Drug actions


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Drug actions

  1. 1. Pharmacology Pharmacokinetics Pharmacodynamics
  2. 2. Pharmacokinetics <ul><li>Time course of drug absorption, distribution, metabolism, excretion </li></ul>How the drug comes and goes.
  3. 3. Pharmacokinetic Processes “ LADME ” is key Liberation Absorption Distribution Metabolism Excretion
  4. 4. Liberation <ul><li>Applies to drugs given orally </li></ul><ul><li>Components </li></ul><ul><ul><li>Release of drug from pill, tablet, capsule </li></ul></ul><ul><ul><li>Dissolving of active drug in GI fluids </li></ul></ul>Ex: Enteric coated aspirin slows absorption in stomach vs non-coated
  5. 5. Absorption <ul><li>Movement from administration site into circulation </li></ul>
  6. 6. Factors Affecting Liberation/Absorption <ul><li>Formulation factors </li></ul><ul><ul><li>Tablet disintegration </li></ul></ul><ul><ul><li>Inert ingredient / solvent effects </li></ul></ul><ul><ul><li>Solubility </li></ul></ul><ul><ul><li>Drug pH </li></ul></ul><ul><ul><li>Concentration </li></ul></ul><ul><li>Patient factors </li></ul><ul><ul><li>Absorbing surface </li></ul></ul><ul><ul><li>Blood flow </li></ul></ul><ul><ul><li>Environmental pH </li></ul></ul><ul><ul><li>Disease states </li></ul></ul><ul><ul><li>Interactions with food, other drugs </li></ul></ul>
  7. 7. Membranes and Absorption Lipid Bilayer Small, uncharged Large, uncharged Small charged ions H 2 O, urea, CO 2 , O 2 , N 2 Glucose Sucrose H + , Na + , K + , Ca 2+ , Cl - , HCO 3 - DENIED! DENIED! Swoosh! Hydrophobic Tails Hydrophilic Heads
  8. 8. LaChatlier’s Principle a.k.a . Mass Action A reaction at equilibrium responds to stress in a way to best return to equilibrium 4 Na + 4 Cl _ 4 NaCl + System at Equilibrium
  9. 9. 4 4 Cl - 4 NaCl + 12 NaCl 1. System at equilibrium  by 8 2. Stress applied to system 3. System responds to stress System not at equilibrium! 4 Na + 4. System returns to equilibrium! 4 NaCl dissociate An example of LaChatlier’s Principle  by 4  by 4 8 Na + 8 Cl - 8 NaCl
  10. 10. Ionization Acids Release/Donate H + H A H + + A - Bases Bind/Accept H + H + + B - H B Ionized form Non-ionized form
  11. 11. Environmental pH and Ionization If we put an acidic drug in an environment with a lot of H + (low pH) what will this equilibrium do? H A H A Non-ionized form predominates! H A H + + A - System at Equilibrium  H + from acid environment
  12. 12. A real live, actual clinical question... Aspirin is an acidic drug. In the stomach will it exist mostly in ionized or non-ionized form? NON-IONIZED Why?
  13. 13. How will this affect aspirin absorption? Lipid Bilayer Ionized form (charged) A - Ionized form (uncharged) H A H A
  14. 14. Moral of the story... <ul><li>Acidic drugs are best absorbed from acidic environments </li></ul>Basic drugs are best absorbed from basic environments
  15. 15. So... To  absorption of an acidic drug… acidify the environment To  absorption of an acidic drug… alkalanize the environment...
  16. 16. Distribution <ul><li>Rate of perfusion </li></ul><ul><li>Plasma protein (albumin) binding </li></ul><ul><li>Accumulation in tissues </li></ul><ul><li>Ability to cross membranes </li></ul><ul><ul><li>Blood-brain barrier </li></ul></ul><ul><ul><li>Placental barrier </li></ul></ul>
  17. 17. Plasma Protein Binding warfarin (Coumadin) is highly protein bound (99%). Aspirin binds to the same site on serum proteins as does Coumadin. If a patient on Coumadin also takes aspirin, what will happen? The available Coumadin will increase. 1) Why? 2) Why do we care?
  18. 18. Blood-Brain Barrier The blood brain barrier consists of cell tightly packed around the capillaries of the CNS. What characteristics must a drug possess to easily cross this barrier? Non-protein bound, non-ionized, and highly lipid soluble
  19. 19. Metabolism (Biotransformation) <ul><li>Two effects </li></ul><ul><ul><li>Transformation to less active metabolite </li></ul></ul><ul><ul><li>Enhancement of solubility </li></ul></ul><ul><li>Liver = primary site </li></ul><ul><li>Liver disease </li></ul><ul><ul><li>Slows metabolism </li></ul></ul><ul><ul><li>Prolongs effects </li></ul></ul>
  20. 20. Hepatic ‘First-Pass’ Metabolism <ul><li>Affects orally administered drugs </li></ul><ul><li>Metabolism of drug by liver before drug reaches systemic circulation </li></ul><ul><li>Drug absorbed into portal circulation, must pass through liver to reach systemic circulation </li></ul><ul><li>May reduce availability of drug </li></ul>
  21. 21. Elimination <ul><li>Kidneys = primary site </li></ul><ul><ul><li>Mechanisms dependent upon: </li></ul></ul><ul><ul><ul><li>Passive glomerular filtration </li></ul></ul></ul><ul><ul><ul><li>Active tubular transport </li></ul></ul></ul><ul><ul><li>Partial reabsorption </li></ul></ul><ul><ul><li>Hemodialysis </li></ul></ul><ul><li>Renal disease </li></ul><ul><ul><li>Slows excretion </li></ul></ul><ul><ul><li>Prolongs effects </li></ul></ul>
  22. 22. Active Tubular Transport Probenecid is moved into the urine by the same transport pump that moves many antibiotics. Why is probenecid sometimes given as an adjunct to antibiotic therapy? It competes with the antibiotic at the pump and slows its excretion.
