1. PHARMACODYNAMICS M.T. Piascik PHA 824 November 11, 2008

2. Learning Objectives The definition of a drug The different types of receptors at which drugs can act The concept of affinity and those factors that cause a drug to bind to a receptor The concept of intrinsic activity The difference between full and partial agonists The definitions of potency and efficacy The definition of ED50

3. Learning Objectives (cont.) The concept of spare receptors The information regarding drugs that can be obtained from the log-dose response curve The properties of a competitive antagonist and how it differs from an irreversible receptor agonist The definition of LD50 The concept of a therapeutic index and how it is calculated

4. True or False? A correct definition of a drug is -- A chemical substance that interacts with a receptor to produce a beneficial therapeutic effect. Answer—FALSE!! Correct definition: A drug is a chemical substance that interacts with a receptor to produce a physiologic effect– regardless whether the effect is beneficial.

5. Drug Properties Drug binding to a receptor is mediated by the chemical structure of the drug that allows it to interact with complementary surfaces on the receptor. Agonists activate cellular signaling pathways to alter physiologic activity. Antagonists bind to the receptor but cannot initiate a change in cellular function. Occupation of the receptor without activation results in blockade of the actions of agonists.

6. Any cellular macromolecule to which a neurotransmitter or drug binds to initiate its effects. The endogenous function of a receptor is to participate in neurotransmission or physiologic regulation. Receptor

7. Receptor Types

8. Proposed Structure of a GPCR

9. Receptor Specificity

10. FACTORS GOVERNING DRUG ACTION

11. Affinity is a measure of the tightness with which a drug binds to the receptor. Intrinsic activity is a measure of the ability of an agonist that is bound to the receptor to generate an activating stimulus and produce a change in cellular activity.

12. UNDERSTANDING THE CONCEPT OF AFFINITY 1)Affinity describes the strength of binding to receptors. 2) k 1 describes the rate at which a drug associates with the receptor while k -1 describes the ease at which a drug dissociates from its receptor.

13. UNDERSTANDING THE CONCEPT OF AFFINITY

14. Affinity = k 1 /k -1 = __[DR]___ [D] [R] The term most often used to represent affinity is the equilibrium dissociation constant or K D K D = k -1/k 1 = ___[D] [R]___ [DR] After appropriate mathematical substitution, it can be stated that; Amount bound to receptor = [D] [D]+KD This equation states that the amount of drug bound to the receptor is dependent on the drug concentration and Kd.

15. UNDERSTANDING THE CONCEPT OF AFFINITY Making the assumption that an effect of a drug is dependent on the number of receptors occupied, it can be stated that at binding equilibrium, the drug effect would be also be constant. Affinity describes the strength of binding to receptors, Drugs that bind with great avidity to the receptors are said to have high affinity. The term most often used to represent affinity is the equilibrium dissociation constant or its abbreviation K D. The description of the strength of binding of drugs to receptors is very important in pharmacology. K D values are often used to compare the potency of different drugs as well as in the characterization of receptors. The units of the equilibrium dissociation are in concentration, for 1 x 10-8M or 10 nanomolar. There is an inverse relationship between the K D and affinity. The smaller the K D, the higher the affinity.

16. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING Make the following simple calculations and graphical representations.

17. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING Amount bound to receptor = [D] [D]+KD Terazosin has an equilibrium dissociation constant of 1.0 nM. Calculate the percentage of receptors occupied at each Terazosin concentration Terazosin % Receptors Occupied 0.5 nM 1.0 nM 4.0 nM 10.0 nM

18. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING = ??? 0.5 0.5 + 1.0 Terazosin at 0.5 nM:

19. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING = 33% Receptor Occupancy 0.5 0.5 + 1.0 Terazosin at 0.5 nM: At 1.0 nM : = 50% Receptor Occupancy 1.0 1.0 + 1.0

20. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING = 33% Receptor Occupancy 0.5 0.5 + 1.0 Terazosin at 0.5 nM: At 1.0 nM : = 50% Receptor Occupancy 1.0 1.0 + 1.0 At 4.0 nM : = 80% Receptor Occupancy 4.0 4.0 + 1.0

21. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING = 33% Receptor Occupancy 0.5 0.5 + 1.0 Terazosin at 0.5 nM: At 1.0 nM : = 50% Receptor Occupancy 1.0 1.0 + 1.0 At 4.0 nM : = 80% Receptor Occupancy 4.0 4.0 + 1.0 At 10.0 nM : = 90% Receptor Occupancy 10.0 10.0 + 1.0

22. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING Amount bound to receptor = [D] [D]+KD Epinephrine has an equilibrium dissociation constant of 100 nM. Calculate the percentage of receptors occupied at each epinephrine concentration: Epinephrine % Receptors Occupied 50.0 nM 100.0 nM 400.0 nM 1000 nM

23. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING = ??? 50.0 50.0 + 100.0 Epinephrine at 50.0 nM:

24. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING = 33% Receptor Occupancy 50.0 50 + 100 At 50.0 nM: At 100.0 nM : = 50% Receptor Occupancy 100.0 100.0 + 100.0 At 400.0 nM : = 80% Receptor Occupancy 400.0 400.0 + 100.0 At 1000.0 nM : = 90% Receptor Occupancy 1000.0 1000.0 + 100.0

25. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING Amount bound to receptor = [D] [D]+KD Terazosin at:Epinephrine at:% Receptors Occupied 0.5 nM50 nM33 % 1.0 nM100 nM50 % 4.0 nM400 nM80 % 10.0 nM1000nM90 % 50% OF RECEPTORS WILL BE OCCUPIED WHEN A DRUG IS GIVEN AT A CONCENTRATION EQUAL TO ITS KD

26. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING Now plot the relationship between concentration and receptor occupancy.

27. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING 50% OF RECEPTORS WILL BE OCCUPIED WHEN A DRUG IS GIVEN AT A CONCENTRATION EQUAL TO ITS KD

28. UNDERSTANDING THE CONCEPT OF INTRINSIC ACTIVITY AN ILLUSTRATION OF INTRINSIC ACTIVITY

29. UNDERSTANDING THE CONCEPT OF INTRINSIC ACTIVITY

30. MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS 1) As the concentration of a drug in a human organ system increases, the response of that system would be expected to increase until a maximal response is obtained. 2) The relationship between the number of receptors occupied and the physiologic response is complex.

31. MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS In many human physiological systems, not all receptors must be occupied by drug to achieve a maximal response. A certain number of receptors are “spare.”

32. MAXIMAL DRUG RESPONSES AND SPARE RECEPTORS The amplification of cellular signaling pathways is responsible for the nonlinear relationship between receptor occupancy and response.

33. DOSE-RESPONSE CURVES 1)Dose-response relationships are a common way to portray data in both basic and clinical science. 2)To present the data, the concentration of the drug is plotted on the x-axis and the effect would be presented on the y-axis. A plot of drug concentration ([D]) versus effect (E/Emax in the graphs) is a rectangular hyperbola. 3)Most often, the log of the drug concentration is plotted versus the effect. A plot of the log of [D] versus Effect is a sigmoid curve.

34. DOSE-RESPONSE CURVES The dose at which 50% of the maximal effect is observed is referred to as the ED50

35. Potency 1) Potency refers to the concentration of a drug required to produce a given physiologic effect. Drugs with high receptor affinity will exhibit greater potency than those with lower affinity.

36. Potency Norepinephrine (NE) has a higher affinity for a receptor than does phenylephrine(PE). The ED50 for norepinephrine is 100 nM while the ED50 for phenylephrine is 35,000 nM. Norepinephrine would be said to have greater potency than phenylephine.

37. Efficacy 1) Efficacy is often used to describe the maximal level of response a drug can produce.

38. Efficacy Norepinephrine would have a greater efficacy than methoxamine which in turn would have a greater efficacy than clonidine.

