Ch02 Drug Receptor Interactions And Pharmacodynamics

1. by Lee Eun Jin
UNIT I:
Introduction to Pharmacology
2
Chapter
Drug-Receptor
Interactions and
Pharmacodynamics

2. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics2
DoseDose EffectEffect
Effect site Effect site
ConcentrationConcentration
Pharmacokinetics Pharmacodynamics
AbsorptionAbsorption
DistributionDistribution
MetabolismMetabolism
Elimination Elimination
Drug interactionsDrug interactions
Tissue/organ sensitivity Tissue/organ sensitivity
(target status)(target status)
What is pharmacodynamics?I. OVERVIEW

3. Lecture Objectives
To understand the basic concepts regarding
pharmacodynamics
 To define agonist and antagonists and other
terms in relation to pharmacodynamics
 To explain the mechanism of drug receptor
interaction
 Define spare receptors
 To differentitate between different tyes of
antagonism
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics3

4. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics4

5. Action of a drug on the body
 receptor interactions,
 mechanisms of therapeutic
dose-response phenomena,
 toxic action.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics5

6. A drug w ill no t w o rk unle s s it is
bo und
PARTICULAR CONSTITUENTS OF
CELLS & TISSUES IN ORDER TO
PRODUCE AN EFFECT
PROTEINS
LIPIDS
DNA
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics6

7. DRUGS THAT ACT WITHOUT

BEING BOUND TO ANY

OF THE TIS S UE

CONS TITUENTS
OSMOTIC DIURETICS
OSMOTIC PURGATIVES
ANTACIDS
HEAVY METALS CHELATING
AGENTS
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics7

8. Drug Re c e pto r
A macromolecular component of a cell with which a
drug interacts to produce a response
Usually a protein
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics8

9. Receptors
Receptors must be biologically important molecules
Receptors must have structural features that permit
drug specificity
Receptors must have a drug-binding site and a
biologically active site
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics9

10. Characteristics of Characteristics of
ReceptorsReceptors
a. specificity a. specificity
b. selectivity of response b. selectivity of response
c. sensitivity c. sensitivity
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics10

11. Molecules capable of serving as Molecules capable of serving as
ReceptorsReceptors
uEnzymes
uMembrane proteins
(glycoproteins, lipoproteins)
uNucleic acids
uComplex polysaccharides
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics11

12. Many drugs inhibit enzymes
in the patient (ACE inhibitors)
in microbes (sulfas, Penicillins)
in cancer cells (5-FU, 6-MP)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics12

13. Type s o f Pro te in

Re c e p to rs
Regulatory – mediate the action of endogenous
chemicals e.g. hormones, NT , autocoids
Enzymes – may be inhibited or activated
e.g. dihydrofolate reductase, receptor for methotrexate

Transport – e.g. Na
+
/K
+
ATP’ase for digitalis
glycosides
Structural – e.g. tubulin,receptor for colchicin
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics13

14. some drugs bind to:
the genome (cyclophosphamide)
microtubules (vincristine)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics14

15. Non-receptor Mediated EffectsNon-receptor Mediated Effects
 Interaction with small molecules
(e.g. binding of heavy metals)
 Interaction with enzymes
(e.g. sulfonamides, digitalis)
 Incorporation into a macromolecule
(e.g. some anticancer agents - purine and pyrimidine
analogues)
 Nonspecific effects (e.g. membrane perturbation by
general anesthetics)
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics15

16. Receptor regulationReceptor regulation
1.1. HomeostasisHomeostasis

2. Up and down regulation 2. Up and down regulation
3. Desensitization 3. Desensitization
4. Tolerance o4. Tolerance or regulationr regulation
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics16
agonists desensitize receptors
 homologous
(decreased receptor number)
 heterologous
(decreased signal transduction

17. a. Occupation theorya. Occupation theory
D + R D + R «« DR DR ÞÞ RESPONSE RESPONSE
:response is proportional to the fraction of occupied :response is proportional to the fraction of occupied
receptors receptors
:maximal response occurs when all the receptors are occupied :maximal response occurs when all the receptors are occupied
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics17

18. AriensAriens
response is proportional to the fraction of response is proportional to the fraction of
occupied receptors occupied receptors ANDAND the the intrinsic activity intrinsic activity
Stephenson Stephenson
response is aresponse is a FUNCTION FUNCTION of occupancy of occupancy
 maximum response can be produced maximum response can be produced
WITHOUT 100% occupation, WITHOUT 100% occupation,
i.e. tissues have i.e. tissues have spare receptorsspare receptors
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics18

