Pharmacotherapy of

Chronic Kidney Diseases

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

Faculty of Pharmaceutical SciencesKhon Kaen University

Advanced Pharmacotherapeutics I/ November 13th 2008

Professional education resources on management of CKD

l National Kidney Foundation, Kidney Disease Outcome Quality Initiative (K/DOQI)www.kidney.org/professionals/doqi/index.cfm

l National Kidney Disease Education Programwww.nkdep.nih.gov

l Veterans Affairs/Department of Defense clinical practice guideline on pre-ESRD carewww.oqp.med.va.gov/cpg/ESRD/ESRD-Base.htm

l Nephrology Section of Yale University of Medicinehttp://kidney.med.yale.edu/pages/Entry.html

Stage of chronic kidney diseaseStage Description GFR

(ml/min/1.73m2)1 Kidney damage with

normal or increase GFR>90

2 Kidney damage withmild decrease GFR

60-89

3 Moderate decrease GFR 30-59

4 Severe decrease GFR 15-29

5 Kidney failure <15 or dialysis

note: Chronic kidney disease is defined as the presence of kidney damage or a reduction in GFR for a period of three months or longer.

K/DOQI = Kidney Disease Outcomes Quality Initiative; GFR = glomerular filtration rate.

National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Am J Kidney Dis 2002;39(2 suppl 1):S46.

Many opportunities exist for pharmacists who practice in the primary care setting to improve the care of patients with CKD.

CKDdeath

Stages in Progression of Chronic Kidney Disease and Therapeutic Strategies

Complications

Screening for CKD

risk factors

CKD riskreduction;

Screening forCKD

Diagnosis& treatment;

Treat comorbid

conditions;Slow

progression

Estimateprogression;

Treatcomplications;

Prepare forreplacement

Replacementby dialysis

& transplant

Normal Increasedrisk

KidneyfailureDamage ↓ GFR

Am J Kidney Dis 39:S1–246, 2002

Optimal care by NKF stages of CKD

components Stage1 2 3 4 5

Dx and Tx yes yes yes yes yesTx of comorbid conditions yes yes yes yes yesSlowing progression yes yes yes yes -CVD risk reduction yes yes yes yes yesEstimating progression - yes yes yes yesEvaluating and treating - - yes yes yes

complicationsPreparation 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 ESRDQuality-of -life

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

no DM, no HTNl H/O gross hematuria from coumadin overdose last admit

14-21/11/50l On coumadin(3) 1x1, Simvastatin(20) 1x1, moduretic 1x1l 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 AF2. Lt. side heart failure3. CKD stage 3

l Lab.29/11/50BUN 42, Scr 2.2, Na 137, K 4.8, Cl 108, Ca 8.9, PO4 4.2, Mg 2.7Hgb 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) ½ tab, po q 8 h

Continue Coumadin(3)1x1 po hsSimvastatin(20) 1x1 po hsDigoxin (0.25) ½ po EOD

Co-morbid conditionCKD stage 3, GFR 30-59 ml/minl Decrease in Ca absorptionl Lipoprotein activity fallsl Malnutritionl Onset of LVHl Onset of anemia (erythropoietin deficiency)l Hypertension (mild)

l improve morbidity and mortalityl prevent or delay progression of

kidney disease

Current Treatment

Biologic consequences of sustained reduction in GFR

Plasma conc.

