1. Renal failure & drug management By Dr. Judith Marin Pharmacist for FHA Renal program 614.0388

2. Outline Influence of kidneys on drugs (vice-versa) Anemia Bone-mineral disorder Cardiovascular drugs Other renal exceptions!!!

3. Kidney Function Regulatory Extra-cellular fluid, acid base balance, osmotic pressure, electrolyte imbalance, blood pressure Excretory Excretion of waste, water Metabolic RAAS, Bone mineral disorders (vitamin D activation), anemia (erythropoietin)

4. CKD… who is at risk?? Elderly patient Elderly patient Transplant patient Diabetics Hypertensive/ Cardiovascular disease Hypertensive/ Cardiovascular disease

5. CKD… who is at risk?? Acute renal failure Acute renal failure ↑ in serum creatinine level X 3.0  in GFR by 75% Serum creatinine level >350 µmol/L with acute increase of >44 µmol/L U/O <0.3 mL/kg/h for 24 hours, or anuria for 12 hours Chronic renal failure Kidney damage or decrease eGFR for more than 3 months

6. CKD Stage

7. Pharmacotherapeutic goals Improve signs and symptoms Improve signs and symptoms Improve patient outcomes and slow progression of disease Improve patient outcomes and slow progression of disease Improve surrogate outcomes Improve surrogate outcomes Reduce risk of hospitalization Minimize adverse drug reactions Improve QOL Improve QOL

8. Pharmacotherapeutic management for CKD Dosage adjustment specific to CrCL Dosage adjustment specific to CrCL Avoid contraindicated medications/ nephrotoxic drugs Avoid contraindicated medications/ nephrotoxic drugs Normalizing bloodwork Normalizing bloodwork Education Education

9. Drug dosage in CKD Cockcroft-Gault equation Cockcroft-Gault equation Expressed renal creatinine clearance Expressed renal creatinine clearance More appropriate than eGFR to base drug dosage adjustment More appropriate than eGFR to base drug dosage adjustment

10. Drug dosage in CKD Depends on drug metabolism and excretion Depends on drug metabolism and excretion Active vs. inactive metabolites renally excreted Active vs. inactive metabolites renally excreted Concerns if ~ 50% or more of drug/active metabolites eliminated by kidney Concerns if ~ 50% or more of drug/active metabolites eliminated by kidney Other PK variations: drug absorption, volume of distribution, protein binding. Other PK variations: drug absorption, volume of distribution, protein binding. Depends on renal function/ AKD or CKD Depends on renal function/ AKD or CKD Drug dosage adjustment starting at eGFR < 60 ml/min Drug dosage adjustment starting at eGFR < 60 ml/min Depends efficacy/adverse drug reaction profile Depends efficacy/adverse drug reaction profile Monitoring available Monitoring available

11. Drug clearance and dialysis Type of dialysis HD and frequency, PD, CVVH HD and frequency, PD, CVVH Drugs properties Molecular weight, charge, water solubility, volume of distribution, dialyzer membrane binding, non renal excretion pathway Dialysis properties Type of dialyser (pore size, surface area), flow rate/blood flow, dialysate composition, volume of dialysate (PD), temperature, pH Patient properties Residual renal function, blood pressure, Kt/v or PRU

12. Case with Mr. Kidd Ney 75 y/o man with PMHx of DM type II, CHF and renal failure (on HD) Admitted to SMH last night for UTI E.coli sensitive to Ciprofloxacin Hospitalist orders Ciprofloxacin 500 mg PO bid x 5 days for UTI Starts Metformin, 500 mg PO tid to improve blood sugar control

13. Case with Mr. Kidd Ney Any intervention??? Ciprofloxacin Ciprofloxacin Dosage adjustment if CrCl < 30 ml/min 30-57% of drug eliminated by kidney Dialysed out by PD and HD At high serum concentration, risk of seizure, myalgia/arthralgia, renal failure, ↑ QTc interval Dosage should be adjusted by to 500 mg po QD x 5 days (dose to be given post-HD on HD days)

14. Case with Mr. Kidd Ney Any intervention??? Metformin Metformin Dosage adjustment if CrCl < 60 ml/min 90% of drug eliminated by kidney Dialysed out by HD At high serum concentration, risk of nausea/vomiting, lactic acidosis, hypotension, hypothermia, tachycardia, tachypnea Metformin contraindicated in ESRD patients

15. References Bennett’s book. Drug Prescribing in Renal Failure. http://www.kdp-baptist.louisville.edu/renalbook/ Drug Monography MicromedexeCPSMedscape Be careful to your references!

16. Examples Drugs should never be held before HD run Drugs should never be held before HD run Except if ordered by physician Except if ordered by physician Antibiotic should be administered after HD run Antibiotic should be administered after HD run Antibiotic minimally dialysed: azithromycin, chloramphenicol, clindamycin, doxycyclin/tetracycline, linezolid Antibiotic minimally dialysed: azithromycin, chloramphenicol, clindamycin, doxycyclin/tetracycline, linezolid Antibiotic Excretion during HD Β-Lactams 10-75% Fluoroquinolones ~ 50% Aminoglycosides40-50%

17. Kidney Quiz… Mr. K.N. is still complaining about UTI symptoms 3 days after starting ciprofloxacin. Another urine culture is done → still growing E.Coli Hospitalist is thinking about about changing antibiotic to tobramycin. The pharmacist on the ward is concerns since aminoglycosides (e.g. tobramycin, gentamycin) are nephrotoxic drugs. What do you think? Would you think differently if patient was a pre-dialysis with eGFR of 25 ml/min?

