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. Biochemistry:
L+S LS

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

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

6. Pharmacodynamics

7. 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

8. 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

9. Ligand-gated Ion Channels
Ca++
Mg++
Ca++
Ca++ K+
Mg++
Na+
Na+

10. Ligand-gated Ion Channels
Mg++
Ca++
Ca++
Na+
Na+
Na+
Ca++ K+
Na+
Na+
Na+
Mg++
Na+

11. G-protein coupled receptors
NH3+
COOH- g a b
GTP

12. G-protein coupled receptors
NH3+
COOH- g a b
GDP

13. Receptor-enzyme
Catalytic site

14. Receptor-enzyme
Catalytic site

15. Cytosolic-Nuclear receptors

16. Cytosolic-Nuclear receptors

17. 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

18. 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.

19. 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.

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

21. 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.

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

23. 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.

24. 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.

25. 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. (EC50: blood concentration that produces a 50% of max response)
Ceiling: Lowest dose that produces a maximal effect.

26. Dose-response curve
Response
Dose

27. Dose-response curve
Response
Dose

28. = Agonist

29. = Agonist

30. = Agonist

31. = Agonist

32. = Agonist

33. = Agonist

34. = Agonist

35. Dose-response curve
Response
Dose

36. Full vs Partial agonists
% Effect
Dose

37. 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.

38. Inverse Agonist
% Effect
Dose

39. Relative Potency
Effect
Dose

40. Relative Potency
Effect
Dose

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

42. Relative Efficacy

43. 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

44. = Agonist
= Antagonist

45. = Agonist
= Antagonist

46. = Agonist
= Antagonist

47. = Agonist
= Antagonist

48. = Agonist
= Antagonist

49. = Agonist
= Antagonist

50. = Agonist
= Antagonist

51. Competition
Effect
ID50 or IC50
log [antagonist]

52. = Agonist
= Antagonist

53. = Agonist
= Antagonist

54. = Agonist
= Antagonist

55. = Agonist
= Antagonist

56. = Agonist
= Antagonist

57. = Agonist
= Antagonist

58. = Agonist
= Antagonist

59. Competitive antagonists
Response
Dose

60. Noncompetitive antagonists
Response
Dose

61. Allosteric and Physiologic antagonists
Response can be irregular

62. Allosteric Antagonism

63. Allosteric Antagonism

64. Allosteric Antagonism

65. Allosteric Antagonism

66. Allosteric antagonists 1
Response
Dose

67. Allosteric antagonists 2
Response
Dose

68. Quantal Dose-Response Curves
Also known as concentration-percent or dose-percent curves
Used when the dose of a drug to produce a specified effect in a single patient is measured (individual effective dose or concentration.)
The percent of subjects responding at a dose is plotted.

69. Quantal Dose-Response Curves
Percent Responders
Dose

70. Cumulative Quantal Dose-Response Curves
Percent Responders
Dose

71. Cumulative Quantal Dose-Response Curves
Percent Responders
Dose

72. 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.

73. 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

74. 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.

75. Desired vs undesired effects: Indices of drug safety.
Safety Index
Therapeutic Index
“Potency means nothing. I can always give a bigger pill.”
J. Hunter

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

77. Therapeutic index: LD50/ED50
Sleep
Death

78. Safety Index vs. Therapeutic Index