19 - Drug use in Renal Failure Flashcards
Glomerular Filtration
- *Excretion =**
- *Filtraton + Secretion - ReAbsorption**
Water + Small MW ions or molecules
PASSIVELY diffuse across glomerular capillary membrane
VVV
Bowman Capsule –> Proximal Tubule
Proteins / protein-bound compounds are TOO LARGE
Amount of soute filtured is related to:
GFR & Extent of Plasma Protein Binding
SECRETION
- *Excretion =**
- *Filtraton + Secretion - ReAbsorption**
ACTIVE TRANSPORT
from renal circulation –> tubular lumen
Renal clearance via secretion can be >GFR (1000mL/min)
Anionic / Cationic Transport Systems
for wide range of endo/exogenous substances
Efflux Proteins (P-gp)
contribute to renal elimination of many drugs
REABSORPTION
- *Excretion =**
- *Filtraton + Secretion - ReAbsorption**
Water + Solutes
reabsorbed throughout nephron
Most Drugs Reabsorbed in
DISTAL Tubule + COLLECTING DUCT
Affects Reabsorption:
Urine Flow Rates
Physicochemical Characteristics
highly IONIZED molecules WONT be reabsorbed
unless urine pH changes –> unionized
What is the Principle Marker of KIDNEY DAMAGE?
Urine Protein / Albumin
Characterizes the Severity of CKD
&
Monitors Disease Progression/regression
most protein is NOT excreted into urine
Urine Dipstick Test
Semi-Quantitative
Detection of Protein in Urine
- *False Positives**
- *Concentrated urine** samples may be considered proteinuria
False negatives
protein may be undetected until excretion gets to HIGH level
Many other reasons for FALSELY Elevated Protein in the urine on a “Spot Check”
Many other reasons for FALSELY Elevated Protein in the urine on a “Spot Check”
Urine Dipstick Tests
EXERCISE within 24 hours
UTI
CHF / HTN
HYPERglycemia
Pregnancy
Hematuria
- *Clinical Proteinuria**
- *Quantitative Diagnosis**
24 hour collection = Spot Protein/Albumin : Cr Ratio
in terms of efficacy
24 Hour Collection
> 300mg/day
albumin or protein
Spot Protein:Cr
> 200 mg/g (> 0.2 mg/mg)
Spot Albumin
> 300 mcg/mg
MicroAlbuminuria
Quantitative Diagnosis
Earliest marker for Diabetic Nephropathy / CV risk
24 hour collection = Spot Protein/Albumin : Cr Ratio
in terms of efficacy
24 Hour Collection
30 - 299 mg/day albumin
Spot Protein:Cr
n/a
Spot Albumin
30 -299 mcg/mg
Qualitative Diagnosis of Kidney Disease
Purpose / Types
To evaluate the ETIOLOGY of the kidney disease
Renal Ultrasound
can detect structural abnormalities (obstruction)
Biopsy
to fascilitate diagnosis when clinical/lab/imaging is inconclusive
evaluate renal parenchymal disease
complications for bleeding risk ( peri-renal hematoma)
Normal GFR
Men / Women
Males
127+20
ml/min/1.73m2
- *Females**
- *118** + 20
Best Exogenous Compound
for Measuring GFR
INULIN
low availability / HIGH COST
assay variability / sample prep
Exogenous Compounds
Measurement of GFR
Markers have to be:
- *FREELY FILTERED**
- NOT - secreted / reabsorbed / metabolized*
- minimally protein bound + minimal non-renal clearance*
INULIN
Iothalamate / Iohexol / RadioIsotopes
Serum Creatinine
Measurement of GFR
Metabolic product of:
Creatine + Phosphocreatine
found almost exclusively in the MUSCLE
- *Endogenous Compound**
- less technical /* MORE variable results
does NOT bind to plasma proteins // freely filtered by glomerulus
Cr undergous VARIABLE TUBULAR SECRETION
VV
OVERestimation of kidney fxn
as renal fxn declines –> tubular secretion of SCr INCREASES
Medications can inhibit tubular secretion:
Trimethoprim / dronedarone / H2blockers
Cockcroft Gault Equation
Most commonly used equation to:
DETERMINE DRUG DOSES
for patients with impaired kidney fxn
- *CrCl** = (140 - AGE) x Weight
- *(SCr x 72)**
*x0.85 for females
Variables:
SCr - Age - Weight
Weight varies on the patient
What Weight to use if
Normal Weight = BMI 18.5-24.9 ?
