Session 9 AND 10 ILOs - Pharmacodynamics Drugs and Drug target interactions

Question 1

Define the concepts of affinity and efficacy with insights into their clinical relevance

Answer 1

Affinity - the strength by which a ligand binds to the receptor
Important clinically as it affects the dose of drug given and specifically in opioids where fentanyl has a very high affinity and therefore cannot be reversed by Naloxone (but can reverse heroin or morphine)

Efficacy - the magnitude of biological response upon binding (often used interchangeably with clinical efficacy where someone might say how well does it cure the headache)

Question 2

Define and discuss quantification of binding affinity and receptor function

Answer 2

Quantifying binding affinity and receptor function:
Plot a graph of drug concentrations versus proportion of bound receptors

Bmax index of receptor number (receptor function)
Kd provides an index of binding affinity - which is drug concentration at half of Bmax

Question 3

Describe the meaning of a ligand, agonist, antagonist and partial agonist

Answer 3

Ligand:
- A substance that binds specifically to a receptor

Agonist:
- A substance that binds specifically to a receptor and elicits a measurable physiological response (i.e. has affinity and efficacy)

Antagonist:
- A substance that binds specifically to a receptor but does NOT elicit a measurable physiological response (i.e. has affinity but NOT efficacy)

Partial agonist:
- A substance that binds to the receptor but does not evoke a maximum response (no spare receptors). Partial agonists have a lower instrinic activity because they have insufficient intrinsic efficacy to cause a maximal response

Question 4

Describe the meaning of orthosteric and allosteric

Answer 4

Orthosteric - binding site for the natural ligand

Allosteric - ligand binds elsewhere on the protein surface (not on the natural ligand binding site)

Question 5

Describe the meaning of potency and intrinsic activity

Answer 5

Potency:
- Potency is the EC50 which is the effective concentration giving 50% of the maximal response

Intrinsic activity:
- Intrinsic activity refers to the maximal possible effect that can be produced by a drug

Question 6

Describe the meaning of functional antagonism, spare receptors, selectivity and specificity

Answer 6

Functional antagonism:
- Antagonism of a cell/tissue event being mediated by one mechanism, by another mechanism

Spare receptors:
- Unoccupied receptors - as a maximum concentration of an agonist producing a maximum response may not result in occupancy of all the receptors. These receptors are said to be “spare”

Selectivity:
- Selectivity is the degree to which a drug acts on a given site relative to other sites

Specificity:
- Specificity is the measure of a receptors ability to respond to a single ligand (low specificity, can bind more substances)

Question 7

Describe the meaning of Kd and Bmax

Answer 7

Kd:
- Kd is the concentration of the drug that occupies 50% of the maximum

Bmax:
- Bmax is the maximum binding capacity of the drug (where all of the receptors are bound)

Question 8

Describe the meaning of EC50 and Emax

Answer 8

Emax:
- Emax is the maximum effect/response elicited by the drug

EC50:
- EC50 is the effective concentration that elicits 50% of the maximal response (also known as potency)

Question 9

Describe the meaning of IC50

Answer 9

IC50:
- IC50 is an index of how much of a particular inhibitory substance is needed to inhibit maximum response by 50% (inhibitory concentration)

Question 10

Describe the meaning of reversible competitive antagonism, irreversible competitive antagonism and non-competitive antagonism

Answer 10

Reversible competitive antagonism:
- Occurs either when the binding of the antagonist can be outcompeted by increasing the concentration of agonist, or when the antagonist dissociates as the free concentration decreases = surmountable

Irreversible competitive antagonism:
- Irreversible antagonists bind via covalent intermolecular forces. Because there is not enough free energy to break covalent bonds in the local environment, the bond is essentially “permanent”, meaning the receptor-antagonist complex will never dissociate = non-surmountable

Non-competitive antagonism:
- Implies that the antagonist, while still opposing the action of the agonist, does so without competing with it for the binding site and this inhibitory effect is not affected by increasing agonist concentration