Pharmacokinetic model, Pharmacodynamic Model, Drug tolerance, Types of Hypersensitivity

1. PRESENTED BY
Dr. Zulcaif Ahmad
(Ph.D. Scholar Pharmaceutics)

2.  Pharmacokinetics is a science dealing with study of biological
fate of drug &/or its metabolite(s) within the body, with the
help of mathematical modeling.
 In simple words it is the study of what body does to the drug.
 It involves the study ofADME.

3. DRUG IN
TISSUES
DRUG IN
SYSTEMIC
CIRCULATION
DOSE
ABSORPTION
ELIMINATION
EXCRETION
AND
METABOLISM
DISTRIBUTION

4.  It refers to the relationship between drug concentration at the
site of action and the resulting effect, including the time
course and intensity of therapeutic and adverse effects.
 In simple words it is the study of what drug does to the body.

5.  Any drug that binds to a receptor and stimulates the
functional activities
 Has both affinity as well as intrinsic activity.
 e.g.Ach
Acetylcholine
ACell
Receptor
Some Effect

6.  It has affinity to receptor but no intrinsic activity.
 It prevents binding of agonist to receptor.
 e.g. atropine
Acetylcholine
Atropine
Dude, you’re
in my way!

7. PK model - describes the time course of drug concentration
in the plasma or blood.
PD model - describes the relationship between drug
concentration at site of action and effect.
PK/PD models use data derived from plasma drug
concentration vs. time profile and from the time course of
pharmacological effect to predict the Pharmacodynamics of
the drug.
Result is summation of Pharmacodynamics and
pharmacokinetics effect.

8. ADVANCED/NON
STEADY-STATE/TIME
DEPENDENT MODELS

9. Linear model
Log-linear
model
Emax model
Sigmoidal Emax
model
Biophase
distribution
model
Signal
transduction
model
Tolerance
model
Mechanism
based indirect
response model
Nonsteady-state & time-
dependent models

10. Linear
model
Log-Linear
Model
maxE ModelSigmoidal
Emax Model
Effect of drug is direct.
Fast mechanism of action.
Rapid equilibrium exists
between site of action and
the sampling biofluids.
PD parameters are time
invariant.

11. Drug effect is directly proportional to drug concentration.
Pharmacodynamically it is explained as:
…..(1)
…..(2)
E ∝ C
E = S×C
where,
E = Effect of drug
C = Drug concentration
S = Slope obtained from E vs C graph
In case of baseline effect (E0), when the drug is absent,
model may be represented as:
E = E0 + S*C …..(3)

12. so,
slope = S
intercept= E0
Effect
E0
Concentration
S
E = E0 +S*C
y = c + mx

13. Advantages
Model is simple and parameter estimation can be easily
performed by linear regression.
Limitations
Applicable at low drug concentrations only
excludes the prediction of maximum effect
Example
Relationship between central activity of diazepam and
plasma drug concentration

14. When the effect of drug is measured over a large range, the
relationship between concentration and effect is not linear
and may be curvilinear and log transformation is needed.
The log concentration-Effect is roughly linear in
concentration range of 20-80% of maximum Effect.
It is given by:
E = E0 + S*log C …(4)
where,
E = effect
E0=Baseline effect
S = slope
C= concentration

15. E

16. Advantage
Unlike linear model it is applicable over large concentration
range.
Limitations
Pharmacological effect cannot be estimated when the
concentration is zero because of the logarithmic function.
Maximum effect cannot be predicted.
Example
This model has been successfully used in predicting the
pharmacological activities of beta blockers and
anticoagulants.

17. This law shows that an increase in drug concentration near
the maximum pharmacological response produces a
disproportionately smaller increase in the pharmacological
response.
This model describes the drug action in the terms of :
E max (maximum effect)
EC50 (the drug concentration that produces 50%
maximum pharmacological effect)
….(5)
E 
Em axC
EC50 C

18. After maximum response (Emax) has reached, no further increase
in pharmacologic response is seen on increase in
concentration of the drug.
EC50 is useful for determining drug concentration that lies
within the therapeutic range.
Emax
E
EC50
C

19. Advantages
Maximum pharmacological response can be found out.
EC50 can be calculated (i.e., concentration needed to
produce half maximum response).
Limitations
In case of highly potent drugs it is not possible to find the
maximum effect because test organisms die long before the
maximum effect is attained.
The method can be time consuming if maximum effect is
obtained at a very high concentration.
Example
Bronchodilator activity of Theophylline is studied by this
model.