Normal range

Total GFR (%of normal)

Overt renal failure

Zone of compensation (adequate renal reserve)

A

B

C

A = creatinineand urea

B = PO4, urate,

K+, H+

C = NaCl

0 25 50 75 100

CKD and complications

lDecrease in Ca absorptionlLipoprotein activity fallslMalnutritionlOnset of LVHlOnset of anemia (erythropoietin deficiency)lHypertension (mild)

30-593

lPTH start to riselHypertension possible

60-892

>901

complicationsGFRStage

CKD and complications

lTriglyceride conc. start to riselHyperphosphatemialMetabolic acidosislTendency to hyperkalemialHypertension (moderate)

15-304

lAzotemia developslHypertension (severe)

<155

complicationsGFRStage

CASE STUDYl ผูปวยหญิงไทยคู อายุ 32 ป หนัก 63 กก 158 ซม มีประวัติเปน type

1 DM 15 ป มีคลื่นไส อาเจียน เพลีย ออนแรงมา 1 สัปดาห ไมยอมคุมระดับน้ําตาลในเลือด สองเดือนท่ีแลวมาตรวจพบ 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 <30 mg/day)

l BP155/102 mmHg, mild pulmonary congestion, 2+ pedal edema,

Findingl CrCl 28 mL/minl Stage 4 CKDl E’Lyte imbalancel Advanced glomerular damagel Volume overload (Na ?? N/V ??)l HT, Congestive pulmonary dz, edemal Matabolic acidosisl Anemial Azotemia

l improve morbidity and mortalityl prevent or delay progression of

kidney disease

Current Treatment

Glycemic control

l DCCT : l intensive glycemic control reduces long-term

microvascular complications in pt with type 1 diabetes.

l Risk of microalbuminuria and albuminuria were reduced 39%(p< 0,002) and 54%(p<0,04), respectively.

l UKPDS33 : l intensive control achieved 25 % reduction of

microvascular complications (p<0.01), microalbuminuria, albuminuria and doubling of Scrwere sig. lower after 9 yrs. of Tx in type 2 diabetes.

Recommendations for glycemic control in DM

Goal valuesNormal value

Glycemicmeasure

American college of Endocrinology

American Diabetes Association

<6.5<7<6HbA1c(%)

NR100-140<110Bedtime

</= 140<180<140Postprandial

</= 11090- 130a<100Preprandial

Blood Glucose (mg/dl)

NR = no recommendation, a plasma glucose values

http://www.medscapes.com/viewarticle/497758

Using of Oral hypoglycemic drugs in CKD

No adjustment needed in renal impairmentThiazolidine dionePioglitazone (Acttos)Rosiglitazone (Avandia)

Excrete unchanged by renal, lactic acidosisAvoid if GFR < 60-70 mL/min

Metformin

Safe in CKD, excrete by liverMeglitinidesRepaglinide (Novonorm)

Metabolized in liver, inactive metabolite excreted by renalAvoid if GFR <10 mL/min

Glipizide(Minidiab)

(CrCL>50 mg/dL) Decrease doseNot recommend if GFR< 50ml.min or Scr>2 mg/dL

Glybenclamide

Avoid if GFR< 50 mL/min or Scr>2 mg/dLChlorpropamide

Using in CKDDrug

Alfa-glucosidase inhibitor ???? (should not be used if GFR <10)

Dipeptidyl Peptidase-IV (DPP-IV) Inhibitors

Sitagliptinl Usual dose: 100 mg ODl CrCl 30-50 ml/min: 50 mg ODl CrCl < 25 mL/min: 25 mg ODVildagliptinl Not yet approved (at June 2008)

l 90% of pt. with renal failure have HTN

l Multiple Risk Factor Intervention Trial (MRFIT) confirmed association between elevated BP and declined in GFR

16 mmHg increase in SBP => 1.8 risk of developing ESRD

compared to optimal BP

l Hypertension Detection and Follow-up Program (HDFP) noted a 5-yr risk of elevated Scr (>2.0mg/dl) was strongly related to baseline DBP (p<0.05)

Blood Pressure Control

Recommendations from Treatment guidelines

ACEI,ARBProteinuria < 1 g/d:<130/80Proteinuria >/= 1 g/d:<125/75

<140/85UK1999BHS

ACEI,ARB, Thiazide

Proteinuria < 1 g/d:<130/80Proteinuria >/= 1 g/d:<125/75

<140/90Canada2002CHWG

ACEI,ARBAll diabetics: <130/80NRUSA2003ADA

ACEI,ARBAlbuminuria or GFR<60ml/min: <130/80

<140/90USA2003JNC 7

ACEI,ARB, Diuretic

<130/80NRUSA2004NKF

CKDNo Kidney disease

Preferred Agent(s)

