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Pharmacodynamics

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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

Quantification of drug receptor interactions and responses

Potency

Schild equation and regression

Competitive and non-competitive antagonism

Spare receptors

Kd, EC50, pD2, pA2

k1

D + R

DR

k2

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

Kd = dissociation constant

k1 = association rate constant

k2 = dissociation rate constant

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)

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)

Adapted fromSchaffhauser et al., 1998

Adapted fromHeitz et al., 1983

(adapted from Clark, 1933)

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

- 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).

- Accessibility
- Affinity
- Intrinsic activity > 0

(adapted from Ariëns et al., 1964)

- Accessibility
- Affinity
- Intrinsic activity = 0

- Accessibility
- Affinity
- 0 < Intrinsic activity < 1

‘inactive’ R

‘active’ R

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

Newman-Tancredi et al., 1997

- Schild Equation
- (C’/C) = 1 + ([I]/Ki)

- log(C’/C - 1) vs. log [I]

Adapted from Altiere et al., 1994

Adapted from Altiere et al., 1994

Adapted from Altiere et al., 1994

3

atropine

pirenzepine

2

1

0

-6

-5

-10

-9

-8

-7

log [antagonist] (M)

Adapted from Altiere et al., 1994

k1

D + R

DR

k2

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

Kd = dissociation constant

k1 = association rate constant

k2 = dissociation rate constant