Ch02 Drug Receptor Interactions And Pharmacodynamics

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Ch02 Drug Receptor Interactions And Pharmacodynamics

  1. 1. UNIT I: Introduction to Pharmacology Chapter 2 Drug-Receptor Interactions and Pharmacodynamics
  2. 2. I. OVERVIEW Chapter 2: Drug-Receptor Interactions and Pharmacodynamics Dose Effect Absorption Distribution Metabolism Elimination Drug interactions Tissue/organ sensitivity (target status) What is pharmacodynamics? Effect site Concentration Pharmacokinetics Pharmacodynamics
  3. 3. Lecture Objectives <ul><li>To understand the basic concepts regarding </li></ul><ul><li>pharmacodynamics </li></ul><ul><li>To define agonist and antagonists and other </li></ul><ul><li>terms in relation to pharmacodynamics </li></ul><ul><li>To explain the mechanism of drug receptor </li></ul><ul><li>interaction </li></ul><ul><li>Define spare receptors </li></ul><ul><li>To differentitate between different tyes of </li></ul><ul><li>antagonism </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  4. 4. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  5. 5. <ul><li>Action of a drug on the body </li></ul><ul><li>receptor interactions, </li></ul><ul><li>mechanisms of therapeutic </li></ul><ul><li>dose-response phenomena, </li></ul><ul><li>toxic action . </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  6. 6. A drug will not work unless it is bound <ul><li>PARTICULAR CONSTITUENTS OF </li></ul><ul><li>CELLS & TISSUES IN ORDER TO </li></ul><ul><li>PRODUCE AN EFFECT </li></ul><ul><li>PROTEINS </li></ul><ul><li>LIPIDS </li></ul><ul><li>DNA </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  7. 7. DRUGS THAT ACT WITHOUT BEING BOUND TO ANY OF THE TISSUE CONSTITUENTS <ul><li>OSMOTIC DIURETICS </li></ul><ul><li>OSMOTIC PURGATIVES </li></ul><ul><li>ANTACIDS </li></ul><ul><li>HEAVY METALS CHELATING AGENTS </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  8. 8. Drug Receptor <ul><li>A macromolecular component of a cell with which a drug interacts to produce a response </li></ul><ul><li>Usually a protein </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  9. 9. Receptors <ul><li>Receptors must be biologically important molecules </li></ul><ul><li>Receptors must have structural features that permit drug specificity </li></ul><ul><li>Receptors must have a drug-binding site and a biologically active site </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  10. 10. <ul><li>Characteristics of Receptors </li></ul><ul><li>  a. specificity </li></ul><ul><li>      b. selectivity of response </li></ul><ul><li>      c. sensitivity </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  11. 11. Molecules capable of serving as Receptors <ul><li>Enzymes </li></ul><ul><li>Membrane proteins </li></ul><ul><li>(glycoproteins, lipoproteins) </li></ul><ul><li>Nucleic acids </li></ul><ul><li>Complex polysaccharides </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  12. 12. <ul><li>Many drugs inhibit enzymes </li></ul><ul><ul><li>in the patient (ACE inhibitors) </li></ul></ul><ul><ul><li>in microbes (sulfas, Penicillins) </li></ul></ul><ul><ul><li>in cancer cells (5-FU, 6-MP) </li></ul></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  13. 13. Types of Protein Receptors <ul><li>Regulatory – mediate the action of endogenous chemicals e.g. hormones , NT , autocoids </li></ul><ul><li>Enzymes – may be inhibited or activated e.g. dihydrofolate reductase, receptor for methotrexate </li></ul><ul><li>Transport – e.g. Na + /K + ATP’ase for digitalis glycosides </li></ul><ul><li>Structural – e.g. tubulin,receptor for colchicin </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  14. 14. <ul><li>some drugs bind to: </li></ul><ul><ul><li>the genome (cyclophosphamide) </li></ul></ul><ul><ul><li>microtubules (vincristine) </li></ul></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  15. 15. <ul><li>Non-receptor Mediated Effects </li></ul><ul><li>Interaction with small molecules (e.g. binding of heavy metals) </li></ul><ul><li>Interaction with enzymes </li></ul><ul><li>(e.g. sulfonamides, digitalis) </li></ul><ul><li>Incorporation into a macromolecule </li></ul><ul><li>(e.g. some anticancer agents - purine and pyrimidine analogues) </li></ul><ul><li>Nonspecific effects (e.g. membrane perturbation by general anesthetics) </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  16. 16. <ul><li>Receptor regulation </li></ul><ul><li>1.   Homeostasis </li></ul><ul><li>   2. Up and down regulation </li></ul><ul><li>   3. Desensitization </li></ul><ul><li>   4. Tolerance o r regulation </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics <ul><li>agonists desensitize receptors </li></ul><ul><li>homologous </li></ul><ul><li>(decreased receptor number) </li></ul><ul><li>heterologous </li></ul><ul><li>(decreased signal transduction </li></ul>
