19 - PK of RENAL DISEASE Flashcards
Age & CKD
- Renal plasma flow declines with age
- 600ml/min –> 350-450 ml/min
-
Linear Decrease in GFR 0.4-1.02 ml/min
- PER YEAR
- Elderly have a Falsely Elevated GFR
- if have a lack of muscle mass
- due to creatinine
Falsely Elevated GFR
for Elderly
Creatinine decreases due to lower muslce mass
Low Serum creatinine (SCr) shows
a greater creatinine clearance (CrCl)
–> Falsely Elevated GFR
Uremia
-
GFR is impaired due to:
-
Increased Fluid
- –> INCREASED Vd
- Accumalation of TOXINS
-
Increased Fluid
- Reduced GFR & Reduced Active Secretion
-
Uremic patients must have dosage adjustment
- F / Vd / CL are affected
Methods of Renal Excretion
Drug Filtration Rate =
GFR x free fraction of drug x drug concentration
- Glomerular Filtration
- All drugs + metabolites
- PROTEIN BINDING
- Renal tubular secretion
- No protein binding influence
- COMPETITION w/ other drugs
-
Reabsorption
- AFFECTS IONS
- affects acids/bases
- AFFECTS IONS
CKD Stages
<60 GFR
(mL/min/1.73m2)
Diagnosed with CKD
- There is G1-G5
-
G3 has a split = G3a &G3b
- this is where u are diagnosed with CKD
-
G3 has a split = G3a &G3b
Normal GFR
mL/min/m2
120-130 mL/min/m2
Declines with age
70+ years old avg GFR = 75
- 1.1/min of blood flows through kidney
- 20% of cardiac output
- 10% if filtered thru glomerulus
Inulin
- More exact measurement of GFR vs CrCl
- but is more expensive
- is std of practice but not used that often.
Creatinine Clearance
ml/min
NOT EQUAL TO GFR
OVERESTIMATES ACTUAL GFR
small amount creatinine eliminated by secretion/non-renally
- Most often used as a measurement of GFR
- but Varies w/ age/gender/weight
- Best to measure 24-hour urine collection
- Based on Cockcroft-Gault Equation
CrCl
Used Carefully in which populations?
-
Elderly / Malnourished
-
low muscle mass -> low SCr
- –> Falsely Increased CrCl
-
low muscle mass -> low SCr
- Obese
-
Body Builders
-
HIGH muscle mass -> HIGH SCr
- –> Falsely low CrCl
-
HIGH muscle mass -> HIGH SCr
IBW for males
50 + 2.3 (#inches over 5 feet)
IN KILOGRAMS
IBW for Females
45.5 + 2.3 (#inches over 5 feet)
IN KILOGRAMS
Cockcroft Gault Equation
CrCl
ClCr = (140-age) x IBW(kg)
72 x SCr
Multiply by 0.85 if female
Problems with Cockcroft-Gault
- Study was mainly with caucasian males
- NOT GOOD for very small or Very obese patients
- OVERESTIMATES GFR by 10-20%
-
Does NOT account for BSA
*
MDRD Equation
Modification of Diet in Renal Disease
eGFR (estimated GFR, also in mL/min/m2)
More accurate than Cockcroft Gault (CrCl)
Can calculate BSA for very small/obese patients
- Larger and more diverse study
- Limitations:
- Can not be used when SCr is NOT stable
- UNDERESTIMATES eGFR @ normal levels
- OVERestimates eGFR when <20
CKD-EPI Equation
Most Accurate Estimator of eGFR
-
More accurate than MDRD
- but limited # of elderly & ethnic minorities
- Better for patients with HIGHER GFR than MDRD
Adjusted Body Weight
Adj BW
Adj BW = IBW + 0.4(Actual BW - IBW)
Used if Actual BW >30% of IBW
CKD’s Affect on Kinetic Parameters
ORAL BIOAVAILABILITY
-
Reduce Bioavailabilty (F)
- Reduced by altered GI motility
- Altered pH
- Increase in Acidity
- Decreased Liver Function
CKD’s Affect on Kinetic Parameters
Volume of Distribution
Vd
-
INCREASE in fluid/ Vd
- Depends on drug-protein binding
- High Uremic patients hold onto more water as kidney loses function
- –> Increase Vd
- Lower levels of Albumin
- MAY Need to Increase loading dose for CKD patients
Small Vd Drugs
<0.7 L/kg
HIGHLY DIALYZABLE
