Renal & Liver Disease PDF

RENAL & LIVER DISEASE Estimating Kidney Function .:... ..... 1 !.....................294 . . . : . " :. : . . . . . . (ij CHAPTER 18 Modifying Drug Therapy ..............••..••..•..•.........................•. 296 RENAL DISEASE Complications of Chronic Kidney Di BACKGROUND Dialysis ..........

RENAL & LIVER DISEASE Estimating Kidney Function .:... ..... 1 !.....................294 . . . : . " :. : . . . . . . (ij CHAPTER 18 Modifying Drug Therapy ..............••..••..•..•.........................•. 296 RENAL DISEASE Complications of Chronic Kidney Di BACKGROUND Dialysis ................................................................................ 303 Factors Affecting Drug Remova Dur ng D alys1s . ..... . J03 1 DEFINITIONS Acute Kidney Injury (AKI) A sudden loss of kidney function due to a non-reiial condition (e.g., drugs). Often reversible (temporary), but can be permanent if the precipitating condition is not corrected. A common cause is dehydration (can present with BUN :SCr ratio > 20:1 plus decreased urine output, dry mucus membranes, tachycardia). Chronic Kidney Disease (CKD) A progressive loss of kidney function over months or years. The degree of kidney function is measured by the glornerular filtration rate (GFR) or creatinine clearance (CrCI), and by how much is in the urine. - End-Stage Renal Disease (ESRD) Total and permanent kidney failure. Fluid and waste accumulates. Dialysis (or transplant) is needed to perform the functions of the kidneys. 292 Approximately 30 million U.S. adults (more than one in seven) have chronic kidney disease (CKD) . The risk is highest in African-Americans, Hispanics, American Indians and Asians. The most common causes are diabetes and hypertension; controlling blood glucose and blood pressure can prevent renal damage and delay progression to end-stage renal disease (ESRD). Less common causes of CKD include polycystic kidney disease, some types of infections, renal artery stenosis (a blocked artery that prevents blood flow to the kidney) and drug-induced kidney disease (caused by nephrotoxic medications). Pharmacists can assess the degree of kidney impairment in CKD patients to ensure safe and effective medication dosing. They can recognize and recommend treatment for related disorders, such as anemia, hypertension, acid-base and electrolyte disturbances and disorders of bone and mineral metabolism (e.g., management of parathyroid hormone, phosphate, calcium and vitamin D levels). RENAL PHYSIOLOGY The nephron is the functional unit of the kidney. Its primary function is to control the concentration of sodium and water. The nephrons reabsorb what is needed back into the blood, and the remainder is excreted in the urine. This regulates blood volume, and in turn, blood pressure. The major parts of the nephron include Bowman's capsule, the glomerulus, the proximal tubule, the loop of Henle, the distal convoluted tubule and the collecting duct (see the figure on the following page). There are roughly one million nephrons in each kidney. RxPREP 2022 COUR SE BO O K GLOMERULUS The afferent arteriole delivers blood into the glomerulus, a large filtering unit that is located within Bowman's capsule. Substances with a molecular weight < 40,000 daltons, including most drugs, pass through the glomerular capillaries into the filtrate (inside the lumen, or tube, of the nephron) and are excreted in the urine. If the glomerulus is healthy, larger substances (e.g., proteins and protein-bound drugs) are not filtered and stay in the blood (exiting the nephron via the efferent al'teriole). If the glomerulus is damaged, some albumin passes into the urine. The amount of albumin in the urine is used, along with the glomerular filtration rate (GFR), to assess the severity of kidney disease (also called nephropathy). See the GFR and Albuminuria for Staging Kidney Disease section for further discussion. PROXIMAL TUBULE Proximal means "close to." The proximal tubule is closest to Bowman's capsule (the entry point of the nephron). Much of the sodium (Na), chloride (Cl), calcium (Ca) and water that are initially filtered out of the blood are reabsorbed back into the bloodstream here. Blood pH is regulated by the exchange of hydrogen and bicarbonate ions. Medications that work here include the SGLT2 inhibitors (see the Diabetes chapter for details) . LOOP OF HENLE As filtrate moves down the loop of Henle (the descending limb), water is reabsorbed into the blood, but Na and Cl ions are not, which increases the concentration of Na and Cl in the filtrate. As the filtrate moves up the loop of Henle (the ascending limb), Na and Cl ions are reabsorbed back into the blood, but water is not. If antidiuretic hormone (ADH) is present, water passes through the walls of the ascending limb and is reabsorbed into the blood; less water is then excreted in the urine (anti-diuresis). ADH is also called vasopressin. The ascending limb of the loop of Henle is the site of reabsorption for about 25% of the filtered Na. When loop diuretics inhibit the Na-K pump in the thick ascending limb of the loop of