2. PHARMACODYNAMICS hangoma.pptx pharmacology

Pharmacology

1. INTRODUCTION TO PHARMACODYNAMICS Dr. Jimmy M. Hangoma BPharm , MClin.Pharm -UNZA Clinical Pharmacist-UTH University of Zambia School of Health Sciences Faculty of Pharmacy

2. Learning Objectives At the end of this session, YOU should be able to: Understand the scientific basis of drug action; Describe the result of interactions of body systems and drug at its site of action; Understand drug-receptor dynamics; Describe the action of ligands on different receptor types Apply fundamental concepts of pharmacodynamics to therapeutics 11/19/2017 2

3. Pharmacodynamics Deals with the study of the biochemical and physiological effects of drugs and their mechanisms of action 11/19/2017 3

4. Pharmacodynamics ‘what the drug does to the body’; i.e. Interaction of drugs with cellular proteins, such as receptors or enzymes, to control changes in physiological function of particular organs Drug-Receptor Interactions Physicochemical & Steric Binding & Activation/Inactivation Signal Transduction Signalling Pathway & Mechanism of action Dose-Response Effect 11/19/2017 4

5. Mechanism of action Mechanism of action refers to receptor interactions that alter the function of the pertinent cellular component thereby initiating biochemical and physiological changes that characterise the pharmacological response to the drug 11/19/2017 5

6. Pharmacodynamics Provides scientific basis for rational therapeutic use of a drug Receptor theory by Paul Ehrlich, 1909 11/19/2017 6

7. Drug Targets: Receptors 11/19/2017 7

8. Receptors The sensing elements in the system of chemical communications that coordinate physiological functions of all diverse cells in the body; Bind mediator substances (ligands) and transduce this binding into an effect (i.e. signal transduction) ; 11/19/2017 8 R eceptor Ligand

9. Classification of Receptors Physiological / Pharmacological Mediators (e.g. Insulin, NE, ACh , estrogen, etc) Biochemical and Biophysical 2 nd messenger systems (e.g. cAMP , PKA, DAG, IP 3 , etc) Molecular or Structural Subunit composition (e.g. 5-HT 1A ) Anatomical Tissue (e.g. muscle & ganglionic nAChRs ) Cellular (i.e. membrane-bound & intracellular) 11/19/2017 9

10. Drug-Receptor Interactions Drug-receptor interactions serve as signals to trigger a cascade of events . This cascade or signaling pathway, is a collection of many cellular responses which serve to amplify the signal and produce a final effect. Effectors are the molecules that translate the drug-receptor interaction into changes in cellular activity.    +          EFFECT DRUG DRUG + RECEPTOR DRUG + RECEPTOR EFFECTOR EFFECTOR INTERACTION COMPLEX SYSTEM STIMULUS BINDING ACTIVATION TRANSDUCTION AMPLIFICATION RESPONSE SIGNALLING PATHWAY 11/19/2017 10

11. Examples of target receptors for drugs: receptors for neurotransmitters, hormones, autacoids, growth factors, transcription factors, and other endogenous chemicals; 11/19/2017 11 morphonix.com

12. Examples of target receptors for drugs: enzymes of crucial metabolic or regulatory pathways (e.g., dihydrofolate reductase , acetylcholinesterase , phosphodiesterases , etc); transport proteins (e.g. ATPases , etc); ion channels ; glycoproteins ; structural proteins (e.g. tubulin , etc) 11/19/2017 12 morphonix.com

13. Receptor Types G-Protein Coupled Receptors (GPCR) Most prevalent receptor type (~80%); Membrane-bound; Consist 7 α- helical transmembrane -spanning loop of amino acid chains with extramembranal sugar residues at different N- glycosylation sites; Binding of mediator molecule induces conformational change of receptor protein; This enables interaction with a Guanyl nucleotide-binding protein (G-protein) in the inner plasmalemma ; G-proteins consist of 3 subunits designated α, β, and γ subunit . 11/19/2017 13 Luellmann, 2010

14. Ligand -gated ion channels Receptor complex consists amino acid loops of transmembrane subunits; Typical examples: Nicotinic Ach receptors, GABA A receptors, NMDA receptors, etc; Receptor activation by ligand brings about conformational change that modifies the gating of ion channel; In Figure: Binding of 2 Ach molecules to 2 α -subunits of nicotinic receptor causes opening of the ion channel allowing influx of Na+ and efflux of K+ ions  Depolarization  AP firing 11/19/2017 14 Luellmann, 2010

15. Ligand -regulated enzyme receptors They are catalytic receptors; Examples: Growth hormone receptor; Insulin receptor protein, etc; Ligand binding ( e.g. Insulin) to extracellular site activates tyrosine kinase (a protein phosphorylating enzyme)  Protein phosphorylation  moderation of cell function ( e.g. glycogenesis ) 11/19/2017 15 Luellmann, 2010

16. Protein synthesis regulating receptors Nucleus and Cytosolic receptors; Examples: Steroid hormone receptors; Thyroid hormone receptors, etc; Hormone-receptor complex initiates/enhances or acts as DNA transcription regulating factor; Hormone-receptor complex interact with DNA in dimeric (pair) form; Cytosolic receptors e.g. Glucocorticoid , mineralocorticoid , androgen receptors, etc; Nucleus receptors e.g. Estrogen , Thyroid hormone receptors, etc 11/19/2017 16 Luellmann, 2010

