Pharmacodynamics is the study of how drugs act on the body and biological system, including receptor interactions and mechanisms of action. Most drugs act by binding to receptors, and spare receptors allow a maximal response even when not all receptors are occupied, as only a portion need to be bound. Agonists activate receptors to produce a response, with full agonists having maximal efficacy and partial agonists having less efficacy than full agonists. Antagonists block the action of agonists without activating the receptors themselves.

1. Pharmacodynamics Dr Rizwan Ashraf

2. Lecture Objectives To understand the basic concepts regarding pharmacodynamics To define agonist and antagonists and other terms in relation to pharmacodynamics To explain the mechanism of drug receptor interaction Define spare receptors To differentitate between different tyes of antagonism

3. WHAT IS PHARMACODYNAMICS ?

5. Action of a drug on the body receptor interactions, mechanisms of therapeutic dose-response phenomena, toxic action .

6. RECEPTOR INTERACTION

7. A drug will not work unless it is bound AGREED or NOT AGREED

8. BOUND WITH WHAT ?

9. PARTICULAR CONSTITUENTS OF CELLS & TISSUES IN ORDER TO PRODUCE AN EFFECT PROTEINS LIPIDS DNA RECEPTORS ?

10. ARE THERE DRUGS THAT ACT WITHOUT BEING BOUND TO ANY OF THE TISSUE CONSTITUENTS YES OR NO

11. YES OSMOTIC DIURETICS OSMOTIC PURGATIVES ANTACIDS HEAVY METALS CHELATING AGENTS

12. BUT PRINCPLES REMAIN TRUE FOR GREAT MAJORITY THAT IS _____________________ ______________________________.

13. Most drugs act through Receptors

14. Receptors

15. Drug Receptor A macromolecular component of a cell with which a drug interacts to produce a response Usually a protein

16. Receptors must be biologically important molecules Receptors must have structural features that permit drug specificity Receptors must have a drug-binding site and a biologically active site

17. Characteristics of Receptors a. specificity b. selectivity of response c. sensitivity

18. Molecules capable of serving as Receptors

19. Enzymes Membrane proteins glycoproteins, lipoproteins) Nucleic acids Complex polysaccharides

20. Many drugs inhibit enzymes in the patient (ACE inhibitors) in microbes (sulfas, Penicillins) in cancer cells (5-FU, 6-MP)

21. Types of Protein Receptors Regulatory – mediate the action of endogenous chemicals e.g. hormones, NT,autocoids Enzymes – may be inhibited or activated e.g. dihydrofolate reductase receptor for methotrexate Transport – e.g. Na + /K + ATP’ase for digitalis glycosides Structural – e.g. tubulin,receptor for colchicine

22. some drugs bind to: the genome (cyclophosphamide) microtubules (vincristine)

23. Non-receptor Mediated Effects Interaction with small molecules (e.g. binding of heavy metals) Interaction with enzymes (e.g. sulfonamides, digitalis) Incorporation into a macromolecule (e.g. some anticancer agents - purine and pyrimidine analogues) Nonspecific effects (e.g. membrane perturbation by general anesthetics)

24. Receptor-independent drug actions Chemically reactive agents Disinfectants Alkylating anticancer drugs Physically active agents Mannitol Hydrogen peroxide Counterfeit biochemical constituents 5-bromouracil

25. Antagonists tend to up regulate receptors Receptor regulation 1. Homeostasis 2. Up and down regulation 3. Desensitization 4. Tolerance agonists desensitize receptors homologous (decreased receptor number) heterologous (decreased signal transduction

26. Pharmacodynamics Drug receptor interaction

27. D + R DR Complex Drug - Receptor Binding Affinity

28. Drug Receptor Interaction DR Complex Effect

29. Theories of the relationship between binding and response

30. a. Occupation theory D + R  DR  RESPONSE :response is proportional to the fraction of occupied receptors :maximal response occurs when all the receptors are occupied

31. Ariens response is proportional to the fraction of occupied receptors AND the intrinsic activity Stephenson response is a FUNCTION of occupancy maximum response can be produced WITHOUT 100% occupation, i.e. tissues have spare receptors

32. BIOLOGICAL STIMULUS PERCENT RECEPTOR OCCUPANCY 0% 100% BIOLOGICAL RESPONSE RECEPTOR RESERVE TRETHOLD 0% 100% Max Effect Threshold Effect Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological response

33. Receptors are said to be spare for a given pharmacological response when the maximal response can be elicited by an agonist at a concentration that does not result in occupancy of the full complement of available receptors

34. Spare receptors More receptors available than needed to elicit maximum response allow maximal response without total receptor occupancy – increase sensitivity of the system Agonist has to bind only a portion of receptors for full effect

36. Some terminologies regarding drug receptor interaction Affinity Efficacy Potency Ligand

37. Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor Efficacy: Potential maximum therapeutic response that a drug can produce. Potency: A mount of drug needed to produce an effect.

38. POTENCY OR EFFICACY Which one is important while selecting a drug for therapy ?

39. Ligand: Molecules that binds to a receptor

40. Classification of Ligands a. agonist b. partial agonist c. antagonist pharmacological vs. physiological vs. chemical pharmacological antagonists - competitive surmountable - noncompetitive

41. AGONIST

42. Agonists Drugs that cause a response Drugs that interact with and activate receptors; They possess both affinity and efficacy Types Full agonists An agonist with maximal efficacy (response) has affinity plus intrinsic activity Partial agonists An agonist with less then maximal efficacy has affinity and less intrinsic activity

43. Agonists differing in potency and maximum efficacy

44. Response Dose Full agonist Partial agonist Agonist Dose Response Curves

45. [D] (concentration units) % Maximal Effect 0.01 0.10 1.00 10.00 100.00 1000.00 0.0 0.2 0.4 0.6 0.8 1.0 Partial agonist Full Agonist Partial agonist PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ.

46. Antagonists Interact with the receptor but do NOT change the receptor Have affinity but NO efficacy Block the action of other drugs Effect only observed in presence of agonist

47. Types of Antagonists Competitive (Surmountable) decrease apparent Potency Noncompetitive decrease apparent maximum efficacy

48. Competitive Antagonist competes with ________for receptor surmountable with increasing agonist concentration displaces agonist dose response curve to the ___________(dextral shift) reduces the apparent affinity of the __________.

49. Noncompetitive Antagonist drug binds to receptor and stays bound irreversible – does not let go of receptor produces slight dextral shift in the agonist DR curve in the low concentration range but, as more and more receptors are bound (and essentially destroyed), the agonist drug becomes incapable of eliciting a maximal effect

50. AGONIST VS ANTAGONIST

52. What happen when you increase agonist concentration even higher

53. How do non competitive antagonist affect receptor function

55. Summary (T or F) Pharmacodynamics is the study of absorption, distribution, metabolism and elimination of drug. Some drugs can act without binding to a receptor spare receptors allow maximum response without full receptor occupancy Efficacy is the amount of drug needed to produce an effect. Affinity is the attractiveness between 2 drug molecules. Agonist are the drugs that block the response. Partial agonist has affinity and maximum efficacy. Antagonist has efficacy but no affinity. Competitive antagonist decreases potency Non competitive antagonist decreases efficacy