Renal failure & drug management By Dr. Judith Marin Pharmacist for FHA Renal program 614.0388.
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Transcript of Renal failure & drug management By Dr. Judith Marin Pharmacist for FHA Renal program 614.0388.
Renal failure & drug Renal failure & drug managementmanagement
By Dr. Judith MarinBy Dr. Judith Marin
Pharmacist for FHA Renal programPharmacist for FHA Renal program
614.0388614.0388
OutlineOutline
Influence of kidneys on drugs (vice-versa)Influence of kidneys on drugs (vice-versa)
AnemiaAnemia
Bone-mineral disorderBone-mineral disorder
Cardiovascular drugsCardiovascular drugs
Other renal exceptions!!!Other renal exceptions!!!
Kidney FunctionKidney Function
RegulatoryRegulatoryExtra-cellular fluid, acid base balance, Extra-cellular fluid, acid base balance, osmotic pressure, electrolyte imbalance, osmotic pressure, electrolyte imbalance, blood pressureblood pressure
ExcretoryExcretoryExcretion of waste, waterExcretion of waste, water
MetabolicMetabolicRAAS, Bone mineral disorders (vitamin D RAAS, Bone mineral disorders (vitamin D activation), anemia (erythropoietin)activation), anemia (erythropoietin)
CKD… who is at risk??CKD… who is at risk??
Elderly patientElderly patient
Transplant patientTransplant patient
DiabeticsDiabetics
Hypertensive/ Cardiovascular Hypertensive/ Cardiovascular diseasedisease
CKD… who is at risk??CKD… who is at risk??
Acute renal failureAcute renal failure↑ ↑ in serum creatinine level X 3.0in serum creatinine level X 3.0
in GFR by 75%in GFR by 75%
Serum creatinine level Serum creatinine level >350>350 µµmol/L with acute mol/L with acute increase of >44 increase of >44 µµmol/L mol/L
U/O <0.3 mL/kg/h for 24 hours, or anuria for 12 U/O <0.3 mL/kg/h for 24 hours, or anuria for 12 hours hours
Chronic renal failureChronic renal failureKidney damage or decrease eGFR for more than Kidney damage or decrease eGFR for more than 3 months3 months
CKD StageCKD Stage
Pharmacotherapeutic Pharmacotherapeutic goalsgoals
Improve signs and symptomsImprove signs and symptoms
Improve patient outcomes and slow progression Improve patient outcomes and slow progression of diseaseof disease
Improve surrogate outcomes Improve surrogate outcomes
Reduce risk of hospitalization Reduce risk of hospitalization
Minimize adverse drug reactions Minimize adverse drug reactions
Improve QOLImprove QOL
Pharmacotherapeutic Pharmacotherapeutic management for CKDmanagement for CKD
Dosage adjustment specific to CrCLDosage adjustment specific to CrCL
Avoid contraindicated medications/ Avoid contraindicated medications/ nephrotoxic drugsnephrotoxic drugs
Normalizing bloodworkNormalizing bloodwork
EducationEducation
Drug dosage in CKD Drug dosage in CKD
Cockcroft-Gault equationCockcroft-Gault equation
Expressed renal creatinine clearanceExpressed renal creatinine clearance More appropriate than eGFR to base drug More appropriate than eGFR to base drug
dosage adjustmentdosage adjustment
Drug dosage in CKD Drug dosage in CKD
Depends on drug metabolism and excretion Depends on drug metabolism and excretion Active vs. inactive metabolites renally excretedActive vs. inactive metabolites renally excreted Concerns if Concerns if ~ 50% or more of drug/active ~ 50% or more of drug/active
metabolites eliminated by kidneymetabolites eliminated by kidney Other PK variations: drug absorption, volume of Other PK variations: drug absorption, volume of
distribution, protein binding.distribution, protein binding.
Depends on renal function/ AKD or CKDDepends on renal function/ AKD or CKD Drug dosage adjustment starting at eGFR Drug dosage adjustment starting at eGFR < 60 < 60
ml/minml/min
• Depends efficacy/adverse drug reaction Depends efficacy/adverse drug reaction profileprofile
• Monitoring availableMonitoring available
Drug clearance and Drug clearance and dialysisdialysis
Type of dialysisType of dialysis HD and frequency, PD, CVVHHD and frequency, PD, CVVH
Drugs propertiesDrugs propertiesMolecular weight, charge, water solubility, volume of Molecular weight, charge, water solubility, volume of distribution, dialyzer membrane binding, non renal excretion distribution, dialyzer membrane binding, non renal excretion pathwaypathway
Dialysis propertiesDialysis propertiesType of dialyser (pore size, surface area), flow rate/blood Type of dialyser (pore size, surface area), flow rate/blood flow, dialysate composition, volume of dialysate (PD), flow, dialysate composition, volume of dialysate (PD), temperature, pH temperature, pH
Patient propertiesPatient propertiesResidual renal function, blood pressure, Kt/v or PRUResidual renal function, blood pressure, Kt/v or PRU
Case with Mr. Kidd NeyCase with Mr. Kidd Ney
75 y/o man with PMHx of DM type II, 75 y/o man with PMHx of DM type II, CHF and renal failure (on HD)CHF and renal failure (on HD)
Admitted to SMH last night for UTIAdmitted to SMH last night for UTIE.coli sensitive to CiprofloxacinE.coli sensitive to Ciprofloxacin
Hospitalist orders Hospitalist orders Ciprofloxacin 500 mg PO bid x 5 days for Ciprofloxacin 500 mg PO bid x 5 days for UTI UTI
Starts Metformin, 500 mg PO tid to Starts Metformin, 500 mg PO tid to improve blood sugar controlimprove blood sugar control
Case with Mr. Kidd NeyCase with Mr. Kidd Ney
Any intervention???Any intervention??? CiprofloxacinCiprofloxacin
Dosage adjustment if CrCl < 30 ml/minDosage adjustment if CrCl < 30 ml/min
30-57% of drug eliminated by kidney30-57% of drug eliminated by kidney
Dialysed out by PD and HDDialysed out by PD and HD
At high serum concentration, risk of seizure, At high serum concentration, risk of seizure, myalgia/arthralgia, renal failure, myalgia/arthralgia, renal failure, ↑ QTc interval↑ QTc interval
Dosage should be adjusted by to 500 mg po QD Dosage should be adjusted by to 500 mg po QD x 5 days (dose to be given post-HD on HD days)x 5 days (dose to be given post-HD on HD days)
Case with Mr. Kidd NeyCase with Mr. Kidd Ney
Any intervention???Any intervention??? MetforminMetformin
Dosage adjustment if CrCl < 60 ml/minDosage adjustment if CrCl < 60 ml/min
90% of drug eliminated by kidney90% of drug eliminated by kidney
Dialysed out by HDDialysed out by HD
At high serum concentration, risk of At high serum concentration, risk of nausea/vomiting, lactic acidosis, hypotension, nausea/vomiting, lactic acidosis, hypotension, hypothermia, tachycardia, tachypneahypothermia, tachycardia, tachypnea
Metformin contraindicated in ESRD patientsMetformin contraindicated in ESRD patients
ReferencesReferences
Bennett’s book. Drug Prescribing in Renal Bennett’s book. Drug Prescribing in Renal Failure.Failure.
http://www.kdp-baptist.louisville.edu/renalbook/http://www.kdp-baptist.louisville.edu/renalbook/
Drug MonographyDrug MonographyMicromedexMicromedex
eCPSeCPS
MedscapeMedscape
Be careful to your references!Be careful to your references!
ExamplesExamples
Drugs should never be held before HD Drugs should never be held before HD runrun
Except if ordered by physicianExcept if ordered by physician Antibiotic should be administered after Antibiotic should be administered after
HD runHD run
Antibiotic minimally dialysed: azithromycin, Antibiotic minimally dialysed: azithromycin, chloramphenicol, clindamycin, doxycyclin/tetracycline, chloramphenicol, clindamycin, doxycyclin/tetracycline, linezolidlinezolid
AntibioticAntibiotic Excretion during Excretion during HDHD
ΒΒ-Lactams-Lactams 10-75%10-75%
FluoroquinolonesFluoroquinolones ~ 50%~ 50%
AminoglycosidesAminoglycosides 40-50%40-50%
Kidney Quiz… Kidney Quiz…
Mr. K.N. is still complaining about UTI Mr. K.N. is still complaining about UTI symptoms 3 days after starting ciprofloxacin. symptoms 3 days after starting ciprofloxacin. Another urine culture is done Another urine culture is done → still growing → still growing E.ColiE.ColiHospitalist is thinking about about changing Hospitalist is thinking about about changing antibiotic to tobramycin.antibiotic to tobramycin.The pharmacist on the ward is concerns since The pharmacist on the ward is concerns since aminoglycosides (e.g. tobramycin, gentamycin) aminoglycosides (e.g. tobramycin, gentamycin) are nephrotoxic drugs. What do you think? are nephrotoxic drugs. What do you think? Would you think differently if patient was a pre-Would you think differently if patient was a pre-dialysis with eGFR of 25 ml/min?dialysis with eGFR of 25 ml/min?