Henle, less Na is reabsorbed back into the blood. There is a significant increase in the concentration of Na in the filtrate, causing less water to be reabsorbed (more stays in the filtrate and is excreted in the urine along with Na). By blocking the pump, loop diuretics cause less Ca reabsorption back into the blood, leading to Ca depletion. Long-term use of loop diuretics can decrease bone density because of this. DISTAL CONVOLUTED TUBULE Distal means "farther away." The distal convoluted tubule is the farthest point away from entry into the nephron. It is involved in regulating K, Na, Ca and pH. Thiazide diuretics I RxPREP ©2021. ©20 22 Nephron Proximal Tubule (--65% of Na and -70'6 of Ca Is reabsorbed here) SGLT2 Inhibitors won( here Potil5ium-sparing diuretics (lndudlng aldosterone antagonists) work in the Distal Convoluted Tubule and Cotlectfng Duct Collecting Ascending limb of the Loop of Henle Duct7 (flnal adjustment of electrolytes occurs here) l-25%of baU. N..MdC, are reabsorbed here) Loop diuretics work here ! iJ;,I iStock.com/TefiM inhibit the Na-Cl pump in the distal convoluted tubule. Only about 5% of Na is reabsorbed at this point, making thiazides weaker diuretics than loops. Thiazides increase Ca reabsorption at the Ca pump in the distal convoluted tubule. Unlike loop diuretics, the long-term use of thiazide diuretics has a protective effect on bones. COLLECTING DUCT The collecting duct is a network of tubules and ducts that connect the nephrons in each kidney to a ureter. The urine filtrate passes from the ureters into the bladder and then out of the body via the urethra (see figure at right). The collecting duct is involved with water urethra and electrolyte balance, which is affected by levels of ADH and aldosterone. Potassium-sparing diuretics (including aldosterone antagonists) work in the distal convoluted tubule and collecting duct to increase Na and water reabsorption and decrease K reabsorption. When aldosterone antagonists (e.g., spfronolactone or eplerenone) block aldosterone, more Na and water are excreted in the urine and serum K increases. DRUG-INDUCED KIDNEY DISEASE Drug-induced kidney disease (DIKD) is linked to numerous medications; it can be acute and reversible if the medication is stopped, but it can be irreversible and progress to CKD. DIKD is especially common in the hospital setting and contributes to morbidity and mortality. Risk factors include reduced renal blood flow (e.g., preexisting kidney disease, chronic or acute heart failure, dehydration, hypotension), increased age, use of multiple nephrotoxic medications at the same time and frequent use or large doses of nephrotoxic medications. 293 18 • I RENAL DISEASE Aminoglycosides NSAIDs Amphotericin B Polymyxins Cisplatin Radiographic contrast dye• Cyclosporine Loop diuretics --- CrCI Cockcroft-Gault equation CrCI (ml/min) - 140 - (patient age) 72 x SCr x weight (kg) Tacrolimus Vancomycin 'Sometimes called contrast media or contrast agent; used during imaging tests (e.g., angiography, MRI, CT, positron emission tomography [PET]). ESTIMATING KIDNEY FUNCTION -- x 0.85 (If female) Use actual body weight if less than IBW, use IBW if normal weight (by BMI), use adjusted body weight if overweight (by BMI)' Medication contraindications and dosing adjustments are typically based on CrCI calculated using the Cockcroft-Gault equation GFR Two common laboratory markers used to estimate kidney function are blood urea nitrogen (BUN) and serum creatinine (SCr). BUN measures the amount of nitrogen in the blood that comes from urea, a waste product of protein metabolism . As kidney function declines, BUN increases. BUN is not used alone to estimate kidney function because other factors besides renal impairment can increase the BUN (primarily dehydration). Creatinine, a waste product of muscle metabolism, is mostly filtered by the glomerulus and is easily measured. As kidney function declines, creatinin e increases (similar to BUN). The normal range of SCr is -0.6 - 1.3 mg/dL. Any creatinine that is not filtered is secreted into the nephron tubules. The amount secreted increases as renal function declines and less creatinine is filtered (a compensatory mechanism). CREATININE CLEARANCE The Cockcroft-Gault equation for CrCl is most commonly used to estimate kidney function when dosing medications. The accuracy of creatinine-based estimation equations is decreased when a patient has very low muscle mass, which is often the case in frail elderly patients (low muscle mass = low SCr). This can lead to an overestimation of CrCl and inappropriate drug dosing for the patient's true kidney function. Obesity, liver disease, pregnancy, high muscle mass and other conditions associated with abnormal muscle turnover can affect the estimation of kidney function using measured SCr. The Cockcroft-Gault equation is not preferable in very young children, in ESRD or in unstable J.!enal function (e.g., SCr is fluctuating or changing over a short period of time). Drug dosing recommendations are generally based on CrCl (using the Cockcroft-Gault equation). A few specific drugs use GFR for dosing adjustment purposes, including the SGLT2 inhibitors and metformin. 