Prinsip Terapi 098229

7/30/2019 Prinsip Terapi 098229

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Dept of pharmacogy and therapy

Faculty of medicineLampung university


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the presence of kidney for > 3 months, asdefined by structural or functionalabnormalities of kidney , with or wothoutdecreased GFR, manifest by either:

Pathological abnormalities ; or Marker of kidney damaged , including abnormalities

in the composition of the blood or urine, orabnormalities in imaging tests.

GFR < 60 mL/min/1,73 m2 for > 3 months,with or without kidney damage


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the stage is defined by the level of GFR, withhigher stages representing lower GFR levels.


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Sympthom

Nausea, fatique, edema systemic , oligourie

Sign

Anemia, hypertensi , ascites, edema tungkai

Laboratorium

Hb

blood ureum & creatinine Hipo proteninemia

GFR

Proteinurie


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Absorbption

the gastrointestinal disturbancesin renal failure(nausea, vomiting, diarrhea and gastrointestinal tractedema) could alter absorption.

Distribution

Renal disease may either increase or decreasevolume of distribution


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Elimination

It becomes obvious that t will be prolongedwhen either VD is increased and/or the rate ofrenal clearance or hepatic metabolismdecreases.

t = 693 x VD

Kr + Km

Note:

VD : Volume distribution

Kr :renal elimination constant

Km : hepatic metabolismelimination constant


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VD (liters) Renal Drug clearance(ml/min)

t (min)

15 700 15

15 100 104

15 50 208

15 10 1.020

15 2 5.220

VD = volume of distributionT = half time


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Renal handling in elimination drugs

Many pharmacologic agents are transported from

the peritubular blood into the urine by varioustubular secretory mechanisms.

Secretion of these compounds tends to be influencedby

other drugs competing for transport sites. Example:diminution of methotrexate excretion by salicylate andother organic anions.

modified by luminal pH.


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Enhanced excretionin alkaline urine(pH> 7)

Enhanced excretionin acid urine(pH


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Glucuronidation is normal in uremia, whilemanyacetylation reactions are slowed. Itbecomes obvious that knowledge of any given

drug's metabolic fate is necessary to predictmetabolic alterations produced by renal failure.


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Metabolic Process Drug Effect of Uremia

Oxidation AcetohexamideDephenylhydantoin

Phenacetin

PhenobarbitalQuinidineTolbutamide

SlowedDrug metabolite inducesincreased oxidationNone

NoneNoneNone

Reduction Hydrocortisone Slowed

Ester hydrolysis Procaine Slowed

Tissue peptidedegradation

Insulin Slowed, probably due tolack of renal metabolism

Glucuronidation ChloramphenicolIndomethacinTyroxineTriiodothyronine

NoneNoneNoneNone


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Metabolic Process Drug Effect of Uremia

Acetylation Hydralazine

Isoniazid

Paraamino salicylicacid

Sulfonamides

Slowed in some people*-genetically determined

slow acetylatorsSlowed in geneticallydetermined slow acetylators*;normal in fast acetylatorsSlowedSlowed


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Increased Sensitivity to Drugs

Reduced plasma protein binding of drugs in renalfailure

the blood-brain barrier may be altered in uremia


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Adjustment of dosage is usually dictated by theprolongation of t1/2 which is in turn, estimated by

the degree of reduction in glomerular filtration rate.


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Various strategies can be used when devising

dosage schedules in renal failure.

the constant dose-varying interval method the reduced dose-constant interval method.

Constant intravenous infusions


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a loading dose should be administered.Therefore, a usual or even slightly increasedinitial dose should be given to ill patients withrenal failure

To adjust maintenance therapy for renalfailure,one of several approaches can be used.


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Dettli and co-workers and Wagner

K%= a + b CLcrNote ;

K % = overall elimination rate constant ,

a = the portion of elimination rate constant due to

non renal losses

B CLcr is the poertion of the elimination rate constantdue to renal losses of the drug

to calculate the elimination t for any given value of

K% in renal failure:

T = 69.3K%


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make dosage adjustment for renalimpairment,

Dr = Dm x patient K%normal K%

Dr : dose in renal failure

Dm : usual maintenance dose

Calculate loading dose :

Vd = DL , to DL= VD x CC

VD: volume distribusi

DL: loading doseC : desire peak blood

level


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Example ;

In order to plan gentamicin therapy for a 70-kg

patient with renal failure and a ClCr Of 10 mlper minute, a normal volume of distributionthe same as extracellular fluid (15 liters) and adesired peak blood level of 10 /g per ml are

assumed.


