PHARMACOKINETICS

INTRODUCTION
1. Definition : Is a study of what the body
does to a drug
-In Pharmacokinetics an attempt is made to
quantify the various dispositional
parameters regarding;
• Absorption
• Distribution ADME
• Metabolism
• Excretion

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 Relationship between dose and
effect
Pharmacokinetics focuses on:
• Dose administered
• Absorption
• Concentration in circulation---- in tissues
• ↕ ---- elimination
• Pharmacodynamics focuses on:
• Drug concentration at site of action
• Pharmacological effect
• Clinical response -effectiveness & toxicity

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 Pharmacokinetics----
• The standard dose of a drug is based on
clinical trials in volunteers and patients
who have average ability to:
• Absorb
• Distribute
• & eliminate the drug
• The doses obtained in clinical trials will in
no way be suitable for every patient
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 Pharmacokinetics---
• Several diseases like heart failure, renal
failure, require dosage adjustments
• These disease conditions modify specific
pharmacokinetic parameters
• The two basic pharmacokinetics
parameters are volume of distribution
and Clearance

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 Single –compartment model

• In this model the human body is considered to

be one compartment, with an apparent Volume
of distribution (Vd):
• Vd relates the amount of drug in the body(Q) to
the concentration of the drug(C) in blood of
plasma according to the following equation:
Amount of drug in body(Q)
Vd= _________Q___________= Units in Vol.
plasma drug concentration(Cp)
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• Therefore Vd = Q/Cp Equation----------1
• Q= Dose administered Cp=plasma concentration
• C can be measured from plasma (Cp) or from blood (Cb)
• The Vd calculated from equation I is an apparent volume
it is not a physical space
• It is a hypothetical space if the drug could be uniformly
distributed in the body
• Vd is calculated from equation ---1 above

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 EXERCISE 1
• Mrs Jones was given the anticoagulant
Warfarin at a dose of 200mg.The plasma
concentration (Cp) was later measured to be
20 micrograms/ml
• Calculate the theoretical Volume of
distribution Vd of Warfarin in this patient
• Approximately in which body water
compartment is your drug likely to occupy in
the table 1 below?
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 Table 1:Distribution of body
water in a man of average build
• Type Vol(Lts) % of body wt
• Plasma 3.5 5
• Interstitial 12 17
• ECF 15.5 22
• ICF 26.5 38
-------- --------
• TBW 42 60

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 Vd-------

• E.g. the Vd for propranolol is 3Ls of plasma this

theoretical volume gives an index of how widely it is
distributed in the body
• Remember that:
• In some cases the Vd of a drug can exceed that of total
body water
• Digoxin Vd is 500 Ls/70 kg man exceeding TBW see the
table 1 above
• The higher the Vd of a drug the more extensively it is
distributed in the body

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 Clearance ( ml/min or Liters/h)
• Drug elimination from the body is
expressed as clearance
• Clearance is the intrinsic ability of the body
or its organs of elimination (usually
kidneys and liver) to remove drug form the
blood or plasma
• Clearance is expressed as a
volume/unit of time
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 Clearance----
• Clearance principles are similar to the
concepts in renal physiology
• CL = Rate of elimination
----------------------------- Equation 2
Concentration
Clearance is expressed in equation 2 above

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 Clearance----
• It is important to recognize that clearance by
itself does not indicate how much drug is being
removal
• Clearance only represents the volume of blood
or plasma which would be completely cleared of
a drug if it were present
• Renal clearance , CLr is defined as the Vd of
plasma containing a drug that is removed by the
kidney in Unit time;

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 Renal clearance (CLr)
Expressed by the equation;
CLr = CuVu
CP
Cu = Urinary Concentration of drug
Vu = Rate of urine flow

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 Total clearance
• CLt = CLm + CLr + CL other
t= total body clearance is a sum of
the different drug clerance mechanisms
m=metabolism
r=renal
t=total
• CL other includes drug clearance by other
routes like the lungs, sweat etc.

