Lecture 11: Mechanisms of drug action

Question 1

Why is the dose-response relationship important in pharmacology?

Answer 1

Concentration of a drug at its site of action controls its effect. Investigating the effects of drugs helps to establish a framework for hazard assessments.

Question 2

What is a normal dose-response relationship?

Answer 2

Normal, excited, getting tired, sedated, coma/death

Question 3

What are agonists?

Answer 3

A chemical that binds to and activates a receptor to produce a biological response; often applies drug response.

Question 4

What are antagonists?

Answer 4

An agent that blocks the actions of an agonist.

Question 5

What are true (silent) antagonists?

Answer 5

A true (silent) antagonist does not produce any biological response on its own.

Question 6

What are competitive antagonists?

Answer 6

Antagonist competes with agonist for the same receptor, e.g. atropine at acetylcholine receptors.

Question 7

Can maximum response be achieved even with a competitive antagonist?

Answer 7

Maximum response can still be obtained if agonist out-competes antagonist.

Question 8

What are non-competitive antagonists?

Answer 8

Antagonist binds irreversibly with the receptor or antagonist interacts with a different part of the receptor and inactivates it (allosteric effect).

Question 9

Can maximum response be achieved even with a non-competitive antagonist?

Answer 9

Maximum response cannot be obtained.

Question 10

Describe the drug-receptor interaction

Answer 10

Lock-and-key model; results in biological response

Question 11

What are the 3 states that drug receptors are found in?

Answer 11

Resting (R) and Active (R*) and Constitutively-active

Question 12

What is drug affinity?

Answer 12

The attractiveness of a drug to its receptor

Question 13

What is the drug dissociation constant?

Answer 13

The ease in which drugs can dissociate from receptor

Question 14

What is the intrinsic activity of a drug?

Answer 14

Refers to the maximal possible effect that can be produced by a drug; activity of drug within the cells

Question 15

What are constitutively-active receptors?

Answer 15

Constitutively-active receptors have a background activity even when an agonist is not present.

Question 16

What causes the background response in constitutively-active receptors?

Answer 16

Slightly more receptors are in the Active (R*) state and this generates a background response. Do not need agonist presence.

Question 17

What are inverse agonists?

Answer 17

Agonists that interact with the same receptor but produce an opposite response. Trigger more receptors to move into resting state.

Question 18

What are partial agonists?

Answer 18

Partial agonists are drugs that bind to receptors and cause them to produce a response but to a lesser extent than full agonists

Question 19

How is agonist affinity effected by activity of receptors?

Answer 19

Agonists have a higher affinity for the receptor in its active state. When R* is activated by an agonist, an increased response is obtained. The equilibrium below moves towards the active state R*.

Question 20

What are the 4 types of drug receptors?

Answer 20

Type 1: receptors on ion channels, eg. GABA-modulated Chloride Channel
Type 2: G-protein-coupled receptors
Type 3: enzyme-coupled receptors
Type 4: Nuclear (intracellular) receptors

Question 21

How do competitive antagonists effect dose-response curves?

Answer 21

Shift curve right; more agonist needed to get a response

Question 22

How do non-competitive antagonists effect dose-response curves?

Answer 22

Maximal response decreases

Question 23

How do type 1 drug receptors work? Receptors on ion channels

Answer 23

GABA molecule interacts with GABAA receptors on chloride channels which triggers chloride to enter cell. Chloride makes depolarisation difficult and so stabilises tissue and triggers sedation.

Question 24

How do type 2 drug receptors work? G-protein-coupled receptors

Answer 24

In asthma, salbutamol binds to beta-2 receptor and activates G protