Pharmacodynamics: receptors Flashcards
Lecture I and II of pharmdynamics
Pharmacodynamic characteristics of a drug include:
- mechanism of action of a drug
- therapeutic uses
- adverse or side effects
Pharmacokinetics refers to the mechanisms by which the body handles a drug. Includes:
- absorption
- distribution
- metabolism
- elimination
Drugs do not create effects, they modify ongoing functions…. In other words, a drug cannot make the body do anything it is not already capable of doing
Corollary
The effects of the body of most drugs are a result of
interactions between the drug and functional macromolecular components of the organism
Dual function of receptors
Binds drugs (or ligands, L) Transduces binding into a response
Some alternatives of drug action other then receptors
a) Enzyme inhibitors
b) Inhibitors of transporters
c) Inhibitors of ion channels
Receptors are excellent targets for drugs, because they provide these three things
a) Specificity:
b) Selectivity:
c) Sensitivity:
a) Specificity:
Only a subset of receptors will be affected by a drug
Only a subset of signal transduction pathways will be affected within a cell
b) Selectivity
c) Sensitivity:
Effects at receptors are amplified within the cell, therefore, only a small amount of drug is needed
Classification schema
a) Pharmacological
b) Biochemical
c) Molecular/Structural
(1) based upon studies of structural features of ligands
2) Used to name receptors (eg muscarinic or nicotinic cholinergic receptors
a) Pharmacological (Classification schema)
Based upon transduction mechanism: (eg nicotinic receptor is a ligand-gated ion channel while muscarinic receptor signals through G protein coupled receptors)
b) Biochemical (Classification schema)
Families of similar gene products
c) Molecular/Structural (Classification schema)
Effect is determined by the relative masses of reactants
The law of mass action:
k1 * [L] * [R] =
k2
- [LR] k2/k1 =
[L]
- [R]/[LR] KD =
k2/k1 (by definition)
KD is
the equilibrium, dissociation constant
Describes the “goodness of fit” between ligand and receptor
KD
KD is Proportionally/Inversely related to the affinity of ligand for the receptor
Inversely
? = [L] * [R]/[LR]
KD
R(T) =
[LR] + [R]
is the total number of receptors in a cell or tissue (bound and unbound)
R(T)
[LR] =
(R(T) * [L])/ (K(D) + [L])
A plot of [L] vs. [LR] results
in a rectangular hyperbola
At very large values of [L], [LR] is
approximately R(T)
When [L] = KD, [LR] = R(T)* KD/(KD+KD)
or [LR] =
1/2 RT
Binding occurs as the result of the formation of _________ between the
ligand and the binding site on the receptor
chemical bonds
Ionic bonds
a) Receptors have ______
charged amino acids
Ionic bonds
b) Many ligands are ______
weak acids or bases and are charged at physiological pH
Ionic bonds are the major determinant of ______
k1
Hydrogen bonds
a) Hydrogen bound to an electronegative atom (O or N) will have ….
a partial positive charge
Hydrogen bonds
are stronger/weaker/same as ionic bonds, and require closer/further proximity
weaker
closer
Van der Waals interactions are:
Hydrophobic interactions
Greatly strengthen the binding interaction and are the major determinant of k2.
Van der Waals interactions
Act only at very close distances
Van der Waals interactions
Effect (E) is ________ to the fraction of the total receptor pool that is occupied by ligand
proportional
(a) E/Emax is proportional to [LR]/RT
(Occupancy theory)
Maximum effect (Emax) occurs when
all of the receptors are occupied
Occupancy theory
E = (Emax * C)/
(KACT + C)
KACT is also called
“EC50”
Problem with occupancy theory
the occupancy theory does not explain the effects of ligands that do not produce a maximal effect; or any effect at all
Solution for occupancy theory
Effect is proportional to the fraction of occupied receptors AND the intrinsic activity (α) of the ligand
E/Emax is proportional to
α * (LR/RT)
Intrinsic activity is
a measure of the ability of the LR
complex to elicit the effect being measured
For a full agonist, α =
1
For an antagonist, α =
0
For a partial agonist
0 < α < 1
Intrinsic activity is also called
efficacy
Is the ratio of the Emax of the ligand of interest to the Emax of a full agonist
Intrinsic activity
Ligand affinity and ligand intrinsic activity are two different properties. A ligand can have high affinity but
low (or no) intrinsic activity.
Problem: the occupancy requires that all receptors be occupied in order for the maximal effect to occur; Stephenson demonstrated that tissues have
“spare receptors”
Together with the normally low affinity of endogenous agonists, the presence of spare receptors allows for
high sensitivity without long activation time.
Solution to spare receptors
the effect is a function of the proportion of occupied receptors; EC50 does not necessarily equal the KD
Tissues can have a _______reserve of spare receptors or ______ _______ ________ between receptors and the signal transduction process
high
variable coupling efficiency
So the function of spare receptors is
to increase the sensitivity of the cell to a low concentration of ligand
When does EC50 not = Kd
when we have spare receptors