Nephrotoxic drugs Nephrotoxic drugs
Drugs caused about 20% of community and Drugs caused about 20% of community and hospital acquired acute renal failurehospital acquired acute renal failure
Risk factors:Risk factors:> 60 years old> 60 years oldeGFR < 60 ml/mineGFR < 60 ml/minDiabetesDiabetesVolume depletionVolume depletionCHFCHFSepsisSepsis
Nephrotoxic drugs Nephrotoxic drugs
Preventive measuresPreventive measures
UUse of alternative nonnephrotoxic drugs se of alternative nonnephrotoxic drugs Identifying and correcting patient-related Identifying and correcting patient-related risk factors that are amenable to therapyrisk factors that are amenable to therapyDDetermining baseline renal function before etermining baseline renal function before starting potentially nephrotoxic therapy to starting potentially nephrotoxic therapy to allow dosage adjustment, monitoring kidney allow dosage adjustment, monitoring kidney function and vital signs during therapyfunction and vital signs during therapyAAvoiding use of nephrotoxic drug voiding use of nephrotoxic drug combinationscombinations
Nephrotoxic drugs Nephrotoxic drugs
Preventive measuresPreventive measures
UUse of alternative nonnephrotoxic drugs se of alternative nonnephrotoxic drugs Identifying and correcting patient-related Identifying and correcting patient-related risk factors that are amenable to therapyrisk factors that are amenable to therapyDDetermining baseline renal function before etermining baseline renal function before starting potentially nephrotoxic therapy to starting potentially nephrotoxic therapy to allow dosage adjustment, monitoring kidney allow dosage adjustment, monitoring kidney function and vital signs during therapyfunction and vital signs during therapyAAvoiding use of nephrotoxic drug voiding use of nephrotoxic drug combinationscombinations
Nephrotoxic drugs Nephrotoxic drugs
AntibioticsAntibioticsAminoglycosides, amphotericine B Aminoglycosides, amphotericine B penicillin, cephalosporin, penicillin, cephalosporin, quinolones acyclovir, sulfaquinolones acyclovir, sulfa
D/C drug if sCr increasesD/C drug if sCr increases
NSAIDs/COX-2 inhibitorsNSAIDs/COX-2 inhibitorsDiclofenac, naproxen, celecoxibDiclofenac, naproxen, celecoxib
Contraction of efferent renal Contraction of efferent renal arteriole; D/C drug and switch arteriole; D/C drug and switch to acetaminophento acetaminophen
ACE inhibitors/ARBsACE inhibitors/ARBsLosartan, irbesartan, ramipril, Losartan, irbesartan, ramipril, captoprilcaptopril
Vasodilation of afferent renal Vasodilation of afferent renal arteriole; D/C drug, hydrationarteriole; D/C drug, hydration
LithiumLithium Interstitial nephritis at high Interstitial nephritis at high dosage; decrease dose; dosage; decrease dose; hydrationhydration
IV contrast dyeIV contrast dye CIN; hydration; holding NSAIDs CIN; hydration; holding NSAIDs and diuretic; N-acetylcysteinand diuretic; N-acetylcystein
Kidney Quiz… Kidney Quiz…
Pt is complaining of being very tired. Nurse Pt is complaining of being very tired. Nurse noticed that blood in urine.noticed that blood in urine.
Hgb comes back to 100 g/LHgb comes back to 100 g/L
Patient has been stable (Hgb 115-120 g/L) Patient has been stable (Hgb 115-120 g/L) while on Darbepoietin 20 mcg IV Qweek while on Darbepoietin 20 mcg IV Qweek and Ferrlecit 125 mg IV Qmonth x 5 monthsand Ferrlecit 125 mg IV Qmonth x 5 months
What should be done? What should be done?
Anemia of CKD Anemia of CKD
Stage of CKDStage of CKD eGFReGFR((ml/min/1.73mml/min/1.73m22))
Anemia Anemia prevalenceprevalence
Stage 3Stage 3 30-5930-59 5.2%5.2%
Stage 4Stage 4 15-2915-29 44.1%44.1%
Stage 5Stage 5 < 15 or < 15 or dialysisdialysis
100%100%
Prevalence higher in african americans and diabetic Prevalence higher in african americans and diabetic patientspatients
Anemia of CKD Anemia of CKD
CausesCauses
EPO deficiencyEPO deficiencyBlood lossBlood lossShorter RBC life spanShorter RBC life spanDecreased bone marrow responsiveness to EPODecreased bone marrow responsiveness to EPOVitamin deficienciesVitamin deficienciesIron deficiency (poor iron absorption)Iron deficiency (poor iron absorption)High uremia levelHigh uremia levelIntoxication impairing RBC development (Aluminium)Intoxication impairing RBC development (Aluminium)Hemolysis (copper, chloramines)Hemolysis (copper, chloramines)Chronic inflammationChronic inflammation
Anemia of CKD Anemia of CKD
Target Hgb level Target Hgb level → 110-120 g/L→ 110-120 g/LHigher hgb level associated with higher risk of Higher hgb level associated with higher risk of mortality, higher BP, higher access thrombosismortality, higher BP, higher access thrombosisMinimal benefit on QOLMinimal benefit on QOLStudies have limitsStudies have limits
Workup before starting ESAWorkup before starting ESACBC, RCCBC, RC
Iron measurements (serum iron, TIBC, Tsat, ferritin)Iron measurements (serum iron, TIBC, Tsat, ferritin)
Occult blood in stoolsOccult blood in stools
Serum vitamin B12 and folateSerum vitamin B12 and folate
iPTH leveliPTH level
Talking about EPO Talking about EPO
Hormone which principal regulator of Hormone which principal regulator of erythropoiesiserythropoiesis
Stimulates proliferation/maturation and inhibits Stimulates proliferation/maturation and inhibits apoptosis of erythroid progenitorsapoptosis of erythroid progenitors
Induce release of reticulocytes into bloodstreamInduce release of reticulocytes into bloodstream
Primarily produced by cells of kidney Primarily produced by cells of kidney peritubular capillary endothelium peritubular capillary endothelium
Talking about EPO Talking about EPO
1.1. Epoietin agentsEpoietin agentsEpoetin alpha (Eprex)Epoetin alpha (Eprex)
11STST recombinant human erythropoietin launched recombinant human erythropoietin launched on the marketon the market
Shorter half-life (administration 1-3 times/week)Shorter half-life (administration 1-3 times/week)
Darbepoetin alpha (Aranesp)Darbepoetin alpha (Aranesp)Longer acting erythropoietin analoguesLonger acting erythropoietin analogues
Administration Q1-2 weeksAdministration Q1-2 weeks
Talking about EPO Talking about EPO
ADRsADRsHypertensionHypertension
20-40% of patients with partial Hb correction20-40% of patients with partial Hb correction
Mainly due to increase systemic vascular resistanceMainly due to increase systemic vascular resistance
Mostly during the first 4 months of therapyMostly during the first 4 months of therapy
Metabolic disturbancesMetabolic disturbances
sCr; sCr; K K++; ; P0 P044
Dializer efficiency; and Dializer efficiency; and appetite appetite
Myalgia and Flu-like illnessMyalgia and Flu-like illness
Only report with IV EPOOnly report with IV EPO
Slow drug infusionSlow drug infusion
Talking about EPO Talking about EPO
ADRsADRs
Thrombotic complicationsThrombotic complicationsVascular access thrombosisVascular access thrombosis
Exacerbation of diabetic retinopathyExacerbation of diabetic retinopathy
SeizureSeizureHypertensive encephalopathyHypertensive encephalopathy
Injection site painInjection site painHypertonic citrate in formulationHypertonic citrate in formulation
Red eye syndromRed eye syndromCorrection Hct > 30%Correction Hct > 30%
Cosmetic syndromCosmetic syndrom
Iron deficiency Iron deficiency
DefinitionDefinitionFerritin < 100 ng/mlFerritin < 100 ng/ml
Iron transferrin saturation < 20%Iron transferrin saturation < 20%
Higher ferritin level could be associated with greater ESA Higher ferritin level could be associated with greater ESA efficacyefficacy
CausesCausesESAESA
GI bleedingGI bleeding
Lab testsLab tests
Phosphate bindersPhosphate binders
Adjuvant to ESAAdjuvant to ESA
Decreased 33-75% in EPO requirement Decreased 33-75% in EPO requirement
Iron deficiency Iron deficiency
PO iron supplementPO iron supplementNo trial looking at PO iron vs placebo in CKDNo trial looking at PO iron vs placebo in CKD
Associated with dyspepsia and constipationAssociated with dyspepsia and constipation
Iron saltsIron salts DosageDosage Elementary ironElementary iron
Ferrous fumarateFerrous fumarate 300 mg300 mg 66 mg66 mg
Ferrous sulfateFerrous sulfate 300 mg300 mg 60 mg60 mg
Ferrous gluconateFerrous gluconate 300 mg300 mg 35 mg35 mg
Iron polysaccharideIron polysaccharide 150 mg150 mg 150 mg150 mg
Iron deficiency Iron deficiency
IV iron supplementIV iron supplement5 trials looking at IV vs po iron5 trials looking at IV vs po iron
Mixed results… but overall IV iron seems more Mixed results… but overall IV iron seems more effectiveeffective
Concern about renal tubular toxicity and damage to Concern about renal tubular toxicity and damage to blood vesselsblood vessels
Administration… bolus vs infusion?Administration… bolus vs infusion?
