Drug receptor interactions

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Drug receptor interactions

  1. 1. Law of Mass Action <ul><li>When a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor. </li></ul><ul><li>D = drug </li></ul><ul><li>R = receptor, </li></ul><ul><li>DR = drug-receptor complex </li></ul><ul><li>k 1 = rate for association and </li></ul><ul><li>k 2 = rate for dissociation. </li></ul><ul><li>K D = Dissociation Constant </li></ul><ul><li>K A = Association Constant </li></ul><ul><li>  </li></ul><ul><li>k 1 </li></ul><ul><li>[D] + [R]  [DR] </li></ul><ul><li> k 2 </li></ul><ul><ul><ul><li>k 2 = K D = [D][R] </li></ul></ul></ul><ul><ul><ul><li>k 1 [DR] </li></ul></ul></ul><ul><li>1 = K A = k 1 = [DR] </li></ul><ul><li>K D k 2 [D] [R] </li></ul>www.freelivedoctor.com
  2. 2. SATURATION CURVE Log [Drug] Drug-Receptor Complex [Drug] nM DR www.freelivedoctor.com
  3. 3. SATURATION CURVE [DR] [Drug] nM R T = Bmax R T = Total number of receptors Bmax = Maximal number of receptors Bound <ul><ul><ul><li>k 2 = K D = [D][R] </li></ul></ul></ul><ul><ul><ul><li>k 1 [DR] </li></ul></ul></ul>[DR] max www.freelivedoctor.com
  4. 4. TIME COURSE [DR] Equilibrium K D = Equilibrium Dissociation Constant <ul><ul><ul><li>k 2 = K D = [D][R] </li></ul></ul></ul><ul><ul><ul><li>k 1 [DR] </li></ul></ul></ul>[D] + [R] = [DR] 0 10 20 30 40 50 60 Time (min) www.freelivedoctor.com
  5. 5. SATURATION CURVE [Drug] nM [DR] K D At equilibrium, the dissociation constant is K D and the affinity is K A = 1/K D Thus when [D] = K D , half the total number of receptors will be occupied. www.freelivedoctor.com
  6. 6. Agonists and Antagonists <ul><li>AGONIST </li></ul><ul><li>A drug is said to be an agonist when it binds to a receptor and causes a response or effect. </li></ul><ul><li>It has intrinsic activity = 1 </li></ul>+ + + + + - - - - + - - www.freelivedoctor.com - - - + + +
  7. 7. Agonists and Antagonists <ul><li>ANTAGONIST </li></ul><ul><li>A drug is said to be an antagonist when it binds to a receptor and prevents (blocks or inhibits) a natural compound or a drug to have an effect on the receptor. An antagonist has NO activity. </li></ul><ul><li>Its intrinsic activity is = 0 </li></ul>www.freelivedoctor.com
  8. 8. Agonists and Antagonists <ul><li>PHARMACOLOGICAL ANTAGONISTS </li></ul><ul><li>Competitive </li></ul><ul><ul><ul><li>They compete for the binding site </li></ul></ul></ul><ul><ul><ul><ul><li>Reversible </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Irreversible </li></ul></ul></ul></ul><ul><li>Non-competitve </li></ul><ul><ul><li>Bind elsewhere in the receptor (Channel Blockers). </li></ul></ul>www.freelivedoctor.com
  9. 9. Agonists and Antagonists <ul><li>FUNCTIONAL ANTAGONISTS </li></ul><ul><li>Physiologic Antagonists </li></ul><ul><li>Chemical Antagonist </li></ul>www.freelivedoctor.com
  10. 10. Agonists and Antagonists <ul><li>Physiologic ANTAGONIST </li></ul><ul><li>A drug that binds to a non-related receptor, producing an effect opposite to that produced by the drug of interest. </li></ul><ul><li>Its intrinsic activity is = 1, but on another receptor. </li></ul>Glucocorticoid Hormones  Blood Sugar Insulin  Blood Sugar www.freelivedoctor.com
  11. 11. Agonists and Antagonists <ul><li>Chemical ANTAGONIST </li></ul><ul><li>A chelator (sequester) of similar agent that interacts directly with the drug being antagonized to remove it or prevent it from binding its receptor. </li></ul><ul><li>A chemical antagonist does not depend on interaction with the agonist’s receptor (although such interaction may occur). </li></ul>Heparin , an anticoagulant, acidic If there is too much  bleeding and haemorrhaging Protamine sulfate is a base. It forms a stable inactive complex with heparin and inactivates it. www.freelivedoctor.com