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Loading dose

DL=VD X C. DL =15 liters X l0 g

loading dose 150 mg

. Maintenance dose

Normal K%= a + b CLcr

= 2 + 0,28 x 100 ml= 30

patient K % = 2 + 0,28 x 10 ml

= 2 + 2,8= 4,8


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TABLE 4.-Elimination Constants and Slopes for VariousAntibiotics (Adapted from Dettli et all and Wagner')

Drug a b Normal K % Normal t 1/2

Ampicillin .......Carbenicillin .....Cephalexin ......Cephalothin .....Chloramphenicol

Colistin .........Doxycycline .....Erythromycin ....5-fluorocytosineGentamicin ......Kanamycin ......

Lincomycin ......Methicillin .......Oxacillin ........Penicillin G ......Streptomycin.Sulfamethoxasole

11.06.03.06.020.0

8.03.013.0.72.01.0

6.017.035.03.01.07.0

.59

.54

.671.34.10

.230.37.2428.24

.091.231.051.37.260

70607014030

31350253025

15140140140277

1.01.21.0.52.3

2.223.01.42.82.32.75

4.6.5.5.52.69.9

drug a b Normal K % Normal t


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For antibiotic drugs where less than 15percent of the drug appears unchanged inthe urine, no dosage modification for renal

failure is necessary. Examples of these would include

lincomycin, clindamycin, isoniazid anddoxycycline.

drug a b Normal K % Normal t

TetracyclineTrimethoprimvancomycin

.82.0.3

.07

.04

.12

8612

8.712.05.8

a= percent hourly loss due to nonrenal processesb = slope of the lineK% =the overall rate constant for eLimination of the drug fromthe body as a percent per hourt/2 =half-life


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Some antibiotics should be avoided in renalfailure. A nitrofurantoin metabolite canaccumulate and cause peripheral neuritis if theGFR iS less than 20 ml per minute. Thetetracycline group, except doxycycline, areantianabolic agents and therefore promote

azotemia and acidosis


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Thiazide diuretics are first-line agents fortreating uncomplicated hypertension, notrecommended if the serum creatinine level ishigher than 2.5 mg per dL (220 mol per L) or

if the creatinine clearance is lower than 30 mL

per minute

Loop diuretics are most commonly used to

treat uncomplicated hypertension in patientswith chronic kidney disease


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Table 4. Antihypertensive Agents: Dosing Requirements in P atients withChronic Kidney Disease

drug Usual dosage Dosage adjustment ( ercentage ofusual dosage) based on GFR ( ml per

minute per 1.73 m2)

> 50 10 to 50 < 10

ACE inhibitorsBenazepril(Lotensin)Captopril(Capoten)

Enalapril (Vasotec)

Fosinopril(Monopril)Lisinopril (Zestril)Quinapril(Accupril)Ramipril (Altace)

10 mg daily25 mg every 8hours5 to 10 mg every12 hours 10 mg daily5 to 10 mg daily

10 to 20 mg daily5 to 10 mg daily

100%100%

100%

100%100%

100%100%

50 75%75%

75-100%

100%50-75%

75-100%50 -75 %

25-50%50%

50%

75-100%25-50%

75%25-50%


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drug Usual dosage Dosage adjustment ( ercentage ofusual dosage) based on GFR ( ml perminute per 1.73 m2)

> 50 10 to 50 < 10

Beta blockersAcebutolol (Sectral)

Atenolol(Tenormin) 5

Bisoprolol (Zebeta)Nadolol (Corgard)5

400-600mg once-twice a day5 100 mg dialy10 mg

40-80 mg dialy

100%

100%100%

1005

50%

50%75%

50%

30-50%

25%50%

25%


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drug Usual dosage Dosage adjustment ( ercentage of usual

dosage) based on GFR ( ml per minuteper 1.73 m2)

> 50 10 to 50 < 10

DiureticsAmiloride (Midamor)Bumetanide (Bumex)Furosemide (Lasix)Metolazone(Zaroxolyn)

