WHAT IS THE RELATIONSHIP BETWEEN AMOUNT OF DRUG IN THE BODY AND THE EFFECT OF THE DRUG?

1. WHAT IS THE RELATIONSHIP BETWEEN AMOUNT OF DRUG IN THE BODY AND THE EFFECT OF THE DRUG?

2. WHY BE CONCERNED ABOUT DOSE-EFFECT RELATIONSHIPS? DOSE-EFFECT RELATIONSHIPS: • Predict the effects of changing the dose. • Reveal the necessary trade-offs between • efficacy and adverse effects. • Facilitate comparisons of alternative medications • for the same indication. • Enhance understanding of how best to use receptor blockers.

3. WHAT DETERMINES THE DOSE-EFFECT RELATIONSHIP? The Dose-Response Causal Chain DOSE OF DRUG [DRUG] AT TARGET SITE [DRUG-RECEPTOR COMPLEX] RESPONSE

4. WHAT IS THE RELATIONSHIP BETWEEN DOSE OF DRUG AND [DRUG] AT TARGET SITE ? Linear DOSE OF DRUG [DRUG] AT TARGET SITE As a rough approximation, the relationship between dose of drug and [drug] is more-or-less linear at a specified time after drug administration. [DRUG] DOSE

5. WHAT IS THE RELATIONSHIP BETWEEN [DRUG-RECEPTOR COMPLEX] AND RESPONSE? Linear CONCENTRATION OF DRUG-RECEPTOR COMPLEX RESPONSE As a rough approximation, the relationship between concentration of drug-receptor complex and response to the drug is more-or-less linear. RESPONSE [DRUG-RECEPTOR]

6. WHAT IS THE RELATIONSHIP BETWEEN [DRUG] AT TARGE SITE AND [DRUG-RECEPTOR COMPLEX]? Non-Linear [DRUG] AT TARGET SITE [DRUG-RECEPTOR COMPLEX] The relationship between [Drug] at target site and [Drug-Receptor Complex] is not linear!

7. WHAT DETERMINES THE DOSE-EFFECT RELATIONSHIP? Linear Non-Linear Linear CONCENTRATION OF DRUG-RECEPTOR COMPLEX DOSE OF DRUG [DRUG] AT TARGET SITE RESPONSE In the causal chain between dose of drug and response, the dominant non-linear step is the formation of the drug-receptor complex. Therefore, it is this step that mainly determines the shape of the dose-effect and the concentration-effect relationships!!

8. WHAT IS THE RELATIONSHIP BETWEEN [DRUG] AND [DRUG-RECEPTOR]? [R] [D] [R-D] + By Law of Mass Action: [R]free x [D]free/[R-D] = KD (Equation #1) (Where KD is the equilibrium dissociation constant) By Conservation of Mass: [R]free + [R-D] = [R]total (Equation #2) Rearranging equation #2 gives: [R]free = [R]total - [R-D] (Equation #3)

9. WHAT IS THE RELATIONSHIP BETWEEN [DRUG] AND [DRUG-RECEPTOR]? [R] [D] [R-D] + Substitution of equation #3 into equation #1 gives: ([R]total - [R-D]) x [D]free/[R-D] = KD (Equation #4) Rearranging equation #4 gives: [R-D] = ([R]total x [D]free)/([D]free + KD) (Equation #5)

10. WHAT IS THE RELATIONSHIP BETWEEN [DRUG] AND [DRUG-RECEPTOR]? [R] [D] [R-D] + Note that equation #5 gives explicit relationship between [R-D], the dependent variable, and [D]free, the independent variable: [R]total x [D]free [R-D] = [D]free + KD

11. WHAT IS THE RELATIONSHIP BETWEEN [DRUG] AND [DRUG-RECEPTOR]? [D]free versus [R-D] Log [D]free versus [R-D] y-axis is [R-D] y-axis is [R-D] Graphs were computer generated using equation #5 with [R]total = 100 and KD = 10

12. WHAT IS THE RELATIONSHIP BETWEEN [DRUG] AND [DRUG-RECEPTOR]? [R] [D] [R-D] + A plot of [D]free versus [R-D] is hyperbolic A plot of log [D]free versus [R-D] is sigmoidal

13. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? If we assume that the response is proportional to [R-D], then: Response = m x [R-D] (Equation #6) and Maximal Response = m x [R-D]maximal = m x [R]total (Equation #7) (where m is the proportionality constant)

14. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Substitution of equations #6 and #7 into equation #5 gives equation #8: Maximal Response x [D]free = Response [D]free + KD

15. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? [D]free versus Response Log [D]free versus Response y-axis is Response y-axis is Response Graphs were computer generated using equation #8 with maximal response = 100 and KD = 10

16. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? [R] [D] [R-D] Response + A plot of [D]free versus response is hyperbolic A plot of log [D]free versus response is sigmoidal

17. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Let: [D]free = KD Maximal Response x [D]free Response = We Know That: [D]free + KD Maximal Response x KD Substituting KD for [D]free: = Response 2KD 1/2 Maximal Response Response = Simplifying:

18. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? 1/2 Maximal Response Let: Response = Maximal Response x [D]free Response We Know That: = [D]free + KD Substituting ½ Maximal Response For Response 1/2 Maximal Response Maximal Response x [D]free = [D]free + KD = KD [D]free Simplifying:

19. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Response = 1/2 Maximal Response [D]free = KD (Equivalence #9) y-axis is Response The [drug] which causes 1/2 maximal response is called the EC50 and corresponds to the KD if there is a linear relationship between [D-R] and response. EC50 Maximal Response 1/2 Maximal Response

20. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Since EC50 corresponds to KD, can substitute EC50 for KD in equation #8 to give equation #10: Maximal Response x [D]free Response = [D]free + EC50

21. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Maximal Response x [D]free Response = [D]free + EC50 Empirically, it has been found that equation #10 (above) describes the concentration-effect relationship for many drugs, even when the assumption of linearity between [R-D] and response does not hold.

22. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Maximal Response x [D]free Response = [D]free + EC50 When the assumption of linearity does not hold, the EC50 no longer approximates the KD. For example, the EC50 will be much smaller than the KD when “spare receptors” are present. A tissue is said to express “spare receptors” when only a small fraction of the receptor population must be occupied by drug to give a maximal response.

23. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Maximal Response x [D]free Response = [D]free + EC50 The term “potency” refers to the EC50 of a drug. The lower the EC50, the greater the potency. A low KD and a high number of spare receptors increases the potency of a drug.

24. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Maximal Response x [D]free Response = [D]free + EC50 The term “efficacy” refers to the maximal response of a drug. The greater the maximal response, the greater the efficacy. The more effectively a drug engages signal-transduction systems in a cell per unit receptor occupied, the greater is the efficacy of that drug.

25. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Maximal Response To Agonist A Maximal Response To Agonist B =, <, or > Drugs that activate a given type of receptor may or may not do so equally, i.e., the maximal response elicited by a given drug may be the same as, less than or more than another drug in the same pharmacological class.

26. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? The “Best in Class” is called a “full agonist”, and any drug that generates a maximal response equal to the “Best in Class” is also referred to as a “full agonist.” Agonist A is “Best in Class”, i.e., no other agonist induces a greater maximal effect. Assume: Maximal Response to Agonist A Maximal Response to Agonist B = Assume: Both Agonist A and agonist B are “full agonists.”

27. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Agonist A Agonist B y-axis is Response Agonist A and agonist B are both full agonists. However, agonist A is more potent than agonist B. Concentration of Agonist

28. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Any drug that generates a maximal response less than that elicited by the “Best in Class” is referred to as a “partial agonist.” Agonist A is “Best in Class”, i.e., no other agonist induces a greater maximal effect. Assume: Maximal Response to Agonist A Maximal Response to Agonist B > Assume: In this case agonist B is a “partial agonist.”

29. WHAT IS THE CONCENTRATION-EFFECT (RESPONSE) RELATIONSHIP? Full Agonist A Partial Agonist B Agonist A is a full agonist and agonist B is a partial agonist. However, agonist A and agonist B have equal potency. y-axis is Response Concentration of Agonist

30. WHAT IS THE DOSE-EFFECT (RESPONSE) RELATIONSHIP? [Drug]free = dose/volume (Equation #11) and EC50 = ED50/volume (Equation #12) (where dose is the amount of the drug in the body at some time after drug administration) (where volume is the apparent volume in which the drug is dispersed) (where ED50 is the dose of drug that generates an EC50)

31. WHAT IS THE DOSE-EFFECT (RESPONSE) RELATIONSHIP? Substitution of equations #11 and #12 into equation # 10 gives equation #13: Maximal Response x Dose = Response Dose + ED50