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 Capacity limited elimination OR Saturable
metabolism
• This is sometimes called saturable
metabolism or saturation pharmacokinetics
• This happens when the concentration of a
drug approaches a value at which its
metabolizing enzymes are saturated, its rate
of metabolism becomes independent of the
amount of drug undergoing the process
• This is called zero order kinetics

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• For any relatively small change in dose
there may be a large change in plasma
concentration if metabolism is saturated
• Examples of drugs which exhibit
saturable metabolism are ethanol,
phenytoin & Aspirin

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 Elimination rate constant (Ke)
• Represents the fraction of volume of
distribution(Vd) which will be cleared of the drug
per unit of time
Ke is expressed by the equation;
Ke = CL ------- Equation 3
vd
E.g . A drug with a clearance of 10L/ day and a Vd
of 1OO L would have an elimination rate
constant (ke) of: 10/100= 0.1
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 Elimination rate constant---
10 L/day =0.1/ day
100L
• This essentially defines “first- order
elimination kinetics” where the fraction
eliminated per unit time remains
unchanged
• Ke represents the fraction of drug
eliminated per unit of time
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 Half life
Half –life of a drug (T1/2)
-Is the time required to change the amount
of drug in the body by one half-during
elimination( or during a constant infusion)
-T1/2 is useful in designing drug dosage
regimens.

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 Half life
T ½ is expressed by the following equation
T1/2 = .693 x vd = 0.7xVd….Equation 4
CL CL
Note; Most drugs exhibit first order kinetics
where the rate of elimination is directly
proportional to drug concentration. Drug
concentrations then decays exponentially

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 Time to reach steady state drug
concentration in plasma/blood(Cpss)
• Steady-state is that equilibrium point where the
amount of drug administered exactly replaces the
amount of drug excreted
• The time to reach steady state drug
concentrations is calculated from the following
equation:
• Cpss = 4-5 x half life
• This means it takes between 4-5 half lives to
reach steady state concentrations in
plasma/blood.
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 Clinical Implications

• In clinical pharmacology, first order

kinetics are considered as a « linear
process », because the rate of elimination
is proportional to the drug concentration.
• This means that the higher the drug
concentration, the higher its elimination
rate.

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• The elimination processes are not
saturated and can adapt to the needs of
the body, to reduce accumulation of the
drug.

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• 95% of the drugs in use at therapeutic
concentrations are eliminated by first order
elimination kinetics.
• A few substances are eliminated by zero-
order elimination kinetics, because their
elimination process is saturated. Examples
are Ethanol, Phenytoin, Salicylates,
Cisplatin, Fluoxetin, Omeprazol

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 EXERCISE 2
• Mr Silver was given drug X 80 mg for a specific
infection. If the half life of drug X is 4 hours
(i)Calculate the time that will be required for drug
X to reach Cpss in plasma
(ii)What will be the drug level in plasma(Cp) after
4 half – lives elimination ?
(iii)Calculate the total drug eliminated from the
body after 4 half - lives

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 Half life and Ke relationship
• If the clearance is 10 ml per minute and
suppose the elimination half -life is 70
minutes
The kel is CL =10 = 0.1 ---equation 5
vd 100
• Kel is also equal to 0.693
(0.693) 70
t1/2 =0.7 = 0.01

70
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 Drug accumulation
• When doses are repeated a drug can
accumulate in the body until dosing stops
-this is because it takes time to eliminate
the drug from the body
• Accumulation will occur if the dosing
interval is shorter than 4 half lives
• An index of accumulation is called
ACUMULATION FACTOR=
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 Drug accumulation
• Accumulation factor 1
= ----------------- equt. 6
Fraction lost in one
dosing interval
or = 1
--------------
1- fraction remaining

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 bioavailability
• Is the fraction(F) of unchanged drug
reaching the systemic circulation following
administration by any route
• The area under the blood concentration
time curve (AUC) is a common measure of
the extent of bioavailability
• AUC = Area under the curve(s)

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 Area under curve(AUC)

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 ASSIGNMENT
• Read on the concept of spare receptors
• Read on differences between graded
responses and quantal responses
• Read on Quantal dose response curves
• Read on the concept of therapeutic index
and its uses
• Allosteric antagonism

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 Rate of drug administration
• Please note the rate of drug administration
can be expressed by the following
equation:
• F X DOSE/-------equation 7
• F= bioavailability
 (tau)= is the dosing interval

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 Exercise 3
• What is the administration rate for digoxin
0.25 mg(250 mcg) given once daily as :
• Tablet and as for elixir
Given that F for the tablet and elixir is 0.62
& 0.77 respectively?
Please give your answers in mcg.

