Download File

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
Metabolism
Excretion
ADME
1
PHARMACOKINETICS--•
•
The relationship between the time course of
drug concentrations attained in different
regions of the body during and after dosing is
termed pharmacokinetics (‘what the body does
to the drugs’)
To distinguish it from pharmacodynamics
(‘what the drug does to the body’ i.e. events
consequent on interaction of the drug with its
receptor or other primary site of action)
2
PHARMACOKINETICS--•
1.
2.
3.
4.
Pharmacokinetic knowledge contributes in many ways
to practice of therapeutics, which include:
Distinguishing between pharmacokinetic and
pharmacodynamic causes of variation in and
unexpected responses to drugs
Evolving concepts that are common to all drugs; thus
information gained about one drug helps in anticipating
the pharmacokinetics of another drug
Often explaining the manner of use of a drug and
occasionally suggesting a more convenient or effective
dosage regimen
Often allowing anticipation of the likely outcome of a
therapeutic manoeuvre.
3
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
4
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
5
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
• (A good strategy for understanding the topic of
pharmacokinetics is to read on the following and tackle
the examples)
6
Single –compartment model
or (One-compartment open model)
• In this model the human body is considered to
be one compartment, consisting of a single well
stirred 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= ____________________= Units in Vol.
plasma drug concentration (Cp)
7
Single –compartment model…
•
•
•
•
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 1 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
8
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? (see next slide)
9
Table 1:Distribution of body water in
a man of average build
•
•
•
•
•
Type
Vol (Lts)
Plasma
3.5
Interstitial
12
ECF
15.5
ICF
26.5
-------• TBW
42
% of body wt
5
17
22
38
-------60
10
Vd------• Remember that:
• In some cases the Vd of a drug can exceed that
of total body water
• E.g. the Vd for propranolol is 3Lts of plasma this
theoretical volume gives an index of how widely
it is distributed in the body
• Digoxin Vd is 500 Lts/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
11
Clearance ( ml/min or Litres /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 from the
blood or plasma
• Clearance is expressed as a
volume/unit of time
12
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
13
Clearance---• It is important to recognize that clearance by
itself does not indicate how much drug is
being removed
• 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;
14
Renal clearance (CLr)
Expressed by the equation;
CLr = CuVu
CP
Cu = Urinary Concentration of drug
Vu = Rate of urine flow
Cp = plasma drug concentration
15
Total clearance
• CLt = CLm +CLr + CL other
• t= total body clearance is a sum of the
different drug clearance mechanisms
• m=metabolism
• r=renal
• t=total
• CL other includes drug clearance by other
routes like the lungs, sweat etc.
16
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
17
Capacity limited elimination OR Saturable
metabolism…
• This is called zero order kinetics
• 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
• Many more drugs exhibit these kinetics at
toxic concentrations
18
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 following equation;
Ke = CL ------- Equation 3
Vd
E.g. A drug with a clearance of 10L/ day and a Vd
of 100 L would have an elimination rate
constant (Ke) of:
19
Elimination rate constant--• 10 L/day =0.1/ day
100L
• 10/100= 0.1/day
• This essentially defines “first- order
elimination kinetics” where the fraction
eliminated per unit time remains
unchanged
20
Half life
•
•
•
Half-life of a drug = T1/2
Is the time required to change the
amount of drug in the body by one halfduring elimination (or during a constant
infusion)
T1/2 is useful in designing drug dosage
regimens.
21
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
22
Time to reach steady state drug
concentration in plasma/blood (Cpss)
• 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.
• Cpss = steady state plasma concentrations
23
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
24
Half life and Ke (elimination rate
constant) 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
t1/2
70
=0.7 = 0.01
70
25
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=
26
Drug accumulation…
• Accumulation factor
1
= ----------------- equtn. 6
Fraction lost in one
dosing interval
or
=
1
-------------1- fraction remaining
27
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)
28
Area under curve (AUC)
29
Rate of drug administration
• Please note that the rate of drug
administration can be expressed by the
following equation:
= F X DOSE-------------------equation 7

• F= bioavailability fraction
• (tau) = is the dosing interval
30
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.
31
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 at the minimum
cost in unwanted effects.
 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
32
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
33
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
34
Loading dose
• When the time to reach Cpss (steady state plasma
concentrations) is long especially with drugs with a long
T1/2
• It is desirable to give an initial loading to promptly
raising the concentration of a drug in plasma to the
target concentration
• 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
35
• F= Bioavailability fraction
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
36
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:
37
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
38
Maintenances dose--• Maintenance dose is calculated in -------------------------equation 8 below:
• Maintenance dose
Dosing rate
= __________ X DI
F
DI=Dosing interval
F = bioavailability (fraction of the dose
absorbed)
39
Example: maintenance dose
calculation
• 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 in table 3-1 on page 41 by Katzung
et al
40
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 9
=2.8 L|h (CL) x 10mg/L (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.
41
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
 = 28mg/hr x 12 hrs/0.96
The maintenance dose = 350 mg 12
hourly
42
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 halflife 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
43
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
44
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
45
Two compartment model
• It is common for drugs with significant lipid
solubility to show evidence of distribution into
more than one compartment after i/v injection.
• The implication is that their concentration does
not behave as though homogenous in one
compartment, but is better modelled by being
considered homogenous in each of two (central
and peripheral) compartments
46
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
• Read more
47
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
• As a mean for predicting drugs levels in
tissues
48
Uses of pharmacokinetics--• As 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
• Lastly, for explaining the manner of a
drug’s use and suggesting improved
dosage regimens
49
• Further Reading!
50