294 Not commonly calculated by pharmacists, but may be reported with a basic metabolic panel (BMP) CKD-EPI and MDRD equations are used Used for staging kidney disease and for dosing select drugs (e.g., metformin, SGLT2 inhibitors) For the exam, if GFR is not provided, CrCI provides a dose estimate to determine contraindications and dosing adjustments 'See the Calculations IV chapter for more information on weights and CrCI. GFR AND ALBUMINURIA FOR STAGING KIDNEY DISEASE GFR [or estimated GFR (eGFR)] is calculated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations. Albumin is the primary protein that is measured in the urine to assess kidney disease; albuminuria is sometimes referred to as proteinuria. The Kidney Disease Improving Global Outcomes (KDIGO) and Kidney Disease Outcomes Quality Initiative (KDOQI) guidelines recommend using the GFR and degree of albuminuria (level of albumin present in the urine), along with the cause of CKD, to determine the degree/stage of renal impairment. The two tables on the following page show how the GFR and degree of albuminuria are used to assess the severity of kidney disease. In the first table, the GFR value is used to determine the severity of renal impairment. The degree of albuminuria is classified according to the second table, where the 1st and 2nd columns are measurements of albumin (in different units) and the 3rd column contains an interpretation of these measurements. The values in these tables, on the following page, do not need to be memorized, but it is important to recognize that a GFR < 60 mL/min/1.73 m 2 and/or albuminuria (ACR or AER ::C: 30) indicates that the patient has CKD and specific treatments are warranted to prevent progression of disease (see Hypertension section). Rx PREP 2022 CO U RS E BOOK I RxPR EP ©2021. ©2022 GFR Categories GFR (mL/mln/1.73 m2) 90 + kidney damage• -60-89 -+ kidney damage* 45-59 ----- TERMS GFR CATEGORY (KDIGO 2012) CKDSTAGE (KDOQI 2002) Normal or high G1 Stage 1 Mild decrease G2 Stage 2 Mild to moderate decrease G3a Stage 3 30-44 Moderate to severe decrease G3b 15-29 Severe decrease G4 Stage 4 < 15 or dialysis dependent Kidney failure GS Stage 5 •Markers of kidney damage include a history of kidney transplant, structural abnormalities on imaging, presence of albuminuria and other factors. Degree of Albuminuria ACR(mg/g) or AER (mg/24 hr) ACR (mg/mmol) TERMS <30 <3 Normal to mild increase (previously called normoalbuminuria) 30-300 3-30 Moderate increase (previously called microalbuminuria) >300 >30 Severe increase (previously called macroalbuminuria) ALBUMINURIA CATEGORY (KDIGO 2012) ~ -2 _ _ _ _ _ _ _ _ _ __ A3 ACR: albumin to creatinine ratio; AER: albumin excretion rate HYPERTENSION AND DIABETES IN CHRONIC KIDNEY DISEASE HYPERTENSION Hypertension causes and worsens CKD. The 2021 KDIGO Guideline on Blood Pressure in CKD recommends a target SBP < 120 mmHg (with strict, standardized office BP monitoring) for those with hypertension and CKD. This is lower than the target BP recommended in the ACC/AHA guidelines for the general population with hypertension, but unlikely to be tested. An ACE inhibitor or ARB is firs t-line for patients with CKD, hypertension and albuminuria (with or without diabetes). Renin-angiotensin-aldosterone system (RAAS) inhibition with an ACE inhibitor or ARB reduces CKD progression (see Study Tip Gal below). When starting treatment with an ACE inhibitor or ARB, the baseline SCr can increase by up to 30%. This is expected, and treatment should not be stopped. If SCr increases by > 30%, the treatment should be discontinued and the patient will generally be referred to a nephrologist. ACE inhibitors and ARBs should never be used together. They increase potassium, which can result in hyperkalemia. The serum creatinine and potassium should be monitored 1 - 2 weeks after initiating an ACE inhibitor or ARB. Patients should be counseled to avoid potassium supplements and salt substitutes (with KCl). It is important to maximize the dose of the ACE inhibitor or ARB for renal protection. Refer to the Hypertension chapter for additional detail. DIABETES Who? Recommended in all patients with albuminuria I Why? I To prevent kidney disease progression How? Inhibit renin-angiotensin-aldosterone system (RAAS), causing efferent arteriolar dilation What? Reduce pressure in the glomerulus, decrease albuminuria and provide cardiovascular protection l- - The 2020 KDIGO Guideline on Diabetes Management in CKD recommends first-line treatment with metformin and a sodium glucose co-transporter 2 (SGLT2) inhibitor for patients with CKD, type 2 diabetes and eGFR 30 mL/min/1.73 m 2• SGLT2 inhibitors (specifically canagliflozin, dapagliflozin and empagliflozin) have demonstrated a reduction in cardiovascular events and CKD progression. If the patient is unable to use these medications or cannot meet glycemic targets on them, a glucagon-like peptide 1 (GLP-1) receptor agonist is recommended. Refer to the Diabetes chapter for additional detail. 