EXcretion Scop

8/6/2019 EXcretion Scop

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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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EXcretion Scop