Pharmacodynamics 1 Flashcards
Pharmodynamics
Mechanisms of Action of Drugs
Therapeutic Uses
Adverse (Side) Effects
Pharmacokinetics
Absorption
Distribution
Metabolism
Elimination
Mechanisms of Drug Action
The effects on the body of most drugs are a result of interactions with functional macromolecular components of the organism
Corollary
Drugs do not create effects, they modify ongoing functions
Ligand + Receptor ⇔
⇔ LR complex → Effect
Occupancy Theory
Occupancy of the receptor by the ligand causes effect
Other Drug Interactions Besides with Receptors
Enzyme inhibitors
Transport inhibitors
Inihibitors of ion channels
Other: eg. Heparin binds to thrombin and antithrombin
Why are receptors an excellent drug target
Provide Specificity
Provide Selectivity
Provide Sensitivity
Classification Schemes of Receptors
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
k1 and k2
k1 = Rate constant for association
k2 = Rate constant for dissociation
Law of Mass Action at Equilibrium
k1 [L] x [R] = k2 [LR]
k1 has units of sec-1M-1
k2 has units of sec-1
Dissociation Constant (equation)
KD = ([L] x [R])/[LR] = k2/k1
What is the function of KD
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)
How is KD determined
KD = k2/k1 = ([L] x [R])/[LR]
RT = [LR] + [R]; so [R] = RT- [LR]
RT = total number of receptors
Substitute and Rearrange
[LR] = (RT x [L])/ (KD + [L])
Implications of this graph
- When [L] is large, [LR] ≈ RT
- When [L] = KD, [LR] = RT x KD/ (KD + KD) or [LR] = ½RT
Ionic Binding
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
Hydrogen Bonds
Hydrogen bound to an electronegative atom (O or N) will have a partial positive charge
Van der Waals interactions
Hydrophobic interactions
Act only at very close distances
Greatly strengthen the binding interaction and are the major determinant of k2
Occupancy Theory Implications (2)
L + R ⇔ LR → Effect
1) Effect (E) is proportional to the fraction of receptors occupied by the ligand
E/Emax = LR/RT
2) Maximal Effect (Emax) Occurs when all receptors are occupied
EC50
Concentration of ligand at which you get 50% maximum effect
Ligand concentration = C
Purpose of this graph
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)
Intrinsic Activity
Intrinsic activity (α) is the ratio of the Emax of the compound of interest to the maxium Emax
Agonist: α = 1
Antagonist: α = 0
Partial agonist: 0<α<1
E/Emax = αLR/RT
Ligand ______ and ligand ______ ______ are independent parameters
Affinity; Intrinsic Activity
Stephenson’s modification to the occupancy theory
Eliminated the requirement that all receptors must be occupide for the maximal effect - Spare Receptors
E/Emax = f(αLR/RT)
Maximum response can be produced without all of the receptors being occupied
EC50 is not equal to KD
If two cells ([R] = 4; [R] = 16) have same number of effectors and are both [L] = 1/3 KD, what is the effect of the ligand in each cell
Use KD equation
[LR]/RT = [L]/ (1/3 KD = [L]); since [L] = 1/3 KD
Then: [LR]/RT = 1/3 KD/ (KD + 1/3 KD)
Or: [LR]/RT = 1/3 KD/KD 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
What is the point of having spare receptors?
Increased sensitivity to the ligand
