Pharmacodynamics

Pharmacology PPT

1. Dr Chintan

2. What the drug does to the body the study of the biochemical & physiological effects of drugs & their mechanisms of action

3. Analgesic Antipyretic Cyclooxygenase (COX) inhibition PG synthesis ↓

4. Mechanism of drug action

5. Based on chemical or physical property Bulk derivatives:physical mass Mannitol:osmosis Radioactive iodine Activated charcoal :adsorbing property

6. Targets of drug action Enzymes Ion channels Transporters RECEPTORS

7. Enzymes E C Substrate Drug Competitive Inhibitor Cholinesterase – Acetylcholine - Physostigmine Enzyme - Substrate - Inhibitor

8. Enzymes E C Substrate Drug Noncompetitive Inhibitor NC Enzyme loses catalytic property Aspirin COX

9. Competitive inhibitors Xanthine oxidase - Allopurinol Cholinesterase - Physostigmine Noncompetitive inhibitors Cyclooxygenase - Aspirin H + K + ATPase - Omeprazole

10. ION CHANNELS Nifedipine – Ca2+ channel blocker Nicorandil – K+ channel opener

11. TRANSPORTERS S T S T Fluoxetine – blocks SERT (serotonin transporter) Probenecid – blocks transport of Penicillin

12. macromolecule located on the surface or inside the cell serves to recognize the drug & initiate response to it RECEPTOR

13. R Nucleus R R DRUG

14. Affinity ability to bind with receptor Efficacy or Intrinsic activity (IA) capacity to induce functional change in the receptor

15. AGONIST Have affinity & maximum intrinsic activity (IA=1) ANTAGONIST Have affinity but NO intrinsic activity (IA=0)

16. G Protein-Coupled Receptors

17. G Protein-Coupled Receptors Membrane receptors 7 segments coupled to intracellular effector systems via G-proteins -interaction with GTP , GDP

18. Agonist Binding site G protein binding site G protein –subunits – α , β , γ Cell

19. Agonist binding to GPCR – change in receptor G protein activation Targets for G proteins Cellular response

20. G α subunits G s - adenylyl cyclase activation G i - adenylyl cyclase inhibition G0 : Ca channel inhibition G q - phospholipase C activation

21. Targets for G proteins Adenylyl cyclase – cAMP pathway ATP cAMP Activation of PK A Alteration of cellular function AC

22. Phospholipase C - IP3-DAG pathway PIP2 - phosphatidylinositol bisphosphate Inositol trisphosphate (IP3) Diacylglycerol (DAG) PLC protein kinase C (PK C ) activation release of Ca 2+ from intracellular stores Targets for G proteins G q

23. Targets for G proteins Ion channels as targets for G-proteins Activated G proteins –can affect Ca 2+ , K + channels do not involve cAMP / IP3 Example: Ca channel opening: β 1 K channel opening:Muscarinic M2

24. cGMP also serves as second messenger Action: Relaxation of vascular smooth muscle Action of cAMP is terminated by phosphodiesterase into 5-AMP

25. Summary GPCRs Membrane receptors , 7 segments GDP, GTP α , β , γ Gs , Gi , Gq *Targets AC – cAMP pathway PLC –IP3-DAG pathway Ion channels

26. Ion Channel Receptors

27. Ion Channel Receptors called ligand gated ion channels Na, K,Ca &CL channel Agonist binding opens the channel and causes depolarization/ hyperpolarization Example:Nicotinic , GABA a

28. Enzyme Linked Receptors

29. Enzyme linked receptors Binding site TK TK TK T T T P P Insulin Growth factors Downstream signals Tyrosine kinase

30. Receptors regulating gene expression

31. R R A Cell function modification N Receptors regulating gene expression

32. Receptors regulating gene expression Thyroid hormone receptor - in nucleus Glucocorticoid receptor - in cytoplasm

33. JAK-STAT binding receptor Cytokines growth hormone Prolactin Interferons

34. Types of receptors GPCRs Ion channels receptors Enzyme linked receptors Receptors regulating gene expression

35. Receptor regulation Up regulation Down regulation

36. Function of receptor To propagate regulatory signals from outside to inside the effectors cell To amplify the signal To integrate various extracellular and intracellular regulatory signals Adapt to short term and long term changes in the regulatory melieu and maintain homeostasis

37. Dose response curve Effects of drug depend on concentration at site of action which is determined by dose of drug administered called dose response relationship Types Graded DRC Quantal DRC

38. Dose Response Curve (DRC) Dose Response 100% Rectangular Hyperbola

39. Log Dose Sigmoid Log Dose Response Curve

40. Log Dose Response Curve Linear relationship in intermediate zone (30-70%) Advantages A wide range of doses can be easily displayed Comparison between agonists & study of antagonists becomes easier

41. Quantal DRC Example: drug causing ovulation

42. Slope of DRC

43. Drug Potency Amount of drug needed to produce a certain response Drug Efficacy Maximum response that can be elicited by the drug Upper limit of DRC

