Renal Disease and PKPD

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Renal Disease and PK/PD

• Anjay Rastogi MD PhD

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Drugs and Kidneys

• Kidney is the major organ of drug elimination
  from the human body
• Renal disease and dialysis alters the
  pharmacokinetics and pharmacodynamics of most
  commonly used drugs
• Polypharmacy is common in renal disease patients
  with a median of 8 drugs being used
• Patients with renal disease on an average suffer
  from adverse effects as compared to the general
  population

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• Estimation of renal function
• Effect of renal disease on PK and PD
• Drug Nephrotoxicity
• Management of poisoning

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Nephron
Reabsorption
Filtration

• Kidney regulates
• Water
• Acid-base balance
• Electrolytes
• Nitrogenous waste
• excretion

Secretion
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GFR as an Indicator of Kidney Function

• GFR is an important indicator of CKD
• Reduced GFR in patients with renal disease
  results from irreversible loss of nephrons1,2
• Greater burden is placed on remaining nephrons
• Hyperfiltration predisposes to further nephron
  destruction
• 50 of nephrons can be lost without functional
  impairment1
• Patients may still be asymptomatic, but are
  progressing toward end-stage chronic renal
  failure1

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1. Ix JH et al. Lange Pathophysiology. Lange
Medical Books/McGraw Hill, Medical Publishing
Division 2006456-481 2. Eaton DC et al.
Vander's Renal Physiology. Lange Medical
Books/McGraw Hill, Medical Publishing Division
200424-36.
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Defining GFR

• Glomerular filtration
• Process by which water and solutes in the blood
  pass from the vascular system through a
  filtration barrier into Bowman space
• This filtrate is similar to blood plasma, with
  large plasma proteins excluded
• GFR
• Volume of filtrate formed per unit of time
• Normal young adult male 180 L/d (125 mL/min/1.73
  m2)
• Entire plasma volume is filtered by kidneys 60
  times per day

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Eaton DC et al. Vanders Renal Physiology. Lange
Medical Books/McGraw Hill, Medical Publishing
Division 20041-23.
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Factors Affecting GFR

• Direct determinants of GFR
• Permeability of capillaries and surface area
  (filtration coefficient)
• Net filtration pressure (hydrostatic pressure in
  capillaries and in Bowman capsule, and glomerular
  capillary osmotic pressure resulting from
  proteins)
• Other factors that affect GFR
• Changes in renal arterial pressure, renal
  arteriolar resistance (dilation or constriction),
  and renal plasma flow
• ? Intratubular pressureobstruction of tubule or
  urinary system
• ? Osmotic pressureincreased protein
  concentration

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Eaton DC et al. Vanders Renal Physiology. Lange
Medical Books/McGraw Hill, Medical Publishing
Division 200424-36.
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Estimation of GFR

• Inulin clearance
• Iothalamate scans
• 24 hour urine collection
• eGFR
• Creatinine

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GFR versus Serum Creatinine
GFR versus Serum Creatinine
9.0
8.0
7.0
6.0
5.0
Serum Creatinine (mg/dL)
4.0
3.0
2.0
1.0
0.0
0
20
40
60
80
100
120
140
160
180
Inulin Clearance (mL/min/1.73 m2)
Available at http//medical.dictionary.thefreedict
ionary.com/. Accessed on March 1, 2005. Johnson
R, et al. Comprehensive Clinical Nephrology.
2000. Mosby. St. Louis. 4.15.14.15.15.
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GFR Equations Compared
Cockcroft-Gault
MDRD
(0.742 if female)
(1.212 if black)
140 - age x weight (kg) 72 x PCr
x
x (0.85 symbol for female)
186.3 x PCr 1.154 x age 0.203 x
6 variable Cr, BUN, age, alb, race, sex 4
variable Cr, age, race, sex
Levey AS, et al. Ann Intern Med.
1999130(6)461-470. Abstract
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Pharmacokinetics
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Pharmacokinetics

• Absorption and bioavailability
• Drug distribution
• Volume of distribution
• Protein binding
• Biotransformation and drug metabolism
• Elimination

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Bioavailability

• Proportion of oral drug reaching systemic
  circulation
• Affected by
• Intestinal and drug permeability
• First pass effect
• Gut motility
• pH

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Plasma Protein Binding

• Acidic drugs bind to albumin and basic drugs to
  a1-acid glycoprotein in the plasma
• There is a decrease in binding of acidic drugs in
  CKD which has been attributed to changes in the
  binding site, accumulation of endogenous
  inhibitors of binding and decreased
  concentrations of albumin.
• On the other hand the concentration of a1-acid
  glycoprotein does not change that much and
  actually might be increased in patients on HD and
  transplanted patients