295 18 I REN A L DISEASE MODIFYING DRUG THERAPY Common scenarios related to medications and kidney disease include: • The drug is eliminated through the kidneys. The dose is reduced and/or the dosing interval is extended to avoid accumulation and side effects/toxicity. The drug can cause or worsen kidney disease (it is nephrotoxic). The drug becomes less effective as kidney function declines (e.g., thiazide diuretics, nitrofurantoin). The drug is contraindicated at a specific level of kidney impairment because drug accumulation is unsafe (e.g., increased bleeding risk with some anticoagulants), the drug can cause further kidney damage (e.g., NSAIDs) or the drug may cause more harmful effects than usual when kidney function is reduced (e.g., hyperkalemia with aldosterone receptor antagonists). Remember the basic principles of medication dosing in patients with impaired renal function. Dose adjustments may be necessary when CrCl is < 60 mL/min; when CrCI is :;;; 30 mL/min, additional adjustments may be needed or the drug may be contraindicated (see Key Drugs Guys below). CrCI (ml/min) CrCI 120 - 125 ml/min • Normal renal function for a young adult CrCI < 60 ml/min• • Moderately reduced kidney function (about ½ of normal) • Drugs may require dosage adjustment CrCI s 30 ml/min • Severely reduced kidney function (about¼ of normal) • Drugs may require additional dosage adjustment • Drugs may be contraindicated iffi ©RxPrep i sELECT DRUGS THAT REQUIRE J. DOSE OR 1' INTERVAL IN CKD ,.,,,~--.~.,,.."""" :- Others: Antl-lnfectlves 1..:.&.a.i,,;~.:.o Aminoglycosides (i dosing interval primarily) Beta-lactam antibiotics (except antistaphylococcal penicillins and ceftriaxone) Fluconazole Quinolones (except moxifloxacin) Vancomycin 1 Cardiovascular Drugs LMWHs (enoxaparin) Rivaroxaban* (for AFib) 7 Amphotericin B Anti-tuberculosis medications (ethambutol, pyrazinamide) Antivirals (acyclovir, valacyclovir, ganciclovir, valganciclovir, oseltamivir) Aztreonam NRTls, including tenofovir Polymyxins Sulfamethoxazole/Trimeth oprim Anti-lnfectives Cardlovascular Drugs Antiarrhythmics (digoxin, disopyramide, dofetilide, procainamide, sotalol*) Statins (most) Apixaban• (for AFib) Pain/Gout Drugs Dabigatran• (for AFib) Metoclopramide Allopurinol Colchiclne Gabapentin, pregabalin Morphine and codeine Tramadol ER Other Others Bisphosphonates* Cyclosporine Tacrolimus Topiramate Gastrointestinal Drugs H2RAs (famotidine, ranitidine) Lithium '-------------------------'Check package labeling for individual drug requirements. r- - - SELECT DRUGS THAT ARE CONTRAINDICATED IN CKD Others: CrCI < 30 ml/min CrCI < 60 ml/min Nitrofurantoin CrCI < 50 ml/min Tenofovir disoproxil fumarate containing products (e.g., Atripla, Comp/era, Delstrigo, Stribild**, Symfi, Symfi Lo) Voriconazole IV (due to the vehicle) CrCI < 30 ml/min Tenofovir alafenamide containing products (e.g., Biktarvy, Descovy, Genvoya, Odefsey, Symtuza) Avanafil Bisphosphonates• Duloxetine Fondaparinux Potassium-sparing diuretics Tadalafil* Tramadol ER Others•..• Dofetilide Edoxaban Glyburide Sotalol* (Betapace AF) NSAIDs Dabigatran* (DVT/PE) Rivaroxaban• (DVT/PE) GFR < 30 ml/min/1.73 m2 SGLT2 inhibitors Metformin*** Other.... 'Medication has indication-specific recommendations. 296 Meperidine • Medication has indication-specific recommendations. "For treated patients; do not start treatment if CrCI < 70 mL!min. "' For treated patients; do not start treatment if GFR,,; 45 mL!min/1.73 m'. ''" Not specified or another CrCI cut-off is used. RxPREP 2022 COURS E BO OK I RxPREP ©2021, ©2022 COMPLICATIONS OF CHRONIC KIDNEY DISEASE See the figure illustrating the common complications of .,,,,..,,,...,,. chronic kidney disease (exam studies should focus on the treatments). I 1 ' I ',, Ulsp from ' I I I I I I CKD mineral and bone disorder (CKD-MBD) is common \ \ I CKD MINERAL AND BONE DISORDER ',, @ ''\ I I I I I in patients with renal impairment and affects almost all @ ,.......::c.......:,caoL....., patients receiving dialysis. CKD-MBD is associated with fractures, cardiovascular disease and increased mortality. Patients with advanced kidney disease require monitoring of parathyroid hormone (PTH), phosphorus (phosphate, P04), Ca and vitamin D levels. Hyperphosphatemia Hyperphosphatemia contributes to chronically elevated PTH levels (secondary hyperparathyroidism) and must be •eaution: l1ypr:rcol"11NO con n!iull wtM'11c~lurn·based phosphate brridtrs o.t=aJwn with viromm Odut to t Ca absorption. treated to prevent bone disease and fractures. Treatment is initially focused on restricting dietary phosphate (e.g., avoid dairy products, cola, chocolate and nuts). As CKD progresses, phosphate binders are often required. Phosphate binders block the absorption of dietary P04 by binding to it in the intestine. They are taken just prior to (or at the start of) each meal. If a dose is missed (and the food is absorbed), the phosphate binder should be skipped, and the patient should resume normal dosing at the next meal or snack. There are three types of phosphate binders: 1) aluminum-based, 2) calcium-based and 3) aluminum-free, calcium-free drugs. The interactions of Ca, P04 and vitamin D in CKD are complex. 