983 A&B 16

Drug therapy individualization for patients with renal insufficiency

1

Drug therapy individualization for patients with renal insufficiency

Overview ? (1)

(2) Continuous renal replacement therapy

(3)

(4)

(5) Five Stage of Chronic Kidney Disease =CKD

GFR ml/min/1.73m2

= Glomerular Filtration Rate

Description

> 90 Kidney Disease Risk factors

1 > 90 Kidney Damage GFR

2 60 89 Kidney DamageGFR mild decrease

3 30 59 GFR moderate decrease

4 15 29 GFR severe decrease

5 < 15 Kidney Failure Dialysis

Pharmacokinetic in Chronic Kidney Disease

2

1. Absorption and Bioavailability (:)

Acute Renal Failure (ARF) Chronic Kidney Disease (CKD)

()

DiabeticUremic Gastroparesis

Sulfonylureas

Gastric Ammonia

Hyperphosphatemia

PH Iron

Ketoconazole

: Fe

H2 BlockersAntacids

Cholestyramine

Warfarin

Digoxin

Chronic Heart Failure

Cirrhosis

Nephrotic syndrome

Furosemide

End Stage Renal Disease (ESRD)

Sevelamer (PO4 Binder)

: Sevelamer

()

Ciprofloxacin 50%

P-GP

Propranolol

Dextropropoxyphene

Dihydrocodeine

Cloxacillin

Encainide

Zidovudine (AZT)

:

!

~

:

A. E.

B. F.

C. G.

D. H.

3

2. Volume of Distribution

End Stage Renal Disease

(ESRD)

WarfarinPhenytoinVPAASA

: 80%

QuinidineLidocaine

Chronic Kidney Disease

(CKD)

Phenytoin

: Phenytoin

uremic byproducts

albumin free

form CKD

phenytoin free form

seizure

(1) Uremic byproducts Phenytoin

albumin

Uremic byproducts

(2)

4-8mg/L 10-20mg/L

:

Phenytoin: Albumin

Low Albumin Cp = Cp/{ (1-0.1) (pt albumin / 4.4) + 0.1} Cp =

binding

Cp =

Low Albumin

Clcr 10 ml/min

()

Cp = Cp /{ 0.48 (1-0.1) (pt albumin/ 4.4) + 0.1}

4

Exercise Albumin 3.3gm/dl Phenytoin

5mg/L?

Ans 2 11.8mg/L

Usual range 10~20mg/Kg

End Stage Renal Disease

(ESRD)

Narrow Therapeutic Range

Free fraction

5

3. Metabolism and Excretion

Chronic Kidney Disease

(CKD)

CYP450

CYP3A4CYP2C9

Nonrenal Clearance

CYP2E1

Cyclophosphamide

FelbamateReboxetine

Roxithromycin

End Stage Renal Disease

(ESRD)

CYP3A4

CYP3A4 28%

()

Nonrenal Clearance

Aztreonam, Bufuralol, Captopril, Cefmenoxime, Cefmetazole, Cefonicid, Cefotaxime, Cefotiam, Cefsulodin, Cefizoxime,

Cilastatin, Cimetidine, Ciprofloxacin, Cortisol, Encainide, Erythromycin, Imipenam, Isoniazid, Methylprednisolone,

Metoclopramide, Moxalactam, Nicardipine, Nimodipine, Nitrendipine, Procainamide, Quinapril, Repalinide, Verapamil,

Zidovudine, Acyclovir

(1) Pharmacologic Activity of drug Metabolites

Drug Metabolites

Codeine Morphine-6-Glucuronide Narcotic Effect

Meperidine Normeperidine

t1/2 : 0.6hr 2 hr

CNS

CNS

Seizure

Morphine Morphine-6- Glucuronide 3-4 BBB

Narcotic Effect

Neurologic Depression

Procainamide

N-acetyl procainamide

70%

>30mg/L

5 Css

: Procainamide N-acetyl procainamide Class IA

Amiodarone class III

: Metabolic Pathway of Codeine Biotransformation - Codeine

~

A.

