3 - Pharmacodynamics

Question 1

What are the five different types of drug receptor classifications?

Answer 1

1 - Intracellular receptors
2 - Receptors with intrinsic enzymatic activity
3 - Receptors that directly associate with intracellular enzymes
4 - Ligand-gated ion channels
5 - 7 membrane spanning receptors (7MSR)

Question 2

Describe intracellular receptors

Answer 2

• Intracellular receptors (meaning they are located within the cell) only bind ligands which are lipophillic
• This is because the ligand needs to first diffuse through the cell membrane (only lipophillic can do that)
• The receptors are located in either the nucleus or the cytoplasm
• Lipophillic ligands which commonly bind to intracellular receptors include steroids, thyroid hormones and vitamins A and D
• Once a ligand binds to an intracellular receptor, it typically increases or decreases gene expression

Question 3

Describe a receptor with intrinsic enzymatic activity

Answer 3

• These receptors are found in the cell membrane and contain an extracellular and intracellular domain
• A ligand outside of the cell binds to the extracellular domain
• The intracellular domain has an enzymatic activity which changes a substrate within the cell (ex. A –> B)

Question 4

What are some examples of receptors with intrinsic enzymatic activity?

Answer 4

1. tyrosine kinases (i.e. insulin receptors, epidermal growth factor receptor)
2. serine/threonine kinases (i.e. transforming growth factor-beta receptors)
3. tyrosine phosphatases (i.e. CD45 receptors)
4. guanylyl cyclases (atrial natriuretic peptide receptors)

Question 5

Describe a receptor that directly associates with intracellular enzymes

Answer 5

Very similar to receptors with intrinsic enzymatic activity, but these don’t have their own enzymatic activity, instead they associate with an enzyme

Question 6

What are some examples of receptors that directly associate with intracellular enzymes?

Answer 6

For example, theses receptors can associate with kinases or proteases and include receptors such as the interleukin-3 receptor, erythropoietin receptor, and leptin receptor

Question 7

Describe a ligand-gated ion channel receptor

Answer 7

• Composed of several transmembrane proteins that form a “barrel” in the cell membrane
• Typically bind with neurotransmitters or hormones
• The pore or center of the barrel is hydrophilic and allows molecules in or out of the cell
• Typically only one of the proteins serves as the receptor for the ligand

Question 8

Give an example of a ligand-gated ion channel receptor

Answer 8

One example of this type of receptor includes the nicotinic acetylcholine receptor (nAchR).

Question 9

Describe 7 membrane-spanning-receptors or 7MSRs

Answer 9

• Drug receptors that have 7 transmembrane domains
• The extracellular domain is the N-terminus
• The intracellular domain is the C-terminus
• Bind with an array of ligands including hormones and neurotransmitters
• The signalling can either be G protein coupling (GDP –> GTP) or independent of G proteins
• If independent of G proteins, signalling usually includes transcription factors or transcriptional regulators

Question 10

Define agonist

Answer 10

• They “go into” the receptor

- Agonist: a drug or ligand that binds to a receptor and produces a molecular, cellular, or physiological response

Question 11

Define antagonist

Answer 11

• They “tag out” something trying to get into the receptor

- Antagonist: a drug or ligand that binds to a receptor and inhibits the response produced by an agonist

Question 12

Define competitive antagonist

Answer 12

agonist and antagonist compete for the same binding site

Question 13

Define non-competitive antagonist

Answer 13

agonist and antagonist bind to different sites, but antagonist induces a conformation change to alter binding site

Question 14

Define partial agonist

Answer 14

a drug that produces a lower maximal response as compared to the agonist

Question 15

Define ED50

Answer 15

ED50 (median effective dose): dose at which 50% of individuals exhibit a specific quantal effect.

Question 16

Define TD50

Answer 16

TD50 (median toxic dose): dose at which a specific toxic effect occurs in 50% of the individuals tested.

Question 17

Define LD50

Answer 17

LD50 (median lethal dose): dose that is lethal for 50% ov individuals tested. This is experimentally defined with animal models.

Question 18

Define the therapeutic index (TI)

Answer 18

From the quantal dose-effect curve an indicator of safety related to a particular drug can be derived. This indicator is referred to as the therapeutic index (TI).

Question 19

How do you calculate therapeutic index?

