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DOSE-RESPONSE RELATIONSHIPS

DOSE-RESPONSE RELATIONSHIPS. D. R. R. Dr. Alexandra Newton January 12 2012. Goal. To understand dose-response relationships and how these are affected by antagonists. D. Molecular. Albuterol. R. R. b 2 adrenergic receptor. Cellular. Organ. [cAMP]. Human. Bronchodilation.

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DOSE-RESPONSE RELATIONSHIPS

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  1. DOSE-RESPONSE RELATIONSHIPS D R R Dr. Alexandra Newton January 12 2012

  2. Goal To understand dose-response relationships and how these are affected by antagonists

  3. D Molecular Albuterol R R b2 adrenergic receptor Cellular Organ [cAMP] Human Bronchodilation D + R DR Response Asthma

  4. D Lecture Outline • Dose-Response Relationships • Law of mass action and reversible binding • Relationship between drug concentration and receptor occupancy • Antagonists (competitive and noncompetitive) • Population responses R R

  5. Law of Mass Action rate constant, units M-1 sec-1 k1 D + R DR Response k-1 rate constant, units sec-1 • D and R associate at rate proportional to both [D] and [R] • DRdissociates at rate proportional to [DR] only • Reversible

  6. k1 D + R DR Response Rate of association = k1[D][R] Rate of dissociation = k-1[DR] ← proportional to both [D] and [R] ← proportional to [DR] only k-1 k1[D][R] = k-1[DR] At steady state, rate of association = rate of dissociation [D][R] [DR] k-1 __ _____ Kd = = k1 equilibrium dissociation constant units = M

  7. Relationship between equilibrium constant and free energy: R=1.98 cal/°mol T=310 °K = 37 °C DG = -RTlnK

  8. D Lecture Outline • Dose-Response Relationships • Law of mass action and reversible binding • Relationship between drug concentration and receptor occupancy • Antagonists (competitive and noncompetitive) • Population responses R R

  9. Relationship between Drug Concentration and Response or Receptor Occupancy Drug concentration at which drug effect (response) is half-maximal = EC50 Drug concentration at which receptor-bound drug (receptor occupancy) is half-maximal = Kd D + R DR Response

  10. Relationship between Kd and Receptor Occupancy Receptor occupancy = fraction of total receptors (RT) occupied by drug (aka fractional saturation) = [DR]/[RT] Fractional saturation = = [DR] [DR] [DR] ___ ___ ___ ← When [D] = Kd, [R] = [DR] and [DR]/[RT] = 0.5 [RT] [RT] [RT] [D][R] 1.0 [DR] [DR] _______ k-1 [R] + [DR] __ _____ Kd = = log Kd k1 log [D]

  11. Agonists 100 Full agonist: maximal response Partial agonist: partial response Inverse agonist: decreases basal response Response 0 0.1 10 1000 [D], nM

  12. D Lecture Outline • Dose-Response Relationships • Law of mass action and reversible binding • Relationship between drug concentration and receptor occupancy • Antagonists (competitive and noncompetitive) • Population responses R R

  13. D D I I I I I Antagonists aka inhibitors (I) Bind to receptor but do not promote response Competitive antagonist Noncompetitive antagonist I I I + R IR No response

  14. Competitive Antagonist I + Kd IR Ki D + R DR Response

  15. I + I + Noncompetitive Antagonist Kd D + IR IRD Ki Ki Kd 1 _______ 1 + [I]/Ki Kd remains unchanged Maximum response is reduced D + R DR Response

  16. More Definitions • Mixed antagonist: binds to separate site but modulates the ability of agonist to bind • Physiological antagonist: a drug (or endogenous mediator) that antagonizes the effect of another drug (or endogenous mediator) by producing an opposing physiological response, typically by a different type of receptor. • Example:epinephrine acting at β1 receptors physiologically opposes the decrease in heart rate that occurs in response to acetylcholine acting at M2 receptors • Reversible antagonist: reversible binding • Irreversible antagonist: irreversible binding (law of mass action not followed) • Allosteric activator: binds to site independent of agonist binding site and enhances activity of agonist • Allosteric inhibitor: binds to site independent of agonist binding site and reduces activity of agonist

  17. Receptor Desensitization Response decreases with time and/or repetitive stimulation

  18. Potency and Efficacy Potency refers to the dose that causes a given effect most potent = lowest EC50 least potent = highest EC50 Efficacy refers to the maximum response (effect) most efficacious = largest response least efficacious = smallest response

  19. D Lecture Outline • Dose-Response Relationships • Law of mass action and reversible binding • Relationship between drug concentration and receptor occupancy • Antagonists (competitive and noncompetitive) • Population responses R R

  20. Quantal Dose-Response Curves Therapeutic index = LD50/ED50 Median effective dose: produces specified effect in 50% of patients ED50 LD50 Median lethal dose

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