  23. 23. Urine pH and Elimination A patient has overdosed on phenobartital. Phenobarbital is an acid. If we ‘alkalinalize’ the urine by giving bicarbonate what will happen to the phenobarbital molecules as they are filtered through the renal tubules? They will ionize...
  24. 24. How will this affect phenobarbital reabsorption by the kidney? Non-ionized H A H + + A - Decreased reabsorption Increased elimination Ionized
  25. 25. Elimination <ul><li>Other sources </li></ul><ul><ul><li>Feces </li></ul></ul><ul><ul><li>Exhaled air </li></ul></ul><ul><ul><li>Breast milk </li></ul></ul><ul><ul><li>Sweat </li></ul></ul>
  26. 26. Biological Half-life (t 1/2 ) <ul><li>Amount of time to eliminate 1/2 of total drug amount </li></ul><ul><li>Shorter t 1/2 may need more frequent doses </li></ul><ul><li>Hepatic disease may increase t 1/2 </li></ul>
  27. 27. A drug has a half life of 10 seconds. You give a patient a dose of 6mg. After 30 seconds how much of the drug remains? Time Amount 0 sec 6 mg 10 sec 3 mg 20 sec 1.5 mg 30 sec 0.75 mg
  28. 28. Administration Routes <ul><li>Intravenous </li></ul><ul><ul><li>Fastest, Most dangerous </li></ul></ul><ul><li>Endotracheal </li></ul><ul><ul><li>Lidocaine, atropine, narcan, epinephrine </li></ul></ul><ul><li>Inhalation </li></ul><ul><ul><li>Bronchodilators via nebulizers </li></ul></ul><ul><li>Transmucosal </li></ul><ul><ul><li>Rectal or sublingual </li></ul></ul>
  29. 29. Administration Routes <ul><li>Intramuscular </li></ul><ul><ul><li>Depends on perfusion quality </li></ul></ul><ul><li>Subcutaneous </li></ul><ul><ul><li>Depends on perfusion quality </li></ul></ul><ul><li>Oral </li></ul><ul><ul><li>Slow, unpredictable </li></ul></ul><ul><ul><li>Little prehospital use </li></ul></ul>
  30. 30. Pharmacodynamics <ul><li>The biochemical and physiologic mechanisms of drug action </li></ul>What the drug does when it gets there.
  31. 31. Drug Mechanisms <ul><li>Receptor interactions </li></ul><ul><li>Non-receptor mechanisms </li></ul>
  32. 32. Receptor Interactions Agonist Receptor Agonist-Receptor Interaction Lock and key mechanism
  33. 33. Receptor Interactions Receptor Perfect Fit! Induced Fit
  34. 34. Receptor Interactions Antagonist Receptor Antagonist-Receptor Complex DENIED! Competitive Inhibition
  35. 35. Receptor Interactions Agonist Receptor Antagonist ‘ Inhibited’-Receptor DENIED! Non-competitive Inhibition
  36. 36. Non-receptor Mechanisms <ul><li>Actions on Enzymes </li></ul><ul><ul><li>Enzymes = Biological catalysts </li></ul></ul><ul><ul><ul><li>Speed chemical reactions </li></ul></ul></ul><ul><ul><ul><li>Are not changed themselves </li></ul></ul></ul><ul><ul><li>Drugs altering enzyme activity alter processes catalyzed by the enzymes </li></ul></ul><ul><ul><li>Examples </li></ul></ul><ul><ul><ul><li>Cholinesterase inhibitors </li></ul></ul></ul><ul><ul><ul><li>Monoamine oxidase inhibitors </li></ul></ul></ul>
  37. 37. Non-receptor Mechanisms <ul><li>Changing Physical Properties </li></ul><ul><ul><li>Mannitol </li></ul></ul><ul><ul><li>Changes osmotic balance across membranes </li></ul></ul><ul><ul><li>Causes urine production (osmotic diuresis) </li></ul></ul>
  38. 38. Non-receptor Mechanisms <ul><li>Changing Cell Membrane Permeability </li></ul><ul><ul><li>Lidocaine </li></ul></ul><ul><ul><ul><li>Blocks sodium channels </li></ul></ul></ul><ul><ul><li>Verapamil, nefedipine </li></ul></ul><ul><ul><ul><li>Block calcium channels </li></ul></ul></ul><ul><ul><li>Bretylium </li></ul></ul><ul><ul><ul><li>Blocks potassium channels </li></ul></ul></ul><ul><ul><li>Adenosine </li></ul></ul><ul><ul><ul><li>Opens potassium channels </li></ul></ul></ul>
  39. 39. Non-receptor Mechanisms <ul><li>Combining With Other Chemicals </li></ul><ul><ul><li>Antacids </li></ul></ul><ul><ul><li>Antiseptic effects of alcohol, phenol </li></ul></ul><ul><ul><li>Chelation of heavy metals </li></ul></ul>
  40. 40. Non-receptor Mechanisms <ul><li>Anti-metabolites </li></ul><ul><ul><li>Enter biochemical reactions in place of normal substrate “competitors” </li></ul></ul><ul><ul><li>Result in biologically inactive product </li></ul></ul><ul><ul><li>Examples </li></ul></ul><ul><ul><ul><li>Some anti-neoplastics </li></ul></ul></ul><ul><ul><ul><li>Some anti-infectives </li></ul></ul></ul>
  41. 41. Drug Response Relationships <ul><li>Time Response </li></ul><ul><li>Dose Response </li></ul>
  42. 42. Time Response Relationships Effect/ Response Time Latency Duration of Response Maximal (Peak) Effect