Answer 19

TI = TD50/ED50

The greater the ratio or the greater the window between the TD50 and the ED50, the safer the drug is for a patient.

Question 20

What is K(d)?

Answer 20

The dissociation constant of a ligand in relation to its receptor

The Kd represents the point at which half of the receptors are occupied with ligand and half the receptors are free

Question 21

What can K(d) be used for?

Answer 21

The Kd represents the affinity of a ligand for its receptor. This can then be used to compare the binding affinity of two ligands that bind to the same receptor. The lower the Kd (or the less drug required for half maximal occupancy), the greater the binding affinity of that drug.

Question 22

What is B(max)?

Answer 22

B(max) represents full receptor occupancy (saturation)

Question 23

Be able to draw and label a ligand binding affinity curve

Answer 23

Look at page 4 of the pharmacodynamics handout

• y-axis = receptor-bound drug
• x-axis = drug concentration
• K(d) = point on the x-axis (concentration of a drug) where the y-axis is at 0.5 (or 50% of the drug is bound)
• B(max) = point on the y-axis where receptor-bound drug is 100% or 1.0 on the graph

Question 24

How can you use a ligand binding affinity curve to distinguish the affinities between two drugs?

Answer 24

Recall from the definition of K(d) that you can use the K(d) (represents the affinity of a ligand for its receptor) to compare two ligands in terms of their binding potential.

This is most easily visualized when plotted as bound drug vs. the log of drug concentration (still a ligand binding affinity curve)

This just converts the hyperbolic curve into a sigmoidal curve and is best for comparison purposes

Question 25

Which line on a ligand binding affinity curve will represent the drug with the highest affinity?

Answer 25

The drug which is closest to the left - this is because it takes less concentration of the drug (less further right on the x-axis) in order to achieve a high percentage of substrate bound to the receptor (y-axis)

Question 26

Define efficacy

Answer 26

Efficacy: the maximal effect a drug can induce (Emax)

Question 27

Define potency

Answer 27

Potency: a measurement of drug dose used to compare the relative affinity and effectiveness of two or more drugs. This is most conveniently done by comparing the EC50 of two or more agents.

Question 28

Describe a dose-response curve

Answer 28

The dose-response curve is plotted as the drug effect or response on the y axis as a function of the of drug concentration on the x axis. As with the ligand binding affinity graphs, plotting the response as a function of drug concentration on a log scale converts the hyperbolic curve (Panel A, below) to a sigmoidal curve (Panel B).

Question 29

On a dose-response curve, how would two drugs with different potency appear?

Answer 29

Since the graph is a plot of maximal effect and concentration of agonist, a drug that is able to produce the same maximal effect (y-axis) at a lesser concentration (x-axis - further to the left), is said to be more potent

Same maximal effect as another drug, but at a lower concentration = more potent

Question 30

On a dose-response curve, how would two drugs with different efficacies appear?

Answer 30

Since the dose-response curve is a plot of maximal effect vs agonist concentration, a drug that is able to produce a higher maximal effect at the same concentration as another is said to have a higher efficacy

Same concentration as another drug, but more effective

Question 31

Describe the impact a competitive inhibitor has on the response induced by an agonist

Answer 31

The competitive antagonist (Panel A, below) induces a shift to the right in the EC50 of the dose response curve but a maximal effect is still achievable with the agonist at higher concentrations

See page 7 on the pharmacodynamics handout

It is a maximal effect vs agonist concentration graph where the addition of a competitive antagonist shifts the sigmoidal curve to the right (need more agonist concentration to get the same effect as before)

This makes sense because they are “competing” for the same spots, so a higher concentration of agonist will “win out” and they can still get a maximal effect with high agonist concentration despite a competitive antagonist

Question 32

Describe the impact a noncompetitive inhibitor has on the response induced by an agonist

Answer 32

The noncompetitive inhibitor (Panel B) causes a decrease in the maximal effect. The agonist’s affinity for the receptor may not change in the presence of the noncompetitive antagonist.

See page 7 on the pharmacodynamics handout

This makes sense because they are not competing, so the agonist can’t win… the more non-competitive antagonist that gets in there, the lower the effect of the agonist. The sigmoidal curve continues to tilt more and more downward with the addition of more non-competitive antagonist until the effect of the agonist is zero.