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 DRUG DOSAGE REGIMENS
• The objective of a dosage regimen in
therapeutics is to prescribe:
-doses, the size whose timing will provide the
maximum therapeutic benefit.
• This is achieved by Considering the
pharmacokinetic factors that determine the dose
concentration relationship
• Calculation of dosage regimens allow
individualization of doses to achieve target
therapeutic concentrations

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 Dosage regimens---
• Target plasma concentration of some tablets
may be available from tables in textbooks
• They are a guide to show you some of the
effective drug concentrations in certain disease
conditions
• However these are not to be relied upon 100%
• Because ,in some cases the target drug
concentration may vary depending on the
severity of a specific disease condition

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 Drug dosage regimens---
• Some of the effective concentration of
some drugs (or target concentrations )
have been worked out
• They are available in some text books

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 Loading dose
• When the time to reach Cpss is long
especially with drugs with a long T1/2
• It is desirable to give an initial loading
dose to promptly raise the concentration
of a drug in plasma to the target
concentration

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• Loading dose is described in the following
equation:
• Loading dose (amount of drug in the body
immediately following the loading dose=
Vd x TC/F ----equation 8
• Vd = volume of distribution
• Tc = Target concentration
• F= Bioavailability
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 EXERCISE 4
• Estimate the loading dose for oral digoxin
which would be necessary to attain a
target plasma level of 1.5 ng/ml. Assume
Vd = 7.3 L/Kg; F of the tablet = 0.62

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 Maintenance dose
Maintenance dose:
• In most clinical situations drugs are
administered to maintain a steady state
concentration in the body (Cpss)
• Enough is given in each dose to replace the
drug eliminated since the preceding dose
• To calculate the maintenance dose proceed as
follows:

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 first calculate the dosing rate
• Dosing rate = CL X TC
• CL=Clearance
• TC= Target concentration
• Then proceed in the next step to calculate
the maintenance dose using the dosing
rate as shown below

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 Maintenances dose---
• Maintenance dose is calculated in
equation 9 below:
• Maintenance dose = Dosing rate X DI
F

DI=Dosing interval
F = bioavailability

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 Example: maintenance dose
calculation
Example of a calculation on maintanance
dose
A target plasma Theophylline concentration
of 10mg|L is desired to relieve acute
bronchial asthma in a patient. If the patient
is a non smoker and otherwise normal
except for bronchial asthma we may use
mean Clearance given as 2.8L/h

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Maintenance dose calculation---
Clearance of theophyline in tables is given as 2.8
L/h| 70 kg . Since the drug will be given I.V
Infusion, F=1
Dosing rate =CL X TC -----equation 10
2.8 L|h(CL) x 10(TC)
: In this patient the proper infusion Or dosing rate
IV will be 28 mg|h
Maintenance dose = dosing rate/F x dosing
interval in time.
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 Maintenance dose--

• The maintenance dose of theophylline will

be given orally (F=0.96 from F tables)
• Maintenance dose is equal to dosing
rate/F x Dosing interval = 28 x 12 hrs/0.96
= 350 mg 12 hrly

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 Effect of repeated doses

Figure 8-9 Predicted behaviour of single-compartment model with continuous or intermittent drug administration. Smooth curve A shows the effect of continuous infusion
for 4 days; curve B the same total amount of drug given in eight equal doses; and curve C the same total amount of drug given in four equal doses. The drug has a half-
life of 17hours and a volume of distribution of 20litres. Note that in each case a steady state is effectively reached after about 2days (about three half-lives), and that the
mean concentration reached in the steady state is the same for all three schedules.

Downloaded from: StudentConsult (on 30 October 2009 09:11 AM)

© 2005 Elsevier

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 Effect of repeated doses
• The figure above shows a relationship
between frequency of dosing and
maximum and minimum plasma
concentrations when a steady state
concentration is desired
• The smooth rising black line shows
plasma concentration achieved by 100mg
by iv infusion

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 Effect of repeated dosing---
• The doses of 100mg twice a day and the
200 mg per day curves are shown on the
same scale
• In each of the three cases the mean
steady state plasma concentration is the
same at 10 mg/L this is achieved when a
steady state concentration of the drug is
reached

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 Two compartment model
• In this model the body is considered to be 2
compartments
• With a central compartment usually the
plasma(intravascular)
• And a peripheral compartment (extra vascular)
• Remember that two compartment model only
affects the periodic time course of drug
action

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 Uses of pharmacokinetics---
• As a diagnostic tool
• As a mean to evaluate the extent and rate
of delivery of a drug
• To predict and understand adverse drug
reactions

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• As a means for predicting drugs levels in
tissues
• As a means of comparing animals within
species or among species in drug handling
• As means for quantitating biological
variability
• As means for mathematically describing
drug levels in a biological system
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• Lastly, for explaining the manner of a drug’
s use and suggesting improved dosage
regimens

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