L39 - Excretion 2

• Give the equation for Renal Clearance

  Renal Clearance = Renal Clood Flow x Renal Extraction Ratio
• What mechanisms are involved in renal excretion?

  
  

  Do they increase or decrease renal clearance?

  -Glomerular Filtration(increases ClR).

  -Reabsorption(decreases ClR).

  -TubularSecretion(increases ClR).
• Give the eqn to describe the additivity of renal clearance.

  Renal Clearance = Cl Filtration + Cl Secretion - Cl Reabsorption

  
• What is Creatinine?

  
  

  What is the value for it's clearance?

  Creatinine= endogenous waste product produced as byproduct of muscle metabolism.- Unbound in plasma and eliminated by glomerular filtration.

  Clearance = 120mL/min = GFR!

  - Renal excretion rate for a free drug (f unbound = 1) that's only filtered would be the same as creatinine.

  
• How can we assess renal function?

  Predict Creatinine Clearance.

  
  

  - Measure [creatinine] conc in serum and use clinical eqns to account for age/gender.
• What does Creatinine [conc] in serum depend on?

  Rate in:muscle metabolism depends on age/sex.

  Rate out: Renal excretion (mainly glomerular filtration).

  
• Give the eqn for Clearance of Creatinine

  Creatinine Cl = Elimination rate / [Creatinine] in serum

  
• Give the eqn for Creatinine Production Rate

  Creatinine Production Rate = [Creatinine] in serum x Cl Creatinine.

  
• Describe the 4 stages of renal failure progression.

  1)Loss of renal reserve- kidneys have capacity to provide more than usual function in response to a stimulus.

  2)Renal insufficiency- serum urea and creatinine levels are increased. Pts asymptomatic.

  3)Chronic renal failure- broad range of biochemical abnormalities. Symptoms mild-severe depending on Creatinine clearance.

  4)End-stage Renal Failure- terminal uraemic state w/ Creatinine Clearance <10mL/min. Dialysis.
• Why is it possible to live with only 1 kidney?

  Because kidney's have renal reserve - can provide more than their usual function in response to a stimulus.
• How does renal insufficiency affect [drug] plasma conc?

  In renal insufficiency, takes longer for peaks to stabilise and reach Css. Leads to higher [drug] plasma conc. so may have to adapt doses.

  
  

  (image - green has full renal capacity, red has stage 2 renal insufficiency.

  
• Give the eqn for renal clearance, linking Clearance of Creatinine


  Renal Clearance = F unbound x 120mL/min.

  
  

  
  

  If a drug is ONLY eliminated by glomerular filtration, and partially bound, then ONLY the free drug can be filtered. This needs to be accounted for to estimate Clfiltration and Renal Clearance for drug.

  
• How can we predict whether a drug is secreted in urine or not?

  Estimate Renal Clearance and compare to Cl Filtration of drug.

  
  

  
  

  Rate of renal excretion for a drug filtered and secreted into urine > filtration rate of drug.

  
• Give the eqn for renal clearance (link filtration, secretion and Cl creatinine)

  - Renal Clearance of a drug will exceed its filtration clearance.

  
  

  Renal Clearance = Cl filtration + Cl Secretion = (Funbound x Cl Creatinine) + Cl secretion.

  
• How to predict which mechanisms contribute to renal clearance?

  1) Predict filtration clearance of drug.(Cl filtration = F unbound X Cl creatinine)

  2) Compare renal clearance with filtration clearance.

  - If Renal Cl > Filtration Cl, there's filtration and secretion.

  - If Renal Cl = Filtration Cl, a drug is only eliminated by filtration.

  - If Renal Cl < Filtration Cl, there's filtration and reabsorption.
• What happens to the renal clearance of a drug eliminated by

  glomerular filtrationandsecretion?Renal Clearance will exceed its filtration clearance.

  
• Describe the effect of plasma binding on clearance.

  - Only free drug can be filtered and interact with transporters for being secreted.

  
• Why is active secretion saturable?

  - Bc it's mediated by transporters!

  
  

  - At low [drug], excretion rate is proportional to [drug] in plasma.

  
  

  - As [drug] increases transporters become more saturated, so curve plateaus until Vmax is reached.

  
• How can we work out if a drug is reabsorbed?

  - Determine Renal Clearance and compare it to Filtration Clearance.

  
  

  - If Renal Cl < Filtration Cl, then the drug is reabsorbed.

  
• For a drug that's filtered and reabsorbed, will renal excretion be more/less than filtration rate?

  
  

  What about Renal Clearance being more/less than filtration clearance?

  - For a drug that's been eliminated by glomerular filtration and reabsorbed, the renal excretion rate will be less than filtration rate.

  
  

  - Renal Cl < Filtration Cl.

  
  

  - Drug was filtered into urine, but reabsorbed back into body so less drug is excreted in urine.
• What drives passive reabsorption?


  - Concentration gradient from water absorption.

  
  

  - If drug not reabsorbed, [drug in urine] = 100 x [drug in plasma].
• What factors affect passive reabsorption?

  -Gradient- for larger urine flow, less water is reabsorbed so drug is more diluted (smaller Cfreeuring). Gradient is smaller so less reabsorption.

  -Mw.

  -Lipophilicity(P).

  -Fraction ionised:consider urine pH/ drug pKa.
• The effect of urine pH on Renal Clearance

  What happens if we increase/decrease pH inacids? In terms of solubility, renal clearance?For acids:- If we increase pH, drug is more ionised in urine.

  - If more ionised in urine, it'll be less reabsorbed by passive diffusion, so larger renal clearance.

  - If we decrease urine pH, more drug will become unionised (more lipophilic) so more will be reabsorbed by passive diffusion and renal clearance will be smaller. Less excreted in urine.

  
• The effect of urine pH on Renal Clearance

  What happens if we increase/decrease pH inbases? In terms of solubility, renal clearance?For bases:

  -Increase in pH:drugs become more unionised (more lipophilic) so renal clearance decreases as drug is better absorbed by passive diffusion. Less excreted in urine.

  -Decrease in pH:drug becomes more ionised (more soluble) so less reabsorbed and more excreted. Gives a larger clearance.
• Why would we want to modify urine pH in patients?

  To speed up excretion of a drug, eg in aspirin overdose.

  
  

  Aspirin is a weak acid, so by increasing pH we can make it more ionised, and more soluble so more can be excreted faster. Passive reabsorption is decreased.