  43. 43. Time Response Relationships Effect/ Response Time IV SC IM
  44. 44. Dose Response Relationships <ul><li>Potency </li></ul><ul><ul><li>Absolute amount of drug required to produce an effect </li></ul></ul><ul><ul><li>More potent drug is the one that requires lower dose to cause same effect </li></ul></ul>
  45. 45. Potency Which drug is more potent? A! Why? Therapeutic Effect Effect Dose A B
  46. 46. Dose Response Relationships <ul><li>Threshold (minimal) dose </li></ul><ul><ul><li>Least amount needed to produce desired effects </li></ul></ul><ul><li>Maximum effect </li></ul><ul><ul><li>Greatest response produced regardless of dose used </li></ul></ul>
  47. 47. Dose Response Relationships Which drug has the lower threshold dose? A B Which has the greater maximum effect? A B Therapeutic Effect Effect Dose
  48. 48. Dose Response Relationships <ul><li>Loading dose </li></ul><ul><ul><li>Bolus of drug given initially to rapidly reach therapeutic levels </li></ul></ul><ul><li>Maintenance dose </li></ul><ul><ul><li>Lower dose of drug given continuously or at regular intervals to maintain therapeutic levels </li></ul></ul>
  49. 49. Therapeutic Index <ul><li>Drug’s safety margin </li></ul><ul><li>Must be >1 for drug to be usable </li></ul><ul><li>Digitalis has a TI of 2 </li></ul><ul><li>Penicillin has TI of >100 </li></ul>
  50. 50. Therapeutic Index Why don’t we use a drug with a TI <1? ED50 < LD50 = Very Bad!
  51. 51. Factors Altering Drug Responses <ul><li>Age </li></ul><ul><ul><li>Pediatric or geriatric </li></ul></ul><ul><ul><li>Immature or decreased hepatic, renal function </li></ul></ul><ul><li>Weight </li></ul><ul><ul><li>Big patients “spread” drug over larger volume </li></ul></ul><ul><li>Gender </li></ul><ul><ul><li>Difference in sizes </li></ul></ul><ul><ul><li>Difference in fat/water distribution </li></ul></ul>
  52. 52. Factors Altering Drug Responses <ul><li>Environment </li></ul><ul><ul><li>Heat or cold </li></ul></ul><ul><ul><li>Presence or real or perceived threats </li></ul></ul><ul><li>Fever </li></ul><ul><li>Shock </li></ul>
  53. 53. Factors Altering Drug Responses <ul><li>Pathology </li></ul><ul><ul><li>Drug may aggravate underlying pathology </li></ul></ul><ul><ul><li>Hepatic disease may slow drug metabolism </li></ul></ul><ul><ul><li>Renal disease may slow drug elimination </li></ul></ul><ul><ul><li>Acid/base abnormalities may change drug absorption or elimination </li></ul></ul>
  54. 54. Influencing factors <ul><li>Genetic effects </li></ul><ul><ul><li>Lack of specific enzymes </li></ul></ul><ul><ul><li>Lower metabolic rate </li></ul></ul><ul><li>Psychological factors </li></ul><ul><ul><li>Placebo effect </li></ul></ul>
  55. 55. Pediatric Patients <ul><li>Higher proportion of water </li></ul><ul><li>Lower plasma protein levels </li></ul><ul><ul><li>More available drug </li></ul></ul><ul><li>Immature liver/kidneys </li></ul><ul><ul><li>Liver often metabolizes more slowly </li></ul></ul><ul><ul><li>Kidneys may excrete more slowly </li></ul></ul>
  56. 56. Geriatric Patients <ul><li>Chronic disease states </li></ul><ul><li>Decreased plasma protein binding </li></ul><ul><li>Slower metabolism </li></ul><ul><li>Slower excretion </li></ul><ul><li>Dietary deficiencies </li></ul><ul><li>Use of multiple medications </li></ul><ul><li>Lack of compliance </li></ul>
  57. 57. www.freelivedoctor.com
  58. 58. www.freelivedoctor.com
  59. 59. DISPOSITION OF DRUGS The disposition of chemicals entering the body (from C.D. Klaassen, Casarett and Doull’s Toxicology , 5th ed., New York: McGraw-Hill, 1996). www.freelivedoctor.com
  61. 61. Plasma concentration vs. time profile of a single dose of a drug ingested orally Plasma Concentration www.freelivedoctor.com
  62. 62. www.freelivedoctor.com
  64. 64. Bioavailability Definition: the fraction of the administered dose reaching the systemic circulation for i.v.: 100% for non i.v.: ranges from 0 to 100% e.g. lidocaine bioavailability 35% due to destruction in gastric acid and liver metabolism First Pass Effect www.freelivedoctor.com
  65. 65. Bioavailability Dose Destroyed in gut Not absorbed Destroyed by gut wall Destroyed by liver to systemic circulation www.freelivedoctor.com
  66. 66. PRINCIPLE For drugs taken by routes other than the i.v. route, the extent of absorption and the bioavailability must be understood in order to determine what dose will induce the desired therapeutic effect. It will also explain why the same dose may cause a therapeutic effect by one route but a toxic or no effect by another . www.freelivedoctor.com
