Exam 3: Renal Clearance Flashcards
Metabolism
Chemical conversion of parent drug
Excretion
Removal of intact drug
Non-volatile/polar drugs:
- Passage through kidney to bladder and removal via urine
* Other fluids: Bile, sweat, saliva, lactation milk
Volatile drugs:
Excretion into expired air
What does the kidney do?
- Removes wastes
- Controls fluid balance
- Regulates balance of electrolytes
Which processes are involved in Removal of wastes
- Glomerular filtration
* Tubular secretion
Reuptake of nutrients
• Tubular reabsorption
Renal artery
takes blood to kidney
Renal Vein
carries blood from the kidney
Kidney Processes lots of fluid:
- ~173 L water/day in
- ~171-172 L water/day returned to body
- ~1-2 L excreted as urine
Anatomy of the Kidney
We have two of them
Urine pools in the collecting duct and leaves via the ureter
Blood enters via
afferent arterioles
Blood leaves via
efferent arterioles
Functional unit of kindey
nephron
~1 million/kidney
Within each nephron is a
glomerulus, proximal tubule,
loop of Henle, distal tubule, and collecting duct
Waste collects as urine
in the collecting duct
Three important processes relevant to drugs take
place in the kidney:
- Glomerular filtration
- Tubular secretion
- Tubular reabsorption
What does glomerular filtration and tubular secretion do
they remove drug from circulation
What does tubular reabsorption do
returns drug to circulation
Filtration happens in the
Glomerulus
Secretion happens in the
Proximal tubule
Reabsorption happens in the
Distal tubule
Glomerulus
Glomeruli have a semi-permeable membrane that separates small ions/molecules from larger constituents of blood
- Easy for small molecules to pass
- Not so easy for large and/or negatively charged molecules
Podocytes
epithelial cells that cover the outer surfaces of glomerular capillaries
As the diameter of the blood vessels decreases
their ability to carry blood decreases
Hydrostatic pressure:
Pressure gradient from the arterial end of the capillaries entering the tissue to the venous capillaries leaving the tissue
How much output dose kidney recieve
The kidneys receive ~20% of the cardiac output
-e.-Lots of blood flow (~1 L/min)
In the kidney, the diameter of the afferent arterioles is
larger than the efferent arterioles
Tubes in kidney
The diameter of the tube going in is larger than the tube going out, hence fluid pressure builds up
• These tubes can relax or be constricted to control blood pressure in the glomerulus
Osmotic Pressure
Net movement of water due to differences in solute concentration
Water diffuses through semipermeable membrane towards region of
higher solute concentration
The higher the solute concentration
the greater driving force for water diffusion
Osmolality differences drive
water uptake/removal
Water diffuses to areas of
higher solute concentration
higher protein conc.
solutes are dissolved in
an aqueous solution
Solutes want to diffuse
to areas of
lower conc.
Water in the glomerulus
Water is freely filtered from the plasma in the glomerulus
• This leaves the remaining plasma proteins and cells more concentrated
colloid osmotic
pressure
protein concentration difference
- drives the reabsorption of water
Net Filtration Pressure
There is a balance between pressure exerted on the capillaries and opposing pressure from the interstitial fluid
• In the kidneys, the hydrostatic pressure at the glomerulus
is ~60 mm Hg
The colloidal osmotic pressure
~18 mm Hg
The capsular hydrostatic pressure
~32 mm Hg
Thus, the net outward pressure
~10 mm Hg
The kidneys receive ~20% of cardiac output
~60 L/hr blood flow
How much blood entering the glomerulus is filtered
~20%
Typical glomerular filtration rate (GFR) is
120 mL/min
Glomerular Filtration
• Location: Occurs in the glomerulus
• Function:
- Retention of cellular components and large plasma proteins
- Passage of small molecules/ions
• Limited by size exclusion – driven by hydrostatic pressure
• Impacted primarily by protein-binding and blood flow
- Passive transport
The proximal convoluted tubule has
lots of surface area
- lots of mitochondria in cells
Different regions of the subsequent tubule structure have different
functions
- Reabsorption of water
- Reabsorption of ions
- Reabsorption of sugars
- Secretion of organic acids/bases
- Excretion of salts/bicarbonate
- Regulation of pH
- Formation of ammonia
Tubular Secretion
- Occurs mainly in the proximal tubule
- Active transport (mostly faciliated)
- Two main secretion processes
- One for weak acids (organic anions)
- One for weak bases(organic cations)
- Impacted primarily by competitive inhibitors
Is an organic anion transporter likely to
transport weak acid or weak base drugs?
weak acid
Tubular Reabsorption
- Occurs mainly in the distal tubule
- Re-uptake of lipid soluble drugs
- Passive transport
- Impacted primarily by urine pH and flow
If urine flow rate increases, how do you think
reabsorption will be impacted?