1) P04 levels increase (because the kidneys cannot eliminate excess P04 absorbed from the diet). 2) Vitamin D can not be activated by the kidney, causing dietary calcium absorption to decrease. Both high P04 (1a) and low Ca (2a) cause increased release of PTH. In a patient with healthy kidneys, PTH would cause the kidneys to increase Ca reabsorption, but in CKD this is not possible and Ca is pulled from the bones, leading to bone demineralization and increased fractures. Normally, when Ca levels return to normal, PTH release is shut down, but the chronically high P04 levels continue to stimulate PTH release and hypercalcemia can persist, causing calcification and cardiovascular disease. 3) In CKD, the kidneys produce less erythropoietin (EPO), resulting in decreased RBC production in the bone marrow which causes anemia. f(!l @RxPrep Phosphate Binders DRUG DOSE SAFETY/SIDE EFFECTS/MONITORING Aluminum-based: potent phosphate binders, but rarely used due to the risk of aluminum accumulation (which can cause nervous system and bone toxicity). Treatment duration is limited to 4 weeks. Aluminum hydroxide Suspension 300-600 mg PO TIO with meals SIDE EFFECTS Aluminum intoxication, •dialysls dementia," osteomalacia, constipation, nausea MONITORING Ca, P04, PTH, s/sx of aluminum toxicity Calcium-based: first-line. --- Calcium acetate (Phoslyra, PhosLo', others) 1,334 mg PO TIO with meals, titrate based on P04 levels SIDE EFFECTS Hypercalcemia, constipation, nausea _1_a_b_le_t._c_a_ps_u_le_,_so_l_uti_·o_n_ _ _ _ _ _ _ _ _ _ __ _ ...., MONITORING Ca, P04, PTH Calcium carbonate (Tums, 500 mg PO TIO with meals others) (can vary with formulation NOTES used), titrate based on P04 Tablet, chewable tablet Calcium acetate binds more dietary phosphorus on an elemental calcium basis levels compared to calcium carbonate Total daily dose of elemental Hypercalcemia is especially problematic with concomitant use of vitamin 0 calcium should be < 2,000 mg (due to increased calcium absorption) (from diet and supplements) 297 18 I REN A L DISEASE DRUG DOSE SAFETY/SIDE EFFECTS/MONITORING Aluminum-free, calcium-free; no aluminum accumulation, less hypercalcemia, but more expensive. Sucroferric oxyhydroxide (Velphoro) 500 mg PO TIO with meals, titrate based on P04 levels WARNINGS Iron absorption occurs with ferric citrate; dosage reduction of IV iron may be necessary; store out of reach of children to prevent accidental overdose Chewable tablet SIDE EFFECTS Ferric citrate (Auryxia) Tablet 2 tablets (420 mg) PO TIO with meals, titrate based on P04 levels Diarrhea, constipation, discolored (black) feces MONITORING Iron, ferritin, TSAT (only with ferric citrate), P04, PTH NOTES Absorption is minimal with sucroferric oxyhydroxide Lanthanum carbonate (Fosrenol) 500 mg PO TIO with meals, titrate based on P04 levels Chewable tablet, powder Must chew tablet thoroughly to reduce risk of severe GI adverse effects Use powder if unable to chew tablets CONTRAINDICATIONS GI obstruction, fecal impaction, ileus WARNINGS GI perforation SIDE EFFECTS Nausea/vomiting, diarrhea, constipa tion, abdominal pain MONITORING Ca, P04, PTH Sevelamer: a non-calcium, non-aluminum based phosphate binder that is not systemically absorbed. Sevelamer carbonate (Renvela) Tablet, powder 800-1,600 mg PO TIO with meals, titrate based on P04 levels Sevelamer hydrochlorlde (RenagelJ Tablet CONTRAINDICATIONS Bowel obstruction WARNINGS Can reduce dietary absorption of vitamins 0, E, Kand folic acid; consider vitamin supplementation Tablets can cause dysphagia and get stuck in the esophagus; consider using powder if swallowing difficulty is present SIDE EFFECTS Nausea/vomiting/diarrhea (all > 20%), dyspepsia, constipation, abdominal pain, flatulence MONITORING Ca, P04, HC03, Cl, PTH NOTES Can lower total cholesterol and LOL by 15-30%. Sevelamer carbonate can maintain bicarbonate concentrations 'Brand discontinued but name still used in practice. Phosphate Binder Drug Interactions Phosphate binders are designed to "bind" and because of this have many drug interactions. Separate administration from levothyroxine and antibiotics that chelate (e.g., quinolones, tetracyclines). Calcium-based phosphate bindel'S interact with many drugs, including guinolones, tetracyclines, oral bisphosphonates and thyroid products. Sucroferric oxyhydroxide and ferric citrate are iron-based phosphate binders. Doxycycline should be taken one hour before both products. Ciprofloxacin should be separated by two hours from ferric citrate. Levothyroxine should not be used with sucroferric oxyhydroxide. 