FormulationFormulation Usual dosageUsual dosage
Iron dextroseIron dextrose 100 mg100 mg
Iron sucroseIron sucrose 100 mg100 mg
Sodium ferric gluconate Sodium ferric gluconate complexcomplex
125 mg125 mg
Iron deficiency Iron deficiency
IV iron supplementIV iron supplementAdverse drug reactionsAdverse drug reactions
Hypotension/hypertension, tachycardia, Hypotension/hypertension, tachycardia, edema, itching, phlebitis, rash, edema, itching, phlebitis, rash, anaphylaxis/immune reaction, legs cramps, anaphylaxis/immune reaction, legs cramps, arthralgia, back pain, headachearthralgia, back pain, headache
Hgb variability Hgb variability
Study by Brier and Aronoff.Study by Brier and Aronoff.With 3 months Hb rolling averageWith 3 months Hb rolling average
66% patients would be in a target range of 110-120 66% patients would be in a target range of 110-120 g/Lg/L
75% patients would be in a target range of 110-75% patients would be in a target range of 110-122.4 g/L122.4 g/L
90% patients would be in a target range of 110-13- 90% patients would be in a target range of 110-13- g/Lg/L
Do not react to the last Hb value to Do not react to the last Hb value to change ESA dosagechange ESA dosage
Patient hydration statusPatient hydration status
Kidney Quiz… Kidney Quiz…
Pt is complaining that he is Pt is complaining that he is “never” receiving his calcium “never” receiving his calcium tablets with his meals and he tablets with his meals and he insists of having his calcium insists of having his calcium tablets before taking the first tablets before taking the first bite of his meal. bite of his meal.
Should we address his concerns?Should we address his concerns?
Bone and mineralsBone and minerals
Bone and mineralsBone and minerals
Bone and mineralsBone and minerals
Bone lesion of excess PTH (high-turnover disease):Bone lesion of excess PTH (high-turnover disease):Increased PTH levels enhance osteoclast activity – increased bone Increased PTH levels enhance osteoclast activity – increased bone resorption. resorption.
As activity increases, marked fibrosis involving the marrow space As activity increases, marked fibrosis involving the marrow space develops. develops.
Bone lesion of defective mineralization:Bone lesion of defective mineralization:Defective mineralization can lead to osteomalacia. Defective mineralization can lead to osteomalacia.
Osteomalacia is caused by delay in rate of bone mineralization and Osteomalacia is caused by delay in rate of bone mineralization and accumulation of excess unmineralized osteoid. accumulation of excess unmineralized osteoid.
Mechanism for osteolmalacia disorder in CKD patients:Mechanism for osteolmalacia disorder in CKD patients:Aluminum overload (most important factor).Aluminum overload (most important factor).
Due to use of aluminum-based phosphate binders. Due to use of aluminum-based phosphate binders.
Relative or absolute deficiency of vitamin D. Relative or absolute deficiency of vitamin D. Vitamin D is responsible for collagen synthesis and maturation, stimulating Vitamin D is responsible for collagen synthesis and maturation, stimulating bone mineralization bone mineralization
OsteoporosisOsteoporosis
HyperphosphatemiaHyperphosphatemia
Phosphorous mainly eliminated by kidney and dialysis not Phosphorous mainly eliminated by kidney and dialysis not effective at removing phosphorous in bloodeffective at removing phosphorous in blood
Decrease phosphorous GI absorptionDecrease phosphorous GI absorption
Hyperphosphatemia associated with itchiness, bone and Hyperphosphatemia associated with itchiness, bone and joint painjoint pain
Oral phosphate bindersOral 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.
HyperphosphatemiaHyperphosphatemia
TypeType ExamplesExamples Trade NamesTrade Names
Calcium-based Calcium-based BindersBinders
Calcium CarbonateCalcium Carbonate Calcium CarbonateCalcium Carbonate
Calcium AcetateCalcium Acetate Calcium AcetateCalcium Acetate
Metal-based Metal-based BindersBinders
Aluminum HydroxideAluminum Hydroxide Aluminum HydroxideAluminum Hydroxide
Magnesium Magnesium HydroxideHydroxide
Various BrandsVarious Brands
Lanthanum Lanthanum CarbonateCarbonate
Fosrenal™Fosrenal™
Noncalcium, Non-Noncalcium, Non-metal-based metal-based BindersBinders
Sevelamer HClSevelamer HCl Renagel®Renagel®
Vitamin DVitamin 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
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 hydroxylation1st hydroxylation
2nd hydroxylation2nd hydroxylation
Vitamin DVitamin D
CalcimimeticCalcimimetic
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
CalcimimeticCalcimimetic
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
HypocalcemiaSeizure Cinacalcet (1.4%) vs. placebo (0.4%)
possibly due to a lowered seizure threshold that can occur with a reduction in serum calcium levels
Kidney Quiz… Kidney Quiz…
Mr K. N. results during BW week:Mr K. N. results during BW week:
Pt has been on same regimen for last 6 monthsPt has been on same regimen for last 6 monthsApo-Cal, 1 tab TID ccApo-Cal, 1 tab TID ccOne-alpha, 0.25 mcg PO 3 times/weekOne-alpha, 0.25 mcg PO 3 times/week
This BWThis BW Last BWLast BW
Corrected CaCorrected Ca 2.32.3 2.242.24PhosphorusPhosphorus 1.51.5 1.01.0iPTHiPTH 6262 3030
Kidney Quiz… Kidney Quiz…
Mr K. N. results during next BW week:Mr K. N. results during next BW week:
This BWThis BW Last BWLast BW
Corrected CaCorrected Ca 2.652.65 2.32.3PhosphorusPhosphorus 1.91.9 1.51.5iPTHiPTH 5555 6262
Kidney Quiz… Kidney Quiz…
Mr K. N. results during next BW week:Mr K. N. results during next BW week:
This BWThis BW Last BWLast BW
Corrected CaCorrected Ca 2.652.65 2.652.65PhosphorusPhosphorus 1.91.9 1.91.9iPTHiPTH 105105 5555
Kidney Quiz… Kidney Quiz…
Today, KToday, K++ :3.2 for Mr K.N. since had :3.2 for Mr K.N. since had diarrhea for the last few days diarrhea for the last few days (hopefully, not (hopefully, not C.difficilesC.difficiles!). Your !). Your colleague suggests calling the colleague suggests calling the hospitalist to order Potassium hospitalist to order Potassium Chloride (Slow KChloride (Slow K®), 600 mg po BID. ®), 600 mg po BID. What do you think about this What do you think about this suggestion?suggestion?
Electrolytes Electrolytes
Potassium mainly eliminated by kidney and Potassium mainly eliminated by kidney and dialysis effective at removing potassium in blooddialysis effective at removing potassium in blood
Hyperkaliemia associated with cardiac arrythmia, Hyperkaliemia associated with cardiac arrythmia, respiratory paralysis, tinglingrespiratory paralysis, tingling
Hypokaliemia associated with muscle weakness, Hypokaliemia associated with muscle weakness, general weakness, ECG abnormalitygeneral weakness, ECG abnormality
KK+ + can be adjusted with dialysate Kcan be adjusted with dialysate K++ bath No need potassium supplement and rarely No need potassium supplement and rarely
need kayaxelateneed kayaxelate
Make sure that nephrologist/dialysis unit are Make sure that nephrologist/dialysis unit are aware of patient Kaware of patient K++ level.
Kidney Quiz… Kidney Quiz…
Mr. K.N. unfortunately felt in hospital Mr. K.N. unfortunately felt in hospital and broke his hip. He had hip surgery and broke his hip. He had hip surgery and he is complaining about pain after and he is complaining about pain after his surgery. You have an order for his surgery. You have an order for morphine on the MAR, but one of your morphine on the MAR, but one of your colleague is telling you that morphine colleague is telling you that morphine is contraindicated in patients with is contraindicated in patients with renal failure. Is it true? What are the renal failure. Is it true? What are the options for pain management?options for pain management?
