12-Pharm Care in CKD

7/28/2019 12-Pharm Care in CKD

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Pharmacotherapy

of

Chronic Kidney Diseases

Denpong Patanasethanont., Ph.D.Division of Pharmacy Practice

Faculty of Pharmaceutical Sciences

Khon Kaen University

Advanced Pharmacotherapeutics I/ November 13th 2008

Professional education resources on

management of CKD

l National Kidney Foundation, Kidney Disease OutcomeQuality Initiative (K/DOQI)

www.kidney.org/professionals/doqi/index.cfm

l National Kidney Disease Education Program

www.nkdep.nih.govl Veterans Affairs/Department of Defense clinical practice

guideline on pre-ESRD care

www.oqp.med.va.gov/cpg/ESRD/ESRD-Base.htm

l Nephrology Section of Yale University of Medicine

http://kidney.med.yale.edu/pages/Entry.html

Stage of chronic kidney disease

Stage Description GFR (ml/min/1.73m2)

1 Kidney damage withnormal or increase GFR

>90

2 Kidney damage with

mild decrease GFR

60-89

3 Moderate decrease GFR 30-59

4 Severe decrease GFR 15-29

5 Kidney failure


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CKD

death

Stages in Progression of Chronic KidneyDisease and Therapeutic Strategies

Complications

Screening

for CKD

risk factors

CKD risk

reduction;

Screening for

CKD

Diagnosis

& treatment;

Treat

comorbid

conditions;

Slow

progression

Estimate

progression;

Treat

complications;

Prepare for

replacement

Replacement

by dialysis

& transplant

NormalIncreased

risk

Kidney

failureDamage GFR

Am J Kidney Dis 39:S1246, 2002

Optimal care by NKF stages of CKD

components Stage

1 2 3 4 5

Dx and Tx yes yes yes yes yes

Tx of comorbid conditions yes yes yes yes yes

Slowing progression yes yes yes yes -

CVD risk reduction yes yes yes yes yes

Estimating progression - yes yes yes yes

Evaluating and treating - - yes yes yes

complications

Preparation for RRT - - - yes -

RRT (if uremia present) - - - - yes

l preparing for end-stage renal disease (ESRD)l initiation of renal replacement therapy (RRT)

l adequate medical and psychological preparation

Critical step in the care of patients with CKD

Timing and quality of care

prior to dialysis

morbidity and mortality of ESRD

Quality-of -life


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Renal insufficiency

Acute renal failure (ARF)

Chronic kidney disease (CKD)

Drug dosing adjustment ?

Closely monitoring?

Renal excretion of drugs

Glomerular filtration

Tubular secretion

Tubular reabsorption

CASE STUDY

65 y/o male, 42 Kg, 168 cm.

CC: Short of breath, urine

l Underlying mod. MR c MS c chronic AF c CKD stage 3,

no DM, no HTN

l H/O gross hematuria from coumadin overdose last admit

14-21/11/50

l On coumadin(3) 1x1, Simvastatin(20) 1x1, moduretic 1x1

l PE: VS; PR 160, BP 98/66, BT 37.2, RR 24

crepitation both lung, active precordium, heaving thrill

positive

l Imp. 1. Mod. MR c MS c chronic AF

2. Lt. side heart failure

3. CKD stage 3

l Lab.29/11/50

BUN 42, Scr 2.2,

Na 137, K 4.8, Cl 108, Ca 8.9, PO4 4.2, Mg 2.7

Hgb 14, Hct 43.6, PT 36.4, PTT 34.6, INR 3.05

l Medication:

One day Lasix (40) IV stat

Digoxin (0.25) IV stat.

Diltiazem (30) tab, po q 8 h

Continue Coumadin(3)1x1 po hs

Simvastatin(20) 1x1 po hs

Digoxin (0.25) po EOD

Co-morbid condition

CKD stage 3, GFR 30-59 ml/min

l Decrease in Ca absorption

l Lipoprotein activity falls

l

Malnutritionl Onset of LVH

l Onset of anemia (erythropoietin deficiency)

l Hypertension (mild)


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l improve morbidity and mortality

l

prevent or delay progression ofkidney disease

Current Treatment

Biologic consequences of sustained reduction in GFR

Plasma conc.

