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Pharmacodynamics. HuBio 543 September 6, 2007 Frank F. Vincenzi. Receptors, signal transduction, transmembrane signaling Agonist, antagonist, partial agonist, inverse agonist, multiple receptor states Intrinsic activity, efficacy, SAR Desensitization, up and down regulation.

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Pharmacodynamics l.jpg

Pharmacodynamics

HuBio 543

September 6, 2007

Frank F. Vincenzi


Learning objectives l.jpg

Receptors, signal transduction, transmembrane signaling

Agonist, antagonist, partial agonist, inverse agonist, multiple receptor states

Intrinsic activity, efficacy, SAR

Desensitization, up and down regulation

Quantification of drug receptor interactions and responses

Potency

Schild equation and regression

Competitive and non-competitive antagonism

Spare receptors

Kd, EC50, pD2, pA2

Learning Objectives


Typical concentration effect curve plotted arithmetically l.jpg
Typical concentration-effect curve(plotted arithmetically)



Typical log concentration effect curve graded dose response curve l.jpg
Typical log concentration-effect curve(graded ‘dose-response’ curve)


Drug d receptor r interaction l.jpg
Drug(D) - Receptor (R) Interaction

k1

D + R

DR

k2

Kd = ([D] * [R]) / [DR] = k2/k1

Kd = dissociation constant

k1 = association rate constant

k2 = dissociation rate constant


Several ways to express agonist potency or apparent affinity of agonists l.jpg
Several ways to express agonist potency &/or apparent affinity of agonists

EC50 (effective concentration, 50%, M)

Kd (apparent dissociation constant, M)

pD2 (negative log of molar concentration (M)

of the drug giving a response, which

when compared to the maximum,

gives a ratio of 2) (i.e., negative log

of half maximal concentration)


The classical concentration effect relationship and the laws of mass action l.jpg
The classical concentration-effect relationship and the laws of mass action

Effect = (Effectmax * conc)/(conc + EC50)

In the previous data slide EC50 ~ 3 x 10-9 M

Thus, the apparent Kd of ACh ~ 3 x 10-9 M

IF (NOTE, BIG IF)

EC50 = Kd then

Bound drug = (Bmax * conc)/(conc + Kd)


Binding of a radioligand to tissue samples l.jpg
Binding of a radioligand to tissue samples of mass action

Adapted fromSchaffhauser et al., 1998


Scatchard analysis of binding of 125 iodocyanopindolol to beta receptors in human heart l.jpg
Scatchard analysis of binding of of mass action125iodocyanopindolol to beta-receptors in human heart

Adapted fromHeitz et al., 1983


Acetylcholine ach one drug with different affinities for two different receptors l.jpg
Acetylcholine (ACh): One drug with different affinities for two different receptors

(adapted from Clark, 1933)


Ach different affinities for different receptors l.jpg
ACh: Different affinities for different receptors two different receptors

  • Muscarinic receptors

    • EC50 = apparent Kd ~ 3 x 10-8 M, pD2 ~7.5

  • Nicotinic receptor

    • EC50 = apparent Kd ~ 3 x 10-6 M, pD2 ~5.5

    • In these experiments, affinity of ACh for muscarinic receptors is apparently ~100 times greater than for nicotinic receptors. ACh is 100 times more potent as a muscarinic agonist than as a nicotinic agonist. So, when injected as a drug, muscarinic effects normally predominate, unless the muscarinic receptors are blocked. (No problem for nerves releasing ACh locally onto nicotinic receptors, however).


  • Properties of an agonist e g ach on receptors lacking spontaneous activity l.jpg
    Properties of an agonist (e.g., ACh) two different receptors (on receptors lacking spontaneous activity)

    • Accessibility

    • Affinity

    • Intrinsic activity > 0


    Different affinities of related agonist drugs for the same receptor different potencies l.jpg
    Different affinities of related agonist drugs for the same receptor: Different potencies

    (adapted from Ariëns et al., 1964)


    Properties of an antagonist on receptors lacking spontaneous activity l.jpg
    Properties of an antagonist receptor: Different potencies (on receptors lacking spontaneous activity)