18. Nephrotoxic drugs Drugs caused about 20% of community and hospital acquired acute renal failure Risk factors: > 60 years old eGFR < 60 ml/min Diabetes Volume depletion CHFSepsis

19. Nephrotoxic drugs Preventive measures Use of alternative nonnephrotoxic drugs Identifying and correcting patient-related risk factors that are amenable to therapy Determining baseline renal function before starting potentially nephrotoxic therapy to allow dosage adjustment, monitoring kidney function and vital signs during therapy Avoiding use of nephrotoxic drug combinations

20. Nephrotoxic drugs Preventive measures Use of alternative nonnephrotoxic drugs Identifying and correcting patient-related risk factors that are amenable to therapy Determining baseline renal function before starting potentially nephrotoxic therapy to allow dosage adjustment, monitoring kidney function and vital signs during therapy Avoiding use of nephrotoxic drug combinations

21. Nephrotoxic drugs Antibiotics Aminoglycosides, amphotericine B penicillin, cephalosporin, quinolones acyclovir, sulfa D/C drug if sCr increases NSAIDs/COX-2 inhibitors Diclofenac, naproxen, celecoxib Contraction of efferent renal arteriole; D/C drug and switch to acetaminophen ACE inhibitors/ARBs Losartan, irbesartan, ramipril, captopril Vasodilation of afferent renal arteriole; D/C drug, hydration Lithium Interstitial nephritis at high dosage; decrease dose; hydration IV contrast dye CIN; hydration; holding NSAIDs and diuretic; N-acetylcystein

22. Kidney Quiz… Pt is complaining of being very tired. Nurse noticed that blood in urine. Hgb comes back to 100 g/L Hgb comes back to 100 g/L Patient has been stable (Hgb 115-120 g/L) while on Darbepoietin 20 mcg IV Qweek and Ferrlecit 125 mg IV Qmonth x 5 months Patient has been stable (Hgb 115-120 g/L) while on Darbepoietin 20 mcg IV Qweek and Ferrlecit 125 mg IV Qmonth x 5 months What should be done? What should be done?

23. Anemia of CKD Stage of CKD eGFR ( ml/min/1.73m 2 ) Anemia prevalence Stage 3 30-595.2% Stage 4 15-2944.1% Stage 5 < 15 or dialysis 100% Prevalence higher in african americans and diabetic patients Prevalence higher in african americans and diabetic patients

24. Anemia of CKD Causes EPO deficiency Blood loss Shorter RBC life span Decreased bone marrow responsiveness to EPO Vitamin deficiencies Iron deficiency (poor iron absorption) High uremia level Intoxication impairing RBC development (Aluminium) Hemolysis (copper, chloramines) Chronic inflammation

25. Anemia of CKD Target Hgb level → 110-120 g/L Higher hgb level associated with higher risk of mortality, higher BP, higher access thrombosis Minimal benefit on QOL Studies have limits Workup before starting ESA CBC, RC Iron measurements (serum iron, TIBC, Tsat, ferritin) Occult blood in stools Serum vitamin B12 and folate iPTH level

26. Talking about EPO Hormone which principal regulator of erythropoiesis Stimulates proliferation/maturation and inhibits apoptosis of erythroid progenitors Induce release of reticulocytes into bloodstream Primarily produced by cells of kidney peritubular capillary endothelium

27. Talking about EPO 1. Epoietin agents Epoetin alpha (Eprex) 1 ST recombinant human erythropoietin launched on the market Shorter half-life (administration 1-3 times/week) Darbepoetin alpha (Aranesp) Longer acting erythropoietin analogues Administration Q1-2 weeks

28. Talking about EPO ADRsHypertension 20-40% of patients with partial Hb correction Mainly due to increase systemic vascular resistance Mostly during the first 4 months of therapy Metabolic disturbances  sCr;  K + ;  P0 4  Dializer efficiency; and  appetite Myalgia and Flu-like illness Only report with IV EPO Slow drug infusion

29. Talking about EPO ADRs Thrombotic complications Vascular access thrombosis Exacerbation of diabetic retinopathy Seizure Hypertensive encephalopathy Injection site pain Hypertonic citrate in formulation Red eye syndrom Correction Hct > 30% Cosmetic syndrom

30. Iron deficiency Definition Ferritin < 100 ng/ml Iron transferrin saturation < 20% Higher ferritin level could be associated with greater ESA efficacy CausesESA GI bleeding Lab tests Phosphate binders Adjuvant to ESA Decreased 33-75% in EPO requirement

31. Iron deficiency PO iron supplement No trial looking at PO iron vs placebo in CKD Associated with dyspepsia and constipation Iron salts Dosage Elementary iron Ferrous fumarate 300 mg 66 mg Ferrous sulfate 300 mg 60 mg Ferrous gluconate 300 mg 35 mg Iron polysaccharide 150 mg

32. Iron deficiency IV iron supplement 5 trials looking at IV vs po iron Mixed results… but overall IV iron seems more effective Concern about renal tubular toxicity and damage to blood vessels Administration… bolus vs infusion? Formulation Usual dosage Iron dextrose 100 mg Iron sucrose 100 mg Sodium ferric gluconate complex 125 mg

33. Iron deficiency IV iron supplement Adverse drug reactions Hypotension/hypertension, tachycardia, edema, itching, phlebitis, rash, anaphylaxis/immune reaction, legs cramps, arthralgia, back pain, headache

34. Hgb variability Study by Brier and Aronoff. With 3 months Hb rolling average 66% patients would be in a target range of 110-120 g/L 75% patients would be in a target range of 110-122.4 g/L 90% patients would be in a target range of 110-13- g/L Do not react to the last Hb value to change ESA dosage Patient hydration status

35. Kidney Quiz… Pt is complaining that he is “never” receiving his calcium tablets with his meals and he insists of having his calcium tablets before taking the first bite of his meal. Should we address his concerns?