Normal range

Total GFR (%of normal)

Overt renal

failureZone of compensation

(adequate renal reserve)

A

B

C

A = creatinine

and urea

B = PO4, urate,

K+, H+

C = NaCl

0 25 50 75 100

CKD and complications

lDecrease in Ca absorption

lLipoprotein activity falls

lMalnutrition

lOnset of LVH

lOnset of anemia

(erythropoietin deficiency)

lHypertension (mild)

30-593

lPTH start to rise

lHypertension possible

60-892

>901

complicationsGFRStage

CKD and complications

lTriglyceride conc. start to rise

lHyperphosphatemia

lMetabolic acidosis

lTendency to hyperkalemia

lHypertension (moderate)

15-304

lAzotemia develops

lHypertension (severe)


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CASE STUDY

l 32 63 158 type1 DM 15 1 BS > 200, A1C>8%

l Na 143, K 5.3, Cl 106, CO2

18, SCr 2.9 mg/dL,

BUN 63, BS 220, PO4 7.6, Ca 8.8, Mg 2.8, uric

acid 8.8

l Hct. 26, Hgb 8.7, WBC 9600, RBC indices

normal, Plt 170000,

l UA: 4+ proteinuria, Alb 700 mg/day (normal


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Recommendations for glycemic control in DM

Goal values

Normal

value

Glycemic

measureAmerican college of

EndocrinologyAmerican Diabetes

Association


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Recommendations from Treatment guidelines

ACEI,ARBProteinuria < 1 g/d:/= 1 g/d:


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Tobacco Cessation

l Smoking, in a dose- dependent manner,increase urinary excretion of albumin

l There is also evidence that smoking may

accelerate a decline in GFR

l The guidelines recommended that all clinicians,

including pharmacists, provide smokingcessation interventions

l Five As is suggested to provide smoking

cessation counseling

Anemia

l progressive erythropoietin deficiency

l Iron deficiency

l normochromic, normocytic anemia

l Early treatment of anemia

l decreased hospitalizations for CVS

complications (LVH)l improved survival, exercise capacity,

cognitive function, quality of life

l CKD => Left ventricular hypertrophy

l 39% in GFR


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Erythropoiesis-stimulating agents

Recommended to read;

l Cardiovascular Risk Reduction in Early Anemia

Treatment with Epoetin Beta (CREATE)(Dreke TB et al. N Engl J Med. 2006;355:2071-2084)

l Correction of Hemoglobin and Outcomes in

Renal Insufficiency (CHOIR) trials

(Singh AK et al. N Engl J Med. 2006;355:2085-2098)


l Epoetin alfa (EPIAO, EPREX, ESPOGEN, HEMAX)l 25 -50 IU/kg iv. or sc. 3X/wk

l Adjust increase 25 IU/Kg q 4 wk then 75 IU/ kg 3X/wk

l Epoetin beta (RECORMON)l Sc. : 20 IU / kg 3x/wk, adjust increase 20 IU / kg q 4 wk.

l iv : 40 IU / kg 3x/wk for 4 wk then adjust increase 80 IU/kg

l Maximum dose : 720 IU/ kg /week

There have been no reports that epoetin alfa differs fromepoetin beta in its clinical efficacy

l Darbepoetin ARANESP

l Half-life: 3x of Epoetin alfa (i.v.)

l 0.45 g/kg once a week.

l 0.75 g/kg q 2 weeks

Administration of Epoetinl The dosage of epoetin is individual with more than

tenfold variability among individuals

l no clinical parameters of predicting the necessarydosage.

l Therapeutic range is very wide (up to 100.000IU/week.)

l The HB concentration, along with the reticulocytecount, must be checked

l Initiation: weekly

l Maintenance: monthly

l stable dose-response: every 2-3 months

l The target Hb concentration 11-12 g/dL ismaintained in 90-95% of the patients by

administering

l 1.000-30.000 IU of epoetin per week or

l 5-150 mcg darbepoetin alpha per weekin the presence of adequate reserves of iron.

l Higher dosages define a state of resistance.

Administration of Epoetin (cont.)


