Transcript Copy of CHAPTER 1

PHT 415
BASIC PHARMACOKINETICS
Course Instructor: Prof. Dr. Hanaa Elsaghir
Assistant lecturers: Doaa Elshora
Text: Hand book of basic pharmacokinetics, Applied
Biopharmaceutics and pharmacokinetics and lab
notes
Grading: Quizzes (5 pt), Midterm (12.5 pt), Final (20 pt),
Practical (10 pt), Attendance (2.5 pt)
Lectures: Saturday10-12
Office Hours: Sunday and Wednesday 8 -10
Email: [email protected],[email protected]
Objectives of the first 4 lectures
(intravenous dose )
The student will be able to:
• Define Pharmacokinetics, intravascular and
extravascular
administration,
absorption,
disposition, distribution, metabolism, excretion,
first-pass
effect,
enterohepatic
cycling,
compartment
• Define the meaning of half- life, elimination rate
constant,
first order process, volume of
distribution, clearance, renal clearance, and
fraction excreted unchanged drug.
•
•
•
Estimate the values of half-life, elimination rate
constant, volume of distribution, and renal
clearance from plasma or blood concentrations
of a drug following an IV dose
Estimate the values of half-life, elimination rate
constant, and fraction excreted unchanged
from urinary excretion data following an
intravenous dose
Estimate the value of renal clearance of a drug
from combined plasma and urine data .
•
Calculate the concentration of drug in the
plasma and the amount of drug in the
body with time following an intravenous
dose, given values for the
pharmacokinetic parameters.
• Some concepts and definition:
• 1-Measurement of a drug in the body is limited
usually to blood or plasma.
• 2- Blood receives drug from the site of
administration as well as carries it to all the
organs, including those in which the drug acts
and those in which it is eliminated.
• 3- Sites of administration may be classified as
either intravascular or extra vascular.
• 4- Intravascular administration refers to the
placement of a drug directly into the blood,
either intravenously or intra-arterially
• 5-Extravascular include the oral,
sublingual, buccal, intramuscular,
subcutaneous, dermal, pulmonary, and
rectal routes
• 6- Drug administered extravascularly must
be absorbed: no absorption step is required
when a drug is administered intravascularly.
• Disposition
• Once absorbed, a drug is distributed to the
various organs of the body. Distribution is
influenced by how well each organ is perfused
with blood, organ size, binding of drug within
blood and in tissues, and permeability of tissue
membranes
• The two principal organs of elimination, the liver
and the kidneys
• The kidneys are the primary site for excretion of
the chemically unaltered, or unchanged, drug.
• The liver is the usual organ for drug metabolism;
however, the kidneys and other organs can also
play an important metabolic role for certain drugs
•
•
•
•
•
The liver may also secrete unchanged drug into
the bile.
The lungs are, or may be, an important route for
eliminating volatile substances e.g. gaseous
anesthetics.
Absorption
Absorption is defined as the process by which
unchanged drug proceeds from site of
administration to site of measurement within the
body.
Absorption is not restricted to oral administration.
It occurs as well following IM, SC, and other extra
vascular routes of administration
•
•
•
•
Monitoring intact drug in blood or plasma
offers a useful means of assessing the
entry of drug into the systemic circulation.
Disposition
May be defined as, all processes that occur
subsequent to the absorption of a drug. By
definition, the components of disposition
are distribution and elimination.
Elimination is the irreversible loss of drug
from the site of measurement
• Excretion is the irreversible loss of
chemically unchanged drug.
• Metabolism is the conversion of one
chemical species to another...
• Elimination occurs by two processes,
excretion and metabolism.
• Mass balance of a drug and related material
with time in the body:
• Dose= amount of drug at absorption site+
amount of drug in the body + amount of drug
excreted +amount of metabolite in the body +
amount of metabolite eliminated
• Biopharmaceutics
• Interrelationship of the physicochemical
properties of the drug, dosage form in
which the drug is given, and the route of
administration on the rate and extent of
systemic drug absorption
• Pharmacokinetics
• Kinetics of drug absorption, distribution,
and elimination (i.e excretion and
metabolism)
• It involve experimental aspect and
theoretical aspect
• Measurement of drug concentrations
• Sensitive, accurate, and precise analytical
methods are available for the direct
measurements of drugs in biologic samples,
such as milk, plasma, and urine.
• Sampling of biologic specimens
• Invasive methods such as sampling blood,
spinal fluid , synovial fluid , tissue biopsy
• Noninvasive methods include sampling of urine,
saliva,feces, expired air,or any biologic material
that can be obtained without parenteral or
surgical intervention
• Drug concentrations in blood, plasma, or serum
• The most direct approach to assessing
pharmacokinetics of the drug in the body is the
measurement of drug concentration in the whole
blood, serum or plasma.
