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


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)


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


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


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


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


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


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


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


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


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


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


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


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


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


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 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


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


Mr K. N. results during next BW week:Mr K. N. results during next BW week:




Mr K. N. results during next BW week:Mr K. N. results during next BW week:




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.


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


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


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


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


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


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


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


DM without Albuminuria

ACEI; thiazide ACEI; thiazide diuretic; DHP-CCBdiuretic; DHP-CCB

- ARB if ACEI intolerant - ARB if ACEI intolerant


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



Initial DoseInitial 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


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



Equivalent Equivalent dosedose


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



nnInitial DoseInitial 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


↑ ↑ 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


↑ ↑ 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





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



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


↑ ↑ 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


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


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


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

Documents

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