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Pharmacodynamics (Mechanisn of drug action)


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A power point presentation on Pharmacodynamics (what drug does to the body) suitable for undergraduate medical students beginning to study Pharmacology

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Pharmacodynamics (Mechanisn of drug action)

  1. 1. Pharmacodynamics Dr. D. K. Brahma Department of Pharmacology NEIGRIHMS, Shillong
  2. 2. What is Pharmacodynamics? What drugs do to the body when they enter? Study of action-effect of drugs and dose-effect relationship Defn.: It is the study of biochemical and physiological effects of drug and their mechanism of action at organ level as well as cellular level Also Modification of action of one drug by another drug
  3. 3. Drug Action by Physical/Chemical properties • Color – Tincture Card co. • Physical mass – Ispaghula • Physical form – Dimethicone (antifoaming) • Smell - Volatile Oils • Taste - Bitters • Osmotic action – Mannitol, Magsulf • Adsorption – Activated Charcoal • Soothing-demulcent – Soothing agents like calamine • Oxidizing property – Pot. Permanganate • Chelation – EDTA, dimercaprol • Radioactivity - Iodine and others • Radio-opacity – Barium sulfate • Chemical properties – Chelating agents (EDTA, dimercaprol) • Scavenging effect – Mesna (with cyclophosphamide)
  4. 4. PRINCIPLES OF DRUG ACTION - Do NOT impart new functions on any system, organ or cell - Only alter the PACE of ongoing activity • STIMULATION • DEPRESSION • IRRITATION • REPLACEMENT • CYTOTOXIC ACTION
  7. 7. 4. Receptors • Drugs usually do not bind directly with enzymes, channels, transporters or structural proteins, but act through specific macromolecules – RECEPTORS • Definition: It is defined as a macromolecule or binding site located on cell surface or inside the effector cell that serves to recognize the signal molecule/drug and initiate the response to it, but itself has no other function, e.g. Muscarinic (M type) and Nicotinic (N type) receptors of Cholinergic system
  8. 8. Some Common Terms • Agonist: An agent which activates a receptor to produce an effect similar to a that of the physiological signal molecule, e.g. Muscarine and Nicotine • Antagonist: an agent which prevents the action of an agonist on a receptor or the subsequent response, but does not have an effect of its own, e.g. atropine and muscarine • Inverse agonist: an agent which activates receptors to produce an effect in the opposite direction to that of the agonist, e.g. DMCM in BDZ receptors • Partial agonist: An agent which activates a receptor to produce submaximal effect but antagonizes the action of a full agonist, e.g. opioids • Ligand: (Latin: ligare – to bind) - any molecule which attaches selectively to particular receptors or sites (refers only binding or affinity but no functional change)
  9. 9. Evidences of Drug action via receptors – Historical 1. Drugs exhibit structural specificity of action: example - Catecholamines 2. Competitive Antagonism: Between agonists and antagonists (Atropine - M type receptors) – by Langley 3. Acetylcholine - 1/6000th of cardiac cell surface – maximal effect – by Clark
  10. 10. Drug – Receptor occupation theory – Clark`s equation (1937) • Drugs are small molecular ligands (pace of cellular function can be altered) • Drug (D) and receptor (R) interaction governed by “law of mass action” • Effect (E) Is the direct function of the Drug-Receptor complex K1 D + R DR E (direct function of DR complex) K2 • But DR complex may not be sufficient to elicit E (response) • D must be able to bring a conformational change in R to get E • Affinity and Intrinsic activity (IA)
  11. 11. Receptor occupation theory – contd. • Affinity: Ability to bind with a Receptor • Intrinsic activity (IA): Capacity to induce functional change in the receptor • Competitive antagonists have Affinity but no IA • Therefore, a theoretical quantity (S) – denoting strength was interposed D + R DR S E K1 K2
  12. 12. Definitions redefined If explained in terms of “affinity and IA”: • Agonist: Affinity + IA (1) • Antagonist: Affinity + IA (0) • Partial agonist: Affinity + IA (0-1) • Inverse agonist: Affinity + IA (0 to -1)
  13. 13. Two-state receptor model
  14. 14. Drug-receptor binding and agonism • Drug- Receptor: D Ri DRa D Ri DRa D Ri DRa D Full agonist DRi DRa Partial agonist Neutral Inverse agonist
  15. 15. Nature of Receptors • Not hypothesis anymore – proteins and nucleic acids • Isolated, purified, cloned and amino acid sequencing done • Cell surface receptors remain floated in cell membrane lipids • Non-polar hydrophobic portion of the amino acid remain buried in membrane while polar hydrophilic remain on cell surface • Major classes of receptors have same structural motif – pentameric etc. • But, majority of individual receptor molecules are made up of non-identical subunits – ligand binding brings about changes in structure or alignment of subutits • Binding of polar drugs in ligand binding domain induces conformational changes (alter distribution of charges and transmitted to coupling domain to be transmitted to effector domain • Many drugs act on Physiological receptors – also true drug receptors