• Serum
• Whole blood is allowed to clot and the serum is
collected from the supernatant after
centrifugation
• Plasma
• Is obtained from supernatant of centrifuged
whole blood to which an anticoagulant, such as
heparin
Plasma level- time curve
1-Is generated by measuring the drug
concentration in plasma samples taken at various
time intervals after a drug product is administered
2- The concentration of drug in each plasma
sample is plotted on rectangular coordinate graph
against the corresponding time at which the
plasma sample was removed.
Drug concentrations in urine
Measurement of drug in urine is an indirect
method to ascertain the bioavailability of a drug.
The rate and extent of drug excreted in the urine
reflects the rate and extent of systemic drug
absorption.
• Measurement of drug in feces may reflect drug
that has not been absorbed after oral dose or
may reflect drug that has been expelled by
biliary secretion after systemic absorption.
• Significance of measuring plasma drug
concentrations
• allows for the adjust men of the drug dosage in
order to individualize and optimize therapeutic
drug regimens
• Guide to the progress of the diseased state and
enable the investigator to modify the drug
dosage accordingly.
• Monitoring the concentration of drugs in the
blood or plasma ascertains that the calculated
dose actually delivers the plasma level required
for therapeutic effect
• Checking the plasma drug level is a responsive
method of monitoring the course of therapy
• Basic pharmacokinetics and pharmacokinetic
model
• 1-Basic pharmacokinetics involves the quantitative
study of various kinetic processes of drug
disposition in the body
• 2- Drugs are in dynamic state within the body
• 3- A model is a hypothesis using mathematical
terms to concisely describe quantitative
relationships.
• 4- Various mathematical models can be devised to
simulate the rate processes of drug absorption,
distribution, and elimination.
• 5- The mathematical model makes possible the
development of equations to describe drug
concentrations in the body as function of time
• 6- A pharmacokinetic function relates an
independent variable( time ) to a dependent
variable (concentration of drug in plasma),
• based on a set of time versus drug concentration
data , a model equation is derived to predict the
drug concentration in plasma with respect to time
• Pharmacokinetic models are used to:
• predict plasma , tissue, and urine drug levels with
any dosage form
• calculate the optimum dosage regimen for each
patient individually
• correct drug concentrations with pharmacologic
or toxicologic activity
• evaluate differences in the rate or extend
between formulations ( Bioequivalence )
• explain drug interactions
• Experimental aspect involves, the development of
biological sampling techniques, analytical methods
for measurement of drugs and metabolites and
procedures that facilitate data collection
• Theoretical aspect involves the development of
pharmacokinetic models that predict drug
disposition after administration
• Pharmacodynamics
• Refer to the relationship between drug
concentrations at the site of action ( receptor) and
pharmacologic response including biochemical,
and physiologic effect that influence the interaction
of drug with receptor
•
•
•
•
•
•
Compartment Models
mammillary model
caternary model
physiologic pharmacokinetic model( Flow model)
Mammillary Model
1- The mammillary model is the most common
compartment model used in pharmacokinetics
• .
•
2-The model consist of one or more peripheral
compartments connected to a central
compartment.
• 3-the central compartment represent plasma and
highly perfused tissues which rapidly equilibrate
with drug.
•
•
•
•
•
Mammillary model is a strongly connected
system since one can estimate the amount of
drug in any compartment of the system after
drug is introduced into a given compartment
.
When an IV dose of drug is given, the drug
enters directly in to the central compartment.
Elimination of drug occurs from the central
compartment since the organs involved in drug
elimination , kidney and liver, are well- perfused
tissues.
Several types of compartment models are
described in the slide
• Drawing of the model has three functions
• enables the pharmacokineticist to write
differential equations to describe drug
concentration changes in each
compartment
• gives visual representation of the rate
process , and
• shows how many pharmacokinetic
constants are necessary to describe the
process adequately.
PK and PD
PK is the study of what the body does to a drug
PD is the study of what a drug does to the body
DRUG THERAPY
Duration of Drug Therapy:
Single Dose:
such as to relieve a headache
For the Rest of the Patient’s Life:
such as in chronic diseases (epilepsy,
diabetes)
DOSAGE REGIMEN
The manner in which a drug is taken is
called a Dosage Regimen
Duration of Drug Therapy and Dosage
regimen will depend on the therapeutic
objective.
Objectives of taking a drug are :
Cure, Mitigation, Prevention
SUCCESSFUL DRUG THERAPY
By optimally balancing the desirable and
undesirable effects
 Accurate diagnosis is made
 Drug of choice
 Knowledge of clinical state of patient
 Understanding the pharmaco-therapeutic
management of the disease
 Answer the questions How much? How
often? and How long?
Answers to Questions??????
How much? Recognizes that the magnitude of
the therapeutic and toxic responses is a
function of the dose given.
How often? Recognizes the importance of
time, in that the magnitude of the effect
eventually declines with time following a single
dose of drug.
How long? Recognizes that a cost (in terms of
side effects, toxicity, economics) is incurred
with continuous drug administration.