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l For all patients:l Adhere to dosing to maintain the recommended target

hemoglobin range of 10 to 12 g/dL.

l Measure hemoglobin twice a week for 2 to 6 weeksafter any dosage adjustment to ensure thathemoglobin has stabilized in response to the dosechange.

l Decrease the dose of the ESA if the hemoglobinincrease exceeds 1 g/dL in any 2-week period.

l For CKD patients:l Measure hemoglobin twice a week after initiating

treatment until hemoglobin has stabilized

US FDA Issues Safety Warning on Erythropoietin

Hyperparathyroidism

and Renal Osteodystrophy

l CKD => hypocalcemia => increase in parathyroidhormone levels => bone metabolism abnormality=> renal osteodystrophy

l Inability of kidney to activate vitamin D needed for

calcium absorption from the gut=> phosphate retention

l complications ; soft tissue calcification, pruritus,proximal myopathy, skin ulceration, soft tissuenecrosis

=> impaired pulmonary & heart

Frequency of Measurement of

PTH, Ca, PO4

Every moEvery 3 mo


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Phosphate Binder

l Calcium product

l Aluminium hydroxide

l Calcium-Aluminum free

Phosphate Binderl Calcium carbonate (40% elemental calcium)

l

l > 6 g/day

l 20-30% absorbed

l 39 mg phosphate bound per 1 g CaCO3

l Try to limit daily intake 1.5 g of elemental Ca per day

l Calcium acetate (25% elemental calcium)l 3 g/dayl

l Absorption with meal: 20%, between meal 40%

l

l Do not exceed 1.5 g of elemental Ca per day

l 45 mg phosphate bound per 1 g Ca acetate

l GI side effects, constipation, hypocalcaemia, extraskeletal calcification

Phosphate Binderl Aluminium hydroxide

l Calcium-Phosphate product > 55 mg2/mL2

l Reserve for short-term 4 weeks

l Do not use concurrently with citrate-containing products

l ADR:

l Constipation/fecal impaction

l Bone mineral defects

lAnemia, Dementia

l Chalky taste, GI distress, N/V

l Liquid: (6.1% suspension)

l Mean binding 22.3 mg phosphate per 5 mL(320 mg/5mL)

l Tablets (500 mg)

l Mean binding 15.3 mg per pill

Phosphate Binder

l Calcium-Aluminum freel Sevelamer hydrochloride (Renagel)

l Sevelamer carbonate (Renvela) less GI S/E

l Poly (allylamine hydrochloride),

l a polymeric amine oral administration

l No absorption

l no hypercalcemia

l Lowers LDL cholesterols, uric acid

l more expensive


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Sevelamer Hydrochloride

l Renagell film-coated tablet 800 mg or 400 mg

l indicated for the control of serum

phosphorus in patients with chronic kidneydisease (CKD) on dialysis

l 80 mg Phosphate bound per mgSevelamer (animal data only)

l Decrease bioavailability of Ciprofloxacin50%


4 tablets three times

daily with meals


daily with meals 9.0 mg/dL


daily with meals


daily with meals

7.5 and

< 9.0 mg/dL


daily with meals

1 tablet three times

daily with meals

> 5.5 and

< 7.5 mg/dL

400 mg800 mgSerum Phosphorus

Product information


5 tablets3 tablets3 tablets

3 tablets2 tablets2 tablets

2 tablets1 tablet1 tablet

400 mg

(Tablets per meal)

800 mg

(Tablets per meal)

Calcium Acetate

667 mg

(Tablets per meal)

Product information


Decrease 1 tablet per meal< 3.5 mg/dL

Maintain current dose3.5 - 5.5 mg/dL

Increase 1 tablet per meal

at 2 week intervals> 5.5 mg/dL

DoseSerum

Phosphorus

Product information

The average dose in a Phase 3 trial designed to

lower serum phosphorus to 5.0 mg/dL or less was

approximately three of 800 mg tablets per meal.

The maximum average daily dose studied was 13 g.