Goal BP(mmHg)

CountryYearGuideline

http://www.medscapes.com/viewarticle/497758_print

Blood Pressure and Diabetic Nephropathy

l Pt with diabetes => largest group of pts to develop diabetic nephropathy.

l Hyperglycemia; a risk factor for nephropathy.l HTN + hyperglycemia => progressive kidney disease

JNC VII guidelinel BP < 130/85 mmHgl BP < 125/75 mmHg if proteinuria > 1g/d

Lipid Management

No preferences are indicated for which fibrate should be used to treat hypertriglyceridemia

Gemfibrozil may be the fibrate of choice for Tx of high TG in pt with CKD

Fibrates are contraindicated in stage 5 CKD.

Fibrates may be used in stage 5 CKD for pt with TG >/= 500 mg/dl, and for pt both TG >/= 200 and non-HDL cholesterol >/= 130 who do not tolerate statins

No recommendations are made for pt< 20 y/o

Recommendations are made for pt< 20 y/o

Initial drug therapy for high LDL level should be with a statin, bile acid sequestrant, or nicotinic acid

Initial drug therapy for high LDL level should be with a statin.

Drug therapy is considered optional for LDL level of 100-129 mg/dl

Drug therapy should be used for LDL level of 100-129 mg/dl after 3 mo of therapeutic life style change.

Evaluation of dyslipidemias should occur every 5 yrs.

Evaluation of dyslipidemias should occur at presentation with CKD, following a change in kidney therapy modality, and annually.

Pt with CKD should not be managed differently from other pts.

Pt with CKD should be considered to be in the highest risk category

Adult Treatment Panel III GuidelinesNKF K/DOQI Guidelines

Treatment goals

l LDL level should be at least less than 130 mg/dll High risk pt (10-yr risk of CHD>20%) should have an

LDL target of < 100 mg/dll The combination of statins and fibrates should be avoided.l Statins + bile acid sequestrants (or nicotinic acid) if TG < 400

mg/dll Potential benefit of combination therapy must be closely

weighed against the increased risk of adverse effects, adherence issues, and cost.

l Consider effect of altered metabolism and elimination of lipid lowering agents, DI, closely assess for S/S, or lab. abnormalities associated with drug toxicity

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 smoking cessation interventions

l Five A’s is suggested to provide smoking cessation counseling

Anemial progressive erythropoietin deficiencyl Iron deficiencyl normochromic, normocytic anemia l Early treatment of anemial decreased hospitalizations for CVS

complications (LVH)l improved survival, exercise capacity,

cognitive function, quality of lifel CKD => Left ventricular hypertrophyl 39% in GFR<25.5 ml/minl 74% in dialysis pt.

Anemia

l Definition of anemia (K/DOQI 2006)l Men and postmenopausal women; Hgb<13.5l Women; Hgb<12

l Target ferritin valuel HD => 200 ng/mLl nonHD CKD => 100 ng/mL

Pharmacist’s key role :Develop administration protocol and monitoring responsel consistent monitoring of Hb and Hct, adverse

events: HTN, seizures, hyperkalemia, and increased risk of blood clots.

l Target Hb 11-13 g/dLFacilitate appropriate iron therapy according to K/DOQI guidelinesto maintain l a transferrin saturation of 20% or greaterand l a serum ferritin level of 100 ng/ml or greater

Erythropoiesis-stimulating agents

Recommended to read;l Cardiovascular Risk Reduction in Early Anemia

Treatment with Epoetin Beta (CREATE) (Drüeke 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)