  67. 67. Drugs appear to distribute in the body as if it were a single compartment. The magnitude of the drug’s distribution is given by the apparent volume of distribution (V d ). Vd = Amount of drug in body ÷ Concentration in Plasma PRINCIPLE (Apparent) Volume of Distribution: Volume into which a drug appears to distribute with a concentration equal to its plasma concentration www.freelivedoctor.com
  68. 68. www.freelivedoctor.com
  69. 69. Examples of apparent Vd’s for some drugs www.freelivedoctor.com Drug L/Kg L/70 kg Sulfisoxazole 0.16 11.2 Phenytoin 0.63 44.1 Phenobarbital 0.55 38.5 Diazepam 2.4 168 Digoxin 7 490
  70. 70. MAJOR MINOR www.freelivedoctor.com
  71. 71. Elimination by the Kidney <ul><li>Excretion - major </li></ul><ul><li>1) glomerular filtration </li></ul><ul><li>glomerular structure, size constraints, protein binding </li></ul><ul><li>2) tubular reabsorption/secretion </li></ul><ul><li>- acidification/alkalinization, </li></ul><ul><li>- active transport, competitive/saturable, organic acids/bases - protein binding </li></ul><ul><li>Metabolism - minor </li></ul>www.freelivedoctor.com
  72. 72. Elimination by the Liver <ul><li>Metabolism - major </li></ul><ul><li>1) Phase I and II reactions </li></ul><ul><li>2) Function: change a lipid soluble to more water soluble molecule to excrete in kidney </li></ul><ul><li>3) Possibility of active metabolites with same or different properties as parent molecule </li></ul><ul><li>Biliary Secretion – active transport, 4 categories </li></ul>www.freelivedoctor.com
  73. 73. The enterohepatic shunt Portal circulation Liver gall bladder Gut Bile duct Drug Biotransformation; glucuronide produced Bile formation Hydrolysis by beta glucuronidase www.freelivedoctor.com
  74. 74. www.freelivedoctor.com
  75. 75. Plasma concentration Influence of Variations in Relative Rates of Absorption and Elimination on Plasma Concentration of an Orally Administered Drug Ka/Ke=10 Ka/Ke=0.1 Ka/Ke=0.01 Ka/Ke=1 www.freelivedoctor.com
  76. 76. Elimination <ul><li>Zero order: constant rate of elimination irrespective of plasma concentration. </li></ul><ul><li>First order: rate of elimination proportional to plasma concentration. Constant Fraction of drug eliminated per unit time. </li></ul><ul><li>Rate of elimination ∝ Amount </li></ul><ul><li>Rate of elimination = K x Amount </li></ul>www.freelivedoctor.com
  77. 77. Zero Order Elimination Pharmacokinetics of Ethanol <ul><li>Ethanol is distributed in total body water. </li></ul><ul><li>Mild intoxication at 1 mg/ml in plasma. </li></ul><ul><li>How much should be ingested to reach it? </li></ul><ul><li>Answer: 42 g or 56 ml of pure ethanol (V d x C) </li></ul><ul><li>Or 120 ml of a strong alcoholic drink like whiskey </li></ul><ul><li>Ethanol has a constant elimination rate = 10 ml/h </li></ul><ul><li>To maintain mild intoxication, at what rate must ethanol be taken now? </li></ul><ul><li>at 10 ml/h of pure ethanol , or 20 ml/h of drink. </li></ul>Rarely Done DRUNKENNESS Coma Death www.freelivedoctor.com
  78. 78. First Order Elimination Plasma concentration C t = C 0 . e – K el • t lnC t = lnC 0 – K el • t logC t = logC 0 – K el • t 2.3 DC/dt = – k • C y = b – a.x dA/dt ∝A DA/dt = – k • A www.freelivedoctor.com
  79. 79. Time Plasma Concentration 0 1 2 3 4 5 6 1 10 100 1000 10000 First Order Elimination logC t = logC 0 - K el . t 2.303 www.freelivedoctor.com
  80. 80. Plasma Concentration Profile after a Single I.V. Injection www.freelivedoctor.com
  81. 81. lnC t = lnC o – K el .t When t = 0, C = C 0 , i.e., the concentration at time zero when distribution is complete and elimination has not started yet. Use this value and the dose to calculate V d . V d = Dose/C 0 www.freelivedoctor.com
  82. 82. lnC t = lnC 0 – K el .t When C t = ½ C 0 , then K el .t = 0.693. This is the time for the plasma concentration to reach half the original, i.e., the half-life of elimination. t1/2 = 0.693/K el www.freelivedoctor.com
  83. 83. PRINCIPLE <ul><li>Elimination of drugs from the body usually follows first order kinetics with a characteristic half-life (t1/2) and fractional rate constant (K el ). </li></ul>www.freelivedoctor.com
  84. 84. First Order Elimination <ul><li>Clearance: volume of plasma cleared of drug per unit time. </li></ul><ul><li>Clearance = Rate of elimination ÷ plasma conc. </li></ul><ul><li>Half-life of elimination : time for plasma conc. to decrease by half. </li></ul><ul><li>Useful in estimating: - time to reach steady state concentration. - time for plasma concentration to fall after dosing is stopped. </li></ul>www.freelivedoctor.com