6

(2)

Drug Metabolites ()

Acetohexamide Hydroxyhexamide

Cyclophosphamide 4-ketocyclophosphamide

Daunorubicin Daunorubicinol

Methyldopa Methyl-O-Sulfate--methyldopamine

Midazolam -hydroxymidazolam

Phenylbutazone Oxyphenbutazone

Primidone Phenybarbital

Propoxyphene Norpropoxyphene

Rifampicin Desacetylated Metabolites

Sodium Nitroprusside Thiocyanate IV

10-12mg/dl

:

(: !!XD)

i. Narcotic analogues

(1) codeine, propoxyphene, dihydrocodeine

CNS

(2) Hydromorphone,

smaller initial doses.

ii. Anti TB

(1) INH,RMP +Vit B6

(2) EMB,PZA

7

:Sodium Nitroprusside

Sodium Nitroprusside Cyanide Thiocyanate

< 2mg/kg/min Cyanide ( Rhodanese ) Thiocyanate

3mg/kg/min < < 10mg/kg/min ()

A. Cyanide ( Rhodanese ) Thiocyanate

B. Cyanide ( Sod. Thiosulfate ) Thiocyanate

a.

b. Cyanide Thiocyanate

>2mg/kg/minRhodanese Cyanide

c. 3-4 10-12 mg/dl

d. Sodium Nitroprusside Fe3+ () Fe2+ ()

(3) Special Considerations for drug use in renal insufficiency

Meperidine Normeperidine seizure

NASIDs

ACEI

Cimetidine

Triamterene

Trimethoprim

Pseudorenal Failure Cr Scr

Chlorpropamide

Metformin Life Threatening Lactic Acidosis

100% Clcr < 60-70 ml/min

( > 1.5mg/ml > 1.4mg/ml)

Insulin

AGs, Vancomycin

TDM

Nifedipine Uremia Mean Emax

29%

:

()

Narcotic

Analgesics

CodeinePropoxyphene()Dihydrocodeine

CNS

Hydromorphone Initial Dose

Anti TB EMBPZATID

INHRMP Vit B6

8

()

Itraconazole Hydroxypropyl--cyclodextrin GI

Clcr 30ml/min

Voriconazole inj SBECD sulfphobutylether

-cyclodextrin

GI

Clcr 50ml/min Scr

ClR = (GFR fu ) + Clsecretion Clreabsorption

PK

Dialyzability 1. Vd

2. Hemodialysis() Peritoneal Dialysis()

: 97

97 14 p36 98 12 p18

1. Dose Modification for Patients with Renal Insufficiency

Antibiotics

Cloxacillin, Clindamycin,

Metronidazole, Macrolides

Atenolol, Nadolol, ACEI CCBs, Minoxidil, ARB, Clonidine,-blockers

Digoxin, Sotalol Amiodarone, Nitrates

Diuretics

(1) Clcr 30ml/min K-sparing Diuretic

(2) Clcr 10ml/min Hydrochlorothiazide

Lipid lowering

agents

HMG-CoA Reductase inhibitors

Benafibrate, Clofibrate

Fenofibrate

Narcotics

Codeine, Meperidine

Fentanyl, Hydromorphone, Morphine

:

Psychotropics

Lithium, Chloral hydrate,

Trazodone, Paroxetine, Primidone,

Gabapentin, Topiramate, Vigabatrin

TCA, Nefazodone, Sertraline

Acarbose, Chlorpropamide, Insulin

Glyburide, Gliclazide, Metformin, Repaglinide, Rosiglitazone

Miscellaneous

Allopurinol , Oxypurinol, Colchicine,

H2 receptor Antagonists, Diclofenac,

Ketorolac, Terbutaline

Proton pump inhibitors

(1) delay release EC granule

Esomeprazole, Omeprazole

(2) DR ECtab

Pantoprazole, Rabeprazole,

(3) lansoprazole

9

2. ACEI :

Prodrug

Prodrug

Benazepril Benazeprilat 32 -12 Captopril

Enalapril Enalaprilat 60-80 Fecal Fosinopril Fosinoprilat 50 50

Lisinopril

Moexipril Moexiprilat 8 53 Fecal

Perindopril Perinodoprilat Quinapril Quinaprilat 60

Fecal

Ramipril Ramiprilat 60 Fecal 40 Trandolapril Trandolaprilat 33 66 ecal

3. Drug-dosage Regimen Design

a.