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Nephrotic Syndrome

• Complex interaction
• Hypoalbuminemia may result in lesser protein
  binding with more free drug in the plasma while
  at the same time there might be loss of albumin
  bound drug in the urine
• Some drugs are also known to produce adverse
  effects more readily in patients with nephrotic
  syndrome eg clofibrate can produce severe muscle
  necrosis

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Volume of Distribution (VD)

• Apparent number as it does not correlate with any
  defined anatomic space
• It is a ratio of the administered dose to plasma
  concentration at equilibrium
• Concept important for predicting the loading dose

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Factors affecting VD

• Protein and tissue binding
• Volume status

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Metabolism

• Drug metabolism occurs in the kidneys but to a
  lesser extent than the liver
• Progressive CKD effects most body biochemical
  reactions including drug biotransformation
• Reduction and hydrolysis reactions are slowed but
  glucuronidation, sulfation, conjugation and
  microsomal oxidation reactions occur at normal
  rates
• Also important to keep in mind is the fact that
  even though the drug might not be eliminated by
  the kidney, their active metabolite might eg
  meperidine, nitrofurantoin and morphine

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Dosing in a patient with renal insufficiency
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Extracorporeal Drug Losses
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Dialysis

• Dialysis is extracorporeal purification of blood
• Artificial Kidney

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Dialysis

• Diffusion of small molecules down their
  concentration gradient across a semipermeable
  membrane

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RRT

• Solute clearance
• Diffusion
• Convection
• Fluid clearance

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Hemo-Dialysis (HD)

• Concentration difference across a semi-permeable
  membrane favors diffusive transport of small
  solutes (lt300 Da)

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Diffusion

• Urea is used as the marker for small molecule
  diffusion during dialysis
• Diffusive clearance is a function of
• Blood flow rate
• Membrane surface area
• Time

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Hemo-Filtration (HF)

• HF refers to the use of a transmembrane
  hydrostatic pressure (TMP) gradient to induce
  filtration of plasma water across the membrane
  which results in the convective transport of
  small and medium sized solutes by solvent drag
  (lt5-10 kDa)
• Plasma concentration of the solute does not
  change
• Replacement Fluid

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Ultra-filtration

• Removal of water during dialysis from the
  patients circulation
• HD Transmembrane pressure gradient
• PD Osmotically driven by glucose

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Ultrafiltration

• UF is a function of three factors
• Transmembrane hydrostatic pressure
• Ultra-filtration coefficient of dialysis membrane
• Duration

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Factors Affecting Drug Clearance by Dialysis

• Drug
• Molecular weight
• Protein binding
• Volume of distribution

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Factors Affecting Drug Clearance by Dialysis

• Dialysis
• Composition of the dialyzer membrane
• Surface area
• Blood and dialysate flow
• Mode IHD, PD or CRRT

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Hemoperfusion

• Extracorporeal form of treatment where large
  volumes of blood is passed over an adsorbent
  surface
• Activated carbon (irreversibly bound by van der
  Waals forces) and resins (not irreversibly
  bound) are the adsorbents most commonly used.
• Higher MW (100-40,000 daltons) are well adsorbed
  with charcoal having greater affinity for water
  soluble and resin for lipid soluble compounds
• Time factor

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MARS

• Molecular Adsorbent Recirculating System
• Effectively removes protein bound toxins

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Diuresis at controlled pH

• Nonionized drugs are lipid soluble and will
  diffuse through cell membranes relatively easily,
  promoting passive absorption of filtered drugs.
  By contrast, drugs in the ionized states are poor
  absorbed. Alteration in the urine pH can alter
  the absorption of weak acids and bases.

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Nephrotoxicity
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Causes of Acute Renal Failure
? GFR
Valeri A, Neusy AJ. Clin Nephrol.
199135(3)110-118. Rao TKS, Friedman EA. Am J
Kidney Dis. 199525(3)390-398. Perazella MA. Am
J Med Sci. 2000319(6)385-391.
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TENOFOVIR

• Tenofovir closely related to adefovir
• Adefovir is a well described nephrotoxin
• Tenofovir freely filtered also secreted by
  proximal tubule
• Nephrotoxicity vigilance in clinical trials

Adefovir
Tenofovir
Blood
Lumen
Proximal Tubule
TDF
OAT1
MRP
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Toxicology
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