36. Bone and minerals

38. Bone lesion of excess PTH (high-turnover disease): Bone lesion of excess PTH (high-turnover disease): Increased PTH levels enhance osteoclast activity – increased bone resorption. As activity increases, marked fibrosis involving the marrow space develops. Bone lesion of defective mineralization: Defective mineralization can lead to osteomalacia. Osteomalacia is caused by delay in rate of bone mineralization and accumulation of excess unmineralized osteoid. Mechanism for osteolmalacia disorder in CKD patients: Aluminum overload (most important factor). Due to use of aluminum-based phosphate binders. Relative or absolute deficiency of vitamin D. Vitamin D is responsible for collagen synthesis and maturation, stimulating bone mineralization Osteoporosis

39. Hyperphosphatemia Phosphorous mainly eliminated by kidney and dialysis not effective at removing phosphorous in blood Phosphorous mainly eliminated by kidney and dialysis not effective at removing phosphorous in blood Decrease phosphorous GI absorption Decrease phosphorous GI absorption Hyperphosphatemia associated with itchiness, bone and joint pain Hyperphosphatemia associated with itchiness, bone and joint pain Oral phosphate binders Oral phosphate binders Should be initiated when phosphorus or PTH levels are not within the target range despite dietary phosphorus restriction Most binders are positive ions that are attracted to a negative charge of the ion (PO4-) When taken with food, these compounds bind phosphate in the gut. Absorption of phosphate into the bloodstream is avoided, and it is instead excreted in the feces.

40. HyperphosphatemiaTypeExamples Trade Names Calcium-based Binders Calcium Carbonate Calcium Acetate Metal-based Binders Aluminum Hydroxide Magnesium Hydroxide Various Brands Lanthanum Carbonate Fosrenal™ Noncalcium, Non- metal-based Binders Sevelamer HCl Renagel®

41. Vitamin D Active Vitamin D increases the amount of total serum calcium and phosphorus that is absorbed from the intestinal tract As kidney function declines in CKD, the kidneys become less able to activate vitamin D, resulting in decreased absorption of calcium and phosphorus from the intestinal tract

42. 7 - dehydrocholesterol Cholecalciferol (Vit D3) 25-OH cholecalciferol 1,25 (OH) 2 Cholecalciferol One-Alpha  (1-OH cholecaciferol) Hectorol  (1-OH ergocaciferol) Rocaltrol  or Calcijex (IV) (1,25 (OH) 2 cholecalciferol) One-Alpha  (1-OH cholecaciferol) Hectorol  (1-OH ergocaciferol) Rocaltrol  or Calcijex (IV) (1,25 (OH) 2 cholecalciferol) 1st hydroxylation 2nd hydroxylation Vitamin D

43. Calcimimetic Cinacalcet (Sensipar®): Calcimimetic agent : Binds on the calcium receptors (CaR), which are the primary regulators of PTH secretion in parathyroid gland   sensitivity of CaR to calcium  inhibition of PTH release Result:  Calcium  Phosphorus  CaXP product

44. Calcimimetic Cinacalcet (Sensipar®): Loading dose - 30 mg PO OD with food Maintenance doses - titrate Q2-4Wk to max of 180 mg Side Effects: Nausea and vomiting Hypocalcemia Seizure Cinacalcet (1.4%) vs. placebo (0.4%)  possibly due to a lowered seizure threshold that can occur with a reduction in serum calcium levels

45. Kidney Quiz… Mr K. N. results during BW week: Pt has been on same regimen for last 6 months Apo-Cal, 1 tab TID cc One-alpha, 0.25 mcg PO 3 times/week This BW Last BW Corrected Ca 2.32.24 Phosphorus1.51.0 iPTH6230

46. Kidney Quiz… Mr K. N. results during next BW week: This BW Last BW Corrected Ca 2.652.3 Phosphorus1.91.5 iPTH5562

47. Kidney Quiz… Mr K. N. results during next BW week: This BW Last BW Corrected Ca 2.652.65 Phosphorus1.91.9 iPTH10555

48. Kidney Quiz… Today, K + :3.2 for Mr K.N. since had diarrhea for the last few days (hopefully, not C.difficiles!). Your colleague suggests calling the hospitalist to order Potassium Chloride (Slow K®), 600 mg po BID. What do you think about this suggestion?

49. Electrolytes Potassium mainly eliminated by kidney and dialysis effective at removing potassium in blood Potassium mainly eliminated by kidney and dialysis effective at removing potassium in blood Hyperkaliemia associated with cardiac arrythmia, respiratory paralysis, tingling Hyperkaliemia associated with cardiac arrythmia, respiratory paralysis, tingling Hypokaliemia associated with muscle weakness, general weakness, ECG abnormality Hypokaliemia associated with muscle weakness, general weakness, ECG abnormality K + can be adjusted with dialysate K + K + can be adjusted with dialysate K + bath No need potassium supplement and rarely need kayaxelate No need potassium supplement and rarely need kayaxelate Make sure that nephrologist/dialysis unit are aware of patient K + Make sure that nephrologist/dialysis unit are aware of patient K + level.

50. Kidney Quiz… Mr. K.N. unfortunately felt in hospital and broke his hip. He had hip surgery and he is complaining about pain after his surgery. You have an order for morphine on the MAR, but one of your colleague is telling you that morphine is contraindicated in patients with renal failure. Is it true? What are the options for pain management?

51. Pain Management Multi-modal Non-PharmacologicalHeat/ColdMassageDistraction Self Management PsychologyPharmacological http://www.brandweeknrx.com/images/2007/05/11/0006.jpg

52. Analgesics for MSK pain Analgesics for MSK pain Acetaminophen Analgesic without anti-inflammatory propriety As effective as NSAIDs in relieving mild-moderate osteoarthritis pain if taken 4 times/day, with less ADRs Tylenol arthritis pain  8 hours duration Topical NSAIDs Localized osteoarthritis pain of superficial joints For mild to moderate pain (score < 4/10) Can also be used as co-analgesic / adjuvant

53. Analgesics for MSK pain Analgesics for MSK pain Oral NSAIDs Analgesic with anti-inflammatory propriety Analgesic with anti-inflammatory propriety Avoid in pre-dialysis patients since can  renal function Avoid in pre-dialysis patients since can  renal function Avoid for long-term treatment, since CKD patient at  risk of bleeding Avoid for long-term treatment, since CKD patient at  risk of bleeding For mild to moderate pain (score < 4/10) Can also be used as co-analgesic / adjuvant