  16. 16. Receptor Subtypes • Evaluation of receptors and subtypes – lead to discovery of various newer target molecules • Example Acetylcholine - Muscarinic and Nicotinic – M1, M2, M3 etc. – NM and NN – α (alpha) and β (beta) …. • Criteria of Classification: – Pharmacological criteria – potencies of selective agonist and antagonists – Muscarinic, nicotinic, alpha and beta adrenergic etc. – Tissue distribution – beta 1 and beta 2 – Ligand binding – Transducer pathway and Molecular cloning
  17. 17. Action – effects ! • Receptors : Two essential functions: • Recognition of specific ligand molecule • Transduction of signal into response • Two Domains: • Ligand binding domain (coupling proteins) • Effectors Domain – undergoes functional conformational change • “Action”: Initial combination of the drug with its receptors resulting in a conformational change (agonist) in the later, or prevention of conformational change (antagonist) • “Effect”: It is the ultimate change in biological function brought about as a consequence of drug action, through a series of intermediate steps (transducers)
  18. 18. The Transducer mechanism • Most transmembrane signaling is accomplished by a small number of different molecular mechanisms (transducer mechanisms) • Large number of receptors share these handful of transducer mechanisms to generate an integrated and amplified response • Mainly 4 (four) major categories: 1. G-protein coupled receptors (GPCR) 2. Receptors with intrinsic ion channel 3. Enzyme linked receptors 4. Transcription factors (receptors for gene expression)
  19. 19. G-protein Coupled Receptors (GPCR) • Large family of cell membrane receptors linked to the effector enzymes or channel or carrier proteins through one or more GTP activated proteins (G-proteins) • All receptors has common pattern of structural organization • The molecule has 7 α-helical membrane spanning hydrophobic amino acid segments – 3 extra and 3 intracellular loops • Agonist binding - on extracellular face and cytosolic segment binds coupling G-protein Transducer 1 ….
  20. 20. GPCR – contd. • G-proteins float on the membrane with exposed domain in cytosol • Heteromeric in composition with alpha, beta and gamma subunits • Inactive state – GDP is bound to exposed domain • Activation by receptor GTP displaces GDP • The α subunit carrying GTP dissociates from the other 2 – activates or inhibits “effectors” • βɣ subunits are also important
  21. 21. GPCR - 3 Major Pathways 1. Adenylyl cyclase:cAMP pathway 2. Phospholipase C: IP3-DAG pathway 3. Channel regulation
  22. 22. 1. Adenylyl cyclase: cAMP pathway PKA Phospholambin Increased Interaction with Faster relaxation Ca++ Troponin Cardiac contractility Other Functional proteins
  23. 23. Adenylyl cyclase: cAMP pathway • Main Results: – Increased contractility of heart/impulse generation – Relaxation of smooth muscles – Lipolysis – Glycogenolysis – Inhibition of Secretions – Modulation of junctional transmission – Hormone synthesis – Additionally, opens specific type of Ca++ channel – Cyclic nucleotide gated channel (CNG) - - -heart, brain and kidney – Responses are opposite in case of AC inhibition
  24. 24. 2. Phospholipase C:IP3-DAG pathway PKc
  25. 25. IP3-DAG pathway • Main Results: – Mediates /modulates contraction – Secretion/transmitter release – Neuronal excitability – Intracellular movements – Eicosanoid synthesis – Cell Proliferation – Responses are opposite in case of PLc inhibition
  26. 26. 3. Channel regulation • Activated G-proteins can open or close ion channels – Ca++, Na+ or K+ etc. • These effects may be without intervention of any of above mentioned 2nd messengers – cAMP or IP/DAG • Bring about depolarization, hyperpolrization or Ca ++ changes etc. • Gs – Ca++ channels in myocardium and skeletal muscles • Go and Gi – open K+ channel in heart and muscle and close Ca+ in neurones
  27. 27. G-proteins and Effectors • Large number can be distinguished by their α- subunits G protein Effectors pathway Substrates Gs Adenylyl cyclase - PKA Beta-receptors, H2, D1 Gi Adenylyl cyclase - PKA Muscarinic M2 D2, alpha-2 Gq Phospholipase C - IP3 Alpha-1, H1, M1, M3 Go Ca++ channel - open or close K+ channel in heart, sm
  28. 28. Intrinsic Ion Channel Receptors Transducer 2 …. • Most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels • The natural ligands include acetylcholine, serotonin, aminobutyric acid (GABA), and the excitatory amino acids (eg, glycine, aspartate, and glutamate)
  29. 29. Animation of GPCR - 1 Heart1.exe
  30. 30. Animation of GPCR - 2 Heart2.exe
  31. 31. Receptors with Intrinsic Ion Channel
  32. 32. Enzyme Linked Receptors • 2 (two) types of receptors: 1. Intrinsic enzyme linked receptors • Protein kinase or guanyl cyclase domain 1. JAK-STAT-kinase binding receptor Transducer 3 ….