298 Lanthanum carbonate can bind to aluminum-, calciumor magnesium-containing antacids; administration of these products should be separated from the lanthanum dose by two hours. Qui nolone antibiotics should be given one hour before or four hours after lanthanum. Separate levothyroxine by at least two hours. Sevelamer can decrease absorption of some medications. Qutnolone antibiotics should be given two hours before or six hours after the sevelamer dose. Mycophenolate, tacrolimus and levothyroxine serum concentrations can be decreased and doses of these medications should be given several hours before sevelamer. RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©2022 Vitamin D Deficiency & Secondary Hyperparathyroidism After controlling hyperphosphatemia, elevations in PTH are treated primarily with vitamin D. Vitamin D deficiency occurs when the kidney is unable to hydroxylate vitamin D to its final active form. 1125-dihydroxy vitamin D. Vitamin D deficiency worsens bone disease, impairs immunity and increases the risk of cardiovascular disease. Vitamin D occurs in two primary forms: vitamin D3 (or cbolecalciferol), which is synthesized in the skin after exposure to ultraviolet light (e.g., the sun), and vitamin D2 (or e.rgocalciferol), which is produced from plant sterols and is the primary dietary source of vitamin D. Supplementation with oral ergocalciferol or cholecalciferol may be necessary, especially in patients with early CKD (e.g., stage 3 and 4). The vitamin D analogs are used in patients with later stages of CKD, or ESRD, to increase calcium absorption from the gut, raise serum calcium concentrations and inhibit PTH secretion. Calcitriol (Rocaltrol) is the active form of. vitamin D3. Newer vitamin D analogs, such as paricalcitol and doxercalciferol, are alternatives that cause less hypercalcemia than calcitriol. Another method of inhibiting PTH release is by increasing the sensitivity of the calcium receptor on the parathyroid gland. Cinacalcet (Sensipar) is a "calcimimetic" which mimics the actions of calcium on the parathyroid gland and causes a further reduction in PTH. It is only used in dialysis patients. Drugs for the Treatment of Secondary Hyperparathyroidism DRUG SAFETY/SIDE EFFECTS/MONITORING DOSING Vitamin D analogs: i intestinal absorption of Ca, which provides negative feedback to the parathyroid gland. CONTRAINDICATIONS Calcitriol (Rocaltrol) CKD: 0.25-0.5 mcg PO daily Capsule, solution, Dialysis: 0.25-1 mcg PO daily or 0.5-4 mcg IV Hypercalcemia, vitamin D toxicity _i_n1_ ·e_ct_io_n_ __ ___3 _x_w _ ee_k_lY_ _ _ _ _ _ _ _ _ _ _ ____, WARNINGS Calcifediol (Raya/dee) Digitalis toxicity potentiated by hypercalcemia CKD Stage 3 or 4: 30 mcg PO QHS I ! SIDE EFFECTS ER capsule _ _ _ _ _ _ _ _ _ _ __ _ _ _ _ _ _ _ _ _ _ ____,. Hypercalcemia, hyperphosphatemia, NN/D (> 10%) CKD: 1-3.5 mcg PO daily Doxercalciferol (Hectorol) Capsule, injection ---------- Paricalcitol (Zemplar) Capsule, injection i Ca, PO4, PTH, 25-hydroxy vitamin D (calcifediol) ---1 CKD: 1-2 mcg PO daily or 2-4 mcg PO 3x weekly Dialysis: 2.8-7 mcg IV 3x weekly Calcimimetic: MONITORING Dialysis: 10-20 mcg PO 3 x weekly or 4 - 18 mcg IV 3x weekly I NOTES Take with food or shortly after a meal to J. GI upset (calcitriol) Calcifediol is a prod rug of calcitriol sensitivity of the calcium-sensing receptor on the parathyroid gland, which causes .J, PTH, .J, Ca, .J, P04. Clnacalcet (SensiparJ Dialysis: 30-180 mg PO daily with food Take tablet whole, do not crush or chew CONTRAINDICATIONS Hypocalcemia WARNING Caution in patients with a history of seizures SIDE EFFECTS Hypocalcemia, N/V/D, paresthesia, HA, fatigue, depression, anorexia, constipation, bone fracture, weakness, arthralgia, myalgia, limb pain, URTls MONITORING Ca, PO4, PTH Etelcalcetide (Parsabiv) Dialysis: 2.5-15 mg IV 3x weekly WARNINGS Hypocalcemia, worsening HF, GI bleeding, decreased bone turnover SIDE EFFECTS Muscle spasms, paresthesia, NN/D MONITORING Ca, PO4, PTH 299 18 I RENAL DISEASE ANEMIA OF CKD Anemia is defined as a hemoglobin level < 13 g/dL. It is common in CKD and is due to a combination of factors. The primary problem is a lack of erythropoietin (EPO), which is normally produced by the kidneys and travels to the bone marrow to stimulate the production of red blood cells (RBCs). RBCs (which contain hemoglobin) are released into the blood where they transport oxygen. As kidney function declines, EPO production decreases. This leads to reduced hemoglobin levels and symptoms of anemia (e.g., fatigue, pale skin). These processes are exacerbated by CKD, causing an inflammatory state, which contributes to decreased EPO production. Anemia of CKD is sometimes referred to as anemia of chronic disease. Erythropoiesis-stimulating agents (ESAs) can prevent the need for blood transfusions. ESAs include epoetin alfa (Procrit, Epogen, Retacrit) and the longer-lasting formulation darbepoetin alfa (Aranesp). ESAs have risks, including elevated blood p1'essure and thrombosis. They should only be used when the hemoglobin is < 10 g/dL. The dose should be held or discontinued if the hemoglobin exceeds 11 g/dL, as the risk for thromboembolic disease (DVT, PE, MI, stroke) is increased with higher hemoglobin levels. ESAs are only effective if adequate iron is available to make hemoglobin. It is important to assess an iron panel (iron, ferritin and TSAT) and provide supplementation to prevent iron deficiency. In ESRD, iron levels can be low due to reduced GI absorption and blood loss from dialysis treatments. Intravenous (IV) iron is given at the dialysis center. See the Anemia chapter for more information on identifying different types of anemia and use of ESAs and IV iron. HYPERKALEMIA A normal potassium level is 3.5 - 5 mEq/L. Hyperkalemia can be defined as a potassium level> 5.3 or> 5.5 mEq/L (ranges vary), though clinicians will be concerned with any level> 5 mEq/L. Potassium is the most abundant intracellular cation and is essential for life. Humans obtain potassium through the diet from many foods, including meats, beans and fruits. Normal daily intake through the GI tract is about 1 mEq/kg/ day. Excess intake is excreted, primarily via the kidneys and partially via the gut. Renal potassium excretion is increased by the hormone aldosterone, diuretics (loops > thiazides), 300 by a high urine flow (via osmotic diuresis) and by negatively charged ions in the distal tubule (e.g., bicarbonate). High dietary potassium intake does not typically cause hyperkalemia unless there is significant renal damage. With normal kidney function, the acute rise in potassium from a meal would be offset by the release of insulin, which causes potassium to shift into the cells. The most common cause of hyperkalemia is decreased renal excretion due to kidney failure. The risk can be increased with a high dietary potassium intake or use of drugs that interfere with potassium excretion. Patients with diabetes are at a higher risk for hyperkalemia, as insulin deficiency reduces the ability to shift potassium into the cells, and many patients with diabetes take ACE inhibitors or ARBs. Hospitalized patients are at higher risk of hyperkalemia than outpatients, primarily due to the concurrent use of drugs and IV solutions. Rarely, acute hyperkalemia can be due to tumor lysis, rhabdomyolysis or succinylcholine administration. A patient with an elevated potassium level may be asymptomatic. When symptoms are present, they can include muscle weakness, bradycardia and fatal arrhythmias. If the potassium is high or the heart rate/rhythm is abnormal, the patient is usually monitored with an ECG. The risk for severe, negative outcomes increases as the potassium level increases. I' SELECT DRUGS THAT RAISE POTASSIUM LEVELS Others: Glycopyrrolate ACE inhibitors Heparin (chronic use) Aldosterone receptor antagonists NSAIDs Aliskiren ARBs Canagliflozin Drospirenone-containing COCs Potassium-containing IV fluids (including parenteral nutrition) Potassium supplements Sulfamethoxazole/Trimethoprim Transplant drugs (cyclosporine, everolimus, tacrolimus) Pentamidine RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©2022 Treatment of Hyperkalemia All potassium sources must be discontinued. If hyperkalemia is severe, there is an urgent clinical need to stabilize the myocardial cells (to prevent arrhythmias, this is done first) and to rapidly shift potassium intracellulatly or induce elimination from the body. The Study Tip Gal below lists the medication options for management of hyperkalemia. Several medications move potassium from the extracellular to the intracellular compartment. One or more of these methods are used in severe hyperkalemia. These drugs work quickly, but they do not lower total body potassium. Interventions to enhance potassium elimination can be used. These methods take longer to reduce potassium and are only used alone in less severe situations; they are mostly used in combination with a drug that shifts potassium intracellularly. MECHANISM INTERVENTION ROUTE OF ADMINISTRATION ONSET NOTES StablOze the heart Calcium gluconate IV 1-2 minutes Does not decrease potassium. Stabilizes myocardial cells to prevent arrhythmias. Regular insulin IV 30 minutes Co-administered with glucose or dextrose to prevent hypoglycemia. Move It Dextrose IV Shift K intracellularly Stimulates insulin secretion, but does not shift K intra cellularly on its own. Sodium bicarbonate IV Used when metabolic acidosis is present. Albuterol Nebulized Monitor for tachycardia and chest pain. Furosemlde IV 5 minutes I Eliminates Kin the urine. Sodium polystyrene sultanate Oral or rectal 1 hour; do Binds K in the 61 tract. Prevent arrhythmias I -- Monitor volume status. Remove It Ellminate K from the body not use oral for acute emergencies L_ I Patlromer Oral -7 hours Oral may take hours to days to work. Rectal route has a faster onset and can be used in acute (emergency) treatment. Binds Kin the GI tract. Not for acute or emergency use due to delayed onset. I Sodium zirconium cyclosilicate IHemodlalysls Oral 1 hour Binds Kin the GI tract. I Not for acute or emergency use due to delayed onset. Immediate, o ce starte· n d Removes K from the blood. I It takes several hours to set up/complete d1alys1s. . . Other methods are generally used in conjunction. 