for CG Equation
IDEAL BODY WEIGHT
IBW Male = 50kg + ( 2.3kg x each inch >5ft )
IBW Female = 45.5kg + ( 2.3kg x each inch >5ft )
- *What Weight to use if
- UNDERweight* = BMI <18.5 ?**
for CG Equation
ACTUAL BODY WEIGHT
ABW for underweight
What Weight to use if
OBESE/OVERWEIGHT = BMI >25 ?
for CG Equation
ADJUSTED BODY WEIGHT
Adjusted BW = IBW + 0.4 (ABW - IBW)
Liver Disease / Renal Transplant / HIV
Special Populations - CG equation
CG tends to OVERESTIMATE measured 24 hr CrCl
Liver Disease
↓SCrfromreduced muscle mass & many other factors
Pregnancy / Elderly
Special Populations - CG equation
CORRELATES WELL
with 24hr CrCl
- *Elderly**
- reduced muscle mass = reduced Scr
- do NOT round SCr up to 1**
Children
Special Populations - CG equation
Use the:
Children SCHWARTZ Equation
CrCl is more dependent on:
- *Child’s AGE & LENGTH**
- rather than weight*
Which Equation do is the MOST ACCURATE for estimating GFR in
PATIENTS WITH CKD?
- *MDRD4**
- CKD-EPI is just AS accurate for GFR <60*
Variables:
SCr / Age / Gender / Race
MDRD6 has SUN & Albumin
LESS ACURATE with pts with GFR > 60
use in caution in:
children / elderly / pregnant / women / critically ill
Which Equation BEST ESTIMATES GFR in the
NON-CKD Population?
CKD-EPI
MORE ACCURATE than MDRD
for GFR > 60
Equal Accuracy as MDRD for GFR <60
Factors:
SCr / Race / Gender / Age
Limitations of SCr-Based Estimation Equations
Use of SCr as filtration marker
affected by age/gender/race/muscle mass
undergoes VARIABLE tubular secretion
affected by unusual dietary habits
CG / MDRD Studies did NOT include this population
pregnant / obese / vegetarian / amputees / liver disease
Transplant / HIV / children / elderly / unstable renal fxn
MDRD ONLY studied CKD patients
IDMS-SCr Assay
Used to STANDARDIZE SCr across institutions
5-20% underestimation of SCr –> overestimates GFR
MDRD-IDMS Equation
CKD-EPI
is ALREADY SET to use IDMS-SCr
What Effect on Drug ADME?
Increased Gastric pH
seen in many CKD patients
Ammonia in gut
Phos Binders / Antacids / H2RA / PPI are often used in CKD’s
↓DRUG ABSORPTION
What Effect on Drug ADME?
- *Gastroparesis**
- delayed GI transit time*
↓DRUG ABSORPTION
Gastroparesis
prolongs the TIME to reach MAX drug concentration
What Effect on Drug ADME?
Vomiting & Diarrhea
↓DRUG ABSORPTION
What Effect on Drug ADME?
CHELATE FORMATION
Many CKD drugs are suceptable:
Mg / Ca / Al-OH / Ferrous SUlfate / SPS
+
TetraCyclines / Fluoroquinolones
↓DRUG ABSORPTION
Chelate formation –> Reduced Absorption
What Effect on Drug ADME?
Bowel Wall Edema
↓DRUG ABSORPTION
What Effect on Drug ADME?
Magnesium Hydroxide + Sodium Bicarbonate
↑DRUG ABSORPTION
Mag-OH + NaBicarb
can INCREASE absorption of weakly acidic drugs
(ibuprofen / glipizide / glyburide)
by increasing their water solubility
What Effect on Drug ADME?
↓INTESTINAL METABOLISM
CKD patients have:
↓intestinal metabolism & ↓p-gp drug transport
↓CYP450 intestinal activity
↑DRUG ABSORPTION
INCREASED BIOAVAILABILITY OF CERTAIN DRUGS
Drugs with increased bioavailability in CKD due to decreased intestinal or liver metabolism:
dextropropoxyphene, dihydrocodeine, propranolol, felodipine, sertraline, cyclosporine
What Effect on Drug ADME?