54. Analgesics for neuropathic pain Anticonvulsants Gabapentin, pregabalin Act on GABA receptors to modulate nerve influx Act on GABA receptors to modulate nerve influx ADRs: somnolence, dizziness, and ataxia Capsaicin cream Stimulates the nerves, to then desensitizes them (depletion of substance P) Also use in osteoarthritic pain Causes erythema and feeling of warmth at application (lidocaine x 2 weeks) Wash hands after using it Can take up to 2-4 weeks before onset of action Maximum response after 4-6 weeks of regular use

55. Analgesics for neuropathic pain Antidepressants Good choice if concomitant depression or insomnia Tricyclic antidepressant (TCAs) Desipramine and nortriptyline preferred agent Less anticholinergic effects ADRs: Cardiac toxicities, orthostatic hypotension, constipation, dry mouth Venlafaxine Less efficacy/safety data available ADRs: HTN, nausea

56. Opioids Efficacy in MSK and neuropathic pain Usually use in conjunction with other analgesics   dose of opioid Opioids have similar efficacy if appropriate dosage conversion Routes (PO/IV/SC/IM) have similar efficacy if appropriate dosage conversion

57. Pain management in CKD Opioids of choice: hydromorphone, oxycodone, fentanyl Opioids of choice: hydromorphone, oxycodone, fentanyl Avoid mepiridine since risk of neurotoxicity (eg. Seizure, tremors, irritability, etc.) related to metabolites accumulation. Avoid mepiridine since risk of neurotoxicity (eg. Seizure, tremors, irritability, etc.) related to metabolites accumulation. Avoid morphine since risk of neurotoxicity (eg. seizure, myoclonia, hallucination, etc.) related to metabolites accumulation. Avoid morphine since risk of neurotoxicity (eg. seizure, myoclonia, hallucination, etc.) related to metabolites accumulation.

58. Opioids Administer on a regular schedule with interval corresponding to duration of action SR formulation use when daily dosage established Appropriate breakthrough dose equal to 10% of daily dosage Q2Hrs PRN ADRs : Sedation, nausea, constipation, hallucinations, hyperalgesia, respiratory depression, cognitive impairment, gait disturbances

59. Methadone Opioid analgesic with an antagonist effect on NMDA receptors (responsible of constant and exaggeration of pain) Option if pain refractory to usual opioids Long half-life High inter-patient variability, multiple drug interaction Physician needs special privilege to prescribe it Physician needs special privilege to prescribe it ADRs: Bradycardia, hypotension, general weakness, sedation, nausea, constipation, respiratory depression, dysphoria, insomnia, anxiety

60. Management of ADRs Nausea/vomiting Usually tolerance after 5-7 days GI stasis and impact on chemoreceptive zone Domperidone/metoclopramideOr/and Prochlorperazine/ Haloperidol

61. Management of ADRs Constipation Proportional to opioid dosage Unlikely to improve overtime Stool softener (docusate) and GI stimulant (sennosides) for all patients on opioids Lactulose, PEGLyte, glycerin supp., bisacodyl supp. are other options To be avoided: fleet phosphate, milk of magnesia, mineral oil

62. Management of ADRs Respiratory Depression Naloxone 0.1-0.4 mg sc or IV initially Effective dose can be repeated every 1-2 hours if SR opioid formulation

63. Management of ADRs Sedation Caused by opioid anticholinergic activity Dose reduction, slow dosage titration Pruritis Caused by opioid histaminic activity Sx also associated with renal failure Antihistaminic Rx (diphenhydramine, hydroxyzine), opioid rotation

64. Management of ADRs Tremors, myoclonus Metabolites accumulation can cause CNS disturbances Metabolites mostly eliminated by kidney, and may be not easily dialyzed Opioid rotation, dosage reduction

65. Management of ADRs Tremors, myoclonus Metabolites accumulation can cause CNS disturbances Metabolites mostly eliminated by kidney, and may be not easily dialyzed Opioid rotation, dosage reduction

66. Kidney Quiz… Mr. K.N. blood pressure is increased post surgery. The mean BP for the past couple of days is 175/90, HR 90. Patient currently taking metoprolol 50 mg po BID and furosemide 40 mg PO QD. Should you flag it to the nephrologist? What other information do you need before making a decision?

67. Goals of BP Therapy Reduce associated morbidity and mortality Target-organ damage BP < 140/90 mmHg Diabetes or chronic kidney disease BP < 130/80 mmHg Proteinuric renal disease (Urinary protein excretion > 1g/24h) BP < 130/80 mm Hg

68. Non-Drug Therapy Weight reduction DASH diet Reduce dietary sodium intake Physical activity Moderate alcohol consumption Smoking cessation

69. Classes of AntiHypertensives Diuretics Angiotensin Converting Enzyme (ACE) Inhibitors Angiotensin Receptor Blockers (ARB) β-Blockers Calcium Channel Blockers (CCB) Non-dihydropyridine (NDHP) Dihydropyridine (DHP)  1 -Blockers Central  2 -Agonists Vasodilators

70. Indications First LineSecond Line Uncomplicated HTN Thiazide diuretic ACEI; ARB; long acting DHP- CCB; β-Blocker HTN Complicated by Co-Morbid Conditions Coronary Artery Disease (CAD)ACEI β-Blocker (stable angina) Long acting CCB Myocardial Infarction (MI) ACEI + β-Blocker - ARB if ACEI intolerant - CCB if β-Blocker is CI or ineffective; avoid NDHP-CCB if heart failure is present Left Ventricular Hypertrophy (LVH) Thiazide diuretic; ACEI; long-acting CCB - ARB if ACEI intolerant - Avoid direct arterial vasodilators (hydralazine, minoxidil) Cerebrovascular Disease ACEI + thiazide diuretic Long acting DHP-CCB