32. WHAT IS THE DOSE-EFFECT (RESPONSE) RELATIONSHIP? Dose versus Response Log Dose versus Response y-axis is Response y-axis is Response Graphs were computer generated using equation #13 with maximal response = 100 and ED50 = 10

33. WHAT IS THE DOSE-EFFECT (RESPONSE) RELATIONSHIP? DOSE [R] [D] [R-D] Response + A plot of DOSE versus response is hyperbolic A plot of log DOSE versus response is sigmoidal

34. WHAT IS THE DOSE-EFFECT (RESPONSE) RELATIONSHIP? Response = 1/2 Maximal Response Dose = ED50 The dose which causes 1/2 maximal response is called the ED50. Although the ED50 is affected by the KD and EC50 it is greatly influenced by the apparent volume in which the drug is distributed. y-axis is Response ED50 is never equal to EC50 or KD! ED50 Maximal Response 1/2 Maximal Response

35. WHAT IS THE EFFECT OF DRUGS THAT BLOCK DRUG-RECEPTOR INTERACTIONS OR THAT INHIBIT SIGNAL TRANSDUCTION MECHANISMS ON THE DOSE- RESPONSE CURVE? [R] [D] [R-D] Response + BLOCKING DRUG

36. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? - Drug Antagonist + Drug Antagonist y-axis is Response SURMOUNTABLE ANTAGONIST Concentration of Agonist

37. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? • CHARACTERISTICS OF SURMOUNTABLE ANTAGONIST: • Produces parallel shift in concentration-response curve of agonist • Full effect of agonist can be restored by increasing • concentration of agonist

38. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? • MOST COMMON MECHANISM OF SURMOUNTABLE • ANTAGONISM: • Competitive interaction between agonist (potency and efficacy) • and antagonist (potency but no or little efficacy) • at binding site on receptor

39. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? Population of Inactive Receptors

40. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? Add an excess of high potency agonist molecules

41. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? Allow system to reach equilibrium

42. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? Add some antagonist molecules

43. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? Allow system to reach new equilibrium

44. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? It can be shown mathematically that the net effect of a competitive antagonist is to increase the apparent KD, or said differently to decrease the apparent potency of the agonist. Maximal Response x [D]free Response = [D]free + apparent KDagonist Where apparent KDagonist = (1 + [Antagonist]/KDantagonist) x actual KDagonist

45. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? Agonist Alone Agonist + Competitive Antagonist y-axis is Response Note apparent shift in EC50 for the agonist. Concentration of Agonist

46. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? - Drug Antagonist + Drug Antagonist y-axis is Response INSURMOUNTABLE ANTAGONIST Concentration of Agonist

47. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? • CHARACTERISTICS OF INSURMOUNTABLE ANTAGONIST: • Produces non-parallel shift in concentration-response curve of agonist • Full effect of agonist cannot be restored by increasing • concentration of agonist

48. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? • MOST COMMON MECHANISMS OF INSURMOUNTABLE • ANTAGONISM: • Competitive but irreversible binding of antagonist to • binding site on receptor • Allosteric modulation of receptor by antagonist so as to • attenuate coupling of receptor to signal transduction • Blockade of signal transduction “downstream” of receptor

49. WHAT IS THE EFFECT OF BLOCKING DRUGS ON CONCENTRATION-RESPONSE CURVES? PHENOMENON SURMOUNTABLE ANTAGONISM INSURMOUNTABLE ANTAGONISM Concentration of Agonist Concentration of Agonist MECHANISM Reversible Competitive Interaction If spare receptors & right dose & time Irreversible Competitive Interaction If spare receptors & right dose Blockade of Signal Transduction If just the right type Allosteric Modulation

50. WE HAVE BEEN DISCUSSING CONCENTRATION- AND DOSE-RESPONSE CURVES WITHIN AN INDIVIDUAL. HOW ARE THESE RELATIONSHIPS EXPRESSED IN A PATIENT POPULATION? We represent the effect of a drug in an INDIVIDUAL as a concentration- or dose-response curve in which the GRADED effects of the drug are related to concentrations or doses of the drug. We represent the effect of a drug in a POPULATION as a concentration- or dose-response curve in which the QUANTAL effect of the drug is related to concentrations or doses of the drug.