  85. 85. Rate of elimination = K el x Amount in body Rate of elimination = CL x Plasma Concentration Therefore, K el x Amount = CL x Concentration K el = CL/V d 0.693/t1/2 = CL/V d t1/2 = 0.693 x V d /CL www.freelivedoctor.com
  86. 86. PRINCIPLE <ul><li>The half-life of elimination of a drug (and </li></ul><ul><li>its residence in the body) depends on its </li></ul><ul><li>clearance and its volume of distribution </li></ul><ul><li>t1/2 is proportional to V d </li></ul><ul><li>t1/2 is inversely proportional to CL </li></ul>t1/2 = 0.693 x V d /CL www.freelivedoctor.com
  87. 87. Multiple dosing <ul><li>On continuous steady administration of a drug, plasma concentration will rise fast at first then more slowly and reach a plateau, where: </li></ul><ul><li>rate of administration = rate of elimination ie. steady state is reached. </li></ul><ul><li>Therefore, at steady state: </li></ul><ul><li>Dose ( Rate of Administration ) = clearance x plasma conc. </li></ul><ul><li>Or </li></ul><ul><li>If you aim at a target plasma level and you know the </li></ul><ul><li>clearance, you can calculate the dose required. </li></ul>www.freelivedoctor.com
  88. 88. Constant Rate of Administration (i.v.)zz www.freelivedoctor.com
  89. 89. Time Plasma Concentration Repeated doses –Maintenance dose Therapeutic level Single dose – Loading dose www.freelivedoctor.com
  90. 90. Concentration due to a single dose Concentration due to repeated doses The time to reach steady state is ~4 t1/2’s www.freelivedoctor.com
  91. 91. Pharmacokinetic parameters <ul><li>Volume of distribution V d = DOSE / C 0 </li></ul><ul><li>Plasma clearance Cl = K el .V d </li></ul><ul><li>plasma half-life t1/2 = 0.693 / K el </li></ul><ul><li>Bioavailability (AUC) x / (AUC) iv </li></ul>Get equation of regression line; from it get K el , C 0 , and AUC www.freelivedoctor.com
  92. 92. But C x dt = small area under the curve. For total amount eliminated (which is the total given, or the dose, if i.v.), add all the small areas = AUC. Dose = CL x AUC and Dose x F = CL x AUC dC/dt = CL x C dC = CL x C x dt www.freelivedoctor.com
  93. 93. Plasma concentration Time (hours) Bioavailability (AUC) o (AUC) iv = i.v. route oral route www.freelivedoctor.com
  94. 94. Variability in Pharmacokinetics Daily Dose (mg/kg) Plasma Drug Concentration (mg/L) 0 5 10 15 0 10 20 30 40 50 60 www.freelivedoctor.com
  95. 95. PRINCIPLE <ul><li>The absorption, distribution and elimination of a drug are qualitatively similar in all individuals. However, for several reasons, the quantitative aspects may differ considerably. Each person must be considered individually and doses adjusted accordingly. </li></ul>www.freelivedoctor.com
  96. 96. www.freelivedoctor.com
  98. 98. WHY BE CONCERNED ABOUT HOW DRUGS WORK? <ul><li>FDA Approved and Unapproved Uses </li></ul><ul><li>Interactions with Other Drugs </li></ul><ul><li>Adverse Effects and Contraindication s </li></ul>AIDS MEMORIZATION OF: www.freelivedoctor.com
  99. 99. WHY BE CONCERNED ABOUT HOW DRUGS WORK? <ul><li>Better assessment of new modalities for using drugs </li></ul><ul><li>Better assessment of new indications for drugs </li></ul><ul><li>Better assessment of new concerns regarding risk-benefit </li></ul>AIDS EVALUATION OF MEDICAL LITERATURE: www.freelivedoctor.com
  100. 100. WHY BE CONCERNED ABOUT HOW DRUGS WORK? The patient has more respect for and trust in a therapist who can convey to the patient how the drug is affecting the patient’s body. AIDS PATIENT-DOCTOR RELATIONSHIP: A patient who understands his/her therapy is more inclined to become an active participant in the management of the patient’s disease. www.freelivedoctor.com
  101. 101. WHY BE CONCERNED ABOUT HOW DRUGS WORK? Knowledge of how a drug works increases the therapist’s confidence that the drug is being used appropriately. PEACE OF MIND! www.freelivedoctor.com
  102. 102. HOW DO DRUGS WORK? <ul><li>Some antagonize, block or inhibit endogenous proteins </li></ul><ul><li>Some activate endogenous proteins </li></ul><ul><li>A few have unconventional mechanisms of action </li></ul>Most work by interacting with endogenous proteins: www.freelivedoctor.com