Highly Water Soluble Drugs
Aminoglycosides / beta lactam antibiotics
Large Vd Drugs
>0.7 L/kg
NOT READILY DIALYZED
-
Lipid-Soluble Drugs
- Fluoroquinolones / macrolides
- Highly Tissue Bound drugs
-
Highly Protein bound drugs
- Phenytoin / Warfarin
Protein Binding & Vd
for CKD patients
CKD Patients may eliminate Albumin in urine
-
DECREASE protein synthesis (protein spill)
- Due to decreased protein intake
- Poor apititite –> lower albumin
-
–> Increase in free drug
- –> possible toxicity
-
–> Increase in free drug
-
Alterations @ tissue binding sites
- Uremic toxins –> bind to receptor sites
- –> Increase in nitrogen metabolites
- Uremic toxins –> bind to receptor sites
Modified Loading Dose
Vd of CKD patient
Modified LD = (Pt’s Vd / Normal Vd) x Ld x weight
Pt’s Vd = Vd of CKD Patient = 0.3-0.35 L/kg
Bioavailability in CKD Patients
-
REDUCED Bioavailability
-
Slowed absorption
- -edema
- Concurrant medications
- Binders for dialysis patients
-
ALKALINE ENVIRONMENT
- Basic due to PPI’s -/-> blocking acidity
-
Slowed absorption
Protein Binding in CKD
-
Decreased Protein Binding
-
Less albumin –> MORE free drug
- –> posible toxicity
- HIGHLY protein bound drugs
- have a low Vd
- because not much protein to bind
-
Less albumin –> MORE free drug
Metabolism in CKD patients
-
Elimination may be IMPAIRED
-
CYP 3A4 / 2C9
- REDUCED by up to 50%
-
Glucoronidation reduced
- polar metabolites
- conjugates can accumalate –> adverse drug events
-
CYP 3A4 / 2C9
- Kidney metabolizes some drugs
-
IF On Helodialysis
- –> INCREASE clearance of meds that are NOT renally cleared
Clearance in CKD patients
-
Decreased:
- GFR
- Active tubular Secretion
- Hepatic Clearance
- Lead to Prolonged Elimination HALF LIVES
- Toxic metabolite accumalation can occur
Elimination in CKD
-
Stage of CKD matters (shows degree of renal insufficiency)
-
Beware of drugs w MOA in renal
- HCTZ
- __Toxicity due to electrolytes retained
- K+ sparing diuretics
-
Beware of drugs w MOA in renal
-
ACUTE RENAL FAILURE
- Always need to adjust dose
- Dosing guidelines are based on CHRONIC renal failure
Residual Renal Function
MISCONCENPTION
There is still renal fxn in patients with CKD
we want to preserve it!
avoid using nephrotoxic agents (NSAIDS/aminoglycosides)
How to Dose Adjust for Patients w/ CKD
Decrease maintanence dose
INREASE dosing interval
OR BOTH!
Loading Dose is based on Vd
Maintanence dose is based on clearance
CKD Dose Adjustment Goal
Attain same drug concentration found in
NORMAL RENAL FXN PATIENTS
Fraction of Drug Excreted (fe)
&
Half Life
Assume that non-renal elimnation remains UNCHANGED
all other factors (like liver and GI ) are the same
- When fe is known
- You can estimate a dosage regimen in CKD patient
- Half life changes when
- clearance or Vd is modified
Dialysis
-
Hemodialysis / Peritoneal Dialysis
- can be outpatient/home
-
CVVH/CVVHD/SLEDD/EDD
- in patient ONLY
-
Most machines are HIGH FLUX
- high permeability, dialyze drugs
- w/ Large MW
- 30k-40k
- w/ Large MW
- Low flux exist but not usually used
- high permeability, dialyze drugs
Hemodialysis
DIALYSANCE
Dialysance = Drug cleared by dialysis
Medications still get cleared by dialysis
- Blood filtered through artifical membrane
- need artery/vein to allow blood to flow back to body
-
400-600ml/min
- done for 4 hours three times a week
Hemodialysis on
Drugs With Small Vd
< 1 L/kg
DIALYZED THE MOST
large amounts are in the PLASMA
small amounts in the tissue
Water soluble
- large Vd drugs are the opposite*
- >2 L/kg*
