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PHARMACOKINETI

C
PARAMETERS

WHAT ARE THE IMPORTANT


PHARMACOKINETIC PARAMETERS:

volume of distribution
(Vd)
2. Half life
3. Clearance
1.

VOLUME OF
DISTRIBUTION

Also referred to as APPARENT


VOLUME OF DISTRIBUTION
As

a general rule, V does not represent a physiological


volume (real volume) but an apparent volume into
which the drug would have to distribute to achieve
the measured concentration.
The

volume of body fluid in which the drug distributes itself


at a concentration which is in equilibrium with the plasma
concentration of the drug
it is not necessary that the volume in which the drug
distributes itself contain equal conc. Of the drug and it is
possible that the drug is present in different concentration
through out its distributed volume
the total body water is called as the REAL VOLUME OF
DISTRAIBUTION

drugs which binds selectively to plasma protein e.g.


WARFARIN have

V <V
app

real

And lie between blood volume and total body water that
is between 6 to 42 liters
drugs which bind selectively to extra vascular tissue
e.g., CHLOROQUINE

V > V
app

real

And always more than 42 liters .

Drugs

Vd lit/70 kg

heparin

digioxin

420

Mathematical formula :
1.

Vd = amount of drug in body


amount of drug in

Case 1 :
plasma

120mg in body
20 mg/ml in
plasma
= 6 liter

Case 2:
120 mg in body
1 mg/ml in
plasma
=120 liter

Low Vd
High drug in plasma

high Vd
Low drug in plasma

The principle of volume of distribution. With Drug A, the measured


concentration in the sampling compartment is 10 mg/l,therefore the
volume is estimated at 10 litre (100 mg/10 mg/l). Drug B is highly bound
to plasma proteins, therefore the measured concentration of 100 mg/l
results in an estimated volume of 1 litre. Drug C is extensively
distributed into the tissues and the measured
concentration of 1mg/l gives an apparent volume of 100 litre.

The volume of distribution is therefore mainly


determined by
the ratio of plasma to tissue binding
and
by how much of the total amount of drug in
the body is outside the sampling compartment (i.e.
the blood).
Other factors, such as lipid and water
solubility, may also be important. For example, the
volume of distribution of chloroquine, which
accumulates in several tissues, is 204 litre/kg7,
while gentamicin, which is water soluble, has a
volume of distribution that approximates to the
extracellular fluid volume.

Volume of distribution (V) can be


defined as a proportionality constant
that links the amount of
drug in the body to the measured
plasma concentration
2 . As the con of the drug in the body
is equal to the given dose so

Vd = dose
Cp
3. if we want to calculate the volume
of distribution at the elimination
phase then we consider the following
graph.

So now the concentarattion in the body is Co hencee

Vd = Co
Cp

CLEARANCE

volume

of body fluid that is completely cleared of drug


per unit time
CLEARANCE =volume = ml
time
min
Voloume of the blood which is cleared of the drug which is
irreversibly removed from the body w.r.t time
Nothing

about the amount of drug but it is volume of


body fluid cleared of drug
When we talk about the amount it is the rate of
elimination
It is the proportionality factor used to determine the
rate of elimination

So ;
Rate of elimination = clearance * concentration
mass / time
volume / time
mass/volume
Zero order
kinetics

clearance
clearance =

Vd

constant )
volume /time

Kel ( 1st order elimination rate

volume

1/ time

K el = cl/Vd
Total clearance

Cl

tatal

= renal clearance + hepatic clearanc + other routes


most important clinically

Rate of eliminatin =Cl

tot

* Cp

Organ clearance

The

volume of blood that is completely cleared of drug per


unit of time by the patient 'organ.
this is the measure of efficiency of the organ in the
elimination of drug from the blood reaching the organ .

is

the product of extraction ratio and blood (or serum) flow


rate
clearance = extraction ratio * flow rate
volume/time
volume
1/time
the units of clearance are therefore volume/time (e.g. litre/h
or ml/min).

Extraction

ratio describes the efficiency with which an organ


of elimination (e.g. liver, kidney, etc) removes a drug from the
blood.
It can be determined by measuring the concentration
entering (Cin) and leaving (Cout) the organ.
If Cout = 0, the drug will be totally removed and the extraction
ratio will be 1.
However, if Cout = Cin, there is no drug removal
and the extraction ratio will be 0.
The extraction ratio generally lies somewhere between these

Flow

rate determines the rate of drug delivery to


the eliminating organ
Clearance represents the irreversible removal of a
drug from the body and determines the average
steady state concentration achieved with a regular
maintenance dose

now,

Organ

clearance =

rate of drug entering organ rate of drug leaving organ


conc of drug enetring organ

Where as
the rate of drug entering the organ = blood flow in artery* conc of drug in plasma
The rate of drug leaving the organ = blood flow in vein* cinc of drug in plasma
For

every drug, each organ of elimination has its own clearance (e.g.
hepatic clearance,renal clearance). The total body clearance results from the addition
of these clearances:
CL=Renal CL+Hepatic CL+ other CL

Renal clearance Clr


Clearance of the drug from the body w.r.t time via kidney is
called as renal clearance
Renal excretory process takes place via
1.
glomerular filtration
2. Active tubular secretion
3. Tubular reabsorobtion
Usually, a drug's renal clearance is proportional to the
patient's renal function. Whether a drug's dosing rate needs to
be modified in patients with renal dysfunction depends on
whether the drug is primarily excreted through the kidneys and
whether increased drug levels are associated with adverse
effects.

