Drug excretion 1 Contents '''

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Drug excretion 1Contents ...

• Renal excretion
• Creatinine clearance

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Excretion
The removal of a drug molecule from the body
without chemical modification. Generally in
urine, but occasionally in bile etc.
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Kidney
Glomerular Fitration Rate (GFR) 125ml/min
Urine 1ml/min
Acid Base
99 of H20 Lipid soluble drugs
Plasma flow 650ml/min
Active
Filtration secretion
Reabsorption
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Processes involved in renal excretion
1Filtration

• Passive process (Pressure driven)
• 20 of plasma volume is filtered
• Small molecules - Yes
• Large molecules - No
• Most proteins not filtered. Drugs which are
  extensively protein bound will also not be
  filtered.

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Processes involved in renal excretion 2Active
secretion

• Energy requiring
• Can generate positive concentration
• gradients
• Two separate mechanisms for acids bases
• Saturable
• Possible interactions

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Processes involved in renal excretion 2Active
secretion
ACIDS BASES
Furosemide Quinine Penicillins
Quaternary Probenecid
ammonium salts
Probenecid and penicillins share same mechanism.
Probenecid competes with penicillins.
Penicillin clearance reduced.
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Processes involved in renal excretion
3Reabsorption

• 99 of water is reabsorbed
• Lipid soluble drugs reabsorbed along
• with the water.
• Only very water soluble molecules can
• be efficiently excreted by the kidneys.

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Ion trapping
Urine pH varies (4.5 - 8.0). Consider a
barbiturate overdose. Sodium bicarbonate may be
given to make the urine alkaline
Urine Rest of body pH 8.0
pH 7.4
Non-ionised Non-ionised
Ionised Ionised
Barbiturate moves into urine - eliminated from
body.
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High renal clearance
If renal clearance is greater than G.F.R. then
there must be active secretion. Max possible
renal clearance is approx. 650 ml/min (All
plasma cleared). e.g. Aminohippuric acid
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Low renal clearance

• If clearance is much less than G.F.R. then
  either
• Not filtered or
• Extensively reabsorbed
• e.g. antipyrine, thiopental

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Creatinine clearance

• Creatinine is a waste product formed continuously
  by muscle.
• Filtered by kidneys Creatinine
  clearance
• Almost no active secretion approximately
  equals
• Almost no reabsorption filtration rate
  (G.F.R.)
• Creatinine clearance used as an estimate of
  G.F.R.

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Why are creatinine clearance and GFR important in
ADME?
The clearances of many renally excreted drugs are
closely linked to GFR. e.g. The clearance of
gentamicin approximately equals GFR and therefore
also approximates to creatinine clearance. When
calculating a dosage regime we can assume that
gentamicin clearance will equal creatinine
clearance
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Factors influencing serum creatinine concentration

• 1) Creatinine production rate depends upon
  muscle mass, which in turn depends upon
• Body weight
• Age ( muscle declines with age)
• Sex (Men have higher muscle than women)
• 2) Creatinine clearance rate

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Cockcroft Gault
Cockcroft Gault took a series of individuals
and measured their serum creatinine
concentrations, ages, weights and creatinine
clearances and found the following
relationships SrCr 1.23 x (140 Age) x Wt
.. in men CrCl
SrCr 1.04 x (140 Age) x Wt . in women
CrCl These can then
be re-arranged to produce equations that estimate
creatinine clearance.
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Estimating creatinine clearance
Cockcroft Gault equation Men CrCl 1.23
x (140 Age) x Wt
SrCr Women CrCl 1.04 x (140 Age) x Wt

SrCr CrCl Creatinine clearance (ml/min) Age
(Years) Wt Weight (kg) SrCr Serum creatinine
(µmol/l)
No. You do not need to learn these equations!
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Cockcroft Gault equation
Applicability There are some situations where
the equation is not applicable (e.g. children and
in pregnancy.) There may also be an over-estimate
of creatinine clearance in obese subjects,
because large amounts of fat are included in the
body weight, but this does not produce
creatinine. Ideal body weight (based on height
and build) will produce a better estimate.
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Case

• A woman, 30 years of age, weighing 70Kg, with a
  serum creatinine of 71 µmol/l .
• Will receive 100mg gentamicin 3 times daily
  (i.v.)
• Target peak concs are 4-8 mg/L trough
  concs lt 2mg/L
• Predict Css,max and Css,min.
• Will regime be satisfactory?

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Outline approach

• Estimate creatinine clearance (and assume
• gentamicin clearance to be the same)
• Predict V from population data
• Predict K from clearance and V
• Predict Css,max and Css,min
• Compare against desirable concentrations.

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Estimate creatinine clearance
For women CrCl 1.04 x (140 Age) x Wt
SrCr CrCl
1.04 x (140 30) x 70
71 113 ml/min 6.8 L/h
Now assume that gentamicin clearance will also be
6.8 L/h
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Predict V and K
V 0.25 L/Kg x 70 Kg 17.5 Litres Cl
K.V K Cl / V 6.8 L/h 17.5 L
0.389 h-1
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Predict Css,max Css,min
Css,max D/V . 1/(1-e-Kt)
100mg/17.5L . 1/(1-e-0.389h-1 x 8h)
5.71mg/L . 1/(1 - e-3.112)
5.71mg/L . 1/(1 - 0.0445)
5.71mg/L . 1/0.956 5.97
mg/L Css,min Css,max - D/V
5.97 - 5.71 mg/L 0.26 mg/L
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Compare to desirable concentrations
Desirable Predicted
OK? -----------------------------------------
---------------- Css,max 4-8 mg/L
5.97 mg/L ? Css,min lt2 mg/L
0.26 mg/L ?
The regime should be satisfactory
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Terms with which you should be familiar ...

• Filtration
• Active secretion
• Reabsorption
• Glomerular Filtration Rate (GFR)
• Creatinine clearance

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What you should be able to do

• Describe the various processes by which drugs may
  be added to or removed from urine.
• Describe how adjustment of urinary pH may be used
  to enhance drug excretion in cases of overdose.
• Estimate creatinine clearance from serum
  creatinine concentration, body weight, age and
  gender.