Erythropoiesis-stimulating agents

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/kgl Maximum dose : 720 IU/ kg /week There have been no reports that epoetin alfa differs from

epoetin beta in its clinical efficacy l Darbepoetin ARANESP®

l Half-life: 3x of Epoetin alfa (i.v.)l 0.45 μg/kg once a week.l 0.75 μg/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 necessary

dosage. l Therapeutic range is very wide (up to 100.000

IU/week.)l The HB concentration, along with the reticulocyte

count, must be checked l Initiation: weeklyl Maintenance: monthlyl stable dose-response: every 2-3 months

l The target Hb concentration 11-12 g/dL is maintained in 90-95% of the patients by administering l 1.000-30.000 IU of epoetin per week orl 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.)

Erythropoiesis-stimulating agents

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 weeks

after any dosage adjustment to ensure that hemoglobin has stabilized in response to the dose change.

l Decrease the dose of the ESA if the hemoglobin increase 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 parathyroid hormone 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 tissue necrosis => impaired pulmonary & heart

Frequency of Measurement of PTH, Ca, PO4

Every moEvery 3 mo<15 or dialysis5

Every 3 moEvery 3 mo15-294

Every 12 moEvery 12 mo30-593

Measurement of Ca/ PO4

Measurement of PHT

GFR range(mL/min/1.73 m2)CKD stage

Recommended Goal Conc. for Bone Disease in CKD

<55<55<55Ca-PO4(mg2/dl2)

8.4-9.58.4- 10.28.4-10.2Ca (mg/dl)

3.5-5.5Evidence

2.7-4.6opinion

2.7-4.6opinion

PO4

(mg/dl)

150-300[16.5-33.0]Evidence

70-110[7.7-12.1]Opinion

35-70[3.85-7.7]Opinion

iPTH pg/mL[pmol/L]

CKD stage 5CKD stage 4CKD stage 3Lab.

parameter

Pt. information: **** Decrease phosphate intake : Legume, Beverage, etc.****

Phosphate Binder

l Calcium product

l Aluminium hydroxide

l Calcium-Aluminum free

Phosphate Binderl Calcium carbonate (40% elemental calcium)

l จับฟอสเฟตไดนอยกวา l อาจตองใช > 6 g/day ซึ่งอาจทําใหไดรับแคลเซียมมากเกินl 20-30% absorbedl 39 mg phosphate bound per 1 g CaCO3

l Try to limit daily intake 1.5 g of elemental Ca per dayl Calcium acetate (25% elemental calcium)

l จับฟอสเฟตไดมากกวา ใชประมาณ 3 g/day l ภาวะกรดดางในกระเพาะอาหารมีผลตอการดูดซึมนอยกวาl Absorption with meal: 20%, between meal 40% l ใหยาทันทีหลังมื้ออาหารl Do not exceed 1.5 g of elemental Ca per dayl 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 weeksl Do not use concurrently with citrate-containing productsl ADR:

l Constipation/fecal impactionl Bone mineral defectsl Anemia, Demential 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 Binderl Calcium-Aluminum free

l Sevelamer hydrochloride (Renagel®) l Sevelamer carbonate (Renvela®) less GI S/E

l Poly (allylamine hydrochloride), l a polymeric amine oral administrationl No absorptionl no hypercalcemial Lowers LDL cholesterols, uric acid l more expensive

Sevelamer Hydrochloride

l Renagel®l film-coated tablet 800 mg or 400 mg

l indicated for the control of serum phosphorus in patients with chronic kidney disease (CKD) on dialysis

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

l Decrease bioavailability of Ciprofloxacin 50%

Sevelamer Hydrochloride

4 tablets three times daily with meals

2 tablets three times daily with meals

≥ 9.0 mg/dL

3 tablets three times daily with meals

2 tablets three times daily with meals

≥ 7.5 and< 9.0 mg/dL

2 tablets three times daily with meals

1 tablet three times daily with meals

> 5.5 and< 7.5 mg/dL

400 mg800 mgSerum Phosphorus

Product information

Sevelamer Hydrochloride

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

Sevelamer Hydrochloride

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.

Vitamin Dl PTH > 110 pg/mLl and/or Ca < 9.5 mg/dLl and/or PO4 < 4.6 mg/dLl Alfacalcidal (0.25 μg, 0.5 μg , 1 μg)

l (Alpha D3®, One-alpha® , Bon-One® )l 0.25-1 μg OD X3/wk

l Calcitriol (0.25 μg)l (Rocaltrol®, Calcit SG®, Decostriol®, Osteo D®)l 2-4 μg OD x3/wk

Vitamin DDosing recommendations for calcitriol

in stage 5 CKD on hemodialysisIf Ca < 9.5 mg/dL, PO4 < 5.5 mg/dL, Ca x PO4 < 55 mg2/dL2

3-7 oral or 3-5 μg IV

>1000

1-4 μg oral or 1-3 μg IV

600-1000

0.5-1.5 μg oral or IV300-600

IV and oral CalcitriolDose per HD

iPTH (pg/mL)

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

Protein Dietl RDA = 0.8 g/kg/dayl 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 (เสริมดวยโปรตีนปริมาณเทาท่ีสูญเสียไปกับปสสาวะ)

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 เนื้อสัตวไมติดมัน, ไข l ควรไดรับมากกวา 60% ของโปรตีนที่ไดรับในแตละวัน

l การประมาณปริมาณโปรตีนl 1 สวนโปรตีน = เนื้อปลา หรือ ไก 2 ชอนโตะ หรือไขขาว 2 ฟองl อาหารโปรตีนต่ํา 0.6-0.75 g/kg/day จะมีโปรตีน

1 สวนตอ 1 มื้ออาหาร (3 สวนตอวัน)

Protein Diet (cont.)ในทางปฏิบัติl งดอาหารที่ประกอบดวยเนื้อสัตวเปนสวนใหญ

l สเต็ก ไกยาง ไกทอด หมูปง หมูสะเตะ l อาหารจานเดียว เชน ขาวมันไก ขาวหมกไก ขาวขาหมูl อาหารวาง เชน ปลาหมึกสดยาง ลูกชิ้นปง

l อาจใหทานl ขาวเหนียวสมตํา (ไทย) หมุปงไมเกินสองไม(เล็ก)ตอมื้อl อาหารที่ใชผักมาก แกงเลียง แกงปา (ระวังปริมาณโซเดียม)l อาหารจานเดียว ขาวผัด ผัดไท ที่ไมมันมาก ขนมจีนl อาหารวาง ปลอดโปรตีน เชน สาคูเปยก บัวลอย(น้ําขิง) ซาหริ่ม

l แนะนําใหรับประทานที่จัดใหครบทุกมื้อ เพื่อปองกันการขาดโปรตีนl ไมแนะนําใหรับประทานอาหารชีวจิต มังสวิรัติ เนื่องจากเปนโปรตีนจากพืชซึ่งมี

กรดอะมิโนท่ีจําเปนไมครบถวน

Salt (NaCl)

According to JNC VIIl Normal BP with

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

l NaCl not more than 6 g/day

l Hypertensionl 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

RemarkNa

(mEq)Na

(mg)NaCl(g)

เกลือแกง 1 ชอนชา หนักประมาณ 5 กรัม

คนปกติไมควรรับเกลือเกิน 10 กรัมตอวันMW Na = 23

Cl = 35.5

Sodium bicarbonatel When HCO3

- < 17 mEq/Ll Supplement 0.5-1.0 mEq/kg/dayl Titrate to bicarbonate level 18-20 mEq/Ll !!! 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 Shohl’s solution (Sodium citrate)

