1. Principles of Pharmacology: Pharmacodynamics
Dennis Paul, Ph.D.

2. Learning Objectives:
Understand the theoretical basis of drug-receptor interactions.
Understand the determinants and types of responses to drug-receptor interactions.
Know the four major families of receptors.
Define potency and efficacy.
Understand how to compare drug potency and efficacy.
Understand the consequences of receptor regulation
Understand measures of drug safety.

3. TEXT:
CHAPTER 2 – “PHARMACODYNAMICS: Mechanisms of Drug Action and the Relationship between Drug Concentration and Effect” – GOODMAN AND GILMAN’S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS – 10th edition

4. Biochemistry:
L+S LS

5. Biochemistry:
L+S LS
Pharmacology:
L+R LR

6. Biochemistry:
L+S LS (Langmuir equation)
Pharmacology:
L+R LR Response

7. Pharmacodynamics

8. Drugs:
Chemical agents that interact with components of a biological system to alter the organism’s function. Examples of such components, sites of drug action, are enzymes, ion channels, neurotransmitter transport systems, nucleic acids and receptors. Many drugs act by mimicking or inhibiting the interactions of endogenous mediators with their receptors

9. Receptors:
Regulatory proteins that interact with drugs or hormones and initiate a cellular response
Ion channels
G-protein coupled receptors
Receptor-enzymes
Cytosolic-nuclear receptors
Act as transducer proteins
Receptor-effector signal transduction
Post-receptor signal transduction provides for amplification of the signal

10. Ligand-gated Ion Channels

11. G-protein coupled receptorsα γ β

12. G-protein coupled receptors
Membrane α γ β

13. G-protein coupled receptorsγ α β

14. Receptor-enzyme
Binding site
Catalytic site

15. Cytosolic-Nuclear receptors

16. Classical Receptor Occupancy TheoryKa
L+R LR Stimulus Response Kd
L: Ligand (Drug)
R: Receptor
LR: Ligand-Receptor Complex
Ka: Association rate constant
Stimulus: initial effect of drug on receptor

17. Properties of drugs
Affinity: The chemical forces that cause the drug to associate with the receptor.
Efficacy: The extent of functional change imparted to a receptor upon binding of a drug.

18. Properties of a biological system
Potency: Dose of drug necessary to produce a specified effect.
Dependent upon receptor density, efficiency of the stimulus-response mechanism, affinity and efficacy.
Magnitude of effect: Asymptotic maximal response
Solely dependent upon intrinsic efficacy.
Also called efficacy.

19. Determinants of Response
Intrinsic Efficacy (ε): Power of a drug to induce a response.
Number of receptors in the target tissue.

20. Spare receptors
Some tissues have more receptors than are necessary to produce a maximal response.
Dependent on tissue, measure of response and intrinsic efficacy of the drug.

21. Active vs Inactive states
Active states initiate cell signaling.
For any cell, there is an equilibrium between active an inactive states. The inactive state usually predominates.
Each state has its own affinity.

22. Classification of a drug based on drug-receptor interactions:
Agonist: Drug that binds to receptors and initiates a cellular response; has affinity and efficacy. Agonists promote the active state.
Antagonist: drug that binds to receptors but cannot initiate a cellular response, but prevent agonists from producing a response; affinity, but no efficacy. Antagonists maintain the active-inactive equilibrium.

23. cont.
Partial agonists: Drug that, no matter how high the dose, cannot produce a full response.
Inverse agonist: Drug that binds to a receptor to produce an effect opposite that of an agonist. Stabilizes receptors in the inactive state.

24. Graded dose-response curves
Individual responses to varying doses
Concepts to remember:
Threshold: Dose that produces a just-noticeable effect.
ED50: Dose that produces a 50% of maximum response.
Ceiling: Lowest dose that produces a maximal effect.

25. Dose-response curve
Response
Dose

26. Dose-response curve
Response
Dose

27. = Agonist

28. = Agonist

29. = Agonist

30. = Agonist

31. = Agonist

32. = Agonist

33. = Agonist

34. Dose-response curve
Response
Dose

35. Full vs Partial agonists
% Effect
Dose

36. Full vs Partial agonists
These terms are tissue dependent on
Receptor density
Cell signaling apparatus
Other receptors that are present
Drug history
Partial agonists have both agonist and antagonist properties.

37. Inverse Agonist
% Effect
Dose

38. Relative Potency
Effect
Dose

39. Relative Potency
Effect
Dose

40. Relative Potency
=ED50B/ED50A
320/3.2=100

41. Relative Efficacy

42. Antagonists
Competitive: Antagonist binds to same site as agonist in a reversible manner.
Noncompetitive: Antagonist binds to the same site as agonist irreversibly.
Allosteric: Antagonist and agonist bind to different site on same receptor
Physiologic: Two drugs have opposite effects through differing mechanisms

43. = Agonist
= Antagonist

44. = Agonist
= Antagonist

45. = Agonist
= Antagonist

46. = Agonist
= Antagonist

47. = Agonist
= Antagonist

48. = Agonist
= Antagonist

49. = Agonist
= Antagonist

50. Competition
Effect
IC50
log [antagonist]

51. = Agonist
= Antagonist

52. = Agonist
= Antagonist

53. = Agonist
= Antagonist

54. = Agonist
= Antagonist

55. = Agonist
= Antagonist

56. = Agonist
= Antagonist

57. = Agonist
= Antagonist

58. Competitive antagonists
Response
Dose

59. Noncompetitive antagonists
Response
Dose

60. Allosteric and Physiologic antagonists
Response can be irregular

61. Allosteric Antagonism

62. Allosteric Antagonism

63. Allosteric Antagonism

64. Allosteric Antagonism

65. Allosteric antagonists 1
Response
Dose

66. Allosteric antagonists 2
Response
Dose

67. Receptor regulation
Reduced responsivity: Chronic use of an agonist can result in the receptor-effector system becoming less responsive
eg. alpha-adrenoceptor agents used as nasal decongestants
Myasthenia gravis: decrease in number of functional acetylcholine nicotinic receptors at the neuromuscular junction.

68. Receptor regulation
Increased responsivity: Chronic disuse of a receptor-effector system can result in an increased responsiveness upon re-exposure to an agonist.
Denervation supersensitivity at skeletal muscle acetylcholine nicotinic receptors
Thyroid induced upregulation of cardiac beta-adrenoceptors
Prolonged use of many antagonists (pharmacological as well as functional) can result in receptor upregulation

69. Receptor Upregulation
Most receptors are internalized and degraded or recycled with age and use.
Antagonists slow use-dependent internalization
Inverse agonists stabilize the receptor in the inactive state to prevent internalization.
The cell continues to produce receptors.

70. Desired vs undesired effects: Indices of drug safety.
Safety Index
Therapeutic Index

71. Safety index: LD1/ED99
ED99
Sleep
Death
LD1

72. Therapeutic index: LD50/ED50
Sleep
Death