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  1. 1. DR. ABHISHEK B L Moderator-DR. C. S. BHARATHAN
  2. 2.  It is the study of physiological & biochemical effects of drugs & their mechanism of action at organ system /subcellular /macromolecular levels.  It deals with what the drug does to the body.  Whereas Pharmacokinetics deals with what the body does to the drug
  3. 3.  This may be desirable therapeutic effects or undesirable adverse effects (A/E)  The A/E may be expected effects of the drug as side effects or toxicity( Quantitative effect)  Unexpected A/ E are seen as hypersensitivity ( allergy ) or Idiosyncrasy ( Qualitative effect)
  4. 4.  Stimulation - Adrenaline on heart/ Pilocarpine on salivary gland  Depression - Diazepam on CNS/ PPI on Gastric acid   Replacement - Hormones - Insulin , Thyroxin/ levodopa in parkinsonism  Cytotoxicity - Anticancer drugs , Antibiotics  Irritation 
  5. 5.  1. 2. 3. 4.   Most drugs act by binding to a particular target protein as follows: Receptors Ion Channels Enzymes Carrier or Transport proteins Certain drugs have no particular target Eg: Alcohol, GA
  6. 6. Receptor It is a macromolecular or binding site located on the surface or inside the effector cell that serves to recognize the signal molecule / drug & initiate the response to it, but itself has no other function Sites of receptors- cell membrane, cytoplasm, nucleus
  7. 7.    Paul Ehrlich The idea that drugs act upon specific sites (receptive substance) began with John New Port Langley (1852-1926) of Cambridge. The word ‘receptor’ was given by Paul Ehrlich (1854- 1915). 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.
  8. 8.  • • Drugs acting on receptors may be : Agonists Antagonists
  9. 9.  Ligand : Any molecule that binds selectively to a specific receptor is called ligand  Affinity : It is the ability of the molecule to bind to a receptor  Intrinsic activity/Efficacy : It is the ability of the molecule to elicit a response after binding with the receptor
  10. 10. Agonist        Has both affinity and intrinsic activity IA= +1 Eg : Adrenaline - α & β receptors, Morphine- opioid receptors Antagonist Has affinty but no intrinsic activity (IA=0). They oppose the action of agonist Eg : Propronolol- β blocker, Atropine-M receptor
  11. 11. PARTIAL AGONIST:    Have affinity & submaximal intrinsic activity IA =between 0 & +1 Eg : Nalorphine, Pentazocin on opioid receptors Inverse Agonists:    These drugs have affinity but produces actions opposite to those produced by agonist. IA = between 0 & -1 Eg: Beta Carboline on BZD receptor
  12. 12. E= +1 Agonists Partial Agonists E= 0 E= -1 Antagonists Inverse Agonists
  13. 13. SPARE RECEPTORS: These are reserve receptors present in the body, gets stimulated only at special situations. SILENT RECEPTORS: These are receptors to which an agonist binds but does not produce a response.
  14. 14.  Continued use & stimulation of receptors by agonist drugs may decrease the number and sensitivity of the receptors.  This phenomenon is called down regulation  Eg: Constant use of β2 agonist (salbutamol) reduce therapeutic response in Asthma
  15. 15.  Continued use and inhibition of receptors by antagonist drugs, may increase the number and sensitivity of the receptors.  This phenomenon is called up regulation.  Eg: sudden withdrawal of anti-anginal drug (Propranolol) may precipitate angina.
  16. 16. 1) Ion channel receptor 2) Transmembrane receptor 3) G-protein coupled receptor 4) Nuclear receptor Receptor which regulate gene transcription.