71. Indications First LineSecond Line HTN Complicated by Co-Morbid Conditions Heart Failure - ACEI + β-Blocker (systolic dysfunction) - Aldosterone antagonists if NYHA class III or IV - ARB if ACEI intolerant - Hydralazine/isosorbide dinitrate if ACEI & ARB intolerant - Diuretics (thiazide), ARB, long acting DHP CCB as additive tx if BP not controlled Non-Diabetic CKD with ProteinuriaACEI - ARB if ACEI intolerant - Thiazide diuretic as additive therapy or loop diuretics if volume overloaded Renovascular Disease Thiazide diuretic; ACEI; long-acting CCB - ARB if ACEI intolerant - Combination therapy if BP not controlled DM with AlbuminuriaACEI - ARB if ACEI intolerant - Combination therapy if BP not controlled DM without Albuminuria ACEI; thiazide diuretic; DHP-CCB - ARB if ACEI intolerant - Combination therapy if BP not controlled

72. Diuretics… Pharmacology

73. Thiazide Diuretics…Pharmacology Inhibition of Na + /Cl - co-transporter in proximal part of distal convoluted tubule Inhibition of Na + /Cl - co-transporter in proximal part of distal convoluted tubule  tubular reabsorption of Na + & Cl -  urinary excretion of Na +, Cl - & H 2 O  extracellular volume  BP  Ca 2+ reabsorption in distal convoluted tubule  Ca 2+ reabsorption in distal convoluted tubule

74. Thiazide Diuretics…PK Onset (h) t 1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose) Chlorthalidone2-340-8024-72R 12.5 mg QD (100) Hydrochloro -thiazide (HCTZ)* 22.5- 14 6-12R12.5 mg QD (50) Indapamide1-24-2236H 1.25 mg QD (5) Metolazone14-2012-24R 2.5 mg QD (5) * Dyazide (HCTZ/Triamterene 50/25 mg)  full benefit * Moduret (HCTZ/Amiloride 50/5 mg)  full benefit (generics) H = Hepatic; R = Renal

75. Thiazide Diuretics…Management Start at low dose Start at low dose Baseline SCr/BUN; Na + ; K + ; Mg 2 + ; Ca 2 + ; Cl - ; BG; lipids; uric acid ↑ dose every 4 weeks ↑ dose every 4 weeks Monitor SCr/BUN; serum electrolytes at 1-2 weeks; then every 3-6 months Monitor SCr/BUN; serum electrolytes at 1-2 weeks; then every 3-6 months

76. Thiazide Diuretics…CI Allergy to sulfonylurea, sulfonamides Allergy to sulfonylurea, sulfonamides Chronic renal failure Chronic renal failure Minimal efficacy if CrCl < 30 ml/min Hx of gout (may precipitate an attack) Hx of gout (may precipitate an attack) HypoNa + HypoNa + HypoK + HypoK + DM DM May worsen glucose control

77. Thiazide Diuretics…ADRs Drowsiness Drowsiness Orthostatic hypotension Orthostatic hypotension Photosensitivity Photosensitivity Urinary incontinence Urinary incontinence HypoK + ; HypoNa + ; HypoMg 2+ ; HyperCa 2+ HypoK + ; HypoNa + ; HypoMg 2+ ; HyperCa 2+ Hyperuricemia Hyperuricemia Hyperglycemia Hyperglycemia ↑ cholesterol & ↑ LDL ↑ cholesterol & ↑ LDL

78. Loop Diuretics…Pharmacology & PK Inhibition of Na+/K + /Cl - co-transporter in ascending limb of the loop of Henle Inhibition of Na+/K + /Cl - co-transporter in ascending limb of the loop of Henle  reabsorption of Na + & Cl -  urinary excretion of Na +, K +, Cl -, Mg 2+ Ca 2+ & H 2 O Onset (h) t 1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose) Furosemide0.5-146-8R20 mg QD (200)

79. Loop Diuretics…Management Start at low dose Start at low dose Baseline SCr/BUN; Na + ; K + ; Mg 2 + ; Ca 2 + ; Cl - ; BG; lipids; uric acid ↑ dose every 1-2 weeks ↑ dose every 1-2 weeks Monitor SCr/BUN; serum electrolytes at 1-2 weeks; 1-2 months, then every 3-6 months Monitor SCr/BUN; serum electrolytes at 1-2 weeks; 1-2 months, then every 3-6 months

80. Loop Diuretics…CI Allergy to sulfonylurea, sulfonamides Allergy to sulfonylurea, sulfonamides Anuria Anuria Increasing azotemia & oliguria on tx Increasing azotemia & oliguria on tx Hepatic coma Hepatic coma Hypovolemia Hypovolemia HypoNa + HypoNa + HypoK + HypoK + Hx of gout Hx of gout DM DM

81. Loop Diuretics…ADRs Tinnitus Tinnitus Orthostatic hypotension Orthostatic hypotension Hypovolemia Hypovolemia HypoK + ; HypoNa + ; HypoMg 2+ ; HypoCa 2+ HypoK + ; HypoNa + ; HypoMg 2+ ; HypoCa 2+ Hyperuricemia Hyperuricemia Hyperglycemia Hyperglycemia Metabolic alkalosis Metabolic alkalosis ↑ cholesterol & ↑ TG ↑ cholesterol & ↑ TG

82. ACE Inhibitors…Pharmacology Angiotensinogen Angiotensin I Angiotensin II Aldosterone Vascular smooth muscles (AT 1 receptor) Na + and H 2 O retention ↑ SVR Renin ACE ACE inhibitors

83. ACE Inhibitors…PK Onset (h) t 1/2 (h) Duration (h) Elimination Equivalent dose (max. daily dose) Benazepril1-21024R/Biliary 10 mg QD (40) 10 mg QD (40) Captopril0.2- 0.3 < 26-12R 12.5 mg TID (450) Cilazapril1924R 2.5 mg QD (10) Enalapril1224R 5 mg QD (40) Fosinopril11224R/H 10 mg QD (40) Lisinopril11224R 10 mg QD (80) Perindopril3-73-1024R 2 mg QD (16) Quinapril1224R/H 10 mg QD (40) Ramipril1-213- 17 24R/H 2.5 mg QD (20) Trandolapri l 1-2624-72R/H 1 mg QD (8)

