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PDAT3 > 19 - Drug use in Renal Failure > Flashcards

19 - Drug use in Renal Failure Flashcards

1
Q

Glomerular Filtration

  • *Excretion =**
  • *Filtraton + Secretion - ReAbsorption**
A

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

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2
Q

SECRETION

  • *Excretion =**
  • *Filtraton + Secretion - ReAbsorption**
A

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

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3
Q

REABSORPTION

  • *Excretion =**
  • *Filtraton + Secretion - ReAbsorption**
A

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

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4
Q

What is the Principle Marker of KIDNEY DAMAGE?

A

Urine Protein / Albumin

Characterizes the Severity of CKD
&
Monitors Disease Progression/regression

most protein is NOT excreted into urine

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5
Q

Urine Dipstick Test

A

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”

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6
Q

Many other reasons for FALSELY Elevated Protein in the urine on a “Spot Check”​

Urine Dipstick Tests

A

EXERCISE within 24 hours

UTI

CHF / HTN

HYPERglycemia

Pregnancy

Hematuria

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7
Q
  • *Clinical Proteinuria**
  • *Quantitative Diagnosis**
A

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

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8
Q

MicroAlbuminuria
​Quantitative Diagnosis

Earliest marker for Diabetic Nephropathy / CV risk

A

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

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9
Q

Qualitative Diagnosis of Kidney Disease

Purpose / Types

A

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)

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10
Q

Normal GFR
Men / Women

A

Males
127+20
ml/min/1.73m2

  • *Females**
  • *118** + 20
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11
Q

Best Exogenous Compound

for Measuring GFR

A

INULIN

low availability / HIGH COST
assay variability / sample prep

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12
Q

Exogenous Compounds

Measurement of GFR

A

Markers have to be:

  • *FREELY FILTERED**
  • NOT - secreted / reabsorbed / metabolized*
  • minimally protein bound + minimal non-renal clearance*

INULIN
Iothalamate / Iohexol / RadioIsotopes

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13
Q

Serum Creatinine

Measurement of GFR

Metabolic product of:
Creatine + Phosphocreatine
found almost exclusively in the MUSCLE

A
  • *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

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14
Q

Cockcroft Gault Equation

A

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

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15
Q

What Weight to use if
Normal Weight = BMI 18.5-24.9 ?

for CG Equation

A

IDEAL BODY WEIGHT

IBW Male = 50kg + ( 2.3kg x each inch >5ft )

IBW Female = 45.5kg + ( 2.3kg x each inch >5ft )

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16
Q
  • *What Weight to use if
  • UNDERweight* = BMI <18.5 ?**

for CG Equation

A

ACTUAL BODY WEIGHT

ABW for underweight

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17
Q

What Weight to use if
OBESE/OVERWEIGHT = BMI >25 ?

for CG Equation

A

ADJUSTED BODY WEIGHT

Adjusted BW = IBW + 0.4 (ABW - IBW)

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18
Q

Liver Disease / Renal Transplant / HIV

Special Populations - CG equation

A

CG tends to OVERESTIMATE measured 24 hr CrCl

Liver Disease
↓SCrfromreduced muscle mass & many other factors

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19
Q

Pregnancy / Elderly

Special Populations - CG equation

A

CORRELATES WELL
with 24hr CrCl

  • *Elderly**
  • reduced muscle mass = reduced Scr
  • do NOT round SCr up to 1**
20
Q

Children

Special Populations - CG equation​

A

Use the:
Children SCHWARTZ Equation

CrCl is more dependent on:

  • *Child’s AGE & LENGTH**
  • rather than weight*
21
Q

Which Equation do is the MOST ACCURATE for estimating GFR in

PATIENTS WITH CKD?

A
  • *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

22
Q

Which Equation BEST ESTIMATES GFR in the

NON-CKD Population?

A

CKD-EPI

MORE ACCURATE than MDRD
for GFR > 60

Equal Accuracy as MDRD for GFR <60

Factors:
SCr / Race / Gender / Age

23
Q

Limitations of SCr-Based Estimation Equations

A

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

24
Q

IDMS-SCr Assay

A

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

25
**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_***
26
**What Effect on Drug ADME?** * *_Gastroparesis_** * **delayed GI transit time***
***_↓DRUG ABSORPTION_*** **Gastroparesis** prolongs the TIME to reach MAX drug concentration
27
**What Effect on Drug ADME?** **_Vomiting & Diarrhea_**
***_↓DRUG ABSORPTION_***
28
**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**
29
**What Effect on Drug ADME?** **_Bowel Wall Edema_**
***_↓DRUG ABSORPTION_***
30
**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**
31
**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**
32
**What Effect on Drug ADME?** **_P-Gp Transport_** ↓**P-Gp activity in CKD**
_↑**DRUG ABSORPTION**_
33
**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**
34
What Effect on ​Drug ADME? * *_ALBUMINURIA_** * **less albumin available to bind in CKD***
_↑**DISTRUBUTION**_ **Since *less albumin binding*** --\> **MORE FREE DRUG**
35
What Effect on ​Drug ADME? **_ACIDIC DRUGS_** especially those bound to albumin **Cephalosporins / PCN Phenytoin / Furosemide / Salicylates Barbituates / Valproate / Warfarin**
_↑**DISTRUBUTION**_
36
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**
37
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*
38
**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_**
39
**CKD's Effect on Drug METABOLISM in KIDNEY ​ADME**
**_*REDUCED* Kidney Metabolism in CKD_** VVV **INCREASED DRUG CONCENTRATION** ## Footnote **APAP / Salicylate / Insulin Oxytocin / Morphine Somatostatin / Vasopressin**
40
**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**
41
**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_**
42
**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
43
**CKD Effect on EXCRETION** ## Footnote **_REABSORPTION_**
Healthy Kidneys: **substantial reabsorption in distal nephron** **_CKD_**: ***REDUCED reabsorption*** VVV **INCREASED URINARY CONCENTRATION of DRUGS** **Aspirin / Lithium**
44
**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**
45
* *_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***

PDAT3 (23 decks)

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