prinsip terapi 098229
TRANSCRIPT
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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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Table 4. Antihypertensive Agents: Dosing Requirements in P atients withChronic Kidney Disease
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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Table 4. Antihypertensive Agents: Dosing Requirements in P atients withChronic Kidney Disease
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