Pain ManagementPain ManagementMulti-modalMulti-modal
Non-Non-PharmacologicalPharmacological
Heat/ColdHeat/Cold
MassageMassage
Distraction Distraction
Self ManagementSelf Management
PsychologyPsychology
PharmacologicPharmacological al
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Analgesics for MSK Analgesics for MSK painpain
AcetaminophenAcetaminophenAnalgesic without anti-inflammatory proprietyAnalgesic without anti-inflammatory proprietyAs effective as NSAIDs in relieving mild-moderate As effective as NSAIDs in relieving mild-moderate osteoarthritis pain if taken 4 times/day, with less osteoarthritis pain if taken 4 times/day, with less ADRsADRsTylenol arthritis pain Tylenol arthritis pain 8 hours duration 8 hours duration
Topical NSAIDsTopical NSAIDsLocalized osteoarthritis pain of superficial jointsLocalized osteoarthritis pain of superficial joints
For mild to moderate pain (score < 4/10)For mild to moderate pain (score < 4/10)Can also be used as co-analgesic / adjuvantCan also be used as co-analgesic / adjuvant
Analgesics for MSK Analgesics for MSK painpain
Oral NSAIDsOral NSAIDs Analgesic with anti-inflammatory Analgesic with anti-inflammatory proprietypropriety Avoid in pre-dialysis patients since can Avoid in pre-dialysis patients since can renal function renal function Avoid for long-term treatment, since Avoid for long-term treatment, since CKD patient at CKD patient at risk of bleeding risk of bleeding
For mild to moderate pain (score < 4/10)For mild to moderate pain (score < 4/10)Can also be used as co-analgesic / adjuvantCan also be used as co-analgesic / adjuvant
Analgesics for Analgesics for neuropathic painneuropathic pain
AnticonvulsantsAnticonvulsantsGabapentinGabapentin, pregabalin, pregabalin Act on GABA receptors to modulate nerve influxAct on GABA receptors to modulate nerve influxADRs: somnolence, dizziness, and ataxia ADRs: somnolence, dizziness, and ataxia
Capsaicin creamCapsaicin creamStimulates the nerves, to then desensitizes them Stimulates the nerves, to then desensitizes them (depletion of substance P)(depletion of substance P)Also use in osteoarthritic painAlso use in osteoarthritic painCauses erythema and feeling of warmth at Causes erythema and feeling of warmth at application (lidocaine x 2 weeks)application (lidocaine x 2 weeks)Wash hands after using itWash hands after using itCan take up to 2-4 weeks before onset of action Can take up to 2-4 weeks before onset of action Maximum response after 4-6 weeks of regular useMaximum response after 4-6 weeks of regular use
Analgesics for Analgesics for neuropathic painneuropathic pain
AntidepressantsAntidepressantsGood choice if concomitant depression or Good choice if concomitant depression or insomniainsomnia
Tricyclic antidepressant (TCAs)Tricyclic antidepressant (TCAs)Desipramine and nortriptyline preferred agentDesipramine and nortriptyline preferred agent
Less anticholinergic effectsLess anticholinergic effects
ADRs: ADRs: Cardiac toxicitiesCardiac toxicities, orthostatic , orthostatic hypotension, constipation, dry mouthhypotension, constipation, dry mouth
VenlafaxineVenlafaxineLess efficacy/safety data availableLess efficacy/safety data available
ADRs: HTN, nauseaADRs: HTN, nausea
OpioidsOpioids
Efficacy in MSK and neuropathic painEfficacy in MSK and neuropathic pain
Usually use in conjunction with other Usually use in conjunction with other analgesicsanalgesics dose of opioid dose of opioid
Opioids have similar efficacy if appropriate Opioids have similar efficacy if appropriate dosage conversiondosage conversion
Routes (PO/IV/SC/IM) have similar efficacy Routes (PO/IV/SC/IM) have similar efficacy if appropriate dosage conversionif appropriate dosage conversion
Pain management Pain management in CKDin CKD
Opioids of choice:Opioids of choice: hydromorphone, hydromorphone, oxycodone, fentanyloxycodone, fentanyl
Avoid mepiridine since risk of Avoid mepiridine since risk of neurotoxicity (eg. Seizure, tremors, neurotoxicity (eg. Seizure, tremors, irritability, etc.) related to metabolites irritability, etc.) related to metabolites accumulation.accumulation.
Avoid morphine since risk of neurotoxicity Avoid morphine since risk of neurotoxicity (eg. seizure, myoclonia, hallucination, etc.) (eg. seizure, myoclonia, hallucination, etc.) related to metabolites accumulation.related to metabolites accumulation.
OpioidsOpioids
Administer on a regular schedule with interval Administer on a regular schedule with interval corresponding to duration of actioncorresponding to duration of action
SR formulation use when daily dosage SR formulation use when daily dosage establishedestablishedAppropriate breakthrough dose equal to Appropriate breakthrough dose equal to 10% of daily dosage Q2Hrs PRN10% of daily dosage Q2Hrs PRN
ADRs : Sedation, nausea, constipation, ADRs : Sedation, nausea, constipation, hallucinations, hyperalgesia, respiratory hallucinations, hyperalgesia, respiratory depression, cognitive impairment, gait depression, cognitive impairment, gait disturbancesdisturbances
MethadoneMethadone
Opioid analgesic with an antagonist effect on NMDA Opioid analgesic with an antagonist effect on NMDA receptors (responsible of constant and exaggeration of receptors (responsible of constant and exaggeration of pain)pain)
Option if pain refractory to usual opioidsOption if pain refractory to usual opioids
Long half-lifeLong half-life
High inter-patient variability, multiple drug interactionHigh inter-patient variability, multiple drug interaction
Physician needs special privilege to prescribe itPhysician needs special privilege to prescribe it
ADRs: Bradycardia, hypotension, general weakness, ADRs: Bradycardia, hypotension, general weakness, sedation, nausea, constipation, respiratory depression, sedation, nausea, constipation, respiratory depression, dysphoria, insomnia, anxietydysphoria, insomnia, anxiety
Management of ADRsManagement of ADRs
Nausea/vomitingNausea/vomitingUsually tolerance after 5-7 daysUsually tolerance after 5-7 days
GI stasis and impact on GI stasis and impact on chemoreceptive zonechemoreceptive zone
Domperidone/metoclopramideDomperidone/metoclopramide
Or/andOr/and
Prochlorperazine/ HaloperidolProchlorperazine/ Haloperidol
Management of ADRsManagement of ADRs
ConstipationConstipationProportional to opioid dosageProportional to opioid dosage
Unlikely to improve overtimeUnlikely to improve overtime
Stool softener (docusate) and GI Stool softener (docusate) and GI stimulant (sennosides) for all patients stimulant (sennosides) for all patients on opioidson opioids
Lactulose, PEGLyte, glycerin supp., Lactulose, PEGLyte, glycerin supp., bisacodyl supp. are other optionsbisacodyl supp. are other options
To be avoided: fleet phosphate, milk of To be avoided: fleet phosphate, milk of magnesia, mineral oilmagnesia, mineral oil
Management of ADRsManagement of ADRs
Respiratory DepressionRespiratory DepressionNaloxone 0.1-0.4 mg sc or IV initiallyNaloxone 0.1-0.4 mg sc or IV initially
Effective dose can be repeated every Effective dose can be repeated every 1-2 hours if SR opioid formulation1-2 hours if SR opioid formulation
Management of ADRsManagement of ADRs
SedationSedationCaused by opioid anticholinergic activityCaused by opioid anticholinergic activity
Dose reduction, slow dosage titrationDose reduction, slow dosage titration
PruritisPruritisCaused by opioid histaminic activityCaused by opioid histaminic activity
Sx also associated with renal failureSx also associated with renal failure
Antihistaminic Rx (diphenhydramine, Antihistaminic Rx (diphenhydramine, hydroxyzine), opioid rotationhydroxyzine), opioid rotation
Management of ADRsManagement of ADRs
Tremors, myoclonusTremors, myoclonusMetabolites accumulation can cause CNS Metabolites accumulation can cause CNS disturbancesdisturbances
Metabolites mostly eliminated by kidney, Metabolites mostly eliminated by kidney, and may be not easily dialyzed and may be not easily dialyzed
Opioid rotation, dosage reductionOpioid rotation, dosage reduction
Management of ADRsManagement of ADRs
Tremors, myoclonusTremors, myoclonusMetabolites accumulation can cause CNS Metabolites accumulation can cause CNS disturbancesdisturbances
Metabolites mostly eliminated by kidney, Metabolites mostly eliminated by kidney, and may be not easily dialyzed and may be not easily dialyzed
Opioid rotation, dosage reductionOpioid rotation, dosage reduction
Kidney Quiz… Kidney Quiz…
Mr. K.N. blood pressure is increased Mr. K.N. blood pressure is increased post surgery. The mean BP for the post surgery. The mean BP for the past couple of days is 175/90, HR 90.past couple of days is 175/90, HR 90.
Patient currently taking metoprolol 50 Patient currently taking metoprolol 50 mg po BID and furosemide 40 mg PO mg po BID and furosemide 40 mg PO QD.QD.
Should you flag it to the nephrologist? Should you flag it to the nephrologist? What other information do you need What other information do you need before making a decision?before making a decision?