P-Gp Transport
↓P-Gp activity in CKD
↑DRUG ABSORPTION
What Effect on Drug ADME?
FIRST PASS METABOLISM in LIVER
AFFECTS ABSORPTION IN BOTH WAYS
↓intestinal absorption & ↓p-gp transport = ↓absorption
↓less protein bound drug = ↓absorption
- Drugs with reduction in 1st pass metabolism*
- *= INCREASED absorption**
What Effect on Drug ADME?
- *ALBUMINURIA**
- less albumin available to bind in CKD*
↑DISTRUBUTION
Since less albumin binding –> MORE FREE DRUG
What Effect on Drug ADME?
ACIDIC DRUGS
especially those bound to albumin
Cephalosporins / PCN
Phenytoin / Furosemide / Salicylates
Barbituates / Valproate / Warfarin
↑DISTRUBUTION
What Effect on Drug ADME?
ALKALINE DRUGS
bind mostly to NON-albumin proteins
like a-1 acid glycoprotein (high in renal dysfunction)
Propranolol / Morphine
Oxazepam / Vancomycin
↓DISTRUBUTION
likely unchanged
Alkaline Drugs bind to a-1 acid glycoprotein
which is ELEVATED in renal dysfunction
What Effect on Drug ADME?
- *TISSUE BINDING**
- usually irrelevant but…*
DIGOXIN
is primarily bound to tissues
↓DISTRUBUTION
Vd is reduced by 50% in CKD stage V
DIGOXIN –> need to REDUCE LOADING DOSE
since digoxin is primarily bond to tissues, not plasma
CKD’s Effect on Drug METABOLISM in LIVER
ADME
- *PHASE 1_ & _PHASE 2** metabolism
- *BOTH SLOWED** in CKD
Phase 1 = Hydrolysis / Reduction / CYP450 oxidation
Phase 2 = Acetylation / Glucuronidaition / Sulfation / Methylaition
INCREASED DRUG CONCENTRATION
CKD’s Effect on Drug METABOLISM in KIDNEY
ADME
REDUCED Kidney Metabolism in CKD
VVV
INCREASED DRUG CONCENTRATION
APAP / Salicylate / Insulin
Oxytocin / Morphine
Somatostatin / Vasopressin
What Effect on Drug ADME?
- *Drugs Metabolized by CYP3A4**
- *Presence of Uremia –> decreased CYP activity**
- *Uremic toxins –> endogenous inhibitors**
- *CKD also alters NON-RENAL clearance of many meds**
- due to uptake / efflux transporters*
REDUCTION IN METABOLISM
VVV
INCREASED DRUG CONCENTRATION
CKD Effects on EXCRETION
Glomerular Filtration
Drugs with:
LOWER Molecular weight** & **LESS Protein-Bound
VVV
MORE LIKELY to be FILTERED
↓filtration rate in CKD
VVV
↓Elmination of filtered drugs
VVV
PROLONGED FREE-DRUG
CKD Effects on EXCRETION
SECRETION
INCREASED DRUG + METABOLITES
Highly Protein-Bound Drugs = less likely to be filtered
CKD: Active transport system of secretion is REDUCED
less so vs filtration
VVV
INCREASED HALF LIFE
Ampicillin, furosemide, salicylic acid, cimetidine, dopamine, neostigmine, procainamide, trimethoprim, quinidine
CKD Effect on EXCRETION
REABSORPTION
Healthy Kidneys:
substantial reabsorption in distal nephron
CKD:
REDUCED reabsorption
VVV
INCREASED URINARY CONCENTRATION of DRUGS
Aspirin / Lithium
Loading Dose Considerations for CKD
- *Normal LD for CKD patients**
- except for DIGOXIN*, –> reduced due to altered tissue binding
Patients with edema –>
fluid overload requires higher LD for increased LD
- *Maintanence Dose**
- *Considerations for CKD**
REDUCED DOSE
lower peak / HIGHER troughs
associated with higher risk of ADR
- *EXTENDED INTERVAL**
- reduced toxicities*, BUT potential for sub-therapeutic periods
BOTH:
Optomizes efficacy / minimize toxicity