301 18 I RENAL DISEASE Drugs for Treatment of Hyperkalemia DRUG DOSE SAFETY/SIDE EFFECTS/MONITORING Sodium polystyrene sulfonate (SPS, Kayexalate•, Kionex) Oral: 15 grams 1-4 times/day WARNINGS Rectal: 30-50 grams Q6H ---------- Electrolyte disturbances (hypernatremia, hypokalemia, hypomagnesemia, hypocalcemia), fecal impaction, GI necrosis (i risk when administered with sorbitol; do not use together) Can bind other or!lf medications (check for drug interactions and separate administration) Powder, oral suspension, rectal suspensi on SIDE EFFECTS N/V, constipation or diarrhea Non-absorbed cation exchange resin MONITORING K, Mg, Na, Ca NOTES Do not mix oral products with fruit juices containing K Patiromer (Veltassa) Powder for oral suspension Non-absorbed cation exchange polymer 8.4 grams PO once daily; max dose is 25.2 grams once daily WARNINGS Instructions: measure 1/3 cup of water and pour half into an empty cup; empty the Veltassa packet contents into the water and stir well; add the remaining water to the mixture and stir well (the mixture will be cloudy); drink the mixture right away (if powder remains in the cup, add additional water and drink; repeat as needed) Binds to many oral drugs; separate by at least 3 hours before or 3 hours after Can worsen GI motility, hypomagnesemia SIDE EFFECTS Constipation, nausea, diarrhea MONITORING K,Mg NOTES Delayed onset of action; not for emergency use Store powder in the refrigerator (must be used within 3 months if stored at room temperature) Sodium zirconium cyclosilicate (Lokelma) Powder for oral suspension Non-absorbed cation exchange polymer 10 g PO TID for up to 48 hours Instructions: empty packet contents into a cup with at least 3 tablespoons of water; stir well and drink immediately (if powder remains in t he cup, add additional water and drink; repeat as needed) WARNINGS Can worsen GI motility, edema, contains sodium (may need to adjust dietary sodium intake) Can bind other drugs; separate by at least 2 hours before or 2 hours after SIDE EFFECTS Peripheral edema NOTES Delayed onset of action; not for em rgency use Store at room temperature 'Brand discontinued but name still used in practice. METABOLIC ACIDOSIS The ability of the kidney to reabsorb bicarbonate decreases as CKD progresses. This can result in the development of metabolic acidosis. In the ambulatory care setting, treatment of metabolic acidosis is initiated when the serum bicarbonate concentration is < 22 mEq/L. Drugs to replace bicarbonate include: Sodium bicarbonate (Neut) o Sodium load can cause fluid retention. o Monitor sodium level and use caution in patients with hypertension or cardiovascular disease. Sodium citrate/citric acid solution (Cytra-2, Oracit, Shohl's solution) o Monitor sodium level. o Metabolized to bicarbonate by the liver; may not be effective in patients with liver failure. 302 RxPREP 2022 COURSE BOOK I RxPREP ©2021, ©2022 DIALYSIS If CKD progresses to failure (stage 5 disease), dialysis is required in all patients who do not receive a kidney transplant. The two primary types of dialysis are hemodialysis (HD) and peritoneal dialysis (PD). In HD, the patient's blood is pumped to the dialyzer (dialysis machine) and runs through a semipermeable dialysis filter, which, using a concentration gradient, removes waste products, electrolytes and excess fluid. HD is a 3 - 4 hour process, several times per week (usually three times). Patients who do HD at home can do it more frequently (e.g., 5- 6 times per week). In PD, a dialysis solution (usually containing glucose) is pumped into the peritoneal cavity (the abdominal cavity surrounding the internal organs). The peritoneal membrane acts as the semipermeable membrane (i.e., as the dialyzer). The solution is left in the abdomen to "dwell" for a period of time, then is drained. This cycle is repeated throughout the day, every day. PD is performed by the patient at home. [Qi khawfangenvi16/5hutterstock.com FACTORS AFFECTING DRUG REMOVAL DURING DIALYSIS When a patient receives dialysis, the pharmacist must consider the amount of medication cleared during dialysis in order to recommend the correct dose and interval. Medications that are removed during dialysis (including many antibiotics) must be given after dialysis or may require a supplemental dose following dialysis. Drug removal during dialysis depends primarily on the factors below. FACTOR EFFECT Drug Characteristic Molecular weight/size Smaller molecules are more readily removed by dialysis Volume of distribution Drugs with a large Vd are less likely to be removed by dialysis Protein-binding Highly protein-bound drugs are less likely to be removed by dialysis Dialysis Factors Membrane High-flux (large pore size) and high-efficiency (large surface area) HD filters remove more substances than conventional/low-flux filters Blood flow rate Higher dialysis blood flow rates increase drug removal over a given time interval Select Guidelines/References Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. KDIGO 2012 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease. Kidney Int., Suppl. 2013;3:1-150. Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Work Group. KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney Int. 2021;99(35):51-587. Kidney Disease: Improving Global Outcomes (KDIGO) Diabetes Work Group. KDIGO 2020 Clinical Practice Guideline for Diabetes Management in Chronic Kidney Disease. Kidney Int. 2020;98(45):51-5115. 303