Goals of BP TherapyGoals of BP Therapy
Reduce associated morbidity and mortalityReduce associated morbidity and mortalityTarget-organ damageTarget-organ damage
BP < 140/90 mmHgBP < 140/90 mmHg
Diabetes or chronic kidney diseaseDiabetes or chronic kidney diseaseBP < 130/80 mmHgBP < 130/80 mmHg
Proteinuric renal disease (Urinary protein Proteinuric renal disease (Urinary protein excretion > 1g/24h)excretion > 1g/24h)
BP < 130/80 mm HgBP < 130/80 mm Hg
Non-Drug TherapyNon-Drug Therapy
Weight reductionWeight reduction DASH dietDASH diet Reduce dietary sodium intakeReduce dietary sodium intake Physical activityPhysical activity Moderate alcohol consumptionModerate alcohol consumption Smoking cessationSmoking cessation
Classes of Classes of AntiHypertensivesAntiHypertensives
DiureticsDiuretics
Angiotensin Converting Enzyme (ACE) InhibitorsAngiotensin Converting Enzyme (ACE) Inhibitors
Angiotensin Receptor Blockers (ARB)Angiotensin Receptor Blockers (ARB)
ββ-Blockers-Blockers
Calcium Channel Blockers (CCB)Calcium Channel Blockers (CCB)Non-dihydropyridine (NDHP)Non-dihydropyridine (NDHP)
Dihydropyridine (DHP)Dihydropyridine (DHP)
11-Blockers-Blockers
Central Central 22-Agonists-Agonists
VasodilatorsVasodilators
Indications Indications First Line Second Line
Uncomplicated HTN
Thiazide diureticThiazide diuretic ACEI; ARB; long acting DHP-ACEI; ARB; long acting DHP-CCB; CCB; ββ-Blocker-Blocker
HTN Complicated by Co-Morbid Conditions
Coronary Artery Disease (CAD)
ACEIACEI
ββ-Blocker (stable -Blocker (stable angina)angina)
Long acting CCBLong acting CCB
Myocardial Infarction (MI)
ACEI + ACEI + ββ-Blocker-Blocker - ARB if ACEI intolerant- ARB if ACEI intolerant
- CCB if - CCB if ββ-Blocker is CI or -Blocker is CI or ineffective; avoid NDHP-ineffective; avoid NDHP-CCB if heart failure is CCB if heart failure is presentpresent
Left Ventricular Hypertrophy (LVH)
Thiazide diuretic; ACEI; Thiazide diuretic; ACEI; long-acting CCBlong-acting CCB
- ARB if ACEI intolerant- ARB if ACEI intolerant
- Avoid direct arterial - Avoid direct arterial vasodilators (hydralazine, vasodilators (hydralazine, minoxidil)minoxidil)
Cerebrovascular Disease
ACEI + thiazide diureticACEI + thiazide diuretic Long acting DHP-CCBLong acting DHP-CCB
IndicationsIndicationsFirst Line Second Line
HTN Complicated by Co-Morbid Conditions
Heart Failure
- ACEI + ACEI + ββ-Blocker -Blocker (systolic dysfunction) (systolic dysfunction) - Aldosterone Aldosterone antagonists if NYHA antagonists if NYHA class III or IVclass III or IV
- ARB if ACEI intolerant ARB if ACEI intolerant - Hydralazine/isosorbide dinitrate if Hydralazine/isosorbide dinitrate if ACEI & ARB intolerantACEI & ARB intolerant- Diuretics (thiazide), ARB, long acting Diuretics (thiazide), ARB, long acting DHP CCB as additive tx if BP not DHP CCB as additive tx if BP not controlledcontrolled
Non-Diabetic CKD with Proteinuria
ACEI ACEI - ARB if ACEI intolerant- ARB if ACEI intolerant
- Thiazide diuretic as additive therapy - Thiazide diuretic as additive therapy or loop diuretics if volume overloadedor loop diuretics if volume overloaded
Renovascular Disease
Thiazide diuretic; Thiazide diuretic; ACEI; long-acting ACEI; long-acting CCBCCB
- ARB if ACEI intolerant - ARB if ACEI intolerant
- Combination therapy if BP not - Combination therapy if BP not controlledcontrolled
DM with Albuminuria
ACEIACEI - ARB if ACEI intolerant - ARB if ACEI intolerant
- Combination therapy if BP not - Combination therapy if BP not controlledcontrolled
DM without Albuminuria
ACEI; thiazide ACEI; thiazide diuretic; DHP-CCBdiuretic; DHP-CCB
- ARB if ACEI intolerant - ARB if ACEI intolerant
- Combination therapy if BP not - Combination therapy if BP not controlledcontrolled
Diuretics…Diuretics…PharmacologyPharmacology
Thiazide Diuretics…Thiazide Diuretics…PharmacologyPharmacology
Inhibition of NaInhibition of Na++/Cl/Cl-- co-transporter in co-transporter in proximal part of distal convoluted tubuleproximal part of distal convoluted tubule
tubular reabsorption of Natubular reabsorption of Na++ & Cl & Cl--
urinary excretion of Naurinary excretion of Na++, Cl, Cl-- & H & H22OO
extracellular volumeextracellular volume
BPBP CaCa2+2+ reabsorption in distal convoluted reabsorption in distal convoluted
tubuletubule
Thiazide Diuretics…PKThiazide Diuretics…PK
OnseOnset (h)t (h)
tt1/2 1/2
(h)(h)DuratioDuration (h)n (h)
EliminatioEliminationn
Initial DoseInitial Dose
(max. daily (max. daily dose)dose)
ChlorthalidoChlorthalidonene
2-32-3 40-40-8080
24-7224-72 RR 12.5 mg QD 12.5 mg QD (100)(100)
Hydrochloro-thiazide (HCTZ)*
2 2.5-14
6-12 R 12.5 mg QD (50)
IndapamideIndapamide 1-21-2 4-224-22 3636 HH 1.25 mg QD (5)1.25 mg QD (5)
MetolazoneMetolazone 11 4-204-20 12-2412-24 RR 2.5 mg QD (5)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
Thiazide Diuretics…Thiazide Diuretics…ManagementManagement
Start at low doseStart at low doseBaseline SCr/BUN; NaBaseline SCr/BUN; Na++; K; K++; Mg; Mg22++; ; CaCa22++; Cl; Cl--; BG; lipids; uric acid ; BG; lipids; uric acid
↑ ↑ dose every 4 weeksdose every 4 weeks
Monitor SCr/BUN; serum electrolytes Monitor SCr/BUN; serum electrolytes at 1-2 weeks; then every 3-6 months at 1-2 weeks; then every 3-6 months
Thiazide Diuretics…CIThiazide Diuretics…CI
Allergy to sulfonylurea, sulfonamidesAllergy to sulfonylurea, sulfonamides Chronic renal failureChronic renal failure
Minimal efficacy if CrCl < 30 ml/minMinimal efficacy if CrCl < 30 ml/min Hx of gout (may precipitate an Hx of gout (may precipitate an
attack)attack) HypoNaHypoNa++ HypoKHypoK++
DMDM
May worsen glucose controlMay worsen glucose control
Thiazide Diuretics…ADRsThiazide Diuretics…ADRs
DrowsinessDrowsiness Orthostatic hypotensionOrthostatic hypotension PhotosensitivityPhotosensitivity Urinary incontinenceUrinary incontinence HypoKHypoK++; HypoNa; HypoNa++; HypoMg; HypoMg22++; HyperCa; HyperCa22++
HyperuricemiaHyperuricemia HyperglycemiaHyperglycemia ↑ ↑ cholesterol & ↑ LDLcholesterol & ↑ LDL
Loop Diuretics…Loop Diuretics…Pharmacology & PKPharmacology & PK
Inhibition of Na+/KInhibition of Na+/K++/Cl/Cl-- co-transporter in co-transporter in ascending limb of the loop of Henleascending limb of the loop of Henle
reabsorption of Nareabsorption of Na++ & Cl & Cl--
urinary excretion of Naurinary excretion of Na++, K, K++, Cl, Cl--, Mg, Mg2+2+ Ca Ca2+2+ & H & H22OO
OnseOnset (h)t (h)
tt1/2 1/2
(h)(h)DuratioDuration (h)n (h)
EliminatioEliminationn
Initial DoseInitial Dose
(max. daily (max. daily dose)dose)
Furosemide
0.5-1 4 6-8 R 20 mg QD (200)
Loop Diuretics…Loop Diuretics…ManagementManagement
Start at low doseStart at low doseBaseline SCr/BUN; NaBaseline SCr/BUN; Na++; K; K++; Mg; Mg22++; ; CaCa22+ + ; Cl; Cl--; BG; lipids; uric acid ; BG; lipids; uric acid
↑ ↑ dose every 1-2 weeksdose every 1-2 weeks
Monitor SCr/BUN; serum Monitor SCr/BUN; serum electrolytes at 1-2 weeks; 1-2 electrolytes at 1-2 weeks; 1-2 months, then every 3-6 months months, then every 3-6 months
Loop Diuretics…CILoop Diuretics…CI
Allergy to sulfonylurea, sulfonamidesAllergy to sulfonylurea, sulfonamides AnuriaAnuria Increasing azotemia & oliguria on txIncreasing azotemia & oliguria on tx Hepatic coma Hepatic coma HypovolemiaHypovolemia HypoNaHypoNa++ HypoKHypoK++
Hx of goutHx of gout DM DM
Loop Diuretics…ADRsLoop Diuretics…ADRs
TinnitusTinnitus Orthostatic hypotensionOrthostatic hypotension HypovolemiaHypovolemia HypoKHypoK++; HypoNa; HypoNa++; HypoMg; HypoMg22++; HypoCa; HypoCa22++
HyperuricemiaHyperuricemia HyperglycemiaHyperglycemia Metabolic alkalosisMetabolic alkalosis ↑ ↑ cholesterol & ↑ TGcholesterol & ↑ TG
ACE Inhibitors…ACE Inhibitors…PharmacologyPharmacology
Angiotensinogen
Angiotensin I
Angiotensin II