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Vitamin D

l PTH > 110 pg/mL

l and/or Ca < 9.5 mg/dL

l and/or PO4 < 4.6 mg/dL

l Alfacalcidal (0.25 g, 0.5 g , 1 g)

l (Alpha D3, One-alpha , Bon-One )

l 0.25-1 g OD X3/wk

l Calcitriol (0.25 g)

l (Rocaltrol, Calcit SG, Decostriol, Osteo D)

l 2-4 g OD x3/wk

Vitamin D

Dosing recommendations for calcitriol

in stage 5 CKD on hemodialysis

If Ca < 9.5 mg/dL, PO4 < 5.5 mg/dL, Ca x PO4 < 55 mg2/dL2

3-7 oral

or 3-5 g IV

>1000

1-4 g oral

or 1-3 g IV

600-1000

0.5-1.5 g oral or IV300-600

IV and oral Calcitriol

Dose per HD

iPTH (pg/mL)

Eknoyan G, Am J Kidney Dis 2003;42:1-201

Protein Diet

l RDA = 0.8 g/kg/day

l Thai RDA = 50 g/day

Recommended for CKD patients (USA)l GFR > 30 mL/min/1.73 m2

(or plus proteinurea >3g/day)

l Protein intake 0.75 g/kg/day

l ( )

l GFR < 30 mL/min/1.73 m2

l Not more than 0.6 g/kg/day

Protein Diet (cont.)

l High biological value protein

l ,l 60%

l l 1 = 2 2

l 0.6-0.75 g/kg/day 1 1 (3 )


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Protein Diet (cont.)

l l l l

l

l () () l ()l l ( )

l l

Salt (NaCl)

According to JNC VII

l Normal BP with

l Type 2 DM, CKD, RRT, Pitting edema, including of

Nephrotic syndrome

l NaCl not more than 6 g/day

l Hypertension

l Not more than 4 g/day (or 5 g/day)

l Avoid instant food, seasoning, Food in restaurant

Salt (NaCl)

Recommend for normal people102.542358.96

Recommended by ESH and ESC 2007

for Hypertension

85.471965.85

Recommended by JNC VII

for Hypertension

68.371572.64

Remark

Na

(mEq)

Na

(mg)

NaCl

(g)

15

10

MW Na = 23

Cl = 35.5

Sodium bicarbonate

l When HCO3- < 17 mEq/L

l Supplement 0.5-1.0 mEq/kg/day

l Titrate to bicarbonate level 18-20 mEq/L

l !! ! Sodium content!!!!

l Sodamint (Sodium bicarbonate) (Sodamint 300 mg)l 1 mEq NaHCO3 = 84 mg (sodium content 23 mg)

l 300 mg = HCO3- ~ 3.7 mEq (sodium content ~82 mg)

l 650 mg = HCO3- ~ 8 mEq (sodium content ~178 mg)

l Shohls solution (Sodium citrate)

l 140 g citric acid and 98 g hydrated crystalline salt ofsodium citrate, distilled water to make 1000 ml;

l 1 mL = 1 mEq

l


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Renal insufficiency

Effect to Pharmacokinetics

l Absorptionl Uremic gastroparesis can alter rate of drug absorption

l Gastric pH

l

Gastrointestinal tract edemal Vomitting and diarrhea

l Antacid or cholestyramine

l Distributionl Edema or ascites

l increase Vd of water soluble drugs

l Uremic statesl alter plasma protein binding

l Tissue protein binding is reduced decrease Vd

l Metabolism

l Hepatic biotransformation may be altered

l Excretion

l

Most important pharmacokinetic parameters alteredl Creatinine clearance is the guiding factor for drug

dosage

l Clinical pharmacokinetics approach for narrow

therapeutic index may be altered

Renal insufficiency

Effect to Pharmacokinetics (cont.)

Steps to Adjust Drug Dosages

for Patients with Renal Insufficiency

Important points for patient with dialysis

Dialysis can remove drug?

Dosing supplementation is necessary?

Resources for More Information

About Dosing Adjustments

in Patients with Chronic Kidney Disease


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Determination of renal function

Clcrusing Cockcrof&Gaults equation**

Clcr= (140-age)(LBW) (0.85 if female)72 Scr

*Unit = mL/min/1.73 m2, A 70 kg/1.73 m2BSA is assumed

MDRD study equation**

GFR = 186 (Scr)-1.154 (Age)-0.203(0.742 if female)

