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

GFR is impaired due to: Increased Fluid --\> INCREASED Vd Accumalation of TOXINS Reduced GFR & Reduced Active Secretion _Uremic patients must have dosage adjustment_ __F / Vd / CL are affected

\<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

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

More exact measurement of GFR vs CrCl but is more expensive is std of practice but not used that often.

Most Accurate Estimator of eGFR More accurate than MDRD but limited of elderly & ethnic minorities Better for patients with HIGHER GFR than MDRD

19 - PK of RENAL DISEASE Flashcards by Karlo Sison

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

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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

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Uremia

GFR is impaired due to:
- Increased Fluid
  - –> INCREASED Vd
- Accumalation of TOXINS
Reduced GFR & Reduced Active Secretion
Uremic patients must have dosage adjustment
- F / Vd / CL are affected

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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

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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

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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

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Inulin

More exact measurement of GFR vs CrCl
- but is more expensive
- is std of practice but not used that often.

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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

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CrCl

Used Carefully in which populations?

Elderly / Malnourished
- low muscle mass -> low SCr
  - –> Falsely Increased CrCl
Obese
Body Builders
- HIGH muscle mass -> HIGH SCr
  - –> Falsely low CrCl

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IBW for males

50 + 2.3 (#inches over 5 feet)

IN KILOGRAMS

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IBW for Females

45.5 + 2.3 (#inches over 5 feet)

IN KILOGRAMS

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Cockcroft Gault Equation

CrCl

ClCr = (140-age) x IBW(kg)

72 x SCr

Multiply by 0.85 if female

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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
*

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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

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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

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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

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
Alterations @ tissue binding sites
- Uremic toxins –> bind to receptor sites
  - –> Increase in nitrogen metabolites

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

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

**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 * **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_** * **__****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 (f_e)** **&** **Half Life**

Assume that non-renal elimnation remains UNCHANGED all other factors (like liver and GI ) are the same * When f_e 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** * Low flux exist but not usually used

**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*