Aldosterone Vascular smooth muscles (AT1 receptor)
Na+ and H2O retention↑ SVR
Renin
ACE ACE inhibitors
ACE Inhibitors…PKACE Inhibitors…PK
Onset Onset (h)(h)
tt1/2 1/2
(h)(h)DuratioDuratio
n (h)n (h)EliminatiEliminati
ononEquivalent Equivalent
dosedose(max. daily (max. daily
dose)dose)
BenazeprilBenazepril 1-21-2 1010 24 24 R/BiliaryR/Biliary 10 mg QD (40)10 mg QD (40)
Captopril 0.2-0.3
< 2 6-12 R 12.5 mg TID (450)
Cilazapril 1 9 24 R 2.5 mg QD (10)
EnalaprilEnalapril 11 22 2424 RR 5 mg QD (40)5 mg QD (40)
FosinoprilFosinopril 11 1212 2424 R/HR/H 10 mg QD (40)10 mg QD (40)
LisinoprilLisinopril 11 1212 2424 RR 10 mg QD (80)10 mg QD (80)
PerindoprilPerindopril 3-73-7 3-103-10 2424 RR 2 mg QD (16)2 mg QD (16)
Quinapril 1 2 24 R/H 10 mg QD (40)
Ramipril 1-2 13-17
24 R/H 2.5 mg QD (20)
Trandolapril
1-2 6 24-72 R/H 1 mg QD (8)
ACE Inhibitors…ACE Inhibitors…ManagementManagement
Start at low doseStart at low dose Baseline SCr/BUN; KBaseline SCr/BUN; K++
↑ ↑ dose at ≥ 2 week intervalsdose at ≥ 2 week intervals
Monitor SCr/BUN; KMonitor SCr/BUN; K++ at 1-2 weeks, 1-3 at 1-2 weeks, 1-3 months, then q6-12 monthsmonths, then q6-12 months
ACE Inhibitors…CIACE Inhibitors…CI
Angioedema or anaphylactic reactionAngioedema or anaphylactic reaction Renal insufficiency (pre-dialysis)Renal insufficiency (pre-dialysis)
>30% increase in SCr>30% increase in SCr HyperKHyperK++
Bilateral renal artery stenosis or Bilateral renal artery stenosis or unilateral disease with solitary kidneyunilateral disease with solitary kidney
Pregnant women (2Pregnant women (2ndnd and 3 and 3rdrd trimester) trimester) risk of major congenital malformations risk of major congenital malformations
Volume depletionVolume depletionElderly, concomitant diuretic therapy, HFElderly, concomitant diuretic therapy, HF
ACE Inhibitors…ADRsACE Inhibitors…ADRs
Tinnitus Tinnitus DysgeusiaDysgeusia Cough (3-50%)Cough (3-50%)
Not dose related Not dose related Rarely improves from switching to a different ACEIRarely improves from switching to a different ACEI
↑ ↑ HR (if volume depleted)HR (if volume depleted) Acute renal failure; proteinuria; oliguriaAcute renal failure; proteinuria; oliguria Angioedema; rashAngioedema; rash Neutropenia; anemiaNeutropenia; anemia HyperKHyperK++
ARBs…PharmacologyARBs…PharmacologyAngiotensinogen
Angiotensin I
Angiotensin II
Aldosterone Vascular smooth muscles (AT1 receptor)
Na+ & H2O retention↑ SVR
Renin
ACE
ARBs
ARBs…PharmacologyARBs…Pharmacology
ARBs are ATARBs are AT11 receptor antagonists & they block receptor antagonists & they block
VasoconstrictionVasoconstriction
Renal NaRenal Na+ + reabsorptionreabsorption
Aldosterone secretionAldosterone secretion
Sympathetic adrenergic activity Sympathetic adrenergic activity
Cardiac & vascular remodeling Cardiac & vascular remodeling
Release of vasopressin, luteinizing hormone, Release of vasopressin, luteinizing hormone, oxytocin, & corticotropin oxytocin, & corticotropin
ARBs…PKARBs…PK
OnseOnset (h)t (h)
tt1/2 1/2
(h)(h)DuratioDuratio
n (h)n (h)EliminatioEliminatio
nnEquivalent Equivalent
dosedose(max. daily (max. daily
dose)dose)
CandesartaCandesartann
2-3 2-3 3-43-4 > 24 > 24 R/HR/H 8 mg QD (32)8 mg QD (32)
EprosartanEprosartan 1-21-2 5-95-9 >24>24 HH 600 mg QD 600 mg QD (800)(800)
IrbesartanIrbesartan 1-21-2 11-11-1515
>24>24 R/HR/H 150 mg QD 150 mg QD (300)(300)
LosartanLosartan 66 1-21-2 10-1510-15 R/HR/H 50 mg QD (100)50 mg QD (100)
TelmisartaTelmisartann
1-21-2 2424 2424 HH 40 mg QD (80)40 mg QD (80)
ValsartanValsartan 2-42-4 66 >24>24 HH 80 mg QD (160)80 mg QD (160)
ARBs…ManagementARBs…Management
Start at low doseStart at low dose Baseline SCr/BUN; KBaseline SCr/BUN; K++; LFTs; LFTs
↑ ↑ dose at interval 2-4 weeksdose at interval 2-4 weeks
Monitor SCr/BUN; KMonitor SCr/BUN; K++ at 1-2 weeks, 1- at 1-2 weeks, 1-3 months, then q6-12 months3 months, then q6-12 months
ARBs…CIARBs…CI
Angioedema due to ARB or ACE inhibitorsAngioedema due to ARB or ACE inhibitors Anaphylactic reactionAnaphylactic reaction Renal insufficiency (pre-dialysis)Renal insufficiency (pre-dialysis) HyperKHyperK++
Bilateral renal artery stenosis or unilateral Bilateral renal artery stenosis or unilateral disease with solitary kidneydisease with solitary kidney
Valvular stenosisValvular stenosis coronary perfusioncoronary perfusion
Pregnant women (2Pregnant women (2ndnd and 3 and 3rdrd trimester) trimester)
ARBs…ADRs ARBs…ADRs
TinnitusTinnitus Cough (3-10%)Cough (3-10%) ↑ ↑ LFTsLFTs Acute renal failure; oliguriaAcute renal failure; oliguria Angioedema; rashAngioedema; rash Neutropenia; anemiaNeutropenia; anemia HyperKHyperK++
-Blockers…Pharmacology-Blockers…Pharmacology
Adrenoreceptors Adrenoreceptors ( (11//22) and ) and ( (11/ / 22))
11-receptors-receptors
HeartHeart ↑ ↑ HRHR ↑ ↑ contractilitycontractility ↑ ↑ AV conductionAV conduction
KidneyKidney ↑↑ renin secretionrenin secretion
-Blockers…-Blockers…PharmacologyPharmacology
22-receptors-receptors
Bronchodilation (lung)Bronchodilation (lung)Vasodilation (peripheral and coronary)Vasodilation (peripheral and coronary) Glycogenolysis and gluconeogenesis (liver)Glycogenolysis and gluconeogenesis (liver)↑ ↑ Insulin/glucagon (pancreas)Insulin/glucagon (pancreas)↑ ↑ KK++ uptake (skeletal muscle) uptake (skeletal muscle)
--Blockers…PKBlockers…PK
Onset Onset (h)(h)
tt1/2 1/2
(h)(h)DuratioDuration (h)n (h)
EliminatioEliminationn
Equivalent Equivalent dosedose
(max. daily (max. daily dose)dose)
Acebutolol 1-2 6-7 12-24 H/R 200 mg (1200)
Atenolol 2-4 6-9 12-24 R 50 mg (100)
Bisoprolol 1-2 9-12 >24 H 10 mg (20)
CarvedilolCarvedilol 1-21-2 7-107-10 >24 >24 HH 50 mg (50)50 mg (50)
Labetolol 0.3-2 2.5-8 8-24 H 200 mg (2400)
Metoprolol 1.5-4 3-4 10-20 H 100 mg (450)
Nadolol 2-4 10-24
17-24 R 80 mg (320)
Pindolol 1-2 2.5-4 12 H/R 7.5 mg (60)
Propranolol
1-2 4-6 6 H 80 mg (640)
Timolol 0.25-0.75
2-2.7 4 H 10 mg (60)
-Blockers…Management-Blockers…Management
Start at low doseStart at low dose
↑ ↑ dose at bi-weekly intervalsdose at bi-weekly intervals
Monitor BP/HR; weight; mental Monitor BP/HR; weight; mental status; circulation in extremitiesstatus; circulation in extremities
-Blockers…CI-Blockers…CI
AbsoluteAbsoluteAsthma/bronchospasmAsthma/bronchospasmHR< 50 bpmHR< 50 bpmAVB (2° or 3°)AVB (2° or 3°)Sick sinus syndrome (SSS)Sick sinus syndrome (SSS)Severe or decompensated HFSevere or decompensated HFPrinzmetal anginaPrinzmetal angina
RelativeRelativePVDPVDSevere depressionSevere depressionDiabetesDiabetesCOPDCOPD
-Blockers…ADRs-Blockers…ADRs
Drowsiness; insomnia; depressionDrowsiness; insomnia; depression ↓↓ HR; HR; ↓↓ peripheral circulation; edema; peripheral circulation; edema;
HFHF BronchospasmBronchospasm ImpotenceImpotence RashRash HypoglycemiaHypoglycemia
CCBs...PharmacologyCCBs...Pharmacology
Block L-type Ca channels Block L-type Ca channels Non-dihydropyridine Non-dihydropyridine vascular smooth vascular smooth muscles and myocardiummuscles and myocardium Coronary vasodilationCoronary vasodilation ↓ ↓ myocardium contractilitymyocardium contractility ↓ ↓ AV node conductionAV node conduction ↓ ↓ Peripheral vascular resistancePeripheral vascular resistance
Dihydropyridine Dihydropyridine vascular smooth vascular smooth musclesmuscles Coronary vasodilationCoronary vasodilation Peripheral vasodilationPeripheral vasodilation
NDHP CCBs…PKNDHP CCBs…PK
Onset Onset (h)(h)
tt1/2 1/2
(h)(h)DuratioDuratio
n (h)n (h)EliminatioEliminatio
nnInitial DoseInitial Dose
(max. daily (max. daily dose)dose)
Diltiazem CD
0.5-1 5-8 12-24 H 120 mg QD (540)
Verapamil SR*
2 6-9 6-8 H 180 mg QD (360)* Verapamil more impact on myocardium contractility
and AV conduction than diltiazem
NDHP CCBs…ManagementNDHP CCBs…Management
Start at low doseStart at low dose