  33. 33. A. Enzyme linked receptors • Extracellular hormone-binding domain and a cytoplasmic enzyme domain (mainly protein tyrosine kinase or serine or threonine kinase) • Upon binding the receptor converts from its inactive monomeric state to an active dimeric state • t-Pr-K gets activated – tyrosine residues phosphorylates on each other • Also phosphorylates other SH2-Pr domain substrate proteins • Ultimately downstream signaling function • Examples – Insulin, EGF ------- Trastuzumab, antagonist of a such type receptor – used in breast cancer
  34. 34. B. JAK-STAT-kinase Binding Receptor • Mechanism closely resembles that of receptor tyrosine kinases • Only difference - protein tyrosine kinase activity is not intrinsic to the receptor molecule • Uses Janus-kinase (JAK) family • Also uses STAT (signal transducers and activators of transcription) • Examples – cytokines, growth hormones, interferones etc.
  35. 35. JAK-STAT-kinase Receptors
  36. 36. Transducer 4 …. Receptors regulating gene expression • Intracellular (cytoplasmic or nuclear) receptors • Lipid soluble biological signals cross the plasma membrane and act on intracellular receptors • Receptors for corticosteroids, mineralocorticoids, thyroid hormones, sex hormones and Vit. D etc. stimulate the transcription of genes in the nucleus by binding with specific DNA sequence – called - “Responsive elements” – to synthesize new proteins • Hormones produce their effects after a characteristic lag period of 30 minutes to several hours – gene active hormonal drugs take time to be active (Bronchial asthma) • Beneficial or toxic effects persists even after withdrawal
  37. 37. Receptors of gene expression - Image
  38. 38. Receptor Regulation • Up regulation of receptors: – In topically active systems, prolonged deprivation of agonist (by denervation or antagonist) results in supersensitivity of the receptor as well as to effector system to the agonist. Sudden discontinuation of Propranolol, Clonidine etc. – 3 mechanisms - Unmasking of receptors or proliferation or accentuation of signal amplification
  39. 39. Receptor Regulation – contd. • Continued exposure to an agonist or intense receptor stimulation causes desensitization or refractoriness: receptor become less sensitive to the agonist • Examples – beta adrenergic agonist and levodopa • Causes: 1. Masking or internalization of the receptors 2. Decreased synthesis or increased destruction of the receptors (down regulation) - Tyrosine kinase receptors
  40. 40. Mechanism of Masking or internalization ßARK (beta-adrenergic receptor kinase) Beta-arrestin
  41. 41. Desensitization • Sometimes response to all agonists which act through different receptors but produce the same overt effect is decreased by exposure to anyone of these agonists – heterologous desensitization • Homologous – when limited to the agonist which is repeatedly activated – In GPCRs (PKA or PKC) Kinases may also phosphorylate the GPCRs Homologous R+ Transducer Ach Hist Heterologous
  42. 42. Functions of Receptors - Summary 1. To Regulate signals from outside the cell to inside the effector cell – signals not permeable to cell membrane 2. To amplify the signal 3. To integrate various intracellular and extracellular signals 4. To adapt to short term and long term changes and maintain homeostasis.
  43. 43. Non-receptor mediated drug action – clinically relevant examples • Physical and chemical means - Antacids, chelating agents and cholestyramine etc. • Alkylating agents: binding with nucleic acid and render cytotoxic activity – Mechlorethamine, cyclophosphamide etc. • Antimetabolites: purine and pyrimidine analogues – 6 MP and 5 FU – antineoplastic and immunosuppressant activity
  44. 44. Dose-Response Relationship • Drug administered – 2 components of dose- response – Dose-plasma concentration – Plasma concentration (dose)-response relationship • E is expressed as Emax X [D] Kd + [D] E max E is observed effect of drug dose [D], Emax = maximum response, KD = dissociation constant of drug receptor complex at which half maximal response is produced
  45. 45. Dose-Response Curve dose Log dose % response % response 100% - 50% - 100% - 50% - E = Emax X [D] Kd + [D]
  46. 46. Dose-Response Curve • Advantages: – Stimuli can be graded by Fractional change in stimulus intensity – A wide range of drug doses can easily be displayed on a graph – Potency and efficacy can be compared – Comparison of study of agonists and antagonists become easier
  47. 47. How we get DRC in vitro Practically?? • Example: Frog rectus muscle and Acetylcholine response – in millimeters – Can compare with a drug being studied for having skeletal muscle contracting property
  48. 48. Potency and efficacy • Potency: It is the amount of drug required to produce a certain response • Efficacy: Maximal response that can be elicited by the drug Response 1 2 3 4 Drug in log conc.