20. It describes the pharmacologic response versus drug
concentration curve for many drugs that appear to be S-
shaped (i.e. Sigmoidal) rather than as described by more
simple Emax model.
The equation for the sigmoid Emax Model is an extension
of the Emax Model:
…(8)
C n
E
EC  C n
50
E m a x
n is an exponent describing the number of drug molecules
that combine with each receptor molecule.
When n=1, the Sigmoid Emax Model reduces to the Emax Model

21. E
CONCENTRATION
EMAX
EC50

22. Biophase
distribution model
Mechanism-based
indirect response
model
Signal
transduction
model
Tolerance model

23. Indirect effect of the drug.
The effect is not immediate.
Distribution of the drug is the rate limiting step.
Slow association and dissociation of drug with the
receptors.

24. For some drugs, the pharmacologic response produced by
the drug may be observed before or after the plasma drug
concentration has peaked. Such drugs may produce
indirect or delayed response.
Drug distribution to the effect site may represent a rate-
limiting step for drugs in exerting their pharmacological
effect.

25. This model has been used to characterize the PK/PD of several
drugs (e.g. midazolam, pancuronium, alprazolam, etc.) whose
plasma concentrations could not be correlated with the effect
being produced.

26. The indirect response model is based on the premise that the
drug response is indirectly mediated by either inhibition or
stimulation of the factors controlling either the production
(Kin) or the dissipation of response (Kout).
EXAMPLES:
These models may be appropriate for various classes of
drugs, including histamine H2-receptor antagonists (such
as cimetidine) and oral hypoglycemic agents (such as
tolbutamide).

27. …(18)
where,
R = response
kin = zero-order rate constant for the production of
response
kout = first order rate constant for the dissipationof
response
outin  k R
dR
 k
dt

28. The pharmacological effects
of drugs may be mediated by a
time-dependent signal
transduction process, in
which the response measured
clinically involves multiple
steps removed from the initial
biochemical effect of the drug.

29.  There are two major classes of receptors involved in signal
transduction process:
1.cell membrane receptors
2.cytosolic/nuclear receptors

30.  Tolerance is characterized by a reduction in pharmacological
response after repeated or continuous drug exposure.
For some drugs, pharmacodynamic parameters like Emax and
EC50 may appear to vary over time, resulting in changes in
pharmacological response despite the presence of constant
concentrations at the effect site.
The development of tolerance can have a significant impact
on the exposure-response relationship and, if not
recognized, can contribute to poor clinical outcome.

32.  Drug tolerance is a decrease in the effect of a
drug as a consequence of repeated exposure.

33.  Metabolic (dispositional) Tolerance
◦ Pharmacokinetic tolerance (dispositional tolerance)
occurs because of a decreased quantity of the substance
reaching the site it affects. This may be caused by an
increase in induction of the enzymes required for
degradation of the drug e.g. CYP450 enzymes.
◦ e.g., Alcohol and barbiturates increased liver
enzyme activity.

34.  Pharmacodynamic, cellular Tolerance
◦ Pharmacodynamic tolerance begins when the cellular
response to a substance is reduced with repeated use. A
common cause of pharmacodynamic tolerance is high
concentrations of a substance constantly binding with the
receptor, desensitizing it through constant interaction.
◦ e.g., receptor affinity or number altered by drug
actions
◦ disruption of homeostatic processes may be critical
 Behavioral Tolerance
◦ Behavioral tolerance occurs with the use of certain
psychoactive drugs, where tolerance to a behavioral effect
of a drug, such as increased motor activity by
methamphetamine, occurs with repeated use.

36.  A condition in which the normally protective
immune system has a harmful effect on the
body.

37. Type I
IgE Mediated
Classic Allergy
Type II
IgG/IgM
Mediated
rbc lysis
Type III
IgG Mediated
Immune
complex
Disease
Type IV
T cell
Delayed
Type
Hypersensitivity
Gel and Coombs classification of hypersensitivities.

38.  Fast response which occurs in minutes, rather
than multiple hours or days. Free antigens
cross link the IgE on mast cells and basophils
which causes a release of vasoactive
biomolecule
 e.g. Atopy, Anaphylaxis & Asthma.

39.  Antibody (IgM or IgG) binds to antigen on a
target cell, which is actually a host cell that is
perceived by the immune system as foreign,
leading to cellular destruction via the MAC.
 e.g. Anemia, Thrombocytopenia etc.

40.  Antibody (IgG) binds to soluble antigen,
forming a circulating immune complex. This
is often deposited in the vessel walls of the
joints and kidney, initiating a local
inflammatory reaction
 e.g. Arthritis, Lupus nephritis etc.

41.  T helper cells (specifically Th1 cells) are
activated by an antigen presenting cell. When
the antigen is presented again in the future,
the memory Th1 cells will activate
macrophages and cause an inflammatory
response. This ultimately can lead to tissue
damage.
 e.g. Dermatitis, Sclerosis etc.

42. Thank You 