Lecture 1 Pharmacodynamics

lecture

1. PharmacodynamicsPharmacodynamics
Dr Rizwan Ashraf

2. Lecture Objectives 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

3. WHAT IS PHARMACODYNAMICS ?

5. Action of a drug on the body
 receptor interactions,
 mechanisms of therapeutic
dose-response phenomena,
 toxic action.

6. RECEPTOR INTERACTION

7. A drug will not work unless it is bound
AGREED or NOT AGREED

8. BOUND WITH WHAT ?

9. PARTICULAR CONSTITUENTS OF
CELLS & TISSUES IN ORDER TO
PRODUCE AN EFFECT
PROTEINS
LIPIDS
DNA
RECEPTORS ?

10. ARE THERE DRUGS THAT ACT WITHOUT ARE THERE DRUGS THAT ACT WITHOUT
BEING BOUND TO ANY OF THE TISSUE BEING BOUND TO ANY OF THE TISSUE
CONSTITUENTSCONSTITUENTS
YES
OR
NO

11. YESYES
OSMOTIC DIURETICS
OSMOTIC PURGATIVES
ANTACIDS
HEAVY METALS CHELATING AGENTS

12. BUTBUT
PRINCPLES REMAIN TRUE FOR
GREAT MAJORITY
THAT IS _____________________
______________________________.

13. Most drugs act through Most drugs act through
ReceptorsReceptors

14. Receptors Receptors

15. Drug ReceptorDrug Receptor
A macromolecular component of a
cell with which a drug interacts
to produce a response
Usually a protein

16. 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

17. Characteristics of ReceptorsCharacteristics of Receptors
a. specificity a. specificity
b. selectivity of response b. selectivity of response
c. sensitivity c. sensitivity

18. Molecules capable of serving Molecules capable of serving
as as
ReceptorsReceptors

19. uEnzymes
uMembrane proteins
glycoproteins, lipoproteins)
uNucleic acids
uComplex polysaccharides

20. Many drugs inhibit enzymes
in the patient (ACE inhibitors)
in microbes (sulfas, Penicillins)
in cancer cells (5-FU, 6-MP)

21. Types of ProteinTypes of Protein Receptors Receptors
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 colchicine

22. some drugs bind to:
the genome (cyclophosphamide)
microtubules (vincristine)

23. 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)

24. Receptor-independent drug actionsReceptor-independent drug actions
u Chemically reactive agents
uDisinfectants
uAlkylating anticancer drugs
u Physically active agents
uMannitol
uHydrogen peroxide
u Counterfeit biochemical constituents
u5-bromouracil

25. Antagonists
tend to
up regulate
receptors
Receptor regulationReceptor regulation
1.1. HomeostasisHomeostasis

2. Up and down regulation 2. Up and down regulation
3. Desensitization 3. Desensitization
4. Tolerance 4. Tolerance
agonists desensitize receptors
 homologous
(decreased receptor number)
 heterologous
(decreased signal transduction

26. PharmacodynamicsPharmacodynamics
Drug receptor interactionDrug receptor interaction

27. D + R DR Complex
Drug - Receptor BindingDrug - Receptor Binding
Affinity

28. Drug Receptor InteractionDrug Receptor Interaction
DR Complex Effect

29. Theories of the Theories of the 
relationship between relationship between 
binding and responsebinding and response

30. 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 occumaximal response occurs when all the receptors are occu
piedpied

31. 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 havei.e. tissues have spare receptorsspare receptors

32. BIOLOGICAL STIMULUSBIOLOGICAL STIMULUS
PERCENT RECEPTOR OCCUPANCYPERCENT RECEPTOR OCCUPANCY
0%0% 100%100%
BIOLOGICAL RESPONSEBIOLOGICAL RESPONSE RECEPTOR RESERVERECEPTOR RESERVETRETHOLDTRETHOLD
0%0% 100%100%
Max EffectMax EffectThreshold EffectThreshold Effect
Schematic representation of the relationship between threshold, receptor Schematic representation of the relationship between threshold, receptor
reserve, receptor occupancy, biological stimulus and biological responsereserve, receptor occupancy, biological stimulus and biological response

33. Receptors are said to be spare
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

34. 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

36. Some terminologies regarding Some terminologies regarding
drug receptor interactiondrug receptor interaction
Affinity
Efficacy
Potency
Ligand

37. 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.

38. POTENCY
OR
EFFICACY
Which one is important while
selecting a drug for therapy ?

39. Ligand:
Molecules that binds to a receptor

40. 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

41. AGONIST

42. AgonistsAgonists
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

43. Agonists differing in potency and
maximum efficacy

44. Response
Dose
Full agonist
Partial agonist
Agonist Dose Response Curves

45. [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
PARTIAL AGONISTS - EFFICACY
Even though drugs may occupy the same # of receptors, the magnitude
of their effects may differ.

46. AntagonistsAntagonists
 Interact with the receptor but do
NOT change the receptor
Have affinity but NO efficacy
Block the action of other drugs
Effect only observed in presence of
agonist

47. Types of AntagonistsTypes of Antagonists
Competitive
(Surmountable)
decrease apparent
Potency
Noncompetitive
decrease
apparent maximum
efficacy

48. Competitive AntagonistCompetitive Antagonist
 competes with ________for receptor
 surmountable with increasing agonist
concentration
 displaces agonist dose response curve to
the ___________(dextral shift)
 reduces the apparent affinity of the
__________.

49. Noncompetitive AntagonistNoncompetitive Antagonist
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

50. AGONIST VS ANTAGONIST

52. What happen when you increase agonist
concentration even higher

53. How do non competitive antagonist affect receptor function

55. 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