17. Receptor Signaling Pathways Adenyl Cyclase (AC) Guanyl Cyclase (GC) Phospholipase-C (PLC) Phospholipase-A 2 (PLA 2 ) Nitric Oxide Synthase (NOS) Ions cAMP cGMP DAG and IP 3 Arachidonic acid Nitric Oxide (NO) Na + , Ca 2+ , K + , Cl - EFFECTORS SECOND MESSENGER 11/19/2017 17

18. Receptor Signaling Pathways R R R R 11/19/2017 18

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20. Receptor Agonist vs. Antagonists Agonist A drug that binds with affinity to physiological receptors and activates them to mimic the regulatory effects of the endogenous signalling compound Antagonist A drug that binds to physiological receptors but does not activate the receptor; its binding to the receptor inhibits (blocks) the binding of agonist or endogenous ligand 11/19/2017 20

21. Classes of Agonists Agonist Class Action Full Agonist Activates receptor with maximal efficacy Partial Agonist Activates receptor but not with maximal efficacy Inverse Agonist Inactivates constitutively active receptor 11/19/2017 21 Classes of Antagonists Antagonist Class Action Effects on Agonist Potency Effects on Agonist Efficacy Competitive Antagonist Binds reversibly to active site of receptor, competes with agonist binding to this site Yes No Non-competitive active site Antagonist Binds irreversibly to active site of receptor, prevents agonist binding to this site No Yes Non-competitive allosteric Antagonist Binds reversibly or irreversibly to site other than active site of receptor, prevents conformational change required for receptor activation No Yes Non-competitive physiologic Antagonist Act via different receptors that affect same variable but opposite effects No No

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23. Receptor Agonist Signaling Pathways 11/19/2017 23

24. Drug-Receptor Interactions Theoretical assumptions of drug-receptor interactions Law of mass action : Drug-Receptor interaction follows simple mass-action relationships, (i.e. one drug molecule occupies each receptor and binding is reversible – theory has exceptions); Receptor occupancy: For a given drug, magnitude of the response is proportional to fraction of total receptor sites occupied by drug molecules; Threshold Agonist-receptor binding signals cellular event which leads to a biological response; Graded Response: response to a drug is graded or dose-dependent. 11/19/2017 24

25. Law of Mass Action When a drug (D) combines with a receptor (R), it does so at a rate (k) which is dependent on the concentration of the drug and the concentration of the receptor: D = drug R = receptor DR = drug-receptor complex k 1 = rate for association k 2 = rate for dissociation K D = Dissociation Constant K A = Affinity Constant   k 1 [D] + [R]  [DR] k 2 k 2 = K D = [D][R] k 1 [DR] 1 = K A = k 1 = [DR] K D k 2 [D] [R] 11/19/2017 25

26. Quantifying Effects of Drugs on Receptors 11/19/2017 26

27. Classification of Drug Effects Action on site i.e. Direct or Indirect Action e.g. NE constricts BV  BP  HR Change in excitability Excitation = function; Inhibition = function (e.g. Amphetamines) (e.g. Barbiturates) Selective Effects e.g. Benzodiazepine effects on CNS, Cardiac glycosides stimulate myocardium Therapeutic effect: affecting functions & pathophysiologic processes i.e. Etiological or Symptomatic treatment 11/19/2017 27

28. Classification of Drug Effects Adverse Effect noxious, unintended & undesirable response, often unrelated to primary mechanism of action Side effect undesirable effect, produced by therapeutic dose of drug, often non-deleterious, may be related or unrelated to mechanism of action Toxic effect noxious effect produced by excessively large dosage of the drug (acute or chronic exposure), often deleterious without treatment 11/19/2017 28

29. Causes of drug adverse effects: Overdosage 11/19/2017 29 Color Atlas of Pharmacology, Lullmann , 2005

30. Causes of drug adverse effects: Increased selectivity e.g. due to hyperactivity of target body function, etc 11/19/2017 30 Color Atlas of Pharmacology, Lullmann , 2005

31. Causes of drug adverse effects: Lack of selectivity e.g. drug does not specifically act on the targeted tissue or organ 11/19/2017 31 Color Atlas of Pharmacology, Lullmann , 2005

32. Dose-Response Relationships 11/19/2017 32

33. Assumption: Response to a drug is proportional to the concentration of receptors that are occupied (bound) . 11/19/2017 33

34. Dose-Response Relationships Graded dose-response curve Describes response to a drug in proportionality to dose (drug concentration) Quantal dose-response curve Describes the concentrations of a drug that produce a given effect in a population Useful for predicting effects of drug when administered to a population 11/19/2017 34

35. 1. Graded Dose-Response Curve 11/19/2017 35 E max EC 50 Dose (log scale) Dose (linear scale) E max EC 50

36. Drug Potency vs. Drug Efficacy Potency The concentration at which the drug elicits 50% of its maximal response (EC 50 ) Efficacy The maximal response produced by the drug ( E max ) - also called Intrinsic Activity 11/19/2017 36

37. Potent drugs are those which elicit a response by binding to a critical number of a particular receptor type at low concentrations (high affinity) compared with other drugs acting on the same system and having lower affinity and thus requiring more drug to bind to the same number of receptors. 11/19/2017 37

38. Efficacy assumption: ‘ the state at which receptor-mediated signalling is maximal (100%)’ Therefore, if this assumption is true for drug efficacy, how is it that some drugs are capable of eliciting a maximal response even when fewer than 100% of receptors are occupied? 11/19/2017 38

39. 2. Quantal Dose-Response Curves 11/19/2017 39