Spironolactone(Aldactone)Thiazides||Torsemide(Demadex)Triamterene

(Dyrenium)

5 mg dailyNo adjustmentNo adjustmentNo adjustment50-100mg daily

25-50mg dailyNo adjustment50-100 2x daily

100%---Every 6-12

hour100%-100%

50%---Every 12-

24 hour100%-100%

Avoid---Avoid

Avoid-avoid


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hypoglycemic Agents: Dosing Requirements in P atients with Chronic

Kidney Disease

drugs Usual dosage Spesial consideration

Acarbose

Chlorpropamide

Glipizide

glyburide

Maximum: 50-100 mgthree times daily

100-500 mg daily

5 mg daily

2,5- 5 mg daily

Lack of data in patient with a serumcreatine level higer than 2 mg / dl ;(180) mol/L);therefore, acarbose

should be avoided in these patientAvoid in patient with a glomerularfiltration rate less than 50 ml/minutebecause of the increase risk ofhypoglycemiaDosage adjustment not necessary inpatient with renal impairment50% of the active metabolite isecreted via the kidney, creating apotensial for severe hypoglicemia;not recommended when creatinine

clearence is less than 50 ml perminutes (0.83 ml/seond)


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hypoglycemic Agents: Dosing Requirements in P atients with ChronicKidney Disease

drugs Usual dosage Spesial consideration

Metformin

Metformin

(extendedrelease)

500 mg twicedaily

500 mg daily

Avoid if serum creatinine level is hagherthan 1.5 mg/dl (130 ml per L) in men orhigher than 1.4 mg per dl ( 120 mol perL) in women, and in patient older than 80years or with chronic heart failure; fixed-

dose combination with metformin shouldbeused carefully in renal impairment;metformin should be temporarilydiscontinued for 24 to 48 hours beforeuse of iodinated contrast agents, not

restarted for 48 hours afterward, andthen restarted only when renal functionhas normalized


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Patients with stage 5 kidney disease are more

likely to experience adverse effects from opioiduse in patients with chronic kidney disease

causing central nervous system and respiratoryadverse effects

Acetaminophen can be used safely in patientswith renal impairment


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Patients at high risk of NSAID-induced kidneydisease should receive serum creatininemeasurements every two to four weeks for

several weeks after initiation of therapybecause renal insufficiency may occur early inthe course of therapy


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statin

statins: Dosing Requirements in P atients with Chronic Kidney Disease

Drug Usual dosage Dosage adjustments based on degreeof renal function

Atorvastatin(lipitor)

Fluvastatin (lescol)

Lovastatin(mevacor)

10 mg daily , max dose: 80 mg daily20-80 mg daily ; 80 mgdaily ( sustainedrelease)

20-40 mg daily ,maximal dosage : 80mg daily ( immediaterelease) or 60 mg daily( extended release)

No adjustment

50% dose reduction in patientwith a GFR less than 30 ml perminute per 1.73 m2

Use with caution in patient with aGFR less than 30 ml per minuteper 1.73m2


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statins: Dosing Requirements in P atients with Chronic Kidney Disease

Drug Usual dosage Dosage adjustments based on degreeof renal function

Pravastatin (pravachol)

Rosuvastatin(crestor)

Simvastatin (zocor)

10-20 mg dailymaximal dosage : 40mg daily

5 40 mg daily

10-20 mg dailymaximal dossage : 80

mg daily

Starting dosage should not exceed10 mg daily in patient with a GFRless than 30 ml per minute per 1.73m2

Recommended starting dossage is5 mg daily in patient with a GFRless than 30 ml per minute per1.73m2 not to exceed 10 mg dailyRecommended starting dossage is5 mg daily in person with a GFR

less than 10 ml per minute per1.73m2


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Other Common Agents: Dosing Requirements in P atients with ChronicKidney Disease

drug Usual dosage Dosage adjustments based on (percentage of usual

dosage ) GFR (mL per minute per 1.73 m2)>50 10-50 60)

-100%

-75%

50%-25%

400-1400 mg2x/day (GFR> 30-59) 200-700 mg daily (GFR > 15-29)

-75%

-50%

25%-10%

100-300 mgdily ( GFR

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