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

l 1 mL = 1 mEql ไมควรใชในผูปวยโรคตับ

Renal insufficiencyEffect to Pharmacokinetics

l Absorptionl Uremic gastroparesis can alter rate of drug absorptionl Gastric pHl Gastrointestinal tract edemal Vomitting and diarrheal Antacid or cholestyramine

l Distributionl Edema or ascites

l increase Vd of water soluble drugsl Uremic states

l alter plasma protein bindingl Tissue protein binding is reduced àdecrease Vd

l Metabolisml Hepatic biotransformation may be altered

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

dosagel Clinical pharmacokinetics approach for narrow

therapeutic index may be altered

Renal insufficiencyEffect 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

Determination of renal functionClcr using Cockcrof&Gault’s equation**

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

*Unit = mL/min/1.73 m2, A 70 kg/1.73 m2 BSA 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-oldl **Unit = mL/min/1.73 m2, > 60 mL/min/1.73m2 is not exact number

Equations for Predicting Creatinine Clearanceor GFR in Adults with Kidney Disease

Estimated baseline creatinine base on MDRD formula

a g e m a le fe m a le20 -24 1 .3 1 .025 -29 1 .2 1 .030 -39 1 .2 0 .940 -54 1 .1 0 .955 -65 1 .1 0 .8>65 1 .0 0 .8

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

Scr ×Tl 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.)

24 hour urine collectionCrCl = 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 เปน g ตอ volume (L) ของ Urine ทั้งหมดที่เก็บ ดังน้ัน หนวยจะตัดกันไปไดเอง

ACEI

25-5050-75100Lisinopril

5075-100100Enalapril5075100Captopril

<1010-50>50

25-5050-75100Ramipril7575-100100Quinapril

75-100100100Fosinopril

% of usual Dose based on GFR mL/min/1.73 m2

Drug

American Family Physician Web site at www.aafp.org/afp

Case Study

l 60 y/o male 90 kg; infected CAPDl PDF : staphylococcus coagulase negative

sensitivity: Vancomycinon Vancomycin 1 G + D5W 200 ml IV in 2 hr.

q 96 hr. start 25/10/50l Vancomycin conc. on 29/10/50 = 7.19 mg/L

Target Vancomycin troughl For MRSA with MIC 2 mcg/mll 50% Protein bindingl Target trough => 4-5 times the MICl Target trough = 15-20 mcg/mll 20% lower response rate in pt. who did not

achieve target trough initially(76% vs 56%, p=.05; Hidayat et al. 2006)

l Predicted Cmax after 1st doseCmax1 = [1000mg/59.5L] x e -0.0056x2

= 16.64 mg/Ll 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/Ll Cssmax = 39.62 mg/Ll 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 carel comprehensive drug historiesl prescribing of appropriate dosages l avoidance of nephrotoxins in pt with underlying

renal problemsl monitoring of nephrotoxic drug therapies

Many pharmacologic agents can cause kidney damage

Avoidance/Precaution for patient with CKD

l Pharmacologic agentsl IV radiographic contrast agentsl selected antimicrobials : AMGs, amphotericin Bl NSAIDs (including COX-2 selective inhibitors)l cyclosporine and tacrolimus

l Volume depletionl Obstruction of the urinary tractl The benefits of ACEI and ARB outweigh the

risks; titrating dosage will minimize the risk of kidney damage

Assessment of nephrotoxicity

Identification of drug-induced nephrotoxicityl a change in Scr of at least 0.5 mg/dL for subjects with a baseline

Scr <2 mg/dL

l an increase of about 30% for those with Scr >2 mg/dL, when correlated 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 the

normal range).

Potential roles and responsibilities

l Attainment of blood pressure goall Attainment of glycemic goals in those with diabetesl Early evaluation and treatment for proteinurial Early evaluation and therapy for anemial Early evaluation and therapy for secondary

hyperparathyroidisml Attainment of lipid goals, where appropriatel Appropriate drug dosing adjustmentsl Minimization of drug-related nephrotoxin exposurel Provision of drug therapy instructionl Screening for ability to afford drugsl Education regarding smoking cessation, where

appropriate