Pharmacology

Question 1

What is Pharmacology?

Answer 1

• Study of drug action.
• Molecular pharmacology attempts to describe this in terms of biochemistry.
• Underpins attempts to discover new drugs and therapeutic targets / strategies.
• Addresses fundamental questions in biology regarding cellular communication.

Question 2

Receptors and Ligands

Answer 2

• “Ligand” is derived from the latin ligandum meaning “binding”.
• A ligand is a molecule that binds to a receptor.
• For example, the ligand of the insulin receptor is insulin.

Some receptors have one ligand whilst others have many.

Different ligands can produce different responses at the same receptor.

Question 3

Ligands can be divided into 3 classes depending on the response they induce at the receptor:

Answer 3

–Agonists – activate receptors.

–Antagonists – block receptors.

–Inverse agonists – deactivate receptors.

•Some ligands / drugs may show mixed behaviours depending on the situation.

Question 4

Draw a graph showing drug concentration vs biological responses

Answer 4

Question 5

Compare the different type of ligand

Answer 5

•Agonists – activate receptors.

–May be partial or full – how do you define full?

•Antagonists – block receptors.

–Stops the natural ligand binding.

–Competitive / non-competitive.

–Reversible / irreversible.

•Inverse agonists – deactivate receptors.

–Many receptors show slight basal (constitutive) activity.

–This can be turned off by inverse agonists.

Question 6

Define Affinity

Answer 6

The tendency (or strength) of a ligand to bind to the receptor

Question 7

Affinity is governed by various properties

Answer 7

–Structure / shape complementarity.

–Intramolecular forces e.g. ionic / hydrogen bonds / VdWs.

–High intramolecular force = high affinity.

–Typically ligand-receptor interactions are reversible.

Question 8

What is fractional occupancy?

Answer 8

The fraction of receptors occupied at a particular ligand concentration.

Question 9

Define Efficacy

Answer 9

The degree to which different agonists produce a response, even when occupying the same proportion of receptors.

Question 10

What is potency?

Answer 10

Amount of drug needed to produce a defined effect.

Question 11

Measuring Affinity

Answer 11

• An equilibrium exists between free and occupied receptors.
• This is reached when the rate of formation of new LR complexes equals the dissociation rate of LR complexes.
• This relates the on rate (k_on) and off rate (k_off).

Question 12

Measuring Affinity: Equations

Answer 12

Question 13

Explain Fractional Occupancy

Answer 13

• Kd means that half of the receptors are occupied by ligand and half are not.
• Fractional occupancy describes the fraction of receptors occupied at a particular ligand concentration.
• This allows us to think about the effects a ligand will have at a particular concentration.

Question 14

Fractional Occupancy: An equation

Answer 14

This is important as we can work out fractional occupancy from the Kd and ligand concentration.

Question 15

K_d and B_max

Answer 15

• K_d represents where 50% of receptors are occupied.
• B_max is the amount of drug required to saturate the population of receptors.
• Can be used to measure the number of receptors present.

Question 16

K_d and B_max on a linear or a semilog plot

Answer 16

Question 18

Compare efficacy and potency

Answer 18

•Efficacy

–The degree to which different agonists produce a response, even when occupying the same proportion of receptors.

–Closely associated with the “maximal agonist effect”.

•Potency

–Amount of drug needed to produce a defined effect.

–Depends on affinity, efficacy and tissue parameters e.g. drug accessibility and receptor numbers.

–EC50 – concentration of agonist that produces 50% of the maximal possible effect for that agonist.

Question 19

Dose Response Curves

Answer 19

•Potency is defined as 1/EC₅₀.

• The red drug is more potent than the black drug (lower EC50).
• The black drug has a higher efficacy.
• The red drug is a partial agonist.

Question 20

Ligand Binding Experiments

Answer 20

• Often use radiolabelled ligand.
• Can determine affinity and binding capacity.
• Can also use competition with a non-radioactive ligand.