9 Pharmacodynamics

Question 1

What is an agonist and what do they require for it to function

Answer 1

Drugs activating the receptor

-Affinity for the receptor
-Intrinsic efficacy

Question 2

What is an antagonist and what do they require for it to function

Answer 2

Drugs binding to receptor and blocking the binding of their ligands (exo/endogenous)

-Affinity for the receptor

Question 3

How is binding measured? Give an example

Answer 3

Calculate the amount of (radio) ligand bound specifically to the receptor

e.g.) binding of fluorescent compounds

Question 4

Difference between pharmacological efficacy and clinical efficacy

Answer 4

Pharmacological efficacy: The ability to activate a receptor and cause conformational change

Clinical efficacy: An indication of how well treatment succeeds in achieve in its aim
E.g.) does this drug lower BP

Question 5

What is Kd and what does a lower value of this suggest

Answer 5

Index of affinity of the drug for the receptor
(half of Bmax)
Lower value = Higher affinity
-Lower conc. required to occupy 50% of receptors

Question 6

E.g.) Drug A: Kd= 10^-9, Drug B: Kd=10^-3 (Both lnM)
Which has a higher affinity ?

Answer 6

Drug AA has a higher affinity

Question 7

When is response against agonist be seen

Answer 7

-change in signalling pathway
-change in cell/tissue behaviour
e.g.) contraction

Response required drug efficacy (agonist)

Question 8

What is the importance of affinity to ligands in pharmacological context ?
Give an example

Answer 8

High affinity allows binding at low conc. of hormones, neurotransmitters

e.g.) Opioid overdose used to be treated by naloxone since it is a high affinity antagonist of m-opioid receptors and outcompetes opioid

Question 9

What is the relationship between the proportion of bound receptors and drug conc.

Answer 9

The proportion of bound receptors is logarithmically changing as the drug conc. increases
NOT linear

Question 10

What is drug POTENCY and what does it depend on

Answer 10

How much drug you require to cause a response

It depends on
-affinity
-intrinsic efficacy
-cell/tissue -specific components (opening the door)

Question 11

What is Bmax

Answer 11

Max. binding capacity of a receptor
(half of Bmax is EC50)

Question 12

What is Emax

Answer 12

Max. threshold rate that a drug can act on a receptor

Question 13

What is EC50

Answer 13

Drug Potency
-effective conc. giving 50% of the max. response

Question 14

Difference between dose and concentration

Answer 14

Dose: Conc. at the site of action, generally unknown
E.g.) dose to a patient in in mg/kg

Conc.: known conc. of drug at site of action

Question 15

What is the difference between selectivity and specificity in terms of ligand-receptor complexes

Answer 15

Specificity: The preference of a ligand for one specific receptor
Selectivity: The preference one a ligand for a receptor over another

Question 16

How is selectivity/specificity achieved in drugs against asthma

Answer 16

Salbutamol:β2- selective efficacy
Salmeterol: no selective efficacy, selectivity based on affinity (β1-↑rate of heart contraction)

β2-adrenoreceptors opens up airways.
Salbutamol is a more suitable drug since it has selective efficacy to act on β2 than β1

Question 17

Relationship between agonist affinity and agonist potency

Answer 17

Expectation: 100% binding, 100% response
Commonly seen: 50% binding, 100% response

The difference is caused by spare receptors

Question 18

What does it mean when EC50 is less than Kd

Answer 18

There are spare receptors
-often seen when receptors are catalytically active e.g.) GPCR

Question 19

Why do spare receptors exist

Answer 19

-Amplification in the signal transduction pathway
-Response is limited by a post-receptor event

Question 20

What is the importance of spare receptors

Answer 20

Increase sensitivity/potency and allow responses at low. conc of agonist

Question 21

What does the receptor no. depend on

Answer 21

-cell type
-level of activity
(low: increase in cell type, high: decrease in cell type)

Question 22

What is intrinsic activity and how is it measured

Question 23

Difference between full agonist and partial agonist

Answer 23

Full agonist: (often endogenous)
Partial agonist: lower intrinsic activity due to lower efficacy

Question 24

What does partial agonist depend on

Answer 24

-ligand type
-receptor no.

Question 25

How can a partial agonist become a full agonist

Answer 25

Increasing receptor no.
(the increased no. of receptors can compensate the low intrinsic efficacy to produce a full response)

Question 26

What is the relevance of partial agonists as drugs
Give an example

Answer 26

Allows a more controlled response
e.g.) Opioids: pain relief, recreational use
BUT respiratory depression can lead to death

Question 27

How is opioid addiction treated by partial agonists

Answer 27

Heroin: produces full response
Buprenorphine: higher affinity (occupies receptors & limits response)

Buprenorphine will inhibit the effect of heroin (provide antagonism)

Question 28

How is antagonism achieved

Answer 28

1. Functional Antagonism (e.g. Effect of drugs on asthma)
2. Antagonist (antagonism of an action of an agonist at its receptor using a ligand)

Question 29

What is a Receptor antagonist and the different types of this

Answer 29

It blocks the effects of agonists

1. Reversible competitive antagonism (common)
2. Irreversible competitive antagonism
3. Non-competitive antagonism

Question 30

Describe Reversible competitive antagonism

Answer 30

Antagonists compete with agonists for binding
-surmountable
-greater [antagonist] = greater inhibition

Question 31

How do Reversible competitive antagonists affect the agonist concentration-response curve?

Answer 31

Causes a parallel shift to the right of the agonist concentration-response curve

Question 32

Clinical example of Reversible Competitive Antagonism

Answer 32

Naloxone: higher affinity than heroin at μ-opioid receptors and competed effectively

Question 33

Describe irreversible competitive antagonism

Answer 33

The antagonist dissociates slowly/not at all
-non-surmountable

Question 34

Give a clinical example of irreversible competitive antagonism

Answer 34

Pheochromocytoma (tumour of adrenal chromaffin cells)

Non-selective irreversible α1-adrenoreceptors blocker: once bound, can’t be outcompeted by high levels of adrenaline

Question 35

Describe non-competitive antagonism

Answer 35

Antagonist binds to allosteric site
-molecules that enhance/reduce effects of agonists
-no competition
-thus negative allosteric modulation

Question 36

Clinical example of non-competitive antagonism

Answer 36

Maraviroc: Negative allosteric modulator of chemokine receptor 5 (used by HIV to enter cells)
-Used in AIDS