excretion scop
TRANSCRIPT
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KIDNEYfiltration
secretion(reabsorption)
LIVERmetabolism
secretion
LUNGSexhalation
OTHERSmother's milk
sweat, saliva etc.
Elimination
of drugs from the body
M
AJ
O
R
MI
N
O
R
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Agents that are excreted in urine are:
Water soluble
Non-volatile
Less than 500 daltons
The ones that are metabolised slowly
Basic functional unit of kidney:
Nephron
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Renal Function1. Glomerular
filtration
2. Active tubularsecretion
3. Passivetubularreabsorption
4. Excretion
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Glomerular Filtration- 1st step in renal drug
excretion
Nonselective,unidirectional
Acts as a negatively charged selective
barrierpromoting retention of anionic compounds
Driving force: hydrostatic presuure of bloodflowing in cappilaries
25% cardiac output---only 10% is filterd through
the glomeruli
Excreted drug = (Filtered+ secreted) - reabsobed
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Drug enters renal tubule as a dissolved
solute
Drug filtration rate= Free drugPlasmaconc. X Glomerular filtration rate
(GFR)
GFR determined by agent excreted
exclusively by filtration & is neither
secreted nor reabsorbed in the tubules.
Excretion rate value of such anagent=120-130ml/min. eg.
Creatinine,inulin, mannitol, sodium
thiosulphate
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ACTIVE TUBULAR SECRETION
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1. System for secretion of organic acids/anions:
penicillins,salicylates, glucuronides, sulphates etc.
uric acid secreted by same system
2. System for secretion of organic bases/cations:
eg. Morphine,mecamyline,hexamethonium,
endogenous amines cholines)
Can be bidirectional eg. Uric acid
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Active Tubular Secretion
-some drugs especially weak acids and bases undergo active
tubular secretion by transport systems located in the proximaltubular cells
Not affected by pH or plasma protein binding as free drug
is transported bound drug dissociates to replace free drug
that has been transported. But dependent on renal blood
flow.
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TUBULAR REABSORPTION Active process
Passive process
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Active tubular reabsorption
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Passive Reabsorption
-most substances are reabsorbed across renal tubular cells
if unionized and lipid soluble
Can manipulate urine pH to ensure drugs are not reabsorbed in
overdose situations
5.8 = 5.8 + logA-/HA= 1= 1:1
Rate of reabsorbtion = 1.2 Qg/mL x 1/2 = 0.6 Qg/mL
increase urine pH to 7.0
7.0 = 5.8 + logA-/HA= 1.2 = 15.8:1= 1.2 Qg/mL x 1/16.8 = 0.071 Qg/mL
RenalClearance= excretion rate/plasma drug concentration (units: L/h)
For penicilin: 1200 ug/min/ 3ug/mL= 400 mL/minx60 min/h=24000mL/h=
24000mL/hX 1L/1000mL= 24L/h
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Clearance: volume of plasma cleared of drugper unit time.
Clearance = Rate of elimination plasma conc.
Half-l
ife of elimination: time for plasma conc.to decrease by half.
Useful in estimating:
- time to reach steady state concentration.
- time for plasma concentration to fall afterdosing is stopped.
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Other routes of excretion:
Biliary excretion- drugs with mwts >300 excreted in to bile
Enterohepatic cycling-
Sweat, Saliva-
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Active secretion requires a carrier and a
supply of energy.This may be a significant pathway for some
compounds such aspenicillins.
Because tubular secretion is an active processthere may be competitive inhibition of the
secretion of one compound by another.
Eg: inhibition of penicillin excretion bycompetition with probenecid.
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Pharmacokinetic Calculations
Rate of elimination
First orderRate =v= [Drug]Plasma k
Where k is the elimination rate
constant
Rate= change in plasma conc/unit time= ([Drug]/min
First- Order Kinetics
Drug elimination= [drug]Plasma x
drug clearance
The elimination rate declines as
the [drug]Plasma declines
Half-life and clearance remain
constant if hepatic and renal
function do not change
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Half-Life (t ) of a 1st order reaction
-time it takes for the plasma concentration to decrease by
t = 0.693/ke0.693 is the natural log (ln) of 2
Factors that affect t
-drugs clearance rate
- volume of distribution
-affects of disease or age
on the above
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t is calculated from this
experiment
ke is the elimination rate constant
t = 0.693/ke @ ke= 0.693/ t
Cl = clearance = Vd x ke
sub for ke
Cl = Vd x 0.693/ t
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Zero-Order Kinetics
-rate of elimination is constant
t w to [drug]plasma
Cl w 1/ [drug]plasma
Zero-Order elimination occurs
in overdose situations the
various processes by which
drugs get eliminated are
saturated
Zero order- independent of the concentration of drug in the plasma
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