Mathematically

Renal excretion rate

renal clearance

* drug plasma conc

that is the rate of drug passing through the kidney is equal to the
drug excreted by the kidney

Renal

clearance = renal excretion rate = blood flow (Q) * E.R


drug in plasma
Cp

Renal clearance = filtration rate +active secretion tubular reabsorbt ion


plasma drug conc

Hepatic clearance
volume of the body fluid cleared of drug per unit of time via
liver
hepatic clearance depend upon
1. hepatic blood flow (e.g. congestive heart failure)
2. plasma protein binding (e.g. hypoalbuminemia,
displacement by other drugs)
3. hepatic enzymatic activity (e.g. liver failure, specific
inhibition or induction by drugs, genetic polymorphism) also
reffered to as intrinsic activity of liver
. Whlie taking about the hepatic clearance a term is
INTRNISIC HEPATIC CLEARANCE , it is the ability of liver to
remove the drug from the body fluid in the absence of
other suppressing factors.(blodd flow and protein binding)

Mathematically
CLH =

Qcpa Qcpv
Cpa
= Q (cpa cpv))
cpa

ORGAN CLEARANCE = RATE OF RATTE OF


DRUG
DRUG
ENTERING
LEAVING
ENETERING

CONC OF DRUG

extraction ration (E.R) = cpa cpv


cpa
CLH = Q* E.R
HENCE RATE OF DRUG ENTERING MINUS LEAVING THE
ORGAN IS NOT EQUAL TO EXTRACTION RATIO

HALF LIFE

INTRODUCTION :
A

drug half life is the time it takes for half of the given
dose to b eliminated from the body or bloodstream
there are two types of half lives
1. BIOLOGICAL OR ELIMINATION HALF LIFE is the time
it takes for the bioactivity of the drug to reduce by 50%
of its initial value
2. PLASMA HALF LIFE is the takes it takes for the
concentration of the drug in the blood stream to reduce
by 50%
. We at this point are more concerned with
PLASMA HALF LIFE
. Plasma half life is the time measurement which starts
when the drug reaches equilibrium that is equal
amount of the drug is at administration site and
in the blood circulation or it is fully absorbed

There

are furthur two tyes of plasma half life


1.
DISTRIBUTION HALF LIFE =when plasma level fall to
half of what they were at equilibrium due to
distribution in body tissues
2. ELIMINATION HALF LIFE =when plasma level fall to half
of what they were at equilibrium due to drug being
metabolized and eliminated
While both half lives contribute to the effects of the drug
on behavior ,it is elimination half life that is used to
determine dosing schedules , to decide when it is safe
to put patient on a new drug, etc
RULE OF 5 HALF LIFE :
5 * elimination half life is equal to the time at which the
drug is completely (97%) eliminated from the body
(assuming that the drug is given in a single orignal
dose )

No of half life
1 x life

Drug removed Remaing drug


%
%
50

50

2 x life

75

25

3 x life

87.5

12.5

4 x life

93.75

6.25

5 x life

96.87

3.13

Half life of 1st order


: kinetics is constant
kinetics
half life of first order
elimination rate constant is not actually a constant and
changes with a change in conc of drug
They enzymes do not have achieved their Vmax
consider the following example

time (hr plasma


)
conc

Eliminati
on rate
= chnge
( mg/lit) in
Cp/chan
ge in
time

8-4 /1 =4

4-2/1= 2

2-1/1= 1

1-

Half life of zero order


kinetics
:
half life is not constant
elimination rate constant is a constant value irrespective of
the conc of the drug
The enzymes have achieved their Vmax
consider the following example

Time
(hr)

Plasma
con
(mg/ml)

Eliminat
ion rate
= chnge
in
cp/chng
e in
time

Some

time a drug may have dual order of kinetics


that is as the time passes the enzymes which were not
previously fully saturated during the 1st order kinetics
become fully saturated and the increase in conc of drug
do not cause an increase in the rate of elimination
which become constant that is independent of conc of
drug so it becomes zero order kinetics
for example , salicylates , ethanol , phenytoin

Zero
order
Cp

1st
order
Time

Mathematically
half life = 0.693 / Kel
This reflects that the elimination half life is inversely
poportional to rate of elimination
More the rate of elimination lesser will be the stay of drug
with in the body and thus shorter will be the half life and
vice versa .

Interrelationship of the
three parameters
t = o.693/ Kel
And ,
Kel = clearance /Vd
So ,
t

= o.693 Vd / clearance

From the equation we can say :


half life has inverse relation with the
clearance , more is the clearance shorter will be
the half life
half life has direct relation with the Vd . More
the Vd more time will be taken by the drud to
elimate and thus more will be half life .