84. ACE Inhibitors…Management Start at low dose Start at low dose Baseline SCr/BUN; K + Baseline SCr/BUN; K + ↑ dose at ≥ 2 week intervals ↑ dose at ≥ 2 week intervals Monitor SCr/BUN; K + at 1-2 weeks, 1-3 months, then q6-12 months Monitor SCr/BUN; K + at 1-2 weeks, 1-3 months, then q6-12 months

85. ACE Inhibitors…CI Angioedema or anaphylactic reaction Angioedema or anaphylactic reaction Renal insufficiency (pre-dialysis) Renal insufficiency (pre-dialysis) >30% increase in SCr HyperK + HyperK + Bilateral renal artery stenosis or unilateral disease with solitary kidney Bilateral renal artery stenosis or unilateral disease with solitary kidney Pregnant women (2 nd and 3 rd trimester) Pregnant women (2 nd and 3 rd trimester)  risk of major congenital malformations Volume depletion Volume depletion Elderly, concomitant diuretic therapy, HF

86. ACE Inhibitors…ADRs Tinnitus Tinnitus Dysgeusia Dysgeusia Cough (3-50%) Cough (3-50%) Not dose related Rarely improves from switching to a different ACEI ↑ HR (if volume depleted) ↑ HR (if volume depleted) Acute renal failure; proteinuria; oliguria Acute renal failure; proteinuria; oliguria Angioedema; rash Angioedema; rash Neutropenia; anemia Neutropenia; anemia HyperK + HyperK +

87. ARBs…Pharmacology Angiotensinogen Angiotensin I Angiotensin II Aldosterone Vascular smooth muscles (AT 1 receptor) Na + & H 2 O retention ↑ SVR Renin ACE ARBs

88. ARBs…Pharmacology ARBs are AT 1 receptor antagonists & they block ARBs are AT 1 receptor antagonists & they blockVasoconstriction Renal Na + reabsorption Aldosterone secretion Sympathetic adrenergic activity Cardiac & vascular remodeling Release of vasopressin, luteinizing hormone, oxytocin, & corticotropin

89. ARBs…PK Onset (h) t 1/2 (h) Duration (h) Elimination Equivalent dose (max. daily dose) Candesartan2-33-4 > 24 R/H 8 mg QD (32) Eprosartan1-25-9>24H 600 mg QD (800) 600 mg QD (800) Irbesartan1-211-15>24R/H 150 mg QD (300) Losartan61-210-15R/H 50 mg QD (100) Telmisartan1-22424H 40 mg QD (80) Valsartan2-46>24H 80 mg QD (160)

90. ARBs…Management Start at low dose Start at low dose Baseline SCr/BUN; K + ; LFTs Baseline SCr/BUN; K + ; LFTs ↑ dose at interval 2-4 weeks ↑ dose at interval 2-4 weeks Monitor SCr/BUN; K + at 1-2 weeks, 1-3 months, then q6-12 months Monitor SCr/BUN; K + at 1-2 weeks, 1-3 months, then q6-12 months

91. ARBs…CI Angioedema due to ARB or ACE inhibitors Angioedema due to ARB or ACE inhibitors Anaphylactic reaction Anaphylactic reaction Renal insufficiency (pre-dialysis) Renal insufficiency (pre-dialysis) HyperK + HyperK + Bilateral renal artery stenosis or unilateral disease with solitary kidney Bilateral renal artery stenosis or unilateral disease with solitary kidney Valvular stenosis Valvular stenosis –  coronary perfusion Pregnant women (2 nd and 3 rd trimester) Pregnant women (2 nd and 3 rd trimester)

92. ARBs…ADRs Tinnitus Tinnitus Cough (3-10%) Cough (3-10%) ↑ LFTs ↑ LFTs Acute renal failure; oliguria Acute renal failure; oliguria Angioedema; rash Angioedema; rash Neutropenia; anemia Neutropenia; anemia HyperK + HyperK +

93.  -Blockers…Pharmacology Adrenoreceptors  (  1 /  2 ) and  (  1 /  2 ) Adrenoreceptors  (  1 /  2 ) and  (  1 /  2 )  1 -receptors  1 -receptorsHeart ↑ HR ↑ HR ↑ contractility ↑ contractility ↑ AV conduction ↑ AV conductionKidney ↑ renin secretion ↑ renin secretion

94.  -Blockers…Pharmacology  2 -receptors  2 -receptors Bronchodilation (lung) Vasodilation (peripheral and coronary) Glycogenolysis and gluconeogenesis (liver) Glycogenolysis and gluconeogenesis (liver) ↑ Insulin/glucagon (pancreas) ↑ K + uptake (skeletal muscle)

95.  - Blockers…PK Onset (h) t 1/2 (h) Duration (h) Elimination Equivalent dose (max. daily dose) Acebutolol1-26-712-24H/R200 mg (1200) Atenolol2-46-912-24R50 mg (100) Bisoprolol1-29-12>24H10 mg (20) Carvedilol1-27-10>24H 50 mg (50) Labetolol0.3-22.5-88-24H200 mg (2400) Metoprolol1.5-43-410-20H100 mg (450) Nadolol2-410- 24 17-24R80 mg (320) Pindolol1-22.5-412H/R7.5 mg (60) Propranolol1-24-66H80 mg (640) Timolol0.25- 0.75 2-2.74H10 mg (60)

96.  -Blockers…Management Start at low dose Start at low dose ↑ dose at bi-weekly intervals ↑ dose at bi-weekly intervals Monitor BP/HR; weight; mental status; circulation in extremities Monitor BP/HR; weight; mental status; circulation in extremities

97.  -Blockers…CI Absolute AbsoluteAsthma/bronchospasm HR< 50 bpm AVB (2° or 3°) Sick sinus syndrome (SSS) Severe or decompensated HF Prinzmetal angina Relative RelativePVD Severe depression DiabetesCOPD

98.  -Blockers…ADRs Drowsiness; insomnia; depression Drowsiness; insomnia; depression ↓ HR; ↓ peripheral circulation; edema; HF ↓ HR; ↓ peripheral circulation; edema; HF Bronchospasm Bronchospasm Impotence Impotence Rash Rash Hypoglycemia Hypoglycemia

