechanism of action of saw palmetto is unknown. The berries of this dwarf palm tree contain beta-sitosterols which might inhibit the activity of male hormones by acting as androgen receptor antagonists and thereby blocking the conversion of testosterone to DHT. Saw Palmetto also may decrease the percentage of epithelial cells in the transition zone. Regardless of the mechanism of action saw palmetto does result in improved symptomatology in many men. A review of 18 controlled trials involving nearly 3,000 men found a 28% greater improvement in overall urinary symptoms among men with BPH taking saw palmetto than those taking a placebo. In addition, the urge to urinate at night improved by 28% and peak urine flow increased by 24%, compared with the placebo. As with other dietary supplements, the FDA does not regulate saw palmetto or oversee the quality or content of its preparations. Saw palmetto cannot be labeled as a treatment for BPH. Results of a study with an extract of saw palmetto are currently under review by the FDA, and may lead to its approval as a prescription drug. But for now, it is available in most health food stores. (In some European countries, saw palmetto is sold as a prescription drug.) Saw palmetto appears to be safe and modestly effective in treating mild to moderate symptoms of BPH.
Conclusion
Patient education about BPH and its effects can help to lessen their loss of control and diminished capabilities. Watchful waiting can also include behavioral techniques such as limiting fluid intake after dinner and avoiding medications that worsen symptoms (e.g., decongestants). Pharmacists must closely monitor all medications and patient complaints in order to balance the benefits with potential adverse effects.
The majority of men with BPH will respond to medical management with either alpha-blockers, 5-alpha reductase inhibitors or a combination of both. As a senior care pharmacist you can help assure optimal medical management by screening for medications that can worsen urinary tract function such as anticholinergic medications. You can also explain to men receiving 5-alpha reductase inhibitors that these agents take time to work and not to stop therapy if they dont perceive any benefit initially. You should warn your patients taking alpha-blockers that they may experience orthostatic hypotension. And you can also guide men in deciding whether to use nutraceuticals like saw palmetto. Overall, about seventy percent of men with benign prostatic hyperplasia have minor symptoms and may best be treated by a combination of watchful waiting, behavioral techniques and supportive therapy. Senior care pharmacists are in a great position to reassess these patients on a regular basis and recommend medical therapy if symptoms become worse.
Resources
For additional information, see: AHCPR (1996),Publication No. 94-0582, February 1996. Clinical Practice Guideline : Benign Prostatic Hyperplasia: Diagnosis and Treatment. May be downloaded from: http://www.ahcpr.gov/) Appell, R.A.(1994). Pathogenesis and medical management of benign prostatic hyperplasia. Sem Nephrol,14(6):531-43 Brendler, C. B.(1994). Disorders of the Prostate. In: Principles of Geriatric Medicine and Gerontology, Hazzard, W.R. et al. eds. Third edition. 1994, chapter 57:657-64. Buzelin JM, Fonteyne E, Kontturi M, et al. Comparison of tamsulosin with alfuzosin in the treatment of patients with lower urinary tract symptoms suggestive of bladder outlet obstruction. European Tamsulosin Group. Br J Urol 1997; 80: 597605. de la Rosette JJ, Kortmann BB, Rossi C, et al. Long-term riskof re-treatment of patients using alpha-blockers for lower urinary tract symptoms. J Urol 2002;167:1734-9 Djavan B, Marberger M. A meta-analysis on the efficacy and tolerability of alpha1-adrenoceptor antagonists in patients with lower urinary tract symptoms suggestive of benign prostatic obstruction. Eur Urol 1999; 36:1 Dull P,(2002). Managing benign prostatic hyperplasia. Am Fam Phys 2002;66(1):77-84,97-8. Lee, M., Sharifi R.(1997). Benign prostatic hyperplasia: diagnosis and treatment guideline. Ann Pharmacother,31:481-86 Lepor, H., et al.(1991). The efficacy and safety of terazosin for the treatment of BPH. Prostate,18:345
Resources
Pascual, J., Woodhouse K.(1994). Pharmacological treatment of benign prostatic hyperplasia. Brit J Clin Prac,48(3):137-8 The Medical Letter: Alfuzosin (Uroxatral) Another Alpha1-Blocker For Benign Prostatic Hyperplasia. Vol. 46 (Issue 1173) January 5, 2004 Wasson, J.H.(1998). Finasteride to prevent morbidity from benign prostatic hyperplasia (editorial). N Engl J Med,338:612-13 Prostate information at http://www.prostatehealth.com NIDDK Health Information http://www.niddk.nih.gov/health/urolog/urolog.htm

Module 17 - Pharmacotherapy For Renal and Urological Disorders

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Geriatric

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Effects of Aging on Renal Function

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Effects of Aging on Renal Function

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Effects of Aging on Renal Function

Pharmacotherapeutic Implications of Age-Related Changes in Renal Function

Assessing Renal Function in Geriatric Patients

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Assessing Renal Function in Geriatric Patients

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Assessing Renal Function in Geriatric Patients

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Assessing Renal Function in Geriatric Patients (continued)

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Assessing Renal Function with the Cockcroft Gault Equation

results by 0.85 if female patient

Assessing Renal Function with the Cockcroft Gault Equation

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Acute Renal Failure (ARF)

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Acute Renal Failure (ARF)

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17.01.09 Treatment of ARF

Sodium bicarbonate (maintain serum bicarb > 15 mEq/L)Dialysis

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HYPERKALEMIA TREATMENT Calcium gluconate 10%

Sodium Bicarbonate (if acidosis) Albuterol

Redistribute K+ (intracellular potassium uptake)

Sodium Polystyrene Sulfonate (Kayexalate)

Potassium binding ion exchange resin: exchanges Na+ for K+

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17.01.09 Treatment of ARF

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Chronic Kidney Disease (CKD)

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Chronic Kidney Disease (CKD)

Chronic Kidney Disease (CKD)

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Treatment of Chronic Kidney Disease

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Treatment of Chronic Kidney Disease

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NKF-K/DOQI Clinical Practice Guidelines for Anemia of CKD

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NKF-K/DOQI Clinical Practice Guidelines for Anemia of CKD

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NKF-K/DOQI Clinical Practice Guidelines for Anemia of CKD

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