  17. 17.   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 Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  18. 18. <ul><li>  Ariens </li></ul><ul><li>response is proportional to the fraction of  </li></ul><ul><li>occupied receptors  AND  the   intrinsic activity  </li></ul><ul><li>Stephenson </li></ul><ul><li>response is a  FUNCTION  of occupancy </li></ul><ul><li>maximum response can be produced  </li></ul><ul><li>WITHOUT 100% occupation,  </li></ul><ul><li>i.e. tissues have  spare receptors </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  19. 19. Schematic representation of the relationship between threshold, receptor reserve, receptor occupancy, biological stimulus and biological response <ul><li>BIOLOGICAL STIMULUS </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics 0% TRETHOLD BIOLOGICAL RESPONSE 100% RECEPTOR RESERVE Threshold Effect Max Effect PERCENT RECEPTOR OCCUPANCY
  20. 20. <ul><li>Receptors are said to be spare spare </li></ul><ul><li>for a given pharmacological response </li></ul><ul><li>when the maximal response can be elicited </li></ul><ul><li>by an agonist at a concentration that does </li></ul><ul><li>not result in occupancy of the full complement </li></ul><ul><li>of available receptors </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  21. 21. <ul><li>Spare receptors </li></ul><ul><li>More receptors available than needed </li></ul><ul><li>to elicit maximum response </li></ul><ul><li>allow maximal response without total receptor occupancy – increase sensitivity of the system </li></ul><ul><li>Agonist has to bind only a portion of receptors for full effect </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  22. 22. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  23. 23. Some terminologies regarding drug receptor interaction <ul><li>Affinity </li></ul><ul><li>Efficacy </li></ul><ul><li>Potency </li></ul><ul><li>Ligand </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  24. 24. <ul><li>Affinity: measure of propensity of a drug to bind receptor; the attractiveness of drug and receptor </li></ul><ul><li>Efficacy: Potential maximum therapeutic response that a drug can produce. </li></ul><ul><li>Potency: A mount of drug needed to produce an </li></ul><ul><li>effect. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  25. 25. <ul><li>Ligand: </li></ul><ul><li>Molecules that binds to a receptor </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  26. 26. <ul><li>Classification of Ligands </li></ul><ul><li>a.   agonist </li></ul><ul><li>b.  partial agonist </li></ul><ul><li>c.  antagonist </li></ul><ul><li>pharmacological vs. physiological vs. chemical </li></ul><ul><li>       pharmacological antagonists </li></ul><ul><li>       -  competitive </li></ul><ul><li>            surmountable </li></ul><ul><li>          -  noncompetitive </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  27. 27. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics k 1 k 2 Drug Receptor Effect Drug-Receptor Complex Ligand-binding domain Effector domain Drug(Ligand)  Receptor interaction Langley (1878) Effect D+R DR k 1 k 2
  28. 28. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics <ul><ul><li>- Primary way for drug to produce an action </li></ul></ul><ul><li>non-specific </li></ul><ul><li>receptors </li></ul><ul><li>neurotransmitters </li></ul><ul><ul><li>hormones </li></ul></ul><ul><li>enzymes </li></ul><ul><li>transport systems </li></ul><ul><ul><li>ion channels </li></ul></ul><ul><ul><li>active transporters, e.g. uptake blockers </li></ul></ul>Drug  Receptor interaction Targets of drug action
  29. 29. III. MAJOR RECEPTOR FAMILIES <ul><li>Figure 2.2 </li></ul><ul><li>Transmembrane signaling mechanisms. A. Lignad binds to the extracellular domain of a ligand-gated channel. B. Ligand binds to a domain of the serpentine receptor, which is coupled to G protein. C. Ligand binds to the extracellular domain of a receptor that activates a kinase enzyme. D. Lipid-soluble ligand diffuses across the membrane to interact with its intracellular receptor. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  30. 30. III. MAJOR RECEPTOR FAMILIES <ul><li>G-protein coupled receptors triggers an increase (or, less often, a decrease) in the activity of adenylyl cyclase. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  31. 31. III. MAJOR RECEPTOR FAMILIES <ul><li>Mechanism of intracellular receptors (e.g. nuclear receptors). </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  32. 32. III. DESENSITIZATION OF RECEPTORS Chapter 2: Drug-Receptor Interactions and Pharmacodynamics <ul><ul><li>- Receptor structure change </li></ul></ul><ul><ul><li>- Receptor inactivation </li></ul></ul><ul><ul><li>(protein inhibitors, modifications) </li></ul></ul><ul><li>- Down regulation of receptor by </li></ul><ul><ul><li>endocytosis or degradation </li></ul></ul>
  33. 33. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics What is a receptor “ agonist ” ? <ul><li>Any drug that binds to a receptor and stimulates the functional activities </li></ul><ul><li>e.g.: adrenaline (epinephrine) </li></ul>Cell Effect Receptor Epinephrine
  34. 34. agonist <ul><li>Drugs that cause a response </li></ul><ul><li>Drugs that interact with and activate receptors; </li></ul><ul><li>They possess both affinity and efficacy </li></ul><ul><li>Types </li></ul><ul><li>Full agonists </li></ul><ul><li>An agonist with maximal efficacy (response) </li></ul><ul><li>has affinity plus intrinsic activity </li></ul><ul><li>Partial agonists </li></ul><ul><li>An agonist with less then maximal efficacy </li></ul><ul><li>has affinity and less intrinsic activity </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  35. 35. Agonists differing in potency and maximum efficacy Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  36. 36. PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics [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
  37. 37. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics What is a receptor “ antagonist ” ? <ul><li>Any drug which can influence a receptor and produce no response </li></ul><ul><li>e.g.: propranolol (a beta blocker) </li></ul>epinephrine propranolol Hey, you’re in my way! <ul><li>Competitive Antagonist : both the drug and its antagonist compete for the same site of the receptor </li></ul><ul><li>Non-competitive Antagonist : the drug and its antagonist do not compete for the same site </li></ul>
  38. 38. <ul><li>NOT change the receptor </li></ul><ul><li>Interact with the receptor but do </li></ul><ul><li>Have affinity but NO efficacy </li></ul><ul><li>Block the action of other drugs </li></ul><ul><li>Effect only observed in presence of </li></ul><ul><li>agonist </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  39. 39. Types of Antagonists <ul><li>Competitive </li></ul><ul><li>(Surmountable) </li></ul><ul><li>decrease apparent </li></ul><ul><li>Potency </li></ul><ul><li>Noncompetitive </li></ul><ul><li>decrease </li></ul><ul><li>apparent maximum </li></ul><ul><li>efficacy </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  40. 40. Competitive Antagonist <ul><li>competes with ________for receptor </li></ul><ul><li>surmountable with increasing agonist </li></ul><ul><li>concentration </li></ul><ul><li>displaces agonist dose response curve to </li></ul><ul><li>the ___________(dextral shift) </li></ul><ul><li>reduces the apparent affinity of the </li></ul><ul><li>__________. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  41. 41. Noncompetitive Antagonist <ul><li>drug binds to receptor and stays bound </li></ul><ul><li>irreversible – does not let go of receptor </li></ul><ul><li>produces slight dextral shift in the agonist DR curve in the low concentration range </li></ul><ul><li>but, as more and more receptors are bound (and essentially destroyed), </li></ul><ul><li>the agonist drug becomes incapable of eliciting a maximal effect </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  42. 42. AGONIST VS ANTAGONIST Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  43. 43. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  44. 44. What happen when you increase agonist concentration even higher Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  45. 45. How do non competitive antagonist affect receptor function Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  46. 46. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  47. 47. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics Monitoring drug responses <ul><li>Level </li></ul><ul><ul><li>Molecular (e.g., enzyme inhibition, receptor binding assay) </li></ul></ul><ul><ul><li>Cellular ( in vitro tissue culture, blood cells) </li></ul></ul><ul><ul><li>Tissue or organ ( in vitro or in vivo ) </li></ul></ul><ul><ul><li>Animal disease model </li></ul></ul><ul><li>Endpoint used to measure the effect may be different at each level </li></ul><ul><li>Overall effect = Sum of multiple drug effects and physiological responses to drug effects </li></ul>
  48. 48. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics Endpoints to monitor drug effects Farnesyltransferase inhibitors for cancer LEVEL ENDPOINT Molecular Farnesyltransferase inhibition Cellular Proliferation rate, Apoptosis Tumor Response (Change in tumor size) Organism Survival, Quality of life
  49. 49. IV. DOSE-RESPONSE RELATIONSHIPS <ul><li>Figure 2.6 </li></ul><ul><li>The effect of dose on the magnitude of pharmacologic response. </li></ul><ul><li>Panel A is a linear graph. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics *EC 50 =drug dose that shows fifty percent of maximal response. *Effect = Effect Max • [Drug] K D + [Drug]
  50. 50. IV. DOSE-RESPONSE RELATIONSHIPS <ul><li>Figure 2.6 </li></ul><ul><li>The effect of dose on the magnitude of pharmacologic response. </li></ul><ul><li>Panel B is a </li></ul><ul><li>semi-logarithmic plot of the same data. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  51. 51. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics Determinants of Drug Activity 1. Potency: the amount of drug to produce an effect of a given magnitude 2. Efficacy: the maximal response (effect) produced by drug Biologic effect Log dose potency efficacy 0 50 100 Biologic effect(%) Log dose (mg) 1 10 100 Morphine Codeine Aspirin
  52. 52. IV. DOSE-RESPONSE RELATIONSHIPS <ul><li>Figure 2.7 </li></ul><ul><li>Typical dose-response curve for drugs showing differences in potency and efficacy. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  53. 53. IV. DOSE-RESPONSE RELATIONSHIPS <ul><li>Figure 2.9 </li></ul><ul><li>Effects of drug antagonists. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  54. 54. IV. DOSE-RESPONSE RELATIONSHIPS <ul><li>Figure 2.10 </li></ul><ul><li>Effects of partial agonists. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics RESPONSE Full Agonist Partial Agonist Antagonist Log([A]/K A ) -1 0 1 2
  55. 55. V. QUANTAL DOSE-RESPONSE RELATIONSHIPS Chapter 2: Drug-Receptor Interactions and Pharmacodynamics Therapeutic Index <ul><li>Therapeutic index = </li></ul><ul><li>toxic dose(LD 50 )/effective dose(EC 50 ) </li></ul><ul><li>This is a measure of a drug ’ s safety </li></ul><ul><ul><li>A large number = a wide margin of safety </li></ul></ul><ul><ul><li>A small number = a small margin of safety </li></ul></ul>
  56. 56. V. QUANTAL DOSE-RESPONSE RELATIONSHIPS <ul><li>Figure 2.11 </li></ul><ul><li>Effects of partial agonists. </li></ul><ul><li>(Continued overleaf) </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  57. 57. V. QUANTAL DOSE-RESPONSE RELATIONSHIPS <ul><li>Figure 2.11 </li></ul><ul><li>Effects of partial agonists. </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics Walter Straub (1874-1944) “ There is only a quantitative difference between a drug and a poison”
  58. 58. <ul><li>Summary </li></ul><ul><li> (T or F) </li></ul><ul><li>Pharmacodynamics is the study of absorption, distribution, </li></ul><ul><li>metabolism and elimination of drug. </li></ul><ul><li>Some drugs can act without binding to a receptor </li></ul><ul><li>spare receptors allow maximum response without </li></ul><ul><li>full receptor occupancy </li></ul><ul><li>Efficacy is the amount of drug needed to produce an </li></ul><ul><li>effect. </li></ul><ul><li>Affinity is the attractiveness between 2 drug molecules. </li></ul><ul><li>Agonist are the drugs that block the response. </li></ul><ul><li>Partial agonist has affinity and maximum efficacy. </li></ul><ul><li>Antagonist has efficacy but no affinity. </li></ul><ul><li>Competitive antagonist decreases potency </li></ul><ul><li>Non competitive antagonist decreases efficacy </li></ul>Chapter 2: Drug-Receptor Interactions and Pharmacodynamics
  59. 59. Chapter 2: Drug-Receptor Interactions and Pharmacodynamics Quiz on Monday (Chap 1 & 2)

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