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Pharmacodynamics
HuBio 543
September 6, 2007
Frank F. Vincenzi
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Learning Objectives
• 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
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Typical concentration-effect curve(plotted arithmetically)
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A slide rule (logarithmic scale)
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Typical log concentration-effect curve(graded ‘dose-response’ curve)
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Drug (D) - Receptor (R) Interaction
Kd = ([D] * [R]) / [DR] = k2/k1
k1
k2
D + R DR
Kd = dissociation constantk1 = association rate constantk2 = dissociation rate constant
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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)
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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)
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Binding of a radioligand to tissue samples
Adapted from Schaffhauser et al., 1998
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Scatchard analysis of binding of 125iodocyanopindolol to beta-receptors in human heart
Adapted from Heitz et al., 1983
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Acetylcholine (ACh): One drug with different affinities for two different receptors
(adapted from Clark, 1933)
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ACh: Different affinities for 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).
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Properties of an agonist (e.g., ACh) (on receptors lacking spontaneous activity)
• Accessibility
• Affinity
• Intrinsic activity > 0
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Different affinities of related agonist drugs for the same receptor: Different potencies
(adapted from Ariëns et al., 1964)
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Properties of an antagonist (on receptors lacking spontaneous activity)
• Accessibility
• Affinity
• Intrinsic activity = 0
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Pharmacological antagonism in an intact animal
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Properties of a partial agonist (on receptors lacking spontaneous activity)
• Accessibility
• Affinity
• 0 < Intrinsic activity < 1
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Theoretical concentration-effect curves for a full and partial agonist of a given receptor
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Multiple receptor conformational states:How to understand agonists, partial agonists
and antagonists
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Simple case: receptor has little or no spontaneous activity in the absence of added drug
‘inactive’ R ‘active’ R
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An agonist binds more tightly to the ‘active’ state of the receptor:
Equilibrium shifts to the active state
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A competitive antagonist binds equally tightly to the ‘inactive’ and active states of the
receptor: No change in equilibrium
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A partial agonist binds to both the ‘inactive’ and ‘active’ states of the receptor:
Partial shift of equilibrium
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Multiple receptor states: How to understand inverse agonists
(in this LESS SIMPLE case, the receptor
has spontaneous (often called constituitive) activity in the absence of added drug)
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The less simple case: Some receptors are ‘active’ even in the absence of added drug
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Inverse agonists bind more tightly to the resting state of the spontaneously active receptor: Equilibrium shifts toward the inactive state
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Receptor activation by agonists, inverse agonists, etc.
Newman-Tancredi et al., 1997
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How to quantify drug antagonism
• 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.
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Antagonism of acetylcholine by atropine
Adapted from Altiere et al., 1994
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Schild plot of antagonism of acetylcholine by atropine
Adapted from Altiere et al., 1994
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Antagonism of acetylcholine by pirenzepine
Adapted from Altiere et al., 1994
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Schild plot: Antagonism of acetylcholine by two different antagonists
Adapted from Altiere et al., 1994
-6 -5-10 -9 -8 -70
1
2
3
log [antagonist] (M)
atropine
pirenzepine
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DifferentpA2
values (affinities)for different receptors of some clinically
useful drugs:
The basis of therapeutic selectivity
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Evidence for the existence of spare receptors
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How nature achieves neurotransmitter sensitivity without a loss of speed:
Spare receptors:
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Drug (D) - Receptor (R) Interaction
Kd = ([D] * [R]) / [DR] = k2/k1
k1
k2
D + R DR
Kd = dissociation constantk1 = association rate constantk2 = dissociation rate constant