201005 bennett sica
TRANSCRIPT
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Kidney Disease: Improving Global Outcomeswww.kdigo.org
Drug Prescribing in Kidney Disease:Initiative for Improved Dosing
Effects of impaired kidney function ondrug pharmacokinetics and
pharmacodynamics
Section Leaders:William Bennett and Domenic Sica
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Passage of a Drug Dose Through the Body
(Pharmacokinetics)
Oralabsorption
EliminationTissue receptor:
action
Parenteral drugadministration
Systemiccirculation
Bound to proteins Free
(Bioavailability is theproportion of an oral dosereaching systemic system)
Liver
First-pass effect
Parent drug
Active/inactive metabolites Pharmacodynamics
Kidneys
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Effects of Age and Renal Dysfunction onPharmacokinetics and Pharmacodynamics
All processes affected by both variables incomplex ways
Drug elimination primarily affected by
GFR(age +/- CKD)
Formulae for GFR estimation not validated fordrug dosing purposes
Biologic readouts better than kinetic surrogatesie. blood levels vs. BP, INR, etc. Drug interactions multiple and personal
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Pharmacokinetic Parameters
Affected by Age/GFRParameter (abbreviation) Clinical ApplicationBioavailability (F) Determines the amount of drug
reaching the systemic circulationand therefore the amount at thesite of action
Volume of Distribution (VD) Determines the size of a loadingdoseClearance (Cl) Determines the maintenance doseHalf-life (T1/2) Determines the amount of time
needed to reach steady stateserum concentrations or eliminatethe drug (four times the T1/2)
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Effect of Renal Dysfunctionon Drug Usage
Accumulation of drugs normally excreted
Accumulation of active metabolites
Change in drug distribution - protein binding
Decrease in renal drug metabolism
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Goals of Therapy
Maintain efficacy
Avoid accumulation and toxicity
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Prescribing for a Patientwith Renal Dysfunction
Ascertain level of renal function (estimatedGFR/C Cr)
Establish integrity of liver metabolism
Establish loading dose Maintenance dose - dose reduction vs. interval
extension Check for drug interactions Decide whether blood level monitoring is indicated
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Estimated GFR MDRDFormula
eGFR (mL/min/1.73 m 2) = 175 [SerumCreatinine (umol/L) x 0.0113] -1.154 x age(years) -0.203
If female, multiply the result by 0.742 If African American, multiply the result by 1.21 Not valid for eGFR > 60 Not valid for very fat, very thin, paraplegics,
elderly
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Cockroft-Gault Equation
140-age x (lean body weight) x 0.85 (if female)72 x serum creatinine
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References Regarding GFREstimation for Drug Dosing
Wango et al., Comparison of MDRD andCG equations for antimicrobial doseadjustments. Ann Pharmacother 2006,
40:1248. Stevens et al., Comparison of drug dosing
recommendations based on measuredGFR and estimating equations. Am JKidney Dis 2009, 54:33.
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The Loading Dose
Loading dose = desired Cp SS x VD x patients weight
Cp SS = plasma concentration of the drug desired at steadystate
VD = volume of distribution
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Methods of Drug Dose Adjustment in Patients with
CKD
Constant DoseVarying Interval
Constant IntervalVarying Dose
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Examples of RenallyExcreted Metabolites in CKD
ActiveDiazepam
Desmethyldiazepam
ToxicMeperidine
Normeperidine
Additive
Procainamide NAPA
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0.1
0.6
1.1
1.6
2.1
2.6
3.1
3.6
2 6 2 8 3 0 3 2 3 3 3 4 3 5 3 7 7 1 7 9 9 4 1 0 5
1 2 3
Time (hours)
u g / m l
N-Acetyl Procainamide (NAPA) Procainamide
Pre-Dialysis
Post-Dialysis
Pre-Dialysis
Post-Dialysis
Pre-Dialysis
Post-Dialysis
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Specific Drugs withRenal Dysfunction
Narcotics
Antibiotics/Antivirals LMW Heparins
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1
10
100
1000
0 4 8 12 16 20 24
Time (hours)
P l a s m a c o
n c e n t r a t i o n ( n m o l / l )
Morphine 3-glucuronideMorphine 6-glucuronideMorphine
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Antibiotics to be Adjusted* Cephalosporins Imipenems:
Syndromes of neurotoxicity described Penicillins: Neurotoxicity/seizures
Acyclovir/Ganciclovir: Leukopenia,neurotoxicity, renal dysfunction
Minimal Adjustments:Fluoroquinolones, sulfonamides
* GFR < 20% normal
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Low Molecular WeightHeparin (LMWH) in CKD)
Lim et al. Annals of Int Med 2006 LMWH excreted by kidneys
eGFR < 30 mL/min lengthens t 1/2 andincreases anticoagulant anti-X a
Increased risk of major bleeding not
easily reversed Need for downward dose adjustment
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Rules of Thumb for ChangingMaintenance Drug Dosage
Available options: Decrease the dose, keeping the interval constant Increase the dose interval, keeping the dose constant
Decide the appropriate dosage regimen for the patientas if renal function were normal
Determine the fraction of drug and active metabolite thatis excreted unchanged by the kidneys
Calculate the dosage adjustment factor. This factor is theratio of the half-life of the drug in the patient to the half-life of the drug in the normal person
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Rules of Thumb for ChangingMaintenance Drug Dosage (contd) Use the dosage adjustment factor in one of the
following ways after considering which is mostappropriate for the individual drug: Divide the dose you determined for normal renal function
by the dosage adjustment factor and continue with the
same dosage interval Continue with the same dose but multiply the dosage
interval you determined for normal renal function by thedosage adjustment factor
A regimen of combined dose reduction and dose intervalprolongation may maintain a more uniform serumconcentration
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Drug Level MonitoringDrug toxicity is serious and occurs at
levels close to therapeutic
Therapeutic and biologic end pointsare not easily defined
To exclude non-compliance or markedinterindividual differences
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Problems with Current Data Kinetic studies performed in few
stable CKD patients withoutcomorbidities, acute illness Liver and non-renal metabolism
varies (age, genetics, illness, otherdrugs)
No cookbook to make rationalindividual patient decisions;Requires Wisdom
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Conclusions Prescribing in CKD is an art not science at
this point
No substitute for knowing the drugpharmacology and the individual patient
Individualize. Go Low/Go Slow is a goodgeneral rule
Review med lists including OTC
supplements at each visit Watch for nephrotoxins
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Kidney Disease: Improving Global Outcomeswww.kdigo.org
Breakout Group 1:
Discussion Questions/Objectives
Effects of impaired kidney function on drug PK and PD
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Kidney Disease: Improving Global Outcomeswww.kdigo.org
Breakout Group 1:
Clinical Recommendations
Effects of impaired kidney function on drug PK and PD
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Breakout Group 1: Research &
Regulatory Recommendations
Effects of impaired kidney function on drug PK and PD