Reabsorption will decrease because there is less residence time/ contact time making the plasma dug conc. lower as well
Hydrophilic molecules are more soluble
in urine and are likely to be excreted
Hydrophobic molecules are less soluble in urine
and are likely to be reabsorbed
Metabolism reduces
reabsorption
The metabolites are typically more
hydrophilic than the parent drug
Most pharmaceutical compounds are
weak acids or bases
Weak acids are predominantly ______ charged at pH values above their pKa
negative
Weak bases are predominantly ______ charged at pH values above their pKa
positive
If a drug is uncharged, we can change
urine pH to prevent reabsorption
increasing the urine pH makes weak acids
negatively charged
Decreasing the urine pH makes weak bases
positively charged
Making a molecule charged makes it
more water soluble and less likely to pass a lipid membrane
-Thus, urinary excretion is increased
Whats the pH or urine
6.0
If the pH of the urine were to become more basic,
a weak acid drug will be more readily excreted
Making a molecule charged makes it
more water soluble and less likely to pass a lipid membrane
urinary excretion can be increased/decreased by
changing pH
‘Ion-trapping’
- Neutral molecules can pass cell membranes
- Weak acids will become (-) in a basic compartment
- Weak bases will become (+) in an acidic compartment
- Once charged, they can’t escape!
Weak acids will accumulate
in a basic compartment
- become negative
Weak bases will accumulate
in an acidic compartment
- become positive
The charged drug will accumulate
in urine and be unable to be reabsorbed
Which renal processes are saturable?
Facilitated and Active Transport
- Tubular secretion
As drug concentrations increase
tubular secretion processes become saturated
• Renal excretion is primarily is a
first order process
The rate is dependent on concentration
Glomerular Filtration and Protein Binding
Drugs that are plasma protein-bound do not undergo glomerular filtration
- Only free drug, not protein-bound, drug is available to be
‘extracted’
More protein-binding
less extraction of drug!
Total drug =
free drug + protein bound drug
• Fraction unbound (fu) =
unbound/total
What is the unit-less parameter that describes the efficiency of an organ in terms of removal of
drug from circulation?
Extraction ratio
Extraction Ratio (E)
Efficacy of an organ to remove a drug from the bloodstream
• Includes both metabolism and excretion
Typical glomerular filtration rate (GFR) is
~120 mL/min. (7.2 L/hr)
Renal clearance is the
sum of clearances from filtration and secretion, less
reabsorption
If renal clearance is ~fu*GFR
then filtration is assumed to be the predominant mechanism
If renal clearance is >fu*GFR
then tubular secretion is contributing
If renal clearance is
then tubular reabsorption is contributing
In renal disease, the GFR can be
reduced
Less blood flow through the glomerulus, less clearance
Creatine
- Endogenous molecule generated in the liver
- Used by muscles as energy source
- Broken down into creatinine
Creatinine removed primarily by
glomerular filtration
If glomerular filtration is impaired, the plasma
concentrations of creatinine will increase/decrease?
increase
Creatinine levels are used to assess
renal function
We can monitor the concentration of creatinine in both plasma and urine
If a high concentration of creatinine is found in the
urine relative to plasma
, it is being effectively cleared
If a low concentration of creatinine is found in the
urine relative to plasma, it is not being effectively
cleared
Creatine is
It is endogenous
• It is already at a steady state concentration in the blood
• The amount produced = the amount removed in a given time
• It is freely filtered and not secreted or reabsorbed
• Usually all the creatinine that is generated in a day is found in the urine
• The creatinine clearance (CrCl) is approximately equal to the GFR
• Clcreatinine~120 mL/min.
• 120 mL blood is cleared of creatinine each minute
How Do We Assess Renal Clearance?
- Collect urine over 24 hours
- Determine urine volume
- Determine concentration of creatinine in urine
- Determine concentration of creatinine in plasma
CrCl=
(Urine concentration of creatinine)(urine volume/time)/(plasma concentration of creatinine)
• CrCl=(mg/mL)(mL/min.)/(mg/mL)
• CrCl=mL/min
Cockcroft-Gault Equation
A common equation used to estimate creatinine clearance based on plasma concentrations
Creating clearance for females
(140- age[years]) x weight [kg] / serum conc. [ umol/L]
Creating clearance for males
(140- age[years]) x weight [kg]* 1.2 / serum conc. [ umol/L]
• In patients with kidney disease, the GFR is
reduced
Conditions that affect blood flow can affect renal function such as
Examples include congestive heart failure and high blood pressure