19. Schematic representation of the relationship Schematic representation of the relationship
between threshold, receptor between threshold, receptor
reserve, reserve, receptorreceptor occupancy, biological stimulus occupancy, biological stimulus
and biological responseand biological response
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics19
BIOLOGICAL STIMULUSBIOLOGICAL STIMULUS
0%0%
TRETHOLDTRETHOLD BIOLOGICAL RESPONSEBIOLOGICAL RESPONSE
100%100%
RECEPTOR RESERVERECEPTOR RESERVE
Threshold EffectThreshold Effect
Max Max
EffectEffect
PERCENT RECEPTOR OCCUPANCYPERCENT RECEPTOR OCCUPANCY

20. Receptors are said to be sparespare
for a given pharmacological response

when the maximal response can be elicited
by an agonist at a concentration that does

not result in occupancy of the full complement
of available receptors
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics20

21. Spare receptors
 More receptors available than
needed
to elicit maximum response
allow maximal response without total
receptor occupancy – increase sensitivity of
the system
Agonist has to bind only a
portion of receptors for full
effect
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics21

22. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics22

23. S o me te rmino lo g ie s re g a rding

drug re c e pto r inte ra c tio n
Affinity
Efficacy
Potency
Ligand
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics23

24. Affinity: measure of propensity of a drug to bind
receptor; the attractiveness of drug and
receptor
Efficacy: Potential maximum
therapeutic response that a drug can
produce.
Potency: Amount of drug needed to produce an
effect.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics24

25. Ligand:
Molecules that binds to a receptor
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics25

26. Classification of Ligands Classification of Ligands
a.a. agonist agonist
b. partial agonistb. partial agonist
c. antagonist c. antagonist
pharmacological vs. physiological vs. chemical pharmacological vs. physiological vs. chemical 
pharmacological antagonistspharmacological antagonists
- - competitive competitive
surmountable surmountable
- - noncompetitive noncompetitive
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics26

27. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics27
kk
11
kk
22
DrugDrug
ReceptorReceptor
EffectEffect
Drug-Receptor Drug-Receptor
ComplexComplex
Ligand-binding Ligand-binding
domain domain
Effector domain Effector domain
Drug(Ligand) « Receptor interaction
Langley (1878)
EffectD+R DR
k
1
k
2

28. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics28
- Primary way for drug to produce an action
non-specific
receptors
neurotransmitters
hormones
enzymes
transport systems
•ion channels
•active transporters, e.g. uptake blockers
Drug « Receptor interaction
Targets of drug action

29. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics29
III. MAJOR RECEPTOR FAMILIES
Figure 2.2
Transmembrane signaling mechanisms. A. Lignad binds to the extracellular domain of a
ligand-gated channel. B. Ligand binds to a domain of the serpentine receptor, which is
coupled to G protein. C. Ligand binds to the extracellular domain of a receptor that
activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to
interact with its intracellular receptor.

30. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics30
III. MAJOR RECEPTOR FAMILIES
G-protein coupled receptors triggers an increase (or, less often,
a decrease) in the activity of adenylyl cyclase.

31. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics31
III. MAJOR RECEPTOR FAMILIES
Mechanism of intracellular receptors (e.g. nuclear receptors).

32. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics32
III. DESENSITIZATION OF RECEPTORS
- Receptor structure change
- Receptor inactivation
(protein inhibitors, modifications)
- Down regulation of receptor by
endocytosis or degradation

33. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics33
What is a receptor “agonist”?
Any drug that binds to a receptor and stimulates the
functional activities
e.g.: adrenaline (epinephrine)
Receptor
Epinephrine
Cell
Effect

34. agonist
Drugs that cause a response
Drugs that interact with and activate receptors;
They possess both affinity and efficacy
Types
Full agonists
An agonist with maximal efficacy (response)
has affinity plus intrinsic activity
Partial agonists
An agonist with less then maximal efficacy
has affinity and less intrinsic activity
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics34

35. Agonists differing in potency and maximum efficacy
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics35

36. -
P ARTIAL AG O N IS TS EFFIC AC Y
#
Ev e n th o u g h d ru g s m a y o c c u p y th e s a m e o f
,
re c e p to rs th e m a g n itu d e
.
o f th e ir e ffe c ts m a y d iffe r
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics36
[D](concentration units)
% Maximal Effect
0.01 0.10 1.00 10.00 100.00 1000.00
0.0
0.2
0.4
0.6
0.8
1.0
Partial agonist
Full Agonist
Partial agonist

37. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics37
What is a receptor “antagonist”?
Any drug which can influence a receptor and produce
no response
e.g.: propranolol (a beta blocker)
epinephrine
propranolol
Hey, you’re
in my way!
Competitive Antagonist: both the drug and its antagonist compete for the same site of the receptor
Non-competitive Antagonist: the drug and its antagonist do not compete for the same site

38. NOT change the receptor
Interact with the receptor but do
Have affinity but NO efficacy
Block the action of other drugs
Effect only observed in presence of
agonist
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics38