39. ADDITIONAL CONCEPTS REGARDING PARTIAL AGONISTS Partial agonists can block the actions of full agonists. To achieve a maximal effect, partial agonists must occupy all receptors to produce a maximal effect. If a full agonist is given in the presence of a receptor saturating dose of a partial agonist, the full agonist cannot access the receptor and hence its actions will be blocked

40. ADDITIONAL CONCEPTS REGARDING PARTIAL AGONISTS

41. ANTAGONISTS Antagonists that bind in a reversible manner are referred to as competitive antagonists. Agonists, if given in high concentrations, can displace the antagonist from the receptor

42. ANTAGONISTS The antagonist [A] and agonist [D] are competing for the same limited number of receptors [R]. [D] + + [A] [R] [DR] [AR] [ + + [A] [R] [DR] [AR]

43. ANTAGONISTS Amount of agonist bound to the receptor = [D] In the presence of an antagonist [D]+Kd(1+[A]/Ka) Examine the effect of terazosin (Ka= 1.0 nM) on the occupancy of the alpha1- adrenergic receptor by epinephrine ( = K D 100 nM). Epinephrine % Receptors %Receptors % Receptors OccupiedOccupiedOccupied (Teraz = 0)(Teraz = 1nM) (Teraz = 10 nM) 50.0 nM33 100.0 nM50 400.0 nM80 1000.0 nM90

44. ANTAGONISTS Amount of agonist bound to the receptor = [D] In the presence of an antagonist [D]+Kd(1+[A]/Ka) Amt Epi bound at 50 nM in the presence= 50 nM of 1 nM terazosin 50 nM+ 100 nM(1+1 nM/1nM) Epinephrine % Receptors %Receptors % Receptors OccupiedOccupiedOccupied (Teraz = 0)(Teraz = 1nM) (Teraz = 10 nM) 50.0 nM3320 100.0 nM50 400.0 nM80 1000.0 nM90

45. ANTAGONISTS Amount of agonist bound to the receptor = [D] In the presence of an antagonist [D]+Kd(1+[A]/Ka) Amt Epi bound at 50 nM in the presence= 50 nM of 1 nM terazosin 50 nM+ 100 nM(1+1 nM/1nM) Epinephrine % Receptors %Receptors % Receptors OccupiedOccupiedOccupied (Teraz = 0)(Teraz = 1nM) (Teraz = 10 nM) 50.0 nM33204 100.0 nM50338 400.0 nM806626 1000.0 nM908347

46. ANTAGONISTS PE alone

47. COMPETITIVE ANTAGONISTS 1) Reversible binding to the receptor. 2) The blockade can be overcome by increasing the agonist concentration. 3) The maximal response of the agonist is not decreased. 4) The agonist dose-response curve in the presence of a competitive antagonist is displaced to the right, parallel to the curve in the absence of agonist.

48. Irreversible Receptor Antagonists 1) Irreversible receptor antagonists are chemically reactive compounds. These ligands first bind to the receptor. Following this binding step, the ligand then reacts with the functional groups of the receptor

49. Irreversible Receptor Antagonists

50. APPLICATIONS TO THERAPEUTICS Few drugs interact with one and only one receptor. Such a drug would be said to be specific. Most drugs interact with more than one receptor class and thus have the capability to produce distinctly different pharmacologic effects. Some of these effects could be beneficial, some could be toxic. Such a drug would be said to be selective.

51. APPLICATIONS TO THERAPEUTICS Assume a drug can interact with two receptor systems with the following characteristics; Receptor System # 1: K D = 0.40, effect- lowering of systemic arterial blood pressure. Receptor System # 2: K D = 40.0, effect- lethal ventricular arrhythmias.

52. APPLICATIONS TO THERAPEUTICS

53. The Therapeutic Index The Therapeutic Index is the ratio of the ED50 of a drug to produce a lethal effect to the ED50 to produce a therapeutic effect. The dose required to produce death in 50% of a population is referred to as the LD50.

54. The Therapeutic Index The ED50 for the beneficial effect of blood pressure lowering is 0.4 nM while the LD50 is 40 nM. Therefore, the therapeutic index will be: TI =LD50 ED 50 TI = 40.0 nM 0.4 nM TI = 100

58. AN ILLUSTRATION OF THE RELATIONSHIP OF AFFINITY AND DRUG BINDING

60. FACTORS GOVERNING DRUG ACTION Drug administration Drug absorption Drug distribution to receptor sites PHARMACOKINETIC Drug in receptor micro- environment Drug binds to receptor Receptor activation of cell signaling Physiologic response PHARMACODYNAMIC