1. Clinical Pharmacokinetics

2. Time course Duration Onset Absorptive phase Elimination phase

3. First order elimination Plasma half-life (T 1/2 ) is independent of dose. Plasma half-life (T 1/2 ) is independent of dose. With multiple dosing, steady-state will occur. With multiple dosing, steady-state will occur. –Steady state occurs after 4-5 half- lives

4. First-order elimination

5. Steady state kinetics Time Plasma Concentration Steady state [

6. Zero-order elimination Plasma half-life is dose- dependent. Plasma half-life is dose- dependent. With multiple dosing, accumulation can occur. With multiple dosing, accumulation can occur.

7. Zero-order elimination

8. Loading dose One or more larger doses given when beginning drug administration to achieve steady state faster. One or more larger doses given when beginning drug administration to achieve steady state faster.

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

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

11. Pharmacodynamics

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

13. Properties of a biological system Potency: Dose of drug necessary to produce a specified effect. 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: Assymtotic maximal response Magnitude of effect: Assymtotic maximal response –Solely dependent upon efficacy.

14. Receptors Regulatory proteins that interact with drugs or hormones and initiate a cellular response Regulatory proteins that interact with drugs or hormones and initiate a cellular response –Ion channels –G-protein coupled receptors –Receptor-enzymes –Cytosolic-nuclear receptors

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

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

17. G-protein coupled receptors NH 3 + COOH -   

18. G-protein coupled receptors NH 3 + COOH -   

19. Receptor-enzyme Catalytic site

20. Receptor-enzyme

21. Cytosolic-Nuclear receptors

23. Classification of a drug based on drug-receptor interactions Agonists: drugs that combine with receptors and initiate a cellular response; has affinity and efficacy. Agonists: drugs that combine with receptors and initiate a cellular response; has affinity and efficacy. Antagonists: drugs that combine with receptors but cannot initiate a cellular response, but prevent agonists from producing a response; affinity, but no efficacy. Antagonists: drugs that combine with receptors but cannot initiate a cellular response, but prevent agonists from producing a response; affinity, but no efficacy.

24. Partial agonists Drugs that, no matter how high the dose, cannot produce a full response Drugs that, no matter how high the dose, cannot produce a full response

25. Inverse Agonist A drug that, when bound to a receptor, produces an effect opposite to the effect of an agonist. A drug that, when bound to a receptor, produces an effect opposite to the effect of an agonist.

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

27. Dose-response curve Dose Response

28. Dose-response curve Dose Response

29. = Agonist

36. Dose-response curve Dose Response

37. Full vs Partial agonists Dose Effect

38. Relative Potency Dose Effect

39. Relative Potency Dose Effect

40. Relative Potency =ED 50 B/ED 50 A 320/3.2=100

41. Relative Efficacy

42. Antagonists Competitive: Antagonist binds to same site as agonist in a reversible manner. Competitive: Antagonist binds to same site as agonist in a reversible manner. Noncompetitive: Antagonist binds to the same site as agonist irreversibly. Noncompetitive: Antagonist binds to the same site as agonist irreversibly. Allosteric: Antagonist and agonist bind to different site on same receptor Allosteric: Antagonist and agonist bind to different site on same receptor Physiologic: Two drugs have opposite effects through differing mechanisms 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 IC 50 log [antagonist] Effect

51. Competitive antagonists Dose Response

52. Noncompetitive antagonists Dose Response

53. Allosteric and Physiologic antagonists Response can be irregular Response can be irregular

54. Allosteric Antagonism

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

59. Safety index: LD 1 /ED 99 SleepDeath LD 1 ED 99

60. Therapeutic index: LD 50 /ED 50 SleepDeath

61. Receptor regulation Reduced responsivity: Chronic use of an agonist can result in the receptor- effector system becoming less responsive Reduced responsivity: Chronic use of an agonist can result in the receptor- effector system becoming less responsive Increased responsivity: Chronic disuse of a receptor-effector system can result in an increased responsiveness upon re-exposure to an agonist. Increased responsivity: Chronic disuse of a receptor-effector system can result in an increased responsiveness upon re-exposure to an agonist.