History OTC recreational drugs

PE (

)

b.

24 Scr Clcr

: Clcr = urine vol. x ( urine Cr / Scr) x (min)

c.

TDM

d. LDMD

Loading Dose

Maintain Dose

:

e.

Scr Clcr

( 98 12 p15)

Same Cave, Cmax, Cmin, Normal dose 24h subtherapeutic

Same Cave, Normal dosing interval

Cp subtherapeutic

trough level

10

4. Clcr GFR

a. Clcr

i. Clcr

Cockroft and Gault ()

CLcr = (140-age) (ABW) / Scr x 72 IBW 30% IBW

0.85

Salazar-Corcoran in obese

ii. Clcr

Schwartz

Clcr (mL/m/1.73m2)= K x L(cm)/Scr

K

0.33 0.55 2-12 13-21

0.45 0.7 13-21

Traub (1-18 )

iii. Clcr

Scr Steady State Clcr

Cockroft and Gault Clcr

:

~

B.

C.

~

D.

Scr 50%

CKD

(Scr 2mg/dl)

Scr 30%

1mg/dl

11

Jelliffe

Ess Ess = Wt 29.3 0.203 age

Ess Ecorr Ecorr = Ess 1.035 0.0337 Scr

Ecorr E E = Ecorr 4 wt (Scr2-Scr1)/ tday

E Clcr CLcr = E/14.4 Scr

Ess Ess = Wt 25.1 0.175 age

Ess Ecorr Ecorr = Ess 1.035 0.0337 Scr

Ecorr E E = Ecorr 4 wt (Scr2-Scr1)/ tday

E Clcr CLcr = E/14.4 Scr

b. GFR-MDRD : http://kidney.tsn.org.tw/pup/p1_07_01.htm GFR

Drug-dosage regimen design peaktroughCss

1. vs vs

(1) (Cp) vs

AGs concentration dependent drug peak level

dosing interval

(2) vs

Quinidinephenobarbitalphenytoin toxicity peak level

: (97 ) trough

(3) (trough concentrationCtroughtCt) vs

Vancomycin peak level

(4) Css (steady-state concentration)

Benzodiazepinescephalosporins peaktrough conc. Css

cephalosporin (-lactam) time-dependent drug

Css

2. PK and Dosing for Drugs in Renal Failure

(1) ceftazidime usual dosage 1 g q8h seizure

(2) CLcr uremic byproducts ()ARF CKD

Imipenem ARF 91 mL/min (CKD 50 mL/min 130 mL/min)

ARF 2 gESRD 1 g

(3) (97) PK individualized regimen

hosts immune status fluid overloaddehydration PK

disposition

12

3. Dosing in renal insufficiency :

(1) Ganciclovir Q doset

(2) Digoxin2 compartment ka ( MD)

(3) Gentamicin LDMD 23 97

a. PK (Cl) MD

b. ( HD)

c. (CVVH)

(4) Zidovudine >>

(5) PenicillinClcr 40ml/min

(6) Vancomycin( HDhigh flux HD)

(7) Enoxaparin 30mL/min

: 97

(8) Acyclovir dose

(9) Amphotericin amphotericin B

(10)Vancomycin on HDhigh flux HDGentamicin on HDhigh flux HD

CVVHCAPD

4. Dosing regimen

(1) usual dose dose Q (ex. Ganciclovir)

(2) Q Q ()

a. Rowland & Tozer unchange cmpd Q = 1- {fe (1 - KF)}

b. Cl = xClcr + y

(3) Cl = ClNl x Q

(4) Dose = Cl x conc.