↑ ↑ dose every 2-3 daysdose every 2-3 days
Monitor BP/HR; LFTsMonitor BP/HR; LFTs
NDHP CCBs…CINDHP 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°) SSSSSS
NDHP CCBs…ADRsNDHP CCBs…ADRs
Dizziness; somnolence (D); insomnia (D)Dizziness; somnolence (D); insomnia (D) ↓↓ HR; edema; HF; flushing (D)HR; edema; HF; flushing (D) DyspneaDyspnea GI bleeding; gingival hyperplasia; constipation GI bleeding; gingival hyperplasia; constipation
(V); nausea (V)(V); nausea (V) Polyuria (D)Polyuria (D) Muscular weakness (D)Muscular weakness (D) RashRash
D = Diltiazem; V = VerapamilV = Verapamil
DHP CCBs… ManagementDHP CCBs… Management
Start at low doseStart at low dose
↑ ↑ dose at interval of 7 to 14 daysdose at interval of 7 to 14 days
Monitor BP/HR; weight; peripheral Monitor BP/HR; weight; peripheral edemaedema
DHP CCBs…PKDHP CCBs…PK
OnseOnset (h)t (h)
tt1/2 1/2
(h)(h)DuratioDuratio
n (h)n (h)EliminatioEliminatio
nnInitial DoseInitial Dose
(max. daily (max. daily dose)dose)
AmlodipineAmlodipine 0.5-10.5-1 35-35-5050
2424 HH 2.5 mg QD (10)2.5 mg QD (10)
Felodipine 2-5 11-16
24 H 2.5-5 mg QD (20)
Nifedipine Nifedipine (XL)(XL)
0.30.3 1010 12-2412-24 HH 30 mg QD (180)30 mg QD (180)* NEVER use short acting nifedipine (especially not in hypertensive emergency)
* Nifedipine has more impact on peripheral vascular resistance
DHP CCBs…CIDHP CCBs…CI
Severe HFSevere HF Cerebral tumor Cerebral tumor Severe aortic stenosisSevere aortic stenosis
Hypertensive crisisHypertensive crisis Acute MIAcute MI
Short acting formulation
DHP CCBs…ADRsDHP CCBs…ADRs
Drowsiness; H/A; nervousness; Drowsiness; H/A; nervousness; shakiness; sleep disturbances shakiness; sleep disturbances
Flushing;Flushing; ↓ ↓ HR; peripheral edema; HF HR; peripheral edema; HF N/D/C; heartburn; gingival hyperplasiaN/D/C; heartburn; gingival hyperplasia ImpotenceImpotence Muscular weakness; muscle crampsMuscular weakness; muscle cramps Rash; dermatitisRash; dermatitis
11-blockers…-blockers…PharmacologyPharmacology
Arterioles and venules Arterioles and venules vasodilation vasodilation
systemic vascular resistancesystemic vascular resistance Less tachyphylaxis than non-Less tachyphylaxis than non-
selective selective -blockers-blockers Retention of fluid & saltsRetention of fluid & salts
11-blockers…PK-blockers…PK
Onset Onset (h)(h)
tt1/2 1/2
(h)(h)Duration Duration
(h)(h)EliminatioEliminatio
nnInitial DoseInitial Dose
(max. daily (max. daily dose)dose)
Doxazosin
2-3 22 > 24 H 1 mg QD (16)
Prazosin 2 2-4 10-24 H 1 mg B-TID (20)
Terazosin
1-2 9-12
>24 H/R 1 mg QD (20)
11-blockers…-blockers…ManagementManagement
Start at low doseStart at low dose
↑ ↑ dose bi-weeklydose bi-weekly
Monitor sitting/supine BP Monitor sitting/supine BP
11-blockers…CI-blockers…CI
Volume depleted or elderlyVolume depleted or elderlyRisk of orthostatic hypotension Risk of orthostatic hypotension or syncopeor syncope
Concurrent use of PDE-5Concurrent use of PDE-5
11-blockers…ADRs-blockers…ADRs
DizzinessDizziness Blurred visionBlurred vision Orthostatic hypotension; edema; Orthostatic hypotension; edema;
palpitation; RSCPpalpitation; RSCP Dry mouthDry mouth Urinary incontinenceUrinary incontinence
Central Central 22-Agonist-Agonist Mechanism of actionMechanism of action
Inhibition of efferent sympathetic activationInhibition of efferent sympathetic activation ClonidineClonidine
Initial dose: 0.1 mg BID (max. 2.4 mg/d)Initial dose: 0.1 mg BID (max. 2.4 mg/d)
ADRs: Drowsiness; depression; agitation; ADRs: Drowsiness; depression; agitation; xerostomia; be careful to withdraw (rebound xerostomia; be careful to withdraw (rebound hypertension); orthostatic hypotension; RSCP; hypertension); orthostatic hypotension; RSCP; N/V/C; nocturia; impotence; rashN/V/C; nocturia; impotence; rash
MethyldopaMethyldopaInitial dose: 250 mg B-TID (max. 3g/d)Initial dose: 250 mg B-TID (max. 3g/d)
ADRs: edema; depression; anxiety; nightmares; ADRs: edema; depression; anxiety; nightmares; H/A; dry mouthH/A; dry mouth
VasodilatorsVasodilators
Mechanism of actionMechanism of actionDirect vascular smooth muscle vasodilationDirect vascular smooth muscle vasodilation
HydralazineHydralazineInitial dose: 10 mg QID (max. 300 mg/d)Initial dose: 10 mg QID (max. 300 mg/d)ADRs: Anxiety; depression; conjunctivitis; ADRs: Anxiety; depression; conjunctivitis; dyspnea; dyspnea; ↑↑ HR; angina; N/V/D/C; urinary HR; angina; N/V/D/C; urinary retention; impotence; muscle cramps; retention; impotence; muscle cramps; muscle weakness; tremorsmuscle weakness; tremors
MinoxidilMinoxidilInitial dose: 5 mg QD (max. 100 mg/d)Initial dose: 5 mg QD (max. 100 mg/d)ADRs: Peripheral edema; ADRs: Peripheral edema; ↑↑ HR; angina; HR; angina; pericarditis; pulmonary edema; pericarditis; pulmonary edema; ↑↑ weight; weight; ↑ ↑ ALPALP; ↑; ↑ SCr/BUN; SCr/BUN; hypertrichosis; pruritishypertrichosis; pruritis
ReferencesReferences
Canadian Hypertension Education Program – Canadian Hypertension Education Program – 2007 Guidelines2007 Guidelines
http://hypertension.ca/chep/
BC Ministry of Health: Guidelines & Protocols BC Ministry of Health: Guidelines & Protocols Advisory Committee Advisory Committee Hypertension Hypertension
http://www.health.gov.bc.ca/gpac/guideline_hypertension.html
Other “heart” problemsOther “heart” problems
DyslipidemiaDyslipidemiaCan be associated with decrease in renal functionCan be associated with decrease in renal function↑ ↑ in Triglyceride and in Triglyceride and HDL HDL
1.1. Diet modificationsDiet modifications
2.2. StatinStatinBest choice if Best choice if ↑ LDL↑ LDLADRs:ADRs: muscle cramps; muscle weakness; muscle muscle cramps; muscle weakness; muscle pain; ↑ CK; rhabdomyolysis; hepatotoxicity; headachepain; ↑ CK; rhabdomyolysis; hepatotoxicity; headache
3.3. FibrateFibrateBest choice if Best choice if ↑ Tg↑ TgLess case of Less case of ↑ serum creatinine with Gemfibrozil↑ serum creatinine with GemfibrozilADRs:ADRs: rash; diarrhea; myalgia; rhabdomyolysis; rash; diarrhea; myalgia; rhabdomyolysis; hepatotoxicityhepatotoxicity
Other “heart” problemsOther “heart” problems
DigoxinDigoxinInhibits sodium-potassium ATPase in heart Inhibits sodium-potassium ATPase in heart → better heart → better heart contraction, decrease sympathetic responsecontraction, decrease sympathetic responseUse in CHF (low dose) and A. FibUse in CHF (low dose) and A. Fib50-70% eliminated by kidney… usually 0.0625 mg po OD to 3 50-70% eliminated by kidney… usually 0.0625 mg po OD to 3 x/weekx/weekAdjustment based on digoxin level (0.8-1.2 for CHF; 0.8 to 2 for Adjustment based on digoxin level (0.8-1.2 for CHF; 0.8 to 2 for A.fib)A.fib)ADRs: diarrhea, N/V, cardiac dysrythmia, headahce, visual ADRs: diarrhea, N/V, cardiac dysrythmia, headahce, visual disturbancesdisturbances
AmiodaroneAmiodaroneAntiarrhythmic drug blocking potassium and sodium channelAntiarrhythmic drug blocking potassium and sodium channelUse for ventricular/Supraventricular arrythmia; A.FibUse for ventricular/Supraventricular arrythmia; A.FibMinimally renally eliminatedMinimally renally eliminatedADRs:ADRs: bradycardia, hypotension, thyroid problems, bradycardia, hypotension, thyroid problems, photosensitivity, nausea/vomiting, neuropathy, visual photosensitivity, nausea/vomiting, neuropathy, visual disturbances, fatigue, hepatotoxicitydisturbances, fatigue, hepatotoxicity
Kidney Quiz… Kidney Quiz…
You and your nursing student is You and your nursing student is reviewing Mr. K.N.’s MAR. He is reviewing Mr. K.N.’s MAR. He is questioning the use of Renavite in questioning the use of Renavite in patient with renal failure… why just patient with renal failure… why just not giving them a regular vitamin?!not giving them a regular vitamin?!