(1.210 if African-American)

l **MDRD: Modification of diet in renal disease

l Age >18 year-old

l **Unit = mL/min/1.73 m2, > 60 mL/min/1.73m2 is not exact number

Equations for Predicting Creatinine Clearance

or GFR in Adults with Kidney Disease

Estimated baseline creatinine

base on MDRD formula

age male female

20-24 1 . 3 1 . 0

25-29 1 . 2 1 . 0

30-39 1 . 2 0 . 9

40-54 1 . 1 0 . 9

55-65 1 . 1 0 . 8

>65 1 . 0 0 . 8

24 hour urine collection (mL/min)CrCl = Ucr V

Scr T

l CrCL= creatinine clearance (mL/min)

l Ucr = urinary creatinine conc. (mg%)l V= Volume of urine during collection period (mL)

l Scr = serum creatinine concentration (mg%)

l T = collection time (min) (if 24 hr = 1440 min)

Determination of renal function (cont.)


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24 hour urine collection

CrCl = Ucr(g/Vol) X Vol (L)

Scr(mg/dL) x T(day)

= Ucr(g/Vol) X Vol (L) x 103

Scr(g/L) x T(min) x (24x60)(102)

CrCl = 6.94(Ucr/Scr)

CrCl ~ 7(Ucr/Scr)

l Protein report g volume (L) Urine

ACEI

25-5050-75100Lisinopril

5075-100100Enalapril

5075100Captopril

50

25-5050-75100Ramipril

7575-100100Quinapril

75-100100100Fosinopril

% of usual Dose

based on GFR mL/min/1.73 m2Drug

American Family Physician Web site atwww.aafp.org/afp

Case Study

l 60 y/o male 90 kg; infected CAPD

l PDF : staphylococcus coagulase negative

sensitivity: Vancomycin

on Vancomycin 1 G + D5W 200 ml IV in 2 hr.

q 96 hr. start 25/10/50

l Vancomycin conc. on 29/10/50 = 7.19 mg/L

Target Vancomycin trough

l For MRSA with MIC 2 mcg/ml

l 50% Protein binding

l Target trough => 4-5 times the MIC

l Target trough = 15-20 mcg/ml

l 20% lower response rate in pt. who did not

achieve target trough initially(76% vs 56%,

p=.05; Hidayat et al. 2006)
http://www.aafp.org/afphttp://www.aafp.org/afp


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l Predicted Cmax after 1st dose

Cmax1 = [1000mg/59.5L] x e -0.0056x2

= 16.64 mg/L

l Cmin1 = 7.19 mg/L (measured level)

l Cmax2 = 7.19 + 16.64 = 23.83 mg/Ll Cmin2 = 23.83 x e -0.0056x96

= 13.82 mg/L

l Cssmax = 39.62 mg/L

l Cssmin = 23.21 mg/L

16.64

7.19

23.83

13.82

39.62

23.21

30

15

Time

Conc.

40

l To help reduce drug-induced CKD in

primary care

l comprehensive drug histories

l prescribing of appropriate dosages

l avoidance of nephrotoxins in pt with underlying

renal problems

l monitoring of nephrotoxic drug therapies

Many pharmacologic agents

can cause kidney damage

Avoidance/Precaution

for patient with CKD

l Pharmacologic agents

l IV radiographic contrast agents

l selected antimicrobials : AMGs, amphotericin B

l NSAIDs (including COX-2 selective inhibitors)

l cyclosporine and tacrolimus

l Volume depletion

l Obstruction of the urinary tract

l The benefits of ACEI and ARB outweigh the

risks; titrating dosage will minimize the risk

of kidney damage


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Assessment of nephrotoxicity

Identification of drug-induced nephrotoxicity

l a change in Scr of at least 0.5 mg/dL for subjects with a baseline

Scr 2 mg/dL, whencorrelated temporally with the initiation of drug therapy

l Serum creatinine or BUN concentrations and urine

collection for creatinine

l intrasubject between-day variability of Scr (20% within thenormal range).

Potential roles and responsibilities

l Attainment of blood pressure goal

l Attainment of glycemic goals in those with diabetes

l Early evaluation and treatment for proteinuria

l Early evaluation and therapy for anemia

l Early evaluation and therapy for secondaryhyperparathyroidism

l Attainment of lipid goals, where appropriate

l Appropriate drug dosing adjustments

l Minimization of drug-related nephrotoxin exposure

l Provision of drug therapy instruction

l Screening for ability to afford drugs

l Education regarding smoking cessation, whereappropriate

Documents

12-Pharm Care in CKD