  17. 17. 1. Ion channel linked 2. Transmembrane linked 3. G protein linked 4. Nuclear (gene) linked
  18. 18. -Voltage gated ion channel -Ligand gated ion channel -Stretch activated ion channel -Temperature activated ion channel
  19. 19.  Protein pores in the membrane  Ions include Na+, K+, Ca2+ , Cl.     plasma Nerves, Skeletal & smooth muscle cells, cardiac tissue Channels open when there is Depolarization of membrane from its resting potential Voltage gated Na+ Channeleg. Local An.-lidocaine Voltage Dependent Ca Channel eg. Nifedipine
  20. 20.  Protein pores in the plasma membrane Ions include Na+, K+, Ca2+ , Cl.  GABA gated Cl- Ion channel - eg. BZD  Glutamate gated cation Ch. (NMDA r)- eg. Ketamine, Galantamine Action occurs very fast in millisecond
  21. 21. G Protein Coupled Receptor
  22. 22. GPCR Structure: • Single polypeptide chain threaded back and forth resulting in serpentine shaped 7 transmembrane alpha helices with 3 loops extracellularly & 3 loops intracellularly. 1 2 3 4 •There’s a G protein attached to the cytoplasmic side of the membrane. 6 5 Gα GDP 7 β γ • Amino terminal lies extracellularly & carboxy terminal on cytosolic side.
  23. 23. Guanine nucleotide binding proteins: participate in reversible, GTP-mediated interactions. Common features:  bind GDP and GTP with high affinity, but adopt different structure depending on the bound nucleotide.  GTP-bound complex has high affinity for other proteins (“acceptor’), affecting their enzymatic activity  possess intrinsic GTPase activity which converts GTP to GDP  Contains , and subunits  -subunit contains the GTP/GDP binding site,
  24. 24.   Gs – Adenyl cyclase Stimulator & Ca channel opener Gi – Adenyl cyclase Inhibitor & K+ channel opener  Gq – Phospholipase C activator  Go – Ca channel inhibitor
  25. 25. cAMP Ca2+/K+ PIP2 Phospholipase C Adenyl Cyclase ATP Gq Gs- Ca2+ Gi- K+ Go-Ca2+
  26. 26. Transmembrane Receptors TM Enzyme Receptor  Thyrosine kinase  Thyrosine phosphatase  Membrane bound GC receptor TM Non-Enzyme Receptor  Cytokine /JAK STAT Receptor  Toll like receptors
  27. 27.  Structure: • Receptors exist as individual polypeptides • Each has an extracellular signal-binding site • An intracellular tail with a number of tyrosines & a single å helix spanning the membrane • Receptor action is slow & occurs in hours Eg: Insulin receptors, EGF & NGF, PDGF, ANF, TGF receptors.
  28. 28. cGMP IP3
  29. 29.          JAK-STAT binding /cytokine receptor Non enzymatic Transmembrane receptor JAK-Janus Kinase (cytosolic tyrosine protein kinase), STAT- Signal Transducer & Activator of Transcription (free moving protein) EX: Cytokines, Growth hormones, Prolactin, Interferons act through this receptor
  30. 30. TR TR TR TR TR TR
  31. 31.  Receptors are seen intracellularly in the cytoplasm, Agonist(drug) cross cell membrane and bind with receptor and form Drug Receptor complex .  DR complex moves to nucleus, interact with DNA, regulate gene transcription , synthesise specific proteins which produce cellular effects.  Nuclear receptor action is very slow and occurs with in hours or days Egs: Corticosteroids, Sex hormones ,Thyroxine, Vitamin D, Vitamin A
  32. 32. HSP90 HSP90 HSP90
  33. 33.        Enzyme Acetyl Cholinesterase Angiotensin Converting En Carbonic anhydrase Cyclo- oxygenase DHFR HMG Co A Reductase Xanthine oxidase Inhibitors - Physostigmine - Captopril - Acetazolamide - Aspirin - Methotrexate - Simvastatin - Allopurinol
  34. 34. Transport proteins Drugs (Carrier mediated ) 1) Choline uptake -Hemicholinium 2) Monoamine uptake Antidepressents, SSRIs -Tricyclic 3) H+/K+ or Proton pump -Omeprazole 4) Na+/K+/Cl- symport -Frusemide
  35. 35. 1) Physical Bulk laxative eg.- Agar Osmotic purgative - Mgso4, Mannitol Adsorption - Charcoal Demulscent - Glycerine Astringent -tannic acids 2) Chemical -Neutralisation of Gastric Hcl by antacids, -Chelating agents with Heavy metals 3) Physico-Chemical -Alcohol
  36. 36.      This is a graph showing dose response relation. Dose is plotted on X-Axis and Response is plotted on Y-Axis. There are two types of DRC: -Graded/simple DRC - Log DRC In Log DRC – dose is converted to logarithmic scale and is plotted Log DRC is more convenient and used