99. CCBs...Pharmacology Block L-type Ca channels Block L-type Ca channels Non-dihydropyridine  vascular smooth muscles and myocardium Coronary vasodilation Coronary vasodilation ↓ myocardium contractility ↓ myocardium contractility ↓ AV node conduction ↓ AV node conduction ↓ Peripheral vascular resistance ↓ Peripheral vascular resistance Dihydropyridine  vascular smooth muscles Coronary vasodilation Coronary vasodilation Peripheral vasodilation Peripheral vasodilation

100. NDHP CCBs…PK Onset (h) t 1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose) Diltiazem CD0.5-15-812-24H120 mg QD (540) Verapamil SR* 26-96-8H180 mg QD (360) * Verapamil  more impact on myocardium contractility and AV conduction than diltiazem

101. NDHP CCBs…Management Start at low dose Start at low dose ↑ dose every 2-3 days ↑ dose every 2-3 days Monitor BP/HR; LFTs Monitor BP/HR; LFTs

102. NDHP CCBs…CI Bradycardia (HR< 50 bpm) Bradycardia (HR< 50 bpm) Patients with LVEF< 40% Patients with LVEF< 40% AV block (2° or 3°) AV block (2° or 3°) SSS SSS

103. NDHP CCBs…ADRs Dizziness; somnolence (D); insomnia (D) Dizziness; somnolence (D); insomnia (D) ↓ HR; edema; HF; flushing (D) ↓ HR; edema; HF; flushing (D) Dyspnea Dyspnea GI bleeding; gingival hyperplasia; constipation (V); nausea (V) GI bleeding; gingival hyperplasia; constipation (V); nausea (V) Polyuria (D) Polyuria (D) Muscular weakness (D) Muscular weakness (D) Rash Rash V = Verapamil D = Diltiazem; V = Verapamil

104. DHP CCBs… Management Start at low dose Start at low dose ↑ dose at interval of 7 to 14 days ↑ dose at interval of 7 to 14 days Monitor BP/HR; weight; peripheral edema Monitor BP/HR; weight; peripheral edema

105. DHP CCBs…PK Onset (h) t 1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose) Amlodipine0.5-135-5024H 2.5 mg QD (10) Felodipine2-511- 16 24H2.5-5 mg QD (20) Nifedipine (XL) 0.31012-24H 30 mg QD (180) * NEVER use short acting nifedipine (especially not in hypertensive emergency) * Nifedipine has more impact on peripheral vascular resistance

106. DHP CCBs…CI Severe HF Severe HF Cerebral tumor Cerebral tumor Severe aortic stenosis Severe aortic stenosis Hypertensive crisis Hypertensive crisis Acute MI Acute MI Short acting formulation

107. DHP CCBs…ADRs Drowsiness; H/A; nervousness; shakiness; sleep disturbances Drowsiness; H/A; nervousness; shakiness; sleep disturbances Flushing; ↓ HR; peripheral edema; HF Flushing; ↓ HR; peripheral edema; HF N/D/C; heartburn; gingival hyperplasia N/D/C; heartburn; gingival hyperplasia Impotence Impotence Muscular weakness; muscle cramps Muscular weakness; muscle cramps Rash; dermatitis Rash; dermatitis

108.  1 -blockers…Pharmacology Arterioles and venules vasodilation Arterioles and venules vasodilation  systemic vascular resistance Less tachyphylaxis than non-selective  -blockers Less tachyphylaxis than non-selective  -blockers Retention of fluid & salts Retention of fluid & salts

109.  1 -blockers…PK Onset (h) t 1/2 (h) Duration (h) Elimination Initial Dose (max. daily dose) Doxazosin2-322> 24H1 mg QD (16) Prazosin22-410-24H1 mg B-TID (20) Terazosin1-29- 12 >24H/R1 mg QD (20)

110.  1 -blockers…Management Start at low dose Start at low dose ↑ dose bi-weekly ↑ dose bi-weekly Monitor sitting/supine BP Monitor sitting/supine BP

111.  1 -blockers…CI Volume depleted or elderly Volume depleted or elderly Risk of orthostatic hypotension or syncope Concurrent use of PDE-5 Concurrent use of PDE-5

112.  1 -blockers…ADRs Dizziness Dizziness Blurred vision Blurred vision Orthostatic hypotension; edema; palpitation; RSCP Orthostatic hypotension; edema; palpitation; RSCP Dry mouth Dry mouth Urinary incontinence Urinary incontinence

113. Central  2 -Agonist Mechanism of action Mechanism of action Inhibition of efferent sympathetic activation Clonidine Clonidine Initial dose: 0.1 mg BID (max. 2.4 mg/d) ADRs: Drowsiness; depression; agitation; xerostomia; be careful to withdraw (rebound hypertension); orthostatic hypotension; RSCP; N/V/C; nocturia; impotence; rash Methyldopa Methyldopa Initial dose: 250 mg B-TID (max. 3g/d) ADRs: edema; depression; anxiety; nightmares; H/A; dry mouth

114. Vasodilators Mechanism of action Mechanism of action Direct vascular smooth muscle vasodilation Hydralazine Hydralazine Initial dose: 10 mg QID (max. 300 mg/d) ADRs: Anxiety; depression; conjunctivitis; dyspnea; ↑ HR; angina; N/V/D/C; urinary retention; impotence; muscle cramps; muscle weakness; tremors Minoxidil Minoxidil Initial dose: 5 mg QD (max. 100 mg/d) ADRs: Peripheral edema; ↑ HR; angina; pericarditis; pulmonary edema; ↑ weight; ↑ ALP ; ↑ SCr/BUN; hypertrichosis; pruritis

115. References Canadian Hypertension Education Program – 2007 Guidelines http://hypertension.ca/chep/ BC Ministry of Health: Guidelines & Protocols Advisory Committee  Hypertension http://www.health.gov.bc.ca/gpac/guideline_hyp ertension.html