  103. 103. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? <ul><li>Antagonists of Cell Surface Receptors </li></ul><ul><li>Antagonists of Nuclear Receptors </li></ul><ul><li>Enzyme Inhibitors </li></ul><ul><li>Ion Channel Blockers </li></ul><ul><li>Transport Inhibitors </li></ul><ul><li>Inhibitors of Signal Transduction Proteins </li></ul>www.freelivedoctor.com
  104. 104. A macromolecular component of the organism that binds the drug and initiates its effect. Definition of RECEPTOR : Most receptors are proteins that have undergone various post-translational modifications such as covalent attachments of carbohydrate, lipid and phosphate. www.freelivedoctor.com
  105. 105. A receptor that is embedded in the cell membrane and functions to receive chemical information from the extracellular compartment and to transmit that information to the intracellular compartment. Definition of CELL SURFACE RECEPTOR : www.freelivedoctor.com
  106. 106. HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? KEY CONCEPTS: <ul><li>Cell surface receptors exist to transmit chemical signals from </li></ul><ul><li>the outside to the inside of the cell. </li></ul><ul><li>Some compounds bind to cell surface receptors, yet do not </li></ul><ul><li>activate the receptors to trigger a response. </li></ul><ul><li>When cell surface receptors bind the molecule, </li></ul><ul><li>the endogenous chemical cannot bind to the </li></ul><ul><li>receptor and cannot trigger a response. </li></ul><ul><li>The compound is said to “antagonize” or “block” the receptor </li></ul><ul><li>and is referred to as a receptor antagonist. </li></ul>www.freelivedoctor.com
  107. 107. Footnote: Most antagonists attach to binding site on receptor for endogenous agonist and sterically prevent endogenous agonist from binding. If binding is reversible - Competitive antagonists If binding is irreversible - Noncompetitive antagonists However, antagonists may bind to remote site on receptor and cause allosteric effects that displace endogenous agonist or prevent endogenous agonist from activating receptor. (Noncompetitive antagonists) HOW DO DRUGS WORK BY ANTAGONIZING CELL SURFACE RECEPTORS? www.freelivedoctor.com
  108. 108. ARE DRUGS THAT ANTAGONIZE CELL SURFACE RECEPTORS CLINICALLY USEFUL? <ul><li>Angiotensin Receptor Blockers (ARBs) for high blood pressure, </li></ul><ul><li>heart failure, chronic renal insufficiency </li></ul><ul><li>(losartan [Cozaar ® ]; valsartan [Diovan ® ]) </li></ul>Some important examples: <ul><li>Beta-Adrenoceptor Blockers for angina, myocardial infarction, </li></ul><ul><li>heart failure, high blood pressure, performance anxiety </li></ul><ul><li>(propranolol [Inderal ® ]; atenolol [Tenormin ® ]) </li></ul>www.freelivedoctor.com
  109. 109. ARE DRUGS THAT ANTAGONIZE NUCLEAR RECEPTORS CLINICALLY USEFUL? <ul><li>Mineralocorticoid Receptor Antagonists for edema due to </li></ul><ul><li>liver cirrhosis and for heart failure </li></ul><ul><li>(spironolactone [Aldactone ® ]) </li></ul>Some important examples: <ul><li>Estrogen Receptor Antagonists for the prevention and treatment </li></ul><ul><li>of breast cancer (tamoxifen [Nolvadex ® ]) </li></ul>www.freelivedoctor.com
  110. 110. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? <ul><li>Antagonists of Cell Surface Receptors </li></ul><ul><li>Antagonists of Nuclear Receptors </li></ul><ul><li>Enzyme Inhibitors </li></ul><ul><li>Ion Channel Blockers </li></ul><ul><li>Transport Inhibitors </li></ul><ul><li>Inhibitors of Signal Transduction Pr oteins </li></ul>www.freelivedoctor.com
  111. 111. HOW DO DRUGS WORK BY INHIBITING ENZYMES? Active Enzyme Substrate Product Cellular Function Inactive Enzyme Substrate Bound Enzyme Inhibitor (Drug) www.freelivedoctor.com
  112. 112. HOW DO DRUGS WORK BY INHIBITING ENZYMES? KEY CONCEPTS: <ul><li>Enzymes catalyze the biosynthesis of products from substrates. </li></ul><ul><li>Some drugs bind to enzymes and inhibit enzymatic activity. </li></ul><ul><li>Loss of product due to enzyme inhibition mediates the </li></ul><ul><li>effects of enzyme inhibitors. </li></ul>www.freelivedoctor.com
  113. 113. ARE DRUGS THAT INHIBIT ENZYMES CLINICALLY USEFUL? <ul><ul><ul><li>Cyclooxygenase Inhibitors for pain relief, </li></ul></ul></ul><ul><li>particularly due to arthritis (aspirin ; ibuprofen [Motrin ® ]) </li></ul>Some important examples: <ul><li>Angiotensin Converting Enzyme (ACE) Inhibitors for </li></ul><ul><li>high blood pressure, heart failure , and </li></ul><ul><li>chronic renal insufficiency </li></ul><ul><li>(captopril [Capoten ® ]; ramipril [Altace ® ]) </li></ul><ul><li>HMG-CoA Reductase Inhibitors for hypercholesterolemia </li></ul><ul><li>(atorvastatin [Lipitor ® ]; pravastatin [Pravachol ® ]) </li></ul>www.freelivedoctor.com