  37. 37. Simple dose Drug Concentration Log Dose
  38. 38.   Large variations in doses can not be plotted on a single graph paper. Comparison between other drug responses is not possible
  39. 39.  Being logarithmic scale , less space only is required for plotting & large variations of dose can be recorded on single graph paper.  Comparison between different drug responses are possible
  40. 40.  To compare the efficacy & potency of drugs  To distinguish between Competitive & Noncompetitive antagonism of drugs  For calculating the Therapeutic Index or Safety margin of drugs
  41. 41.    Efficacy is the maximum effect produced by the drug. The maximum height of DRC shows the efficacy. Clinically efficacy is more important. Potency is the amount of drug required to produce the response. in case of less potent drug , DRC shifts to right. Steeper slope of DRC indicates marked increase in response with slight increase in dose
  42. 42. Morphine 10mg Pethidine 100mg Drug Concentration (log scale)
  43. 43. AG alone EC50 AG + ANT EC50 Drug Concentration (log scale)
  44. 44. % Max response AG alone AG + NC ANT AG + higher dose NC ANT Log Drug Concentration
  45. 45.  The gap between therapeutic effect DRC and adverse effect DRC defines the safety margin or therapeutic index (TI)  It can be calculated as ratio between LD50 and ED50  TI = median Lethal Dose = LD50 median Effective Dose ED50 TI should be more than one , it indicates safety of drug. Greater the TI , more will be the safety of the drug
  46. 46.  Median effecive dose means the 50% of test population showing therpeutic effect.  Median lethal dose means the 50% of test population showing lethal effect.   Drugs with wide TI – Diazepam , Penicillin Drugs with narrow TI – Digoxin , Lithium, phenytoin,Theophyllin
  47. 47. This is the dose range of drug bounded by the dose which produces minimal therapeutic effect and the dose which produce maximal acceptable adverse effect. Also known as Therapeutic Window.
  48. 48. Minimal therapeutic effect Maximal acceptable adverse effect Therapeutic window Drug Concentration (log scale)
  49. 49. Combined effect of Drug Synergism Antagonism -Physical Antagonism Additive synergism Supradditive synergism -Chemical Antagonism -Physiological Antagonism -Receptor Antagonism
  50. 50. 1. Additive synergism: If the total effect of drugs is equal to sum of their individual effects, it is called additive synergism ( eg: 2+2 = 4) Egs: Aspirin + paracetamol (analgesic effect) Theophyllin + ephedrine (Br.Asthma) 2. Supra additive synergism : If the added up effect is greater than sum of their individual effects, it is called supra-additive synergism ( eg: 2+2 > 4) Egs: Levodopa + carbidopa (Parkinsonism)
  51. 51. 1.Physical antagonism:  The effect of one drug is inhibited by physical property of another drug.  Eg: Charcoal adsorbs poisons on its surface & useful in alkaloid poisoning 2.Chemical antagonism :  Here two drugs interact chemically and one drug neutralise the effect of the other.  Egs :Antacids neutralise gastric acidity Ca EDTA useful in lead poisoning
  52. 52. Here two drugs act on different receptors/ sites; but their pharmacological effects are opposing each other functionally Examples:  Histamine (H1) produce bronchospasm  Adrenaline (β2) produce bronchodilation   Insulin reduce blood sugar Glucagon increase blood sugar
  53. 53. A. Competitive reversible Both agonists & antagonist drugs compete for same receptor.  Antagonistic effect is completely reversible.  Eg: Morphine & naloxone on opioid receptor Adrenalin & Prazosin on alpha receptor
  54. 54. AG alone EC50 AG + ANT EC50 Drug Concentration (log scale)
  55. 55. B. Competitive irreversible both drugs act on the same receptor . But Antagonistic effect is not reversible .  Eg: Adrenaline & Phenoxybenzamin (α rec.) C. Non Competitive antagonism  The drugs act at different sites of the same receptor or pathway.  Eg: Adrenaline & Verpamil.
  56. 56. % Max response AG alone AG + NC ANT AG + higher dose NC ANT Log Drug Concentration
  57. 57. THANK YOU