  49. 49. Potency and efficacy - Examples • Aspirin is less potent as well as less efficacious than Morphine • Pethidine is less potent analgesic than Morphine but eually efficacious • Diazepam is more potent but less efficacious than phenobarbitone • Furosemide is less potent but more efficacious than metozolone • Potency and efficacy are indicators only in different clinical settings e.g. Diazepam Vs phenobarbitone (overdose) and furosemide vs thaizide (renal failure)
  50. 50. Slope of DRC • Slope of DRC is also important • Steep slope – moderate increase in dose markedly increase the response (individualization) • Flat DRC – little increase in response occurs in wide range of doses (standard dose can be given to most ptients) • Example: Hydralazine and Hydrochlorothiazide DRC in Hypertension Hydralazine Thiazide Fall in BP
  51. 51. Selectivity • Drugs produce different effects – not single • DRC of different effects may be different • Example – Isoprenaline – Bronchodilatation and cardiac stimulation – same DRC • Salbutamol – different (selective bronchodilatation)
  52. 52. Therapeutic index (TI) • In experimental animals • Therapeutic Index = Median Lethal Dose (LD50) Median Effective dose (ED50) Idea of margin of safety Margin of Safety
  53. 53. Therapeutic index (TI) • It is defined as the gap between minimal therapeutic effect DRC and maximal acceptable adverse effect DRC (also called margin of safety)
  54. 54. Risk-benefit Ratioo • Estimated harm (ADRs, Cost, inconvenience) Vs • Expected advantages (relief of symptoms, cure, reduction of complications, mortality, improvement of lif etc)
  55. 55. Combined Effects of Drugs • Drug Synergism: – Additive effect (1 + 1 = 2) • Aspirin + paracetamol, amlodipine + atenolol, nitrous oxide + halothane – Supra-additive effect (1 + 1 = 4) • Sulfamethoxazole + trimethoprim, levodopa + carbidopa, acetylcholine + physostigmine Folate synthase Dihydrofolate • PABA DHFA Reductase THFA Sulfamethoxazole Trimethoprim
  56. 56. Drug Antagonism 1. Physical: Charcoal 2. Chemical: KMnO4, Chelating agent 3. Physiological antagonism: Histamine and adrenaline in bronchial asthma, Glucagon and Insulin 4. Receptor antagonism: a. Competitive antagonism (equilibrium) b. Non-competitive c. Non-equilibrium (competitive)
  57. 57. Receptor antagonism - curves o Competitive: o Antagonist is chemically similar to agonist and binds to same receptor molecules o Affinity (1) but IA (0), Result – no response o Log DRC shifts to the right o But, antagonism is reversible – increase in concentration of agonist overcomes the block o Parallel shift of curve to the right side o Non-competitive: o Allosteric site binding altering receptor not to bind with agonist o No competition between them – no change of effect even agonist conc. .is increased o Flattening of DRC of agonist by increasing the conc. Of antagonist
  58. 58. Receptor antagonism - curves • Non – equilibrium: – Antagonists Binds receptor with strong bond – Dissociation is slow and agonists cannot displace antagonists (receptor occupancy is unchanged) – Irreversible antagonism developes – DRC shifts to the right and Maximal response lowered
  59. 59. Drug antagonism DRC
  60. 60. Drug antagonism DRC – non-competitive antagonism Response Agonist + CA (NE) Shift to the right and lowered response Agonist Drug in log conc.
  61. 61. Spare Receptor • When only a fraction of the total population of receptors in a system, are needed to produce maximal effect, then the particular system is said to have spare receptors • Example – Adrenaline (90%)
  62. 62. Competitive Vs NC antagonism Competitive • Binds to same receptor • Resembles chemically • Parallel right shift of DRC in increasing dose of agonist • Intensity depends on the conc. Of agonist and antagonist • Example – Ach and atropine, Morphine and Naloxone Noncompetitive • Binds to other site • No resemblance • Maximal response is suppressed • Depends only on concentration of antagonist • Diazepam - Bicuculline
  63. 63. Summary • Basic Principles of Pharmacodynamics • Mechanisms of drug action – Enzymes, Ion channels, Transporters and Receptors with examples • Definitions of affinity, efficacy, agonist and antagonists etc. • Drug transducer mechanisms • GPCR and different GPCR transducing mechanisms – cAMP, Protein kinase etc. • Up regulation and down regulation of receptors and desensitization • Principles of dose response curves and curves in relation to agonist, competitive antagonist etc. • Therapeutic index, margin of safety and risk-benefit ratio concepts • Combined effects of drugs – synergism etc. • Dose response curve (DRC) – agonist and antagonist
  64. 64. Thank you