Pharmacodynamics 1

Question 1

Pharmodynamics

Answer 1

Mechanisms of Action of Drugs

Therapeutic Uses

Adverse (Side) Effects

Question 2

Pharmacokinetics

Answer 2

Absorption

Distribution

Metabolism

Elimination

Question 3

Mechanisms of Drug Action

Answer 3

The effects on the body of most drugs are a result of interactions with functional macromolecular components of the organism

Question 4

Corollary

Answer 4

Drugs do not create effects, they modify ongoing functions

Question 5

Ligand + Receptor ⇔

Answer 5

⇔ LR complex → Effect

Question 6

Occupancy Theory

Answer 6

Occupancy of the receptor by the ligand causes effect

Question 7

Other Drug Interactions Besides with Receptors

Answer 7

Enzyme inhibitors

Transport inhibitors

Inihibitors of ion channels

Other: eg. Heparin binds to thrombin and antithrombin

Question 8

Why are receptors an excellent drug target

Answer 8

Provide Specificity

Provide Selectivity

Provide Sensitivity

Question 9

Classification Schemes of Receptors

Answer 9

1) Pharmacological - Based on structure activity studies, basis of most receptor names
2) Biochemical - Based on transduction mechanism
3) Molecular/Structural - Families of similar gene products

Question 10

k₁ and k₂

Answer 10

k1 = Rate constant for association

k2 = Rate constant for dissociation

Question 11

Law of Mass Action at Equilibrium

Answer 11

k₁ [L] x [R] = k₂ [LR]

k₁ has units of sec^-1M^-1

k₂ has units of sec^-1

Question 12

Dissociation Constant (equation)

Answer 12

K_D = ([L] x [R])/[LR] = k₂/k₁

Question 13

What is the function of K_D

Answer 13

Describes the “goodness of fit” between L and receptor

Inversely related to the affinity of L for the receptor

Has units of concentration (mols/liter or molar (M), for example)

Question 14

How is K_D determined

Answer 14

K_D = k₂/k₁ = ([L] x [R])/[LR]

R_T = [LR] + [R]; so [R] = R_T- [LR]

R_T = total number of receptors

Substitute and Rearrange

[LR] = (R_T x [L])/ (K_D + [L])

Question 15

Implications of this graph

Answer 15

1. When [L] is large, [LR] ≈ R_T
2. When [L] = K_D, [LR] = R_T x K_D/ (K_D + K_D) or [LR] = ½R_T

Question 16

Ionic Binding

Answer 16

Receptors have charged amino acids

Many Ligands are weak acids or bases and are charged at physiological pH

Major determinate of k₁

Work at greatest distance

Question 17

Hydrogen Bonds

Answer 17

Hydrogen bound to an electronegative atom (O or N) will have a partial positive charge

Question 18

Van der Waals interactions

Answer 18

Hydrophobic interactions

Act only at very close distances

Greatly strengthen the binding interaction and are the major determinant of k₂

Question 19

Occupancy Theory Implications (2)

Answer 19

L + R ⇔ LR → Effect

1) Effect (E) is proportional to the fraction of receptors occupied by the ligand

E/E_max = LR/R_T

2) Maximal Effect (E_max) Occurs when all receptors are occupied

Question 20

EC50

Answer 20

Concentration of ligand at which you get 50% maximum effect

Ligand concentration = C

Question 21

Purpose of this graph

Answer 21

Side chain analogs decrease activation of the receptor (not always dependent on concentration)

Some compounds are intrinsically able to produce a full reaction of the receptor while others are not (bind but don’t fully activate)

Question 22

Intrinsic Activity

Answer 22

Intrinsic activity (α) is the ratio of the E_max of the compound of interest to the maxium E_max

Agonist: α = 1

Antagonist: α = 0

Partial agonist: 0<α<1

E/E_max = αLR/R_T

Question 23

Ligand ______ and ligand ______ ______ are independent parameters

Answer 23

Affinity; Intrinsic Activity

Question 24

Stephenson’s modification to the occupancy theory

Answer 24

Eliminated the requirement that all receptors must be occupide for the maximal effect - Spare Receptors

Question 25

E/E_max = f(αLR/RT)

Answer 25

Maximum response can be produced without all of the receptors being occupied

EC50 is not equal to K_D

Question 26

If two cells ([R] = 4; [R] = 16) have same number of effectors and are both [L] = 1/3 K_D, what is the effect of the ligand in each cell

Answer 26

Use K_D equation

[LR]/R_T = [L]/ (1/3 K_D = [L]); since [L] = 1/3 K_D

Then: [LR]/R_T = 1/3 K_D/ (K_D + 1/3 K_D)

Or: [LR]/R_T = 1/3 K_D/K_D x (1 + 1/3)

(1/3)/ (4/3) = 1/4

So: 1/4 of the total receptor pool is occupide

Thus: When R = 4, 1 receptor and 1 effector are activated

When R = 16, 4 receptors and 3 effectors are activated

Question 27

What is the point of having spare receptors?

Answer 27

Increased sensitivity to the ligand