  12. 12. Competition Binding Log [I] nM IC50 Binding of Drug D I = Competitor www.freelivedoctor.com
  13. 13. Competition Binding RANK ORDER OF POTENCY: A > B > C > D www.freelivedoctor.com Log [I] nM IC50 A B C D Four drugs
  14. 14. Drug Concentration Response SEMILOG DOSE-RESPONSE CURVE Effect or www.freelivedoctor.com
  15. 15. Drug Concentration Response SEMILOG DOSE-RESPONSE CURVE www.freelivedoctor.com ED50 50% Effect Maximal Effect Effect or
  16. 16. SEMILOG DOSE-RESPONSE CURVE www.freelivedoctor.com EFFECT POTENCY EFFICACY ED50 Maximal Effect Log [Dose]
  17. 17. SEMILOG DOSE-RESPONSE CURVE RANK ORDER OF POTENCY: A > B > C > D www.freelivedoctor.com A B C D EFFECT Log [Dose]
  18. 18. SEMILOG DOSE-RESPONSE CURVE RANK ORDER OF POTENCY: A > B > C > D RANK ORDER OF EFFICACY: A = C > B > D ED50 www.freelivedoctor.com A B C D RESPONSE
  19. 19. Agonists and Antagonists <ul><li>PARTIAL AGONIST </li></ul><ul><li>A drug is said to be a partial agonist when it binds to a receptor and causes a partial response. </li></ul><ul><li>It has intrinsic activity < 1. </li></ul>www.freelivedoctor.com
  20. 20. Agonists and Antagonists <ul><li>1. COMPETITIVE ANTAGONIST </li></ul><ul><li>Reversible & Surmountable </li></ul><ul><li>The effect of a reversible antagonist can be overcome by more drug (agonist). A small dose of the antagonist (inhibitor) will compete with a </li></ul>fraction of the receptors thus, the higher the concentration of antagonist used, the more drug you need to get the same effect. www.freelivedoctor.com
  21. 21. Agonists and Antagonists <ul><li>RECEPTOR RESERVE OR SPARE RECEPTORS. </li></ul><ul><ul><ul><li>Maximal effect does not require occupation of all receptors by agonist. </li></ul></ul></ul><ul><ul><ul><li>Low concentrations of competitive irreversible antagonists may bind to receptors and a maximal response can still be achieved. </li></ul></ul></ul><ul><ul><ul><li>The actual number of receptors may exceed the number of effector molecules available. </li></ul></ul></ul>www.freelivedoctor.com
  22. 22. Agonists and Antagonists <ul><li>1. COMPETITIVE ANTAGONIST </li></ul><ul><li>Irreversible & Non-surmountable </li></ul><ul><li>The effect of irreversible antagonists cannot be overcome by more drug (agonist). The antagonist inactivates the receptors. </li></ul>www.freelivedoctor.com
  23. 23. Drug Concentration LINEWEAVER-BURKE PLOT 1 www.freelivedoctor.com 1 K D 1 Effect 1 Bmax K D Bmax 1 [D]
  24. 24. Agonists and Antagonists <ul><li>Synergism </li></ul><ul><li>The combined effect of two drugs is higher than the sum of their individual effects. </li></ul><ul><li>Additivity </li></ul><ul><li>The combined effect of two drugs is equal to the sum of their individual effects. </li></ul>www.freelivedoctor.com
  25. 25. Quantal Dose-response Curves <ul><li>Frequency of distribution </li></ul><ul><li>% population responding to drug A </li></ul>www.freelivedoctor.com 1 10 20 30 40 50 60 70 80 90 100 Dose (mg/kg) % population responding
  26. 26. Quantal Dose-response Curves <ul><li>Cumulative distribution of population responding to drug A </li></ul>1 10 100 Dose (mg/kg) log scale % population responding ED50 ED90 ED10 www.freelivedoctor.com
  27. 27. Therapeutic Index Toxic effect www.freelivedoctor.com
  28. 28. Therapeutic index <ul><li>Therapeutic Index = TxD50 </li></ul><ul><li>ED50 </li></ul><ul><li>As long as the slopes of the curves are similar, however, if not similar, we use the Standard Margin of safety: </li></ul><ul><li>Standard Margin of safety = TxD1–1 x 100 </li></ul><ul><li>ED99 </li></ul><ul><li>Which determines the percent to which the dose effective in 99% of the population must be raised to cause toxicity in 1% of the population. </li></ul>www.freelivedoctor.com
