Drug-Receptor Interactions

  • Signal Transduction

    • Agonist: a chemical signal that triggers a specific response

    • Antagonist: a chemical signal that blocks a specific response

      • may block receptor

      • may bind different receptor

    • Drug-receptor complex

      • Inactive (R) vs active (R*)

        • full vs partial agonist

  • Receptor Families

    • transmembrane ligand-gate ion channels

    • transmembrane G protein coupled receptors

      • unoccupied receptor does not interact with G protein → occupied receptor changes shape and interacts with G protein, G protein releases GDP and binds GTP → alpha subunit of G protein dissociates and activates adenylyl cyclase → when hormone is no longer present, the receptor reverts to its resting state, GTP on the alpha subunit is hydrolyzed to GDP, and adenylyl cyclase is deactivated

    • enzyme linked receptors

    • intracellular receptors

  • Advantages/Disadvantages

    • signal amplification

    • desensitization/down-regulation

  • Dose Response Relationship

    • increase dose = increase efficacy

      • potency

        • reference is EC50

          • 50% of receptors occupied

        • can be related to duration of occupation

      • efficacy

        • reference is Emax

        • concentration is required to get to Emax

        • depends upon number of receptors occupied

        • requires receptors to be occupied and activated

    • increased dose does not equal increased effect

      • dependent upon kinetics of receptor binding or dissociation constant Kd

        • [DR]/[Rt] = [D]/Kd+[D]

        • [E]/[Emax] = [D]/Kd+[D]

  • Intrinsic Activity

    • full agonists

      • maximal biologic effect

        • mimics endogenous compound

        • binds to and activates the receptor

          • intrinsic activity = 1

    • partial agonists

      • 0 < intrinsic activity < 1

      • reduced biologic effect

      • activity may interfere with other endogenous/exogenous activity

        • can be used to reduce a response

    • inverse agonists

      • stabilize receptor inactive (binds to and inactivates the receptor)

      • biologic activity < 0

  • Antagonists

    • competitive

      • binds to same site on receptor as agonist

        • Emax depends upon the Kd of both the agonist and antagonist

      • reduces potency (increases EC50) but Emax remains the same

    • irreversible

      • covalently binds to active site on receptor

      • reduces Emax, but potency (EC50) remains the same

    • allosteric

      • binds to a different site than the agonist

      • reduces Emax, but potency (EC50) remains the same

    • functional

      • binds to completely separate receptor

  • Quantal Dose-Response Relationships

    • therapeutic index

      • the range between effective does (ED50) and toxic dose (TD50)

      • TI= TD50/ED50

      • clinical usefulness

        • disease states can alter TI