1 - Pharmacodynamics 1a: Receptors

Question 1

Do drugs create effects? How do they have their effects?

Answer 1

NO, They modify ongoing functions.

Their effects on the body are a result of interactions with functional macromolecular components of the organism such as receptors.

Question 2

What does the Law of Mass action state? What is an example of this that has to do with drug actions?

Answer 2

That things have a mass and interact with other things based on how much of each component is present.

The amt of ligand and receptor present determines the effect.

Question 3

Do all drugs produce effects via interactions with receptors? What do each of these things have in common?

Answer 3

NO.

There can be enzyme inhibitors, transport inhibitors, ion channel inhibitors, etc.

First step in any action of a drug is reversible binding to something.

Question 4

What are three things that receptors provide?

Answer 4

Specificity: only a subset of receptors will be affected by a drug

Selectivity: since receptors are coupled to specific pathways

Sensitivity: receptor binding events are amplified intracellularly

Question 5

What are three ways that receptors can be classified?

Answer 5

1. Pharmacologically based on activity studies
2. Biochemically based on transduction mechanism
3. Molecular/structural based on families of similar gene products

Question 6

What rate constant describes the association of ligand and receptor to become the LR complex? What describes the dissociation?

Answer 6

k1: rate constant for association
k2: rate constant for dissociation

Question 7

What equation allows you to calculate the rate of k2/k1? What does this rate tell us?

Answer 7

[L][R]/[LR]

This rate of k2/k1 is called KD, or the equilibrium dissociation constant.

Question 8

What does KD tell you about the LR complex? What are the units of KD?

Answer 8

It’s directly proportional to how fast the complex falls apart into the two reactants.

It describes the goodness of fit between the ligand and receptor.

Units are moles/L (M)

Question 9

What is KD inversely related to?

Answer 9

The affinity of the ligand for it’s receptor.

The higher the affinity between the ligand and its receptor, the lower the KD (ie the lower likelihood that they will dissociate).

Question 10

Because the number of receptors not bound, [R], is difficult to measure, what variable is used instead? What is this new value equal to?

Answer 10

RT, the number of total receptors which is equal to the concentration of the LR complex plus the number of receptors not bound, R.

Rt = [LR] + [R]

Question 11

If you substitute RT into the KD equation, what is the resulting equation to solve for [LR]?

Answer 11

[LR] = [RT][L]/[KD]+[L]

The concentration of total receptors times the concentration of the ligand, divided by KD plus the concentration of the ligand.

Question 12

What is this shape of graph that plots the concentration of ligand receptor complex [LR] vs. the concentration of the ligand [L]? What does it mean if the amount of ligand present is very high?

Answer 12

It’s a rectangular hyperbolic graph.

High [L] means that the amount of LR copmlex made is ~RT (the total number of receptors)

Question 13

On a graph that plots the concentration of ligand receptor complex [LR] vs. the concentration of the ligand [L], when does the concentration of the ligand [L] = KD?

Answer 13

When half of the receptors are bound (LR = 1/2 RT) then the concentration of ligand = the KD.

Question 14

How would you solve a problem to determine the fraction of available receptors that are occupied?

Answer 14

You would need to find out LR/RT (bound divided by total) by rearranging the equation:

[LR] = [RT][L]/ KD + [L]

Question 15

What is an ionic bond? What are their ligands?

Answer 15

Receptors that have charged amino acids.

Many ligands are weak acids or bases and are charged at physiological pH.

Major determinate of k1.

Question 16

What two bond types are important for tight fit resistant to dissociation?

Answer 16

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

Van der Waals interactions that act only at close distances and are multiplicative to greatly strengthen binding interactions and determine k2

Question 17

What is the occupancy theory? What are it’s implications?

Answer 17

That the bound form of a receptor is what produces effects:

1. Effect [E] is proportional to the fraction of receptors occupied by the ligand
2. Maximal effect (Emax) occurs when all receptors are occupied.

Question 18

Based on the structure activity study done by EJ Ariens, what was determined about the occupancy theory?

Answer 18

That it wasn’t just the occupancy of receptors that determined the effect, but also the INTRINSIC ACTIVITY.

Question 19

What is intrinsic activity (alpha)?

Answer 19

The ratio of the Emax of the compound of interest to the maximum Emax.

Question 20

What are the varying levels of intrinsic factor, alpha, and what does each mean?

Answer 20

alpha = 1: Agonist; means it’s an agonist (activator)

alpha = 0: Antagonist; means they can bind but are incapable of transducing the binding into an effect

0

Question 21

How are ligand affinity and ligand intrinsic activity related?

Answer 21

They are independent parameters.

Most ligands bind similarly, but not all produce the same effect based on the intrinsic activity.

Question 22

How was the occupancy theory further modified in the 1970s?

Answer 22

The modification was made to eliminate the requirement that all receptors must be occupied for the maximal effect to occur.

Question 23

After it was discovered that the max effect can occur without all of the receptors being occupied, what could be concluded?

Answer 23

That either tissues have spare receptors and that not all need to be occupied to have the effect, or that the coupling efficiency varies.

Question 24

Why does KD not equal EC50?

Answer 24

EC50 is the concentration needed to produce half the maximum effect, and KD is the concentration required to fill up half of the receptors available.

Since we now know that not all receptors need to be filled to get the max effect, we know the concentration needed to produce half of the max effect (EC50) will usually be less than KD.

Question 25

What is the purpose of having spare receptors?

Answer 25

Increased sensitivity to the ligand.

This stems from the law of mass action that states the effect depends on both the amount of ligand and the amount of receptors.