  29. 29. Therapeutic Index Toxic effect ED99 ED13 ED1 www.freelivedoctor.com
  30. 30. APPENDIX www.freelivedoctor.com
  31. 31. Law of Mass Action <ul><li>When a drug (D) combines with a receptor (R), it does so at a rate which is dependent on the concentration of the drug and the concentration of the receptor. </li></ul><ul><li>k 1 </li></ul><ul><li>[D] + [R]  [DR] (1) </li></ul><ul><li>k 2 </li></ul><ul><li>D = drug </li></ul><ul><li>R = receptor, </li></ul><ul><li>DR = drug-receptor complex </li></ul><ul><li>k 1 = rate for association and </li></ul><ul><li>k 2 = rate for dissociation.   </li></ul>www.freelivedoctor.com
  32. 32. Law of Mass Action <ul><li>At equilibrium, the rate at which the radioligand binds to the receptor is equal to the rate at which it dissociates: </li></ul><ul><li>  </li></ul><ul><li>association rate = dissociation rate </li></ul><ul><li>  </li></ul><ul><ul><ul><li>k 1 [D][R] = k 2 [DR] (2) </li></ul></ul></ul><ul><ul><ul><li>  </li></ul></ul></ul><ul><ul><ul><li>k 2 = [D][R] </li></ul></ul></ul><ul><ul><ul><li>k 1 [DR] (3) </li></ul></ul></ul><ul><ul><ul><li>  </li></ul></ul></ul><ul><ul><ul><li>k 2 = K D = [D][R] </li></ul></ul></ul><ul><ul><ul><li>k 1 [DR] (4) </li></ul></ul></ul><ul><ul><ul><li>  </li></ul></ul></ul><ul><li>Where K D is the equilibrium dissociation constant. The units for the K D are concentration units (e.g. nM). </li></ul>www.freelivedoctor.com
  33. 33. Law of Mass Action <ul><li>Another constant related to the K D is the affinity (K A ) which is essentially equivalent to the reciprocal of the K D . The units for the K A are inverse concentration units (e.g. nM -1 ). </li></ul><ul><li>  </li></ul><ul><li>1 = K A = k 1 = [DR] </li></ul><ul><li>K D k 2 [D] [R] (5) </li></ul><ul><li>The relationship between the binding of a drug to a receptor at equilibrium and the free concentration of the drug provides the basis for characterizing the affinity of the drug for the receptor. The mathematical derivation of this relationship is given below: </li></ul><ul><li>  </li></ul><ul><li>K D = [D][R] </li></ul><ul><li>[DR] (6) </li></ul><ul><li>  </li></ul><ul><li>K D [DR] = [D][R] (7) </li></ul>www.freelivedoctor.com
  34. 34. Law of Mass Action <ul><li>Substitutions: </li></ul><ul><li> [R T ] = [R] = [DR] </li></ul><ul><li>… [R] = [R T ] - [DR] (8) </li></ul><ul><li>  </li></ul><ul><li>K D [DR] = [D]([R T ] - [DR]) (9) </li></ul><ul><li>  </li></ul><ul><li>K D [DR] = [D][R T ] - [D][DR] (10) </li></ul><ul><li>  </li></ul><ul><li>K D [DR] + [D][DR] = [D][R T ] (11) </li></ul><ul><li> </li></ul><ul><li>[DR](K D + [D]) = [D][R T ] (12) </li></ul><ul><li>[DR] = [D][R T ] (13) </li></ul><ul><li>[D] + K D </li></ul><ul><li>R T : Total number of receptors </li></ul>www.freelivedoctor.com
  35. 35. Law of Mass Action <ul><li>[DR] = [D][R T ] (13) </li></ul><ul><li>[D] + K D </li></ul><ul><li>  </li></ul><ul><li>This relationship between specific binding [DR] and the free drug concentration [D] in (13) is essentially the same as the relationship between the substrate concentration ([S]) and the velocity of an enzymatic reaction (v) as described by the Michaelis-Menten relationship: </li></ul><ul><li>    v = [S] V max </li></ul><ul><li>[S] + K M </li></ul><ul><li>  </li></ul><ul><li>Michaelis-Menten Relationship </li></ul><ul><li>   </li></ul><ul><li>where V max denotes the maximum rate of the reaction and K M denotes the Michaelis constant, which is equivalent to the concentration of substrate required for half-maximal velocity </li></ul>www.freelivedoctor.com

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