BP 3 – Agonists and dose response curves

Question 1

What is an agonist?

Answer 1

Ligand (drug, hormone/ neurotransmitter) combines with receptors to give a cell action

Question 2

What does salbutamol treat?

Answer 2

Asthma

Question 3

What is the interaction of salbutamol as a drug?

Answer 3

• Combines with ß2 adrenoreceptor forming a complex
• Increased cAMP
• Bronchodilation

Question 4

Why is dose important?

Answer 4

Too much - toxic

Too little - useless

Question 5

What does a dose-response log graph show?

Answer 5

Therapeutic range
Where there is no more effect 
No effect
Over effect 
Max response - efficacy
50% response - potency

Question 6

What is the difference between graded and quantal dose-response relationships?

Answer 6

Graded

• Individual measure
• Response of a particular system – isolated tissue, animal or patient
• Measured against agonist conc

Quantal

• Drug doses – agonist/ antagonist
• Produce a specified response determined in each member of a population
• Population data – number of …
• All or nothing – absolute measure – show range

Question 7

What shape is the correct quantal dose-response curve?

Answer 7

Bell shaped

Question 8

Define affinity.

Answer 8

Strength of which an agonist/drug binds to the receptor

Question 9

What determines a drug to have high affinity?

Answer 9

The forward reaction of the drug binding to the receptor having a larger response relative to the dissociation from the receptor having a small response. Therefore the forward reaction is greater than the backwards reaction.

Question 10

What is easy and hard to measure in drug binding?

Answer 10

Easy - saturation of receptors - no max binding sites

Hard - affinity of a drug

Question 11

What is the equilibrium dissociation constant?

Answer 11

Kd

small d

Question 12

What can Kd quantitively compare?

Answer 12

Affinity of diff drugs on the SAME receptor

Question 13

What does a Kd value show?

Answer 13

Tighter ligand-receptor interaction – higher affinity.

Question 14

What is the potency of a drug?

Answer 14

Drug amount needs to produce a given effect (EC50)

Potent drugs give a response by binding to a critical number of receptors at a low conc (high affinity)

Question 15

What is said about the efficacy of a drug that has a lower EC50?

Answer 15

Greater potency

Question 16

What is potency dependent on?

Answer 16

Affinity, efficacy, receptor density and efficiency of stimulus-response mechanisms used

Question 17

What are receptor reserves?

Answer 17

Linear relationship between receptor occupation and biological effect then Kd and EC50 are equal

But …

• Many receptors can amplify signal duration and intensity
• Due to amplification only, a fraction of total receptors for a specific ligand may need to be occupied to elicit a maximal response from a cell
• Systems that have this behaviour are said to have spare receptors

Max response with only a small fraction of the receptors occupied

Question 18

What is the efficacy of a drug?

Answer 18

Ability of agonist to activate a receptor

Refers to the max effect an agonist can produce (regardless of the dosage)

Question 19

What is the efficacy of… and number of receptors occupied by…

1. Full agonist
2. Partial agonist

Answer 19

1. High efficacy, producing max tissue response, occupying few available receptors
2. Low efficacy, no producing capable max response and occupying all available receptors

Question 20

What is the use of these partial agonists and what receptors do they target?

1. Varenicline
2. Tamoxifen
3. Aripiprazole

Answer 20

1. Nicotine receptor partial agonist for smoking cessation
2. Estrogen receptor partial agonists for use in estrogen dependent breast cancer
3. Antipsychotic – partial agonists at selected dopamine receptors

Question 21

What do inverse agonists have higher affinity for?

Answer 21

Prefer to be in the inactive complex of drug-receptor instead of the active state, which would in turn cause a response

Question 22

What is a positive allosteric modulator?

Answer 22

Not active alone but can increase affinity and/or efficacy of endogenous agonists

Question 23

What is a negative allosteric modulator?

Answer 23

Not active alone but can decrease affinity and/or efficacy of endogenous agonists

Question 24

Give examples of positive allosteric modulators.

Answer 24

PAM - Diazepam, Propofol, Isoflurane

Question 25

What is tachyphylaxis of a drug?

Answer 25

Drug effect reduces with continual/repeated administration

Question 26

What are the contributing factors to the desensitisation of receptors?

Answer 26

• Conformational changes in receptors
• Internalisation of receptors
• Depletion of mediators
• Altered drug metabolism