Principles of Pharmacology: Pharmacodynamics

1. Principles of Pharmacology:Pharmacodynamics Dennis Paul, Ph.D. dpaul@lsuhsc.edu

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 Theory Ka L+R LRStimulus 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