What is your answer? Should we What is your answer? Should we switch Mr. K.N. to Centrum, 1 tablet switch Mr. K.N. to Centrum, 1 tablet PO daily?PO daily?
Vitamins in CKDVitamins 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 ODDO NOT GIVE liposoluble vitamins because of toxicity risk
Vitamin A: in excess, cause osteodystrophy, anemia, hypercalcemia, skin problemsVitamin D: ineffectiveVitamin E: generally elevated in CKD ptVitamin K: sufficient quantity available and hypercoagulabitlity
Vitamins in CKDVitamins in CKD
ZincDialysable, reduced absorption as bound to calcium, poor dietary intakeZinc deficiency is associated with:
Impaired taste and poor appetiteHair lossPoor wound healing
Recommended dose is 15 mg/day (if deficiency is suspected)
Zinc sulfate 50 mg 3 x/weekZinc gluconate 10-20 mg po QDReassess after 4-8 weeks
APPETITE STIMULANTSAPPETITE STIMULANTS
Malnutrition accounts for significant Malnutrition accounts for significant morbidity and mortalitymorbidity and mortality
Moderate-severe malnutrition ~ 30% of Moderate-severe malnutrition ~ 30% of dialysis patients dialysis patients
Improving nutrition in dialysis patientsImproving nutrition in dialysis patientsoptimize dialysis durationoptimize dialysis durationimprove oral diet with enteral supplements improve oral diet with enteral supplements total parenteral nutrition (intradialytic)total parenteral nutrition (intradialytic)drug therapy (megestrol acetate)drug therapy (megestrol acetate)
MEGESTEROL ACETATE MEGESTEROL ACETATE (Megace)(Megace)
Progesterone derivative with appetite Progesterone derivative with appetite stimulating propertiesstimulating properties
HPB approved for cancer- or AIDS-HPB approved for cancer- or AIDS-related cachexia, anorexia or weight related cachexia, anorexia or weight lossloss
Currently being studied in dialysis Currently being studied in dialysis patients as an appetite stimulantpatients as an appetite stimulant
MEGESTEROL ACETATE MEGESTEROL ACETATE (Megace)(Megace)
Dose: 160-800 mg daily (study Dose: 160-800 mg daily (study dose = 800 mg daily)dose = 800 mg daily)
Amount and Type of Weight Amount and Type of Weight Gained:Gained:
average 2-5 kg weight gain within 1-3 average 2-5 kg weight gain within 1-3 months months
fat versus lean body massfat versus lean body mass
MEGESTEROL ACETATE MEGESTEROL ACETATE (Megace)(Megace)
Side Effects:Side Effects:sexual dysfunction (4-26%)sexual dysfunction (4-26%)deep vein thrombosis (< 5%)deep vein thrombosis (< 5%)withdrawal menses or breakthrough withdrawal menses or breakthrough
bleeding (early)bleeding (early)hyperglycemia (within first 3 months)hyperglycemia (within first 3 months)gastrointestinal complaintsgastrointestinal complaintsexcess weight gain (>10 kg)excess weight gain (>10 kg)
Contraindications: thromboembolic diseaseContraindications: thromboembolic disease
GASTROINTESTINAL GASTROINTESTINAL DISORDERSDISORDERS
RefluxReflux
Peptic Ulcer DiseasePeptic Ulcer Disease
Motility DisordersMotility Disorders
NauseaNausea
CAUSESCAUSES
Diabetes gastroparesisDiabetes gastroparesisMedications: Calcium, Aluminum Medications: Calcium, Aluminum phosphate binders, Diavite, and Iron, phosphate binders, Diavite, and Iron, prednisone and cyclophosphamideprednisone and cyclophosphamideUremia of renal failure and infusion of Uremia of renal failure and infusion of peritoneal dialysis fluidperitoneal dialysis fluidConstipation: due to fluid restriction, Constipation: due to fluid restriction, restriction of fruits and fruit juices, iron restriction of fruits and fruit juices, iron supplements, phosphate binderssupplements, phosphate binders
IMPORTANCE OF IMPORTANCE OF MANAGEMENTMANAGEMENT
Maintenance of nutritionMaintenance of nutrition
Symptom controlSymptom control
MEDICAL MANAGEMENTMEDICAL MANAGEMENT
Determine cause or source of problemDetermine cause or source of problem
Nausea due to medications - taking with some food (if Nausea due to medications - taking with some food (if no interactions)no interactions)
Antiemetics such as prochlorperazine, haloperidol or Antiemetics such as prochlorperazine, haloperidol or dimenhydrinatedimenhydrinate
If gastroparesis - prokinetic agentsIf gastroparesis - prokinetic agents
If suspected reflux - ranitidine If suspected reflux - ranitidine
(not cimetidine - impact on serum creatinine and (not cimetidine - impact on serum creatinine and interstitial nephritis)interstitial nephritis)
If reflux resistant to ranitidine or UGIB– omeprazole, If reflux resistant to ranitidine or UGIB– omeprazole, rabeprazole etc.rabeprazole etc.
PROKINETIC AGENTSPROKINETIC AGENTS
Metoclopramide Metoclopramide Adverse effects - extrapyramidal Adverse effects - extrapyramidal symptoms (EPS) at higher doses + symptoms (EPS) at higher doses + in childrenin children
Start dose of 5 mg qid (max: 20 Start dose of 5 mg qid (max: 20 mg po QID)mg po QID)
Domperidone Domperidone 10 - 40 mg PO tid-qid10 - 40 mg PO tid-qid
UREMIC PRURITUSUREMIC PRURITUS
Causes unknownCauses unknown
Mechanism poorly Mechanism poorly understoodunderstood
CLINICAL ASPECTSCLINICAL ASPECTS
25-33% predialysis 25-33% predialysis patientspatients
60-86% dialysis patients60-86% dialysis patients
10-14% less in capd vs. 10-14% less in capd vs. hemodialysishemodialysis
Non age or gender Non age or gender dependentdependent
PersistentPersistent
POSSIBLE CAUSESPOSSIBLE CAUSES
Uremic skinUremic skin
Cutaneous mast cell Cutaneous mast cell proliferationproliferation
Atrophy of the sebaceous and Atrophy of the sebaceous and sweat glandssweat glands
Increased skin pHIncreased skin pH
Secondary hyperparathyroidismSecondary hyperparathyroidism
Divalent-ion abnormalitiesDivalent-ion abnormalities
POSSIBLE CAUSESPOSSIBLE CAUSES
Hypervitaminosis AHypervitaminosis A
Iron deficiency anemiaIron deficiency anemia
Peripheral neuropathyPeripheral neuropathy
Middle weight moleculesMiddle weight molecules
Bile acidsBile acids
MANAGEMENTMANAGEMENT
Regular intensive dialysisRegular intensive dialysis
Restricted phosphate dietRestricted phosphate diet
Phosphate bindersPhosphate binders
Erythropoietin and iron Erythropoietin and iron supplementationsupplementation
Emollients/topical corticosteroids Emollients/topical corticosteroids (1% HC, 3% SA, 5% PG, 10% urea in (1% HC, 3% SA, 5% PG, 10% urea in glaxal base)glaxal base)
UVB/UVAUVB/UVA
MANAGEMENTMANAGEMENT
AntihistaminesAntihistamines
CholestyramineCholestyramine
Activated charcoalActivated charcoal
Subtotal parathyroidectomySubtotal parathyroidectomy
Oatmeal/baking soda/salt Oatmeal/baking soda/salt water/bath oilswater/bath oils
100% Cotton wear100% Cotton wear