In the Past
Questions were answered by trial and error,
i.e. the dose, interval between doses, and route
of administration were selected and the
patient’s progress was followed. This empirical
approach established many dosage regimens
but left many questions unanswered!!!!!!
This empirical approach did not contribute
toward establishing a safe, effective dosage
regimen of another drug, i.e. did not help us
understand how drugs work?
Event that follows drug administration
Plasm a Theophylline Concentration (m g/L)
6
5
4
3
2
1
0
0
12
24
36
48
Hours
Plasma conc of theophylline after an oral dose of 600-mg
Application of Pharmacokinetics
Rarely is a drug placed at its site of action,
most drugs are given orally and yet they act in
the brain, heart, or elsewhere!!!!
Which means a drug has to move from the site
of administration to the site of action.
Therefore to administer drugs optimally,
knowledge is needed not only of the
mechanisms of drug absorption, distribution,
and elimination but also the kinetics of these
processes, that is PK
Following Drug Administration 2
phases can be distinguished
Pharmacokinetic Phase: in which the
adjustable elements of dose, dosage form,
frequency, and route of administration are
related to drug level-time relationships in the
body.
Pharmacodynamic Phase: in which the
conc of drug at the site of action(s) is related
to the magnitude of the effect(s) produced.
Aimes of PK and PD
Knowing the PK and PD of drugs will aid
in designing a dosage regimen to achieve
the therapeutic objective.
OPTIMIZE PATIENT
DRUG THERAPY BY
MONITORING PK&PD
RESPONSES
Advantages over the Empirical
Approach
1- Distinction can be made between PK and
PD causes of an unusual drug response.
2- Information gained about the PK of one drug
can help in anticipating the PK of another drug.
3- Understanding the PK of a drug often
explains the manner of its use.
4- Knowing the PK of a drug aids the clinician
in determining the optimal dosage regimen for
a patient and in predicting what may happen
when a dosage regimen is changed.
An Approach to the Design of a Dosage
Regimen
Pharmacokinetics
Dosage
Regimen
Pharmacodynamics
Plasma
Concentration
Site
of
Action
Effects
Where to Measure Concentration?
Rarely can the concentration of the
drug at the site of action be
measured directly; instead the
concentration is measured at an
alternative and more accessible
site, the plasma.
What is then an optimal
dosage regimen?
It is the one that maintains
the plasma concentration of a
drug within the therapeutic
window and then maintaining
this concentration by
replacing the amount of drug
lost with time.
Initial and Maintenance Dose
Two different regimens A and B, B=2A
Plasma conc
Regimen B
Therapeutic
Window
Regimen A
Time
Therapeutic Window (TW)
 The size and frequency of the maintenance
dose depends on the width of the therapeutic
window and the speed of drug elimination.
 When the window is narrow and the drug is
eliminated rapidly, small doses must be given
often to achieve therapeutic success.
 Both cyclosporine and digoxin have a narrow
TW, but because cyclosporine is eliminated
much more rapidly than digoxin, it has to be
given…?…?…?…?…? ( more frequently or
less frequently)
Oxytocin
 Oxytocin is an extreme example, it also has
a narrow TW, but it is eliminated within
minutes. The only means to ensure a
therapeutic conc is to infuse it at a precise and
constant rate directly into the blood (i.v.
infusion). Oxytocin can not be given orally
because it is destroyed in the GIT.
 Morphine can not also be given orally
because it is extensively metabolized in the
liver.
PROBLEM!!!
Variability in Clinical Response
 Sources of variability: patient’s age,
weight, degree of obesity, type and severity of
disease, the patient’s genetic makeup, others
drugs concurrently administered and
environmental factors.
 Result: A standard dosage regimen of a
drug may prove therapeutic in some patients,
ineffective in others and toxic is still others.
Dosage Regimen Adjustment
The need is greatest for drugs with narrow
TW:
 Digoxin used to treat cardiac disorders.
 Phenytoin used to prevent epileptic
convulsions
 Theophylline used to diminish chronic
airway resistance in athmatics.
 Cyclosporine used as immunosuppressant
in organ transplantation.
 Warfarin used as oral anti-coagulant.
Drug-Drug Interaction
Interactions that result in a change in PK of
a drug could be due to:
 Stimulation of drug metabolizing enzymes
therefore increasing drug loss.
 Inhibition of drug metabolizing enzymes
therefore slowing drug elimination and
increasing its concentration in the blood.
 Interference with drug absorption.
SOLUTION
A pragmatic approach to this problem
would be to adjust the dosage until the
desired objective is achieved.
Control on a dosage basis alone,
however, has proved difficult.
Control is achieved more readily and
accurately when plasma drug
concentration data and the PK of the drug
are known.
DRUG IS A VERY COMPLEX SYSTEM
WHAT WE WILL DO IN
THIS CLASS?
 Although the details of drug kinetics are
complicated, it is fortunate that we can often
approximate drug kinetic processes using
“SIMPLE MATHEMATICAL MODELS”.
 The use of PK equations, rather than the
derivation of the equations will be taught in
this class.