  114. 114. HOW DO DRUGS ANTAGONIZE, BLOCK OR INHIBIT ENDOGENOUS PROTEINS? <ul><li>Antagonists of Cell Surface Receptors </li></ul><ul><li>Antagonists of Nuclear Receptors </li></ul><ul><li>Enzyme Inhibitors </li></ul><ul><li>Ion Channel Blockers </li></ul><ul><li>Transport Inhibitors </li></ul><ul><li>Inhibitors of Signal Transduction Proteins </li></ul>www.freelivedoctor.com
  115. 115. ARE DRUGS THAT BLOCK ION CHANNELS CLINICALLY USEFUL? <ul><li>Calcium Channel Blockers (CCBs) for angina and high blood pressure </li></ul><ul><li>(amlodipine [Norvasc ® ]; diltiazem [Cardizem ® ]) </li></ul>Some important examples: <ul><li>Sodium Channel Blockers to suppress cardiac arrhythmias </li></ul><ul><li>(lidocaine [Xylocaine ® ]; amiodarone [Cordarone ® ]) </li></ul>www.freelivedoctor.com
  116. 116. ARE DRUGS THAT INHIBIT TRANSPORTERS CLINICALLY USEFUL? <ul><li>Selective Serotonin Reuptake Inhibitors (SSRIs) for the </li></ul><ul><li>treatment of depression </li></ul><ul><li>(fluoxetine [Prozac ® ]; fluvoxamine [Luvox ® ]) </li></ul>Some important examples: <ul><li>Inhibitors of Na-2Cl-K Symporter (Loop Diuretics) in </li></ul><ul><li>renal epithelial cells to increase urine and sodium </li></ul><ul><li>output for the treatment of edema </li></ul><ul><li>(furosemide [Lasix ® ]; bumetanide [Bumex ® ]) </li></ul>www.freelivedoctor.com
  117. 117. <ul><li>Tyrosine Kinase Inhibitors for chronic myelocytic leukemia </li></ul><ul><li>(imatinib [Gleevec ® ]) </li></ul>Some important examples: <ul><li>Type 5 Phosphodiesterase Inhibitors for erectile dysfunction </li></ul><ul><li>(sildenafil [Viagra ® ]) </li></ul><ul><li>This is a major focus of drug development </li></ul>ARE DRUGS THAT INHIBIT SIGNAL TRANSDUCTION PROTEINS CLINICALLY USEFUL? www.freelivedoctor.com
  118. 118. HOW DO DRUGS WORK BY ACTIVATING ENDOGENOUS PROTEINS? <ul><li>Agonists of Cell Surface Receptors </li></ul><ul><li>(e.g. alpha-agonists, morphine agonists) </li></ul><ul><li>Agonists of Nuclear Receptors </li></ul><ul><li>(e.g. HRT for menopause, steroids for inflammation) </li></ul><ul><li>Enzyme Activators </li></ul><ul><li>e.g. nitroglycerine (guanylyl cyclase), pralidoxime </li></ul><ul><li>Ion Channel Openers </li></ul><ul><li>e.g. minoxidil (K) and alprazolam (Cl) </li></ul>www.freelivedoctor.com
  119. 119. HOW DO CHEMICALS WORK BY ACTIVATING CELL SURFACE RECEPTORS? KEY CONCEPTS: <ul><li>Cell surface receptors exist to transmit chemical signals from </li></ul><ul><li>the outside to the inside of the cell. </li></ul><ul><li>Some chemicals bind to cell surface receptors and </li></ul><ul><li>trigger a response. </li></ul><ul><li>Chemicals in this group are called receptor agonists. </li></ul><ul><li>Some agonists are actually the endogenous chemical signal, </li></ul><ul><li>whereas other agonists mimic endogenous chemical signals. </li></ul>www.freelivedoctor.com
  120. 120. HOW DO CHEMICALS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION? <ul><li>Disrupting of Structural Proteins </li></ul><ul><li>e.g. vinca alkaloids for cancer, colchicine for gout </li></ul><ul><li>Being Enzymes </li></ul><ul><li>e.g. streptokinase for thrombolysis </li></ul><ul><li>Covalently Linking to Macromolecules </li></ul><ul><li>e.g. cyclophosphamide for cancer </li></ul><ul><li>Reacting Chemically with Small Molecules </li></ul><ul><li>e.g. antacids for increased acidity </li></ul><ul><li>Binding Free Molecules or Atoms </li></ul><ul><li>e.g. drugs for heavy metal poisoning, infliximab (anti-TNF) </li></ul>www.freelivedoctor.com
  121. 121. HOW DO DRUGS WORK BY UNCONVENTIONAL MECHANISMS OF ACTION (Continued)? <ul><li>Being Nutrients </li></ul><ul><li>e.g. vitamins, minerals </li></ul><ul><li>Exerting Actions Due to Physical Properties </li></ul><ul><li>e.g. mannitol (osmotic diuretic), laxatives </li></ul><ul><li>Working Via an Antisense Action </li></ul><ul><li>e.g. fomivirsen for CMV retininitis in AIDS </li></ul><ul><li>Being Antigens </li></ul><ul><li>e.g. vaccines </li></ul><ul><li>Having Unknown Mechanisms of Action </li></ul><ul><li>e.g. general anesthetics </li></ul>www.freelivedoctor.com