116. Other “heart” problems Dyslipidemia Dyslipidemia Can be associated with decrease in renal function ↑ in Triglyceride and  HDL 1.Diet modifications 2.Statin Best choice if ↑ LDL ADRs: muscle cramps; muscle weakness; muscle pain; ↑ CK; rhabdomyolysis; hepatotoxicity; headache 3.Fibrate Best choice if ↑ Tg Less case of ↑ serum creatinine with Gemfibrozil ADRs: rash; diarrhea; myalgia; rhabdomyolysis; hepatotoxicity

117. Other “heart” problems Digoxin Digoxin Inhibits sodium-potassium ATPase in heart → better heart contraction, decrease sympathetic response Use in CHF (low dose) and A. Fib 50-70% eliminated by kidney… usually 0.0625 mg po OD to 3 x/week Adjustment based on digoxin level (0.8-1.2 for CHF; 0.8 to 2 for A.fib) ADRs: diarrhea, N/V, cardiac dysrythmia, headahce, visual disturbances Amiodarone Amiodarone Antiarrhythmic drug blocking potassium and sodium channel Use for ventricular/Supraventricular arrythmia; A.Fib Minimally renally eliminated ADRs: bradycardia, hypotension, thyroid problems, photosensitivity, nausea/vomiting, neuropathy, visual disturbances, fatigue, hepatotoxicity

118. Kidney Quiz… You and your nursing student is reviewing Mr. K.N.’s MAR. He is questioning the use of Renavite in patient with renal failure… why just not giving them a regular vitamin?! What is your answer? Should we switch Mr. K.N. to Centrum, 1 tablet PO daily?

119. Vitamins in CKD Water soluble vitamins are dialysable; especially vitamin C, vitamins B and folic acid. Important to replenish dialysable vitamin for HD patients. → Replavite, 1 tab po OD DO NOT GIVE liposoluble vitamins because of toxicity risk Vitamin A: in excess, cause osteodystrophy, anemia, hypercalcemia, skin problems Vitamin D: ineffective Vitamin E: generally elevated in CKD pt Vitamin K: sufficient quantity available and hypercoagulabitlity

120. Vitamins in CKD Zinc Dialysable, reduced absorption as bound to calcium, poor dietary intake Zinc deficiency is associated with: Impaired taste and poor appetite Hair loss Poor wound healing Recommended dose is 15 mg/day (if deficiency is suspected) Zinc sulfate 50 mg 3 x/week Zinc gluconate 10-20 mg po QD Reassess after 4-8 weeks

121. APPETITE STIMULANTS Malnutrition accounts for significant morbidity and mortality Moderate-severe malnutrition ~ 30% of dialysis patients Improving nutrition in dialysis patients optimize dialysis duration improve oral diet with enteral supplements total parenteral nutrition (intradialytic) drug therapy (megestrol acetate)

122. MEGESTEROL ACETATE (Megace) Progesterone derivative with appetite stimulating properties HPB approved for cancer- or AIDS-related cachexia, anorexia or weight loss Currently being studied in dialysis patients as an appetite stimulant

123. MEGESTEROL ACETATE (Megace) Dose: 160-800 mg daily (study dose = 800 mg daily) Amount and Type of Weight Gained: average 2-5 kg weight gain within 1-3 months fat versus lean body mass

124. MEGESTEROL ACETATE (Megace) Side Effects: sexual dysfunction (4-26%) deep vein thrombosis (< 5%) withdrawal menses or breakthrough bleeding (early) hyperglycemia (within first 3 months) gastrointestinal complaints excess weight gain (>10 kg) Contraindications: thromboembolic disease

125. GASTROINTESTINAL DISORDERS Reflux Reflux Peptic Ulcer Disease Peptic Ulcer Disease Motility Disorders Motility Disorders Nausea Nausea

126. CAUSES Diabetes gastroparesis Medications: Calcium, Aluminum phosphate binders, Diavite, and Iron, prednisone and cyclophosphamide Uremia of renal failure and infusion of peritoneal dialysis fluid Constipation: due to fluid restriction, restriction of fruits and fruit juices, iron supplements, phosphate binders

127. IMPORTANCE OF MANAGEMENT Maintenance of nutrition Symptom control

128. MEDICAL MANAGEMENT Determine cause or source of problem Nausea due to medications - taking with some food (if no interactions) Antiemetics such as prochlorperazine, haloperidol or dimenhydrinate If gastroparesis - prokinetic agents If suspected reflux - ranitidine (not cimetidine - impact on serum creatinine and interstitial nephritis) (not cimetidine - impact on serum creatinine and interstitial nephritis) If reflux resistant to ranitidine or UGIB– omeprazole, rabeprazole etc.

129. PROKINETIC AGENTS Metoclopramide Adverse effects - extrapyramidal symptoms (EPS) at higher doses + in children Start dose of 5 mg qid (max: 20 mg po QID) Domperidone 10 - 40 mg PO tid-qid

130. UREMIC PRURITUS Causes unknown Mechanism poorly understood

131. CLINICAL ASPECTS 25-33% predialysis patients 60-86% dialysis patients 10-14% less in capd vs. hemodialysis Non age or gender dependent Persistent

132. POSSIBLE CAUSES Uremic skin Cutaneous mast cell proliferation Atrophy of the sebaceous and sweat glands Increased skin pH Secondary hyperparathyroidism Divalent-ion abnormalities

133. POSSIBLE CAUSES Hypervitaminosis A Iron deficiency anemia Peripheral neuropathy Middle weight molecules Bile acids

134. MANAGEMENT Regular intensive dialysis Restricted phosphate diet Phosphate binders Erythropoietin and iron supplementation Emollients/topical corticosteroids (1% HC, 3% SA, 5% PG, 10% urea in glaxal base) UVB/UVA

135. MANAGEMENT AntihistaminesCholestyramine Activated charcoal Subtotal parathyroidectomy Oatmeal/baking soda/salt water/bath oils 100% Cotton wear