39. Type s o f Anta g o nis ts
Competitive
(Surmountable)
decrease apparent
Potency
Noncompetitive
decrease
apparent maximum
efficacy
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics39

40. Co mpe titive Anta g o nis t
competes with ________for receptor
surmountable with increasing agonist
concentration
displaces agonist dose response curve to

the ___________(dextral shift)
reduces the apparent affinity of the
__________.
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics40

41. No nc o mpe titive Anta g o nis t
drug binds to receptor and stays bound
irreversible – does not let go of receptor
produces slight dextral shift in the agonist DR curve
in the low concentration range
but, as more and more receptors are bound (and
essentially destroyed),
the agonist drug becomes incapable of eliciting a
maximal effect
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics41

42. AGONIS T VS ANTAGONIS T
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics42

43. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics43

44. Wha t ha ppe n w he n yo u inc re a s e

a g o nis t

c o nc e ntra tio n e ve n hig he r
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics44

45. Ho w do no n c o mpe titive

a nta g o nis t a ffe c t re c e pto r
func tio n
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics45

46. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics46

47. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics47
Monitoring drug responsesMonitoring drug responses
LevelLevel
Molecular (e.g., enzyme inhibition, receptor Molecular (e.g., enzyme inhibition, receptor
binding assay)binding assay)
Cellular (Cellular (in vitroin vitro tissue culture, blood cells) tissue culture, blood cells)
Tissue or organ (Tissue or organ (in vitroin vitro or or in vivoin vivo))
Animal disease modelAnimal disease model
Endpoint used to measure the effect may be different Endpoint used to measure the effect may be different
at each levelat each level
Overall effect = Sum of multiple drug effects and Overall effect = Sum of multiple drug effects and
physiological responses to drug effectsphysiological responses to drug effects

48. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics48
Endpoints to monitor drug effectsEndpoints to monitor drug effects
LEVEL ENDPOINT
Molecular Farnesyltransferase inhibition
Cellular Proliferation rate, Apoptosis
Tumor Response (Change in tumor size)
Organism Survival, Quality of life
Farnesyltransferase inhibitors for cancerFarnesyltransferase inhibitors for cancer

49. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics49
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.6
The effect of dose on the
magnitude of
pharmacologic response.
Panel A is a linear graph.
*Effect =*Effect =
EffectEffect
MaxMax • [Drug] • [Drug]
KK
DD + [Drug] + [Drug]
*EC
50
=drug dose that shows fifty
percent of maximal response.

50. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics50
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.6
The effect of dose on the
magnitude of
pharmacologic response.
Panel B is a
semi-logarithmic plot of the
same data.

51. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics51
Determinants of Drug Activity
1. Potency: the amount of drug to produce an effect
of a given magnitude

2. Efficacy: the maximal response (effect) produced
by drug
Biologic effect
Log dose
potency
efficacy
0
50
100
Biologic effect(%)
Log dose (mg)
1
10 100
Morphine
Codeine
Aspirin

52. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics52
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.7
Typical dose-response
curve for drugs showing
differences in potency
and efficacy.

53. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics53
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.9
Effects of drug antagonists.

54. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics54
IV. DOSE-RESPONSE RELATIONSHIPS
Figure 2.10
Effects of partial agonists.
-1 0 1 2
R
E
S
P
O
N
S
E
Full Agonist
Partial Agonist
Antagonist
Log([A]/KA)

55. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics55
Therapeutic Index
Therapeutic index =
toxic dose(LD
50
)/effective dose(EC
50
)
This is a measure of a drug’s safety
•A large number = a wide margin of safety
•A small number = a small margin of safety
V. QUANTAL DOSE-RESPONSE RELATIONSHIPS

56. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics56
V. QUANTAL DOSE-RESPONSE RELATIONSHIPS
Figure 2.11
Effects of partial agonists.
(Continued overleaf)

57. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics57
V. QUANTAL DOSE-RESPONSE RELATIONSHIPS
Figure 2.11
Effects of partial agonists.
Walter Straub (1874-1944)
“There is only a quantitative difference between a drug and a poison”

58. Summary
(T or F)
 Pharmacodynamics is the study of absorption,
distribution,
metabolism and elimination of drug.
 Some drugs can act without binding to a receptor
 spare receptors allow maximum response without
full receptor occupancy
 Efficacy is the amount of drug needed to produce an
effect.
 Affinity is the attractiveness between 2 drug
molecules.
 Agonist are the drugs that block the response.
 Partial agonist has affinity and maximum efficacy.
 Antagonist has efficacy but no affinity.
 Competitive antagonist decreases potency
 Non competitive antagonist decreases efficacy
Chapter 2: Drug-Receptor Interactions and Pharmacodynamics58

59. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics59
Quiz on Monday (Chap 1 & 2)