  122. 122. Characteristics of Drug-Receptor Interactions <ul><li>Chemical Bond: ionic, hydrogen, hydrophobic, Van der Waals, and covalent. </li></ul><ul><li>Saturable </li></ul><ul><li>Competitive </li></ul><ul><li>Specific and Selective </li></ul><ul><li>Structure-activity relationships </li></ul><ul><li>Transduction mechanisms </li></ul>www.freelivedoctor.com
  123. 123. www.freelivedoctor.com
  124. 124. NH 4 + -CH 2 (n)-NH 4 + www.freelivedoctor.com
  125. 125. Receptor Transduction Mechanisms <ul><li>Ion channel linked receptors e.g. Ach nicotinic (Na + ) and GABA (Cl - ) </li></ul><ul><li>Second messenger generation, </li></ul><ul><li>adenylate cyclase stimulation or inhibition - cAMP, </li></ul><ul><li>guanylate cyclase - cGMP, </li></ul><ul><li>phospholipase C - IP3, DAG </li></ul><ul><li>Some receptors are themselves protein kinases </li></ul><ul><li>Intracellular receptors (e.g. corticosteroids, thyroid hormone) </li></ul>www.freelivedoctor.com
  126. 126. k1 D + R <=> DR k2 By Law of Mass Action: [D] • [R] • K 1 = [DR] • K 2 Therefore K 2 /K 1 = K d = [D] • [R]/[DR] If R T = total # of receptors, then R T = [R] + [DR] Replace [R] by (R T -[DR]) and rearrange: [DR] [D] RT Kd + [D] = OCCUPATION THEORY OF DRUG-RECEPTOR INTERACTIONS EFFECT effect Max. effect = www.freelivedoctor.com
  127. 127. www.freelivedoctor.com
  128. 128. Receptor Binding % Bound Concentration of Ligand K d www.freelivedoctor.com
  129. 129. [D] (concentration units) [DR]/R T 0.01 0.10 1.00 10.00 100.00 0.00 0.25 0.50 0.75 1.00 Kd=1 kd=5 Kd=0.5 Compounds Have Different Affinities for the Same Receptor www.freelivedoctor.com
  130. 130. Competitive Noncompetitive Types of Receptor Antagonists www.freelivedoctor.com
  131. 131. www.freelivedoctor.com
  132. 132. [D] (concentration units) % Maximal Effect 0.01 0.10 1.00 10.00 100.00 1000.00 0.0 0.2 0.4 0.6 0.8 1.0 Partial agonist Full Agonist Partial agonist PARTIAL AGONISTS - EFFICACY Even though drugs may occupy the same # of receptors, the magnitude of their effects may differ. www.freelivedoctor.com
  133. 133. www.freelivedoctor.com
  134. 134. Drug (D) Ri DRi DRa Ra CONFORMATIONAL SELECTION HOW TO EXPLAIN EFFICACY? The relative affinity Of the drug to either conformation will determine the effect of the drug www.freelivedoctor.com
  135. 135. R R 1 * R 2 * R 3 * R R R 1 * R 1 * R 2 * R 2 * R 3 * R 3 * www.freelivedoctor.com
  136. 136. Spare Receptors www.freelivedoctor.com
  137. 137. Receptor Regulation <ul><li>Sensitization or Up-regulation </li></ul><ul><li>1. Prolonged/continuous use of receptor blocker </li></ul><ul><li>2. Inhibition of synthesis or release of hormone/neurotransmitter - Denervation </li></ul><ul><li>Desensitization or Down-regulation </li></ul><ul><li>1. Prolonged/continuous use of agonist </li></ul><ul><li>2. Inhibition of degradation or uptake of agonist </li></ul><ul><li>Homologous vs. Heterologous </li></ul><ul><li>Uncoupling vs. Decreased Numbers </li></ul>www.freelivedoctor.com
  138. 138. www.freelivedoctor.com
  139. 139. www.freelivedoctor.com
  140. 140. www.freelivedoctor.com
  141. 141. GRADED DOSE-RESPONSE CURVE ED50 ED50 www.freelivedoctor.com
  142. 142. QUANTAL DOSE-RESPONSE CURVE Frequency Distribution Cumulative Frequency Distribution www.freelivedoctor.com
  143. 143. www.freelivedoctor.com
  144. 144. Morphine Aspirin www.freelivedoctor.com
  145. 145. THERAPEUTIC INDEX – AN INDEX OF SAFETY Hypnosis Death www.freelivedoctor.com
  146. 146. Margin of Safety = LD 1 ED 99 ED 50 A ED 99 A LD 1 A www.freelivedoctor.com
  147. 147. Causes of Variability in Drug Response <ul><ul><li>Those related to the biological system </li></ul></ul><ul><ul><li>1. Body weight and size </li></ul></ul><ul><ul><li>2. Age and Sex </li></ul></ul><ul><ul><li>3. Genetics - pharmacogenetics </li></ul></ul><ul><ul><li>4. Condition of health </li></ul></ul><ul><ul><li>5. Placebo effect </li></ul></ul>www.freelivedoctor.com
  148. 148. Causes of Variability in Drug Response <ul><li>Those related to the conditions of administration </li></ul><ul><li>1. Dose, formulation, route of administration. </li></ul><ul><li>2. Resulting from repeated administration of drug: </li></ul><ul><li>drug resistance; drug tolerance-tachyphylaxis; drug allergy </li></ul><ul><li>3. Drug interactions: </li></ul><ul><li>chemical or physical; </li></ul><ul><li>GI absorption; </li></ul><ul><li>protein binding/distribution; </li></ul><ul><li>metabolism (stimulation/inhibition); </li></ul><ul><li>excretion (ph/transport processes); </li></ul><ul><li>receptor (potentiation/antagonism); </li></ul><ul><li>changes in pH or electrolytes. </li></ul>www.freelivedoctor.com