(5) KV = Clt1/2 = 0.693/K Vd

5. Drug-dosage regimen design for CKD () :

(1) Rowland and Tozer Cl k

a. CLk Clcr

b.

c. first order (liner) kinetic (one compartment model)

(2)

a. Q = 1 - {fe (1 - KF)}

Fe = (unchanged)

KF () = Clcr/120mL/min (120 Clcr)

b. 1 85% unchange Clcr = 10mL/min

Q = 1 - {0.85 (1 - 10/120)} = 0.22

total body clearance CLpt = CLnorm() x Q

13

c. 2 80 500 mgq8h

Clcr 50 mL/min

1 mg

Q = 1 - {fe (1 - KF)}

Q = 1 - {0.8 (1 - 50/100)}

Q = 1 - 0.4 = 0.6

500 x 0.6 = 300 mg

2 dosing interval

8 0.6 13 13 q12h

Dosing for drugs in renal failure : 1. Ganciclovir dosage regimen : cytomegalovirus(CMV) infection)

(1) Clcr = 10 mL/min (usual dose5 mg/kg q12h)

(2) Vd

(3) IC50 0.1-2.8 mcg/mL 500 mg pow. for inj.

(4) Trough conc.2.6 mcg/mL (neutropenia)

(5) CL (mL/min/1.8 m2) = 1.25 CLcr + 8.57

(6) CLcr = 10 mL/min ( Clcr = 120 mL/min) :97 !!!!

CL = 1.25 x 10 + 8.57 = 21.1 mL/min/1.8 m2 ( 158.6 mL/min/1.8 m2)

Q = CLfail /CLnorm = 21.1/ 158.6 = 0.133 ( a, b, c A, B, C )

a. Df = Dn x QDf = 5 mg/Kg x 0.133 = 0.67 mg/Kg

b. f = n / Qf = 12 / 0.133 = 90 hr ()

c. Df = {Dn x Q x f } / p = 5 mg/Kg x 0.133 x 24 /12 = 1.33 mg/Kg ()

Df = {Dn x Q x f } / p = 5 mg/Kg x 0.133 x 48 /12 = 2.66 mg/Kg ()

Clcr = 10 mL/min 1.33 mg/kg q24h 2.66 mg/kg q48h

a. A

0.67 mg/kg q12h

trough level(2.6 mcq/ml)

neutropenia

b. B

5 mg/kg q90h

c. Cchanging both

2.66 mg/kg q48h

14

2. Acyclovir dosage regimen

(1) Acyclovir :97

a. 70-80%

b. Acyclovir

c. hydration urine flow 1h

d.

(2) 28 y/o AIDS herpes simplexScr = 4.5 mg/dLClcr = 20 mL/min

a. acyclovir (usual dose 5mg/Kg q8h)

CL (mL/min/1.73 m2) = 3.4 Clcr + 28.7= 3.4 x 20 +28.7 = 97 mL/min ()

CL 300 mL/min 5mg/Kg/d

:

CL210-330 mL/min (normal renal function) vs 29-34 mL/min (ESRD)

T1/23 h (normal renal function) vs 20 h (ESRD)

b. ? : 97

i. Conventional HD 6h 60% ()

ii. T1/2 on HD 6ht1/2 off HD 20hdialysis clearance 80 mL/min

iii. FD = 1 - e-(Cl+ Cldial) (t/V

d) = 1 - e-(0.693 / t1/2

on)(t) = 1 - e-(0.693 / 6) x 6 = 0.5

Ans

50% 5 mg/Kg 50% = 2.5 mg/kg

(3) ()

PK(Renal function and PK parameters)

Drug Estimation rate constant Total body clearance

Acyclovir CL = 3.37 Clcr + 0.41

Amikacin K = (0.0024 Clcr ) + 0.01 CL = 0.6 Clcr + 9.6

Aztreonam CL = 0.8 Clcr + 26.6

Cefazolin K = (0.0028 Clcr ) + 0.022 CL = 0.34 Clcr + 6.6

Ceftazidime K = (0.004 Clcr ) + 0.004 CL = 1.15 Clcr + 10.6

Ciprofloxacin CL = 2.83 Clcr + 363

Digoxin CL = 0.88 Clcr + 23

Gentamicin K = (0.0029 Clcr ) + 0.015 CL = 0.983 Clcr

Imipenem CL = 1.42 Clcr + 54

Lithium CL = 0.235 Clcr

Ofloxacin CL = 1.04 Clcr + 38.7

Piperacillin K = (0.0049 Clcr ) + 0.21 CL = 1.36 Clcr + 1.5

Tobramycin K = (0.0029 Clcr ) + 0.01 CL = 0.801 Clcr

Vancomycin K = (0.00083 Clcr ) + 0.0044 CL = 0.69 Clcr + 3.7

15

3. Digoxin ( CHF)dosage regimen

(1)

a. Vd Clcr VdCl

b. KV = Cl

c. Digoxin 2 compartment katp

d. CmaxCminkatp

e. MD

(2) 70 kg CLcr = 12 mL/min/1.73 m2 in digoxin

a. VD (L) = 226 + {298 (Clcr )/ 29.1 + (Clcr)}= 313 L (digoxin Vd)

CLfail = 0.33 x BW + 0.9 CLcr = 33.9 mL/min (CHF 23 ml/m + 0.88 Clcr)

kf = CLfail / VD = 33.9 mL/min x 1440 min/d /313 L = 0.156 day-1

Tpeak = 2 h (2/24 = 0.083 d)

ka = 0.76h-1 (18 day-1) ( ka)

f = {(- 1/kf)(ln [Cmin / Cmax)) + tpeak

f = {(- 1/0.156) (ln [0.8 / 1.4)) + 2 h

b. range 0.82 mg CHF trough level 0.8mgpeak level 1.4 mg

f = 3.6 d + 2 h = 4 d

Dosepo = {SF Cp VD (ka - k) }/ {ka (e-kt / 1 - e-k) - (e-ka

t / 1 - e-ka)

Dosepo = {1.4 (313) (18 - 0.156)} / {18 (e-0.156 (0.083) / 1 - e-0.15 (4)) - (e-18 (0.083) / 1 - e -18 (4) )

= 0.212 mg

0.25 mg q4d ()

i. 0.25 mg

ii. digoxin 46

iii. digoxin F 0.70.8 Cp = (SFD/)/Cl MD = 0.223 mg

.

4. Gentamicin dosage regimen : pseudomonas aeruginosa

(1) 1

a. Clcr Cl Vd

b. LD = Vd x Cp (Cp 6 8 mg/L)

c. KV = Clt1/2 = 0.693/K

d. 2 t1/2 ( 75%)

e. Rule of eights8 Scr

f. MD (q8h IV bolus model )

g. Ctrough 2 mg/L

(2) 131 IBW 70 kg Scr 3.4 mg/dLClcr 27 mL/min Pseudomonas

aeruginosa Gentamicin dosage

a. Cockroft & Gault equation Clcr (stable renal function) = 27 mL/min

(!!)menCLcr = (140-age) ABW / Scr x 72 womenCLcr 0.85

16

b. gentamicin clearance

i. CLcr = 1.6 L/h

ii. CLGM (mL/min/kg) = 0.65 CLcr (mL/min/kg) + 3.7 = 21.25 mL/min = 1.275 L/h

c. Vd0.25L/kg (normal or impaired renal function) ()

Vd = 0.25 x 70 = 17.5 L (obesityfluid overloadVd)

d. LD = Vd (desired Cp) peak level 6-8 mg/L ( 7 mg/L) in pseudomonas

LD = 17.5 x 7 = 122.5 mg (120 mg )

e. Kd = CL/Vdt1/2 = 0.693 /Kd

Kd = 1.275 / 17.5 = 0.071 h-1 ( 1.6 L/h Kd = 0.09 h

-1)

T1/2 = 0.693 / 0.07 = 9.9 h (7.7 h)

f. q24h : t1/2trough < 2 mg/L

2 t1/2 ( 75% GM trough < 2 mg/L)

: 12 24

Rule of EightsMD() = 1-1.5 mg/kg IBW = Scr (3.4) x 8 24 h

:

g. peak level 30 30

h. MD ( IV bolus model ) = {Cp (1 - e -Kd ) Vd}/e-kdt (t = = 1 h)

MD = 7 mg/L (1 - e-0.071 h -1 x 24 h ) x 17.5 L /e-0.071h-1 1h = 108 mg

i. Cp = 7 mg/L Ctrough = Cp x e-kd tsample

Ctrough = 7 x e-0.071 h -1 x 24 h = 1.274 mg/L

120 mg q24h ( 80 mg) 3

gentamicin 30 (

IV infusion model ) Dose = {CL Cp (1 - e-Kd ) tin}/1 - e

-kd tin ) eKd

(3) 2

CL () K MD

Ctrough < 2 mg/L

(4) 2 ( CpCtrough dosage regimen)

Gentamicin 120 mg q24h

Cp = 7.6Ctrough =2.6 mg/L Scr = 4.8 mg/dL

trough level > 2 mg/L 48 h

a. new Kd = ln (Cp1 /Cp2) /t ={ ln (7.6/2.6) }/23 = 0.047 h-1

b. CLrevised ( Vd) = Vd x Kd = 17.5 x 0.047 = 0.82 L/h

c. MD = {Cp (1 - e-Kd ) Vd}/e-kd t = 7 mg/L (1 - e-0.047 x 48 x 17.5 / e-0.047 x 1 h = 115 mg

d. Ctrough = Cp x e-kd tsample = 7 x e-0.047 x 48 = 0.73 mg/L ( < 2 mg/L)

48 hr 120 mg q48h

(5)

a. penicillin-susceptible viridans streptococci penicillin G +

Gentamicin Cp = 3 g/mlCtrough < 1 g/ml

17

b. Gentamicin used in G(-) infection

Cp = 4 10 g/mlCtrough = 1 2 g/ml (multiple daily dose)

Cp = 16 24 g/mlCtrough < 1 g/ml (once daily dose)

5. Zidovudine dosage regimen

(1) AZT (zidovudine) HIV?

(1 mg/kg q4h Clcr < 15 ml/m PD HD 1 mg/kg q6 - 8h)

: HDhemodialysis PDPeritoneal dialysis

a. AZT(glucuronide metabolite)GAZT18%

b. AZT267Vd = 1 - 2.2 L/kg = 34 - 38% plasma Cl 1200

mL/min () vs dialysis Cl 63 mL/minGAZT plasma level

c. t1/2 1 - 1.4 h 1.4 - 1.9 h (2.9 h)

d. AZT plasma level ( erythropoietin

WBC)

6. Penicillin - dosage regimen

(1) (Meningococcal meningitis) IV PN G

20-24MU

(2) (50 58%)

(3) t1/2< 1 h () vs 4 10 h (ESRD)

(4) (myoclonus)(generalized seizure)

(encephalopathy)(coma)

penicillinalbumin(protein binding 65%)

Uremia() BBB CSF CSF level

(5) CL mL/min = 35.5 + 3.35CLcr ()

a. CLcr < 40 mL/mindose MU/daily = 3.2 + CLcr / 7

b. CLcr = 20 mL/mindose = 3.2 + 20/7 = 6 MU/d ( = 2 MU q8h)

(6) CarbapenemImipenem cilastatin

(7) Piperacillin (68% unchanged by the kidney clearance, 10 20% feces)

a. CL = 2.6 ml/min/kgt1/2 = 1 h

b. ESRDCL = 0.7 ml/min/kgt1/2 = 3.3 h

c. PK

d. Clcr < 40 ml/min

e. CLcr = 20 - 40 mL/min 3 4 g q8h

f. CLcr 20 mL/min 3 4 g q12h

g. 2 4 g q4 6h

18

7. Vancomycin -dosage regimen

(1) Vancomycin

a. G(+) MRSA streptococcus faecalisEnterococcus faecalis

b. () G(+)

c. Cp 25 40 mg/LCtrough 10 15 mg/L 80 mg/L (auditory

dysfunction)

d. t1/23 9 h (normal renal function) vs 129 189 h (ESRD)

e.

f. 60( gray-man syndrome)

30( 1.5 h)(distribution phase) peak

level trough level

(2) 1

a. Vancomycin Cl Vd K

b. CpCtrough usual range

(3) 144 y/o 70 kg acute nonlymphocytic leukemia BT 39.4

sepsis Scr 2.6 mg/dLBUN 38 mg/dL vancomycin 500 mg qd

a. CL = 0.65 CLcr (60 - 70% of CLcr)

CLcr = (140 - 44) x 70 x 0.85/ 72 x 2.6 = 30.5 mL/min

CL = 0.65 x 30.5 = 19.8 mL/min (1.2 L/h)

b. Vd= 0.7 L/kg = 0.7 x 70 = 49 L

c. Kd= CL / Vd = 1.2 / 49 = 0.024 h-1

d. Cp = (dose /Vd) / 1 - e-Kd = (500 mg /49 L) / 1 - e-0.024 x 24 h = 23 mg/L (25 40 mg/L)

e. Ctrough = Cp e-Kd = 23 x e-0.024 x 21.5 h = 13.7 mg/L (10 15 mg/L)

( 24 h)

(4) 2 hemodialysis

a. t1/2 = 5 7 dvancomycin clearance = 3 4 mL/min

b. Conventional hemodialysis = 1 g q7-10d (q4d)

c. 500 mg qw Cp = 40Ctrough = 16

d. MW = 1400ESRD conventional HDsingle dose

vancomycin vancomycin(

7%)

e. High flux hemodialysis (Frescenius polysulfone dialyzer) membrane surface area

vancomycin 45 160 mL/min 50% rebound

phenomenon < 50%

f. 500 mg (10 15 mg/kg)

19

(5) Vancomycin in dialysis

Conventional dialysis High flux dialysis

trough

Peak

8. Enoxaparin (direct thrombin inhibitor) : a b

(1) Enoxaprin LMWHESRD() t1/2 PK

anti factor IIaantithrombin IIIhemostatsis

a. Clcr < 30 mL/min anti-Xa activity

b. DVT 30 mg qd 1 mg/kg/d

c. STEMI < 75 y/oIV 30 mgMD1 mg/kg/d

75 y/oSC 1 mg/kg/d

d. UANSRTEMI SC 1 mg/kg/d

(2) Heparin induced thrombocytopenia(HIT) argatrobanlepirudin(direct thrombin

inhibitor thrombin catalytic site

argatroban)

(3) Lepirudin (recombinant hirudin)35%Clcr < 15 mL/m

(4) Argatroban15%

9. Drug therapy in HD

(1) Antihypertensive agentsvasoactive drugs (

)

(2) Antihypertensive agents BPantiarrhythmia agents

~

E.

F.

~

G.

H.

20

(4)1. National Kidney Foundation CKD

(1)Clcr ml/min (2)GFR ml/min (3) Clcr ml/min/1.73m2 (4) GFR ml/min/1.73m2

(C)2.

(A) Cockcroft (B)

Siersback (C) Schwartz (D)

Traub

(4)3. 40 155cm 100kg BUN Scr 120 5.5mg/dLFENa+ 0.78%

(1)Clcr=60-90ml/min(2)Clcr30-59ml/min

(3)Clcr=15-29ml/min(4)Clcr

21

(C)10.volume of distribution

8 1 L/kg 20 g/mL 48 Scr

= 1.1 mg/dL64kgI.V. Infusion rate

(A)111 g/hr (B)68 g/hr (C)111 mg/hr (D)68 mg/hr

(C) 11. 80%500 mgq8hClcr50 mL/min

mgClcr100 mL/min

(A) 100 (B) 200 (C) 300 (D) 400

(D)12.

(A) Carboplatin, cytarabine (B) Cyclophosphamide, bleomycin

(C) Topotecan, cisplatin (D) Gemcitabine, paclitaxel

(C)13. lamivudine, lisinopril, labetalolmetforminClCr15 mL/min

( A ) lamivudine

( B ) lisinoprilfosinopril

( C ) labetalol

( D ) metforminglyburide

(B) 14.7020glyburide 10 mg bid5

BUN 30 mg/dL, SrCr

: 1.6 mg/dL

glucose: 50 mg/dL, BUN: 70 mg/dL, SrCr

: 3.2 mg/dL

( A ) glyburide

( B ) metformin

( C )

( D ) glimepiride

(C)15. phenytoin 100mg tid 15mg/LScr = 1.6mg/dLAlbumin = 2g/dL free conc

free conc. CNl = Cobserved / 0.25Alb+0.1

(A)7.5mg/L (B) 9mg/L (C) 25mg/L(D) 30mg/L

16. phenytoin

phenytoin Albumin phenytoin

17. LD phenytoin

18. phenytoin 300mg/d 4 phenytoin 9.2g/ml Albumin

4.4g/dL

22

(1)19.phenytoin 100mg tid7 5g/ml 200mg tid

(1) (2) 10-20g/ml

(3) 150mg tid(4) IM

(D)20. 89 phenytoin 300 mg hs

albumin 2.2 g/dLphenytoin 15 mcg/mL

(A) 20%

(B) 20%

(C) albumin phenytoin albumin

(D) albumin

(C)21. 40ataxiadizzy

phenytoin 100 mg tid phenytoin 50 mg/L20

40 mg/L 10 mg/L

(A) globulinphenytoin

(B) phenytoin6212410

mg/L

(C) phenytoin

(D) phenytoin therapeutic range10-20 mg/L free drug

(B)22. Phenytoin

(A) Michaelis-Menten kinetics (B) 30 mg/kg/day (C)

(D)

phenytoin

(B)23.

(A)Carbamazepine (B)Phenobarbital (C)Phenytoin (D)Valproic acid

(A)24. diazepamoxazepam

(A) (B) (C) (D)

(3)25. captopril coughclonidine doxazosine losartan

propranolal

(2)26.Clc r= 23ml/min ACEIbenazepril enalapril fosinopril

trandolapril

(3)27.Clcr = 25ml/min ? (1) lamivudine (2) lisinopril (3) labetalal (4) digoxin

(B)28.

Ethambutol Isoniazid Pyrazinamide Rifampin

(A) (B) (C) (D)

23

(1)29.? (1) phenytoin (2) digoxin (3) vancomycin (4) Li

(3)30.? (1) amikacin (2) digoxin (3) phenobarbital (4)

procainamide

(A)31.

(A)Meperidine (B)Hydromorphone (C)Morphine (D)Fentanyl

(4)32. Meperidine Normeperidine CNS stimulant

meperidine N-demethylation

(12)33.? Enalapril Hydrochlorothiazide Diltiazem

Minoxidil

(C)34.33 160 cm 50 kg 15 fasting blood

sugar200 mg/dLserum creatinine3.0 mg/dL 148/95 mmHg

HbAlc8% 4+creatinine clearance

mL/min

(A)75 (B)50 (C)25 (D)12.5

(B)35.

(A) 130/80 mmHg (B)fasting blood sugar150 mg/dL (C)

post-prandial blood sugar180 mg/dL (D)HbA1c7%

(A)36. 2+pitting edema

(A)Trichlormethiazide (B)Furosemide (C)Na restriction (D)fluid restriction

(B)37.

(A)Isradipine (B)Enalapril

(C)

120/80 mmHg (D)captopril valsartan

38.78 Gentamicin klebsiella pneumonia 3h

8g/ml 11h 4g/ml 8h K= ? 0.087

39.Gentamicin 200mg q12h IV (9AM9PM) 10 AM 9PM

12g/ml 6g/ml t1/2= 11h

(B)40. gentamicin 40% gentamicin

2 (A)3 (B)5 (C)7 (D)9

(A)41. 64 170 70 Scr 1.0 mg/dL

Streptococcus viridans penicillin G gentamicin

gentamicin

(A)60 mg q8h (B)120 mg q8h (C)180 mg q8h (D)300 mg qd

24

(D)42. gentamicin 5 2.3 g/mL

(A) (B)

(C) gentamicin (D) gentamicin

(D)43.ClT 1.8 L/hr 5 g/mL

mg/day

(A)9 (B)90 (C)180 (D)216

(1)44.?

(1) Digoxin Clcr (2) phenytoin(3) Theophylline

30-40g/ml (4) Vancomycin

?(A)45. 70 digoxin 0.125 mg qd 2.1

ng/mL

(A) (B) (C)pH (D)

(B)46. dialyzability

(A) (B) Vd (C) (D)

983 A&B 16 ~ ~

983 A&B

O