    • Accessibility

    • Affinity

    • Intrinsic activity = 0


    Pharmacological antagonism in an intact animal l.jpg
    Pharmacological antagonism in an intact animal receptor: Different potencies


    Properties of a partial agonist on receptors lacking spontaneous activity l.jpg
    Properties of a partial agonist receptor: Different potencies (on receptors lacking spontaneous activity)

    • Accessibility

    • Affinity

    • 0 < Intrinsic activity < 1


    Theoretical concentration effect curves for a full and partial agonist of a given receptor l.jpg
    Theoretical concentration-effect curves for a full and partial agonist of a given receptor


    Multiple receptor conformational states how to understand agonists partial agonists and antagonists l.jpg
    Multiple receptor conformational states: partial agonist of a given receptorHow to understand agonists, partial agonists and antagonists


    Simple case receptor has little or no spontaneous activity in the absence of added drug l.jpg
    Simple case: receptor has little or no spontaneous activity in the absence of added drug

    ‘inactive’ R

    ‘active’ R


    Slide21 l.jpg
    An agonist binds more tightly to the ‘active’ state of the receptor: Equilibrium shifts to the active state


    Slide22 l.jpg
    A competitive antagonist binds equally tightly to the ‘inactive’ and active states of the receptor: No change in equilibrium


    Slide23 l.jpg
    A partial agonist binds to both the ‘inactive’ and ‘active’ states of the receptor: Partial shift of equilibrium


    Slide24 l.jpg

    Multiple receptor states: ‘active’ states of the receptor:How to understand inverse agonists(in this LESS SIMPLE case, the receptorhas spontaneous (often called constituitive) activity in the absence of added drug)



    Slide26 l.jpg
    Inverse agonists bind more tightly to the resting state of the spontaneously active receptor: Equilibrium shifts toward the inactive state


    Receptor activation by agonists inverse agonists etc l.jpg
    Receptor activation by agonists, the spontaneously active receptor: Equilibrium shifts toward the inactive stateinverse agonists, etc.

    Newman-Tancredi et al., 1997


    How to quantify drug antagonism l.jpg
    How to quantify drug antagonism the spontaneously active receptor: Equilibrium shifts toward the inactive state

    • Schild Equation

      • (C’/C) = 1 + ([I]/Ki)

  • Schild plot or Schild regression

    • log(C’/C - 1) vs. log [I]

  • pA2 = -log([I] giving a dose ratio of 2)

  • Where [I] = Kd of antagonist at its receptor.


  • Antagonism of acetylcholine by atropine l.jpg
    Antagonism of acetylcholine by atropine the spontaneously active receptor: Equilibrium shifts toward the inactive state

    Adapted from Altiere et al., 1994


    Schild plot of antagonism of acetylcholine by atropine l.jpg
    Schild plot of antagonism of acetylcholine by atropine the spontaneously active receptor: Equilibrium shifts toward the inactive state

    Adapted from Altiere et al., 1994


    Antagonism of acetylcholine by pirenzepine l.jpg
    Antagonism of acetylcholine by pirenzepine the spontaneously active receptor: Equilibrium shifts toward the inactive state

    Adapted from Altiere et al., 1994


    Schild plot antagonism of acetylcholine by two different antagonists l.jpg
    Schild plot: Antagonism of acetylcholine by two different antagonists

    3

    atropine

    pirenzepine

    2

    1

    0

    -6

    -5

    -10

    -9

    -8

    -7

    log [antagonist] (M)

    Adapted from Altiere et al., 1994


    Slide33 l.jpg
    Different antagonistspA2 values (affinities)for different receptors of some clinically useful drugs:The basis of therapeutic selectivity



    How nature achieves neurotransmitter sensitivity without a loss of speed spare receptors l.jpg
    How nature achieves neurotransmitter antagonists sensitivity without a loss of speed: Spare receptors:


    Drug d receptor r interaction36 l.jpg
    Drug antagonists(D) - Receptor (R) Interaction

    k1

    D + R

    DR

    k2

    Kd = ([D] * [R]) / [DR] = k2/k1

    Kd = dissociation constant

    k1 = association rate constant

    k2 = dissociation rate constant