44. Examples Furosemide is less potent but more efficacious diuretic than metolazone Diazepam is more potent but less efficacious CNS depressant than pentobarbitone Pethidine is less potent but equally efficacious analgesic as morphine

45. Therapeutic Index

46. Therapeutic Index Therapeutic Index Median lethal dose (LD50) Median effective dose (ED50) = LD50 – dose which kills 50 % of the animals ED50 – dose which produces the specified effect in 50% of the animals SAFETY In animals

47. T herapeutic I ndex = L D50 / E D50 TI LE

48. In humans Therapeutic Range

49. Therapeutic effect Adverse effect Log Dose effect Minimal therapeutic effect Maximal acceptable adverse effect Therapeutic Range Therapeutic Range In humans

50. ANTAGONISM When one drug decreases or abolishes the action of another drug

51. Physical antagonism Based on the physical property of the drugs Examples Charcoal adsorbs alkaloids & prevent their absorption

52. Physical antagonism Chemical antagonism Physiological antagonism Receptor antagonism Types of antagonism

53. Chemical antagonism Two drugs react chemically & form an inactive product Examples Penicillamine chelates copper (Cu) KMnO4 oxidizes alkaloids—used for gastric lavage in poisoning. • Tannins + alkaloids—insoluble alkaloidal tannate is formed. Chelating agents

54. Physiological / Functional antagonism Two drugs act on different receptors Have opposite effects on the same physiological function Examples Adrenaline - bronchodilation & Histamine - bronchoconstriction Glucagon and insulin on blood sugar leve l Hydrochlorothiazide and triamterene on urinary K+ excretion.

55. Receptor antagonism One drug (antagonist) blocks the receptor action of the other (agonist)

56. Receptor antagonism R A Anta Competitive antagonism Same site on receptor

57. Competitive antagonism Equilibrium type antagonist binding reversible * Acetylcholine x Atropine Nonequilibrium type antagonist binding strong –irreversible Phenoxybenzamine

58. Competitive antagonism Log dose -Agonist Response A A + X A + 10 X 100 %

59. R A Anta different site on receptor Noncompetitive antagonism prevent receptor activation GABA X Picrotoxin

60. Noncompetitive antagonism Log dose -Agonist Response 100 % A A + X A + 10 X

61. Competitive antagonism Same receptor site Parallel shift –rightward Max response can be attained Examples: ACh —Atropine Noncompetitive antagonism different receptor site flattening Max response is suppressed EX:Diazepam—Bicuculline

62. SYNERGISM

63. SYNERGISM When the action of one drug is facilitated or increased by the other ---Synergistic Combination

64. ADDITIVE Effects of drugs A+B = effect of drug A + effect of drug B Examples: Aspirin + Paracetamol Nitrous oxide + halothane as general Anaesthetic Amlodipine + atenolol as antihypertensive Ephedrine + theophylline as bronchodilator

65. Supraadditive Effects of drugs A+B > effect of drug A + effect of drug B Effects of combination is greater than the individual effects Examples Sulfamethoxazole + Trimethoprim Levo dopa+carbidopa Ach+physostigmine

66. THANK YOU

67. True about G protein coupled receptors is: (a) G proteins bind to hormones on the cell surface (b) All the three subunits alpha, beta and gamma should bind to each other for G proteins to act (c) G proteins act as inhibitory and excitatory because of difference in alpha subunit (d) G protein is bound to GTP in resting state

68. Regarding efficacy and potency of a drug, all are true except (a) In a clinical setup, efficacy is more important than potency (b) In the log dose response curve, the height of the curve corresponds with efficacy (c) ED50 of the drug corresponds to the efficacy (d) Drugs that produce a similar pharmacological effect can have different levels of efficacy

69. All are second messengers except: (a) Cyclic amp (b) Guanylyl cyclase (c) Diacylglycerol (d) Inositol triphosphate

70. A partial agonist has: (a) High affinity but low intrinsic activity (b) High affinity but no intrinsic activity (c) Low affinity but high intrinsic activity (d) Low affinity and low intrinsic activity

71. Physiological antagonism is found in: (a) Isoprenaline and salbutamol (b) Isoprenaline and adrenaline (c) Isoprenaline and propanolol (d) Adrenaline and histamine

72. Two drugs having opposite action on different receptors is which type of antagonism? (a) Physical antagonism (b) Competitive antagonism (c) Non competitive antagonism (d) Physiological antagonism

73. Therapeutic index is a measure of: (a) Drug safety (b) Bioavailability (c) Potency (d) Efficacy

74. Efficacy of a drug refers to: (a) Affinity of drug to bind to receptors (b) Affinity of drug that binds to receptors and activates it (c) Dose that requires to produce response (d) Maximum response a drug can produce

75. All the following drugs act on ionic channels except: (a) Nicotine (b) Insulin (c) Glibenclamide (d) Diazepam

76. All of the following agents act by intracellular receptors EXCEPT (a) Thyroid hormones (b) Vitamin D (c) Insulin (d) Steroids

77. Action of alpha subunit of G-protein is: (a) Binding of agonist (b) Conversion of GDP to GTP (c) Breakdown of GTP to GDP (d) Internalization of receptors