Pharmacodynamics

1. Pharmacodynamics Collected and Prepared By S.Bohlooli, PhD

2. LOCUS OF ACTION “RECEPTORS” TISSUE RESERVOIRS Bound Free Free Bound ABSORPTION EXCRETION Free Drug SYSTEMIC CIRCULATION Bound Drug BIOTRANSFORMATION

3. Molecular pharmacology : • Molecular pharmacology is concerned with studies of basic mechanisms of drug actions on biological systems. • The idea that drugs act upon specific sites (receptive substance) began with John New Port Langley (1852-1926) of Cambridge. • However the word ‘receptor’ is given by Paul Ehrlich (1854- 19 15). • The receptor concept which forms a key note in the development of molecular pharmacology became firmly established by the quantitative work of Alfred Joseph Clark (1885-1941), a professor of pharmacology at Kings College London.

4. Receptor (key element) • In addition to its usefulness for explaining biology, the receptor concept has important practical consequence for • The development of drugs • Arriving at therapeutic decisions in clinical practice.

5. Receptors: • Largely determine the quantitative relations between dose or concentration of drug and pharmacologic effects • Are responsible for selectivity of drug action • Mediate the actions of pharmacologic antagonists

6. Macromolecular nature of drug receptors • Regulatory proteins • Enzymes • Transport proteins • Structural proteins

7. Quantitative aspects of drug-receptor interaction

8. Drug-Receptor Interactions Obey the Law Of Mass Action At equilibrium By law of mass action: Therefore:

9. Total number of receptors: Rt = [R] + [DR] [R] = Rt – [DR] After rearrangement:

10. When [D] = KD [DR] RT = 0.5 1.00 0.75 [DR]/Rt 0.50 0.25 0.00 0 5 10 15 20 [D] KD

11. Receptor Binding % Bound KD Concentration of Ligand The dose-response relationship (from C.D. Klaassen, Casarett and Doull’s Toxicology, 5th ed., New York: McGraw-Hill, 1996).

12. Relation between drug dose & clinical response

13. Drugs are described based on the magnitude of two properties: • Affinity for the receptor. Affinity is related to potency. • Efficacy once bound to the receptor. Efficacy refers to the maximal effect the drug can elicit.

14. Agonists and Antagonists • AGONIST - Has affinity for receptor and efficacy. • ANTAGONIST - Has affinity but no efficacy. • Competitive Antagonist • Noncompetitive Antagonist • Partial Agonist or Partial Antagonist – • Has affinity but lower efficacy than full agonist.

15. Receptor ligand types

16. Full Agonists (i.e., equal efficacies) that Differ In Potency: A B C % Max Response Compare the EC50s Drug Concentration (log scale)

17. A B C % Max response Log Drug Concentration Agonists That Differ in Efficacy

19. Full and partial agonist occupancy and response relationship 100 Response (full agonist) Occupancy (both) Response(%) 50 Response (partial Agonist) 0.0 1.0 0.01 0.1 10.0 Concentration (umol/l)

20. Inverse agonist Inverse agonist can exist where an appreciable level of activation may exist even when no ligand is present For example: receptors for benzodiazepines, cannabinoids and dopamine Under such condition it may be possible for a ligand to reduce the level of activation. such drugs are known as inverse agonist

21. Competitive Antagonism Shifts The Agonist D-R Curve (Potency) AG + ANT AG alone % Max Response EC50 EC50 Drug Concentration (log scale)

22. AG alone AG + NC ANT AG + higher dose NC ANT % Max response Log Drug Concentration Noncompetitive Antagonism Decreases Agonist Efficacy

23. Spare receptor 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 not result in occupancy of the full complement of available receptors Emax Agonist alone Agonist with noncompetitive antagonist in presence of spare receptor Agonist with noncompetitive antagonist in absence of spare receptor Respones(%) Log Concentration

24. Agonist like to bind to receptor in R’ state and shifts the equilibrium toward more LR’ and makes effect Antagonist like to bind to receptor in R and R” state without any preference and makes no shifts in net equilibrium R R’ L L Effect No effect LR’ LR Inverse agonist has more affinity to receptor in R state and shifts the equilibrium toward more LR and make negative response than resting state. Partial agonist has a little more affinity for receptor in R’ states than R state and makes partial effect Possible mechanism for the partial agonist phenomenon.

25. Desensitization and Tachyphylaxis • Changes in receptor • Loss of receptor • Exhaustion of mediators • Increased metabolic degradation • Physiological adaptation • Active extrusion of drug from cells • Desensitization • Tolerance • Refractoriness • Drug resistance How?

26. Drug Antagonism Propranolol & norepinephrine Pharmacologic Dimercaprol & heavy metals Chemical Pharmacokinetic Phenobarbital & warfarine Physiologic Epinephrine & histamine

27. Signaling mechanism &drug action

28. Type of receptors • Ligand gated ion channels • G protein coupled receptors • Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases • Cytokine Receptors • Intracellular receptors

29. Ligand gated ion channel (iontropic receptors) • -amino butyric acid (GABA) • Glycine • Aspartate • Glutamate • Acethylcholine • Serotonin

30. Ligand gated ion channel (iontropic receptors) ions R Hyper polarization or depolarization Cellular effects

31. G protein coupled receptors • Adernocorticotropic hormone • Acetylcholine • Angiotensin • Catecholamines • Chrionic gonadotropin • Follicle stimulating hormone • Glucagon • Histamine • Luteinizing Hormone • Seretonin • Vasopressin

32. G protein coupled receptors Ions R E G G + - + - Change in excitability Second messengers Protein phosphorylation Ca2+ release other Cell effects

33. Kinase linked receptors • Ligand -regulated transmembrane enzyme including receptor tyrosine kinases • Insulin • Epidermal growth factor (EGF) • Platelet-derived growth factor (PDGF) • Arterial natriuretic factor (ANF) • Transforming growth factor (TGF- ) • Cytokine receptors • Growth hormone • Erythropoietin • Interferones

34. Kinase linked receptors R/E Protein phosphorylation Gene transcription Protein synthesis Cellular effects

37. Nuclear receptors Nucleus R Gene transcription Protein synthesis Cellular effects

39. Well Established Second Messengers • Cyclic Adenosine Monophosphate (cAMP) • Calcium and Phosphoinositides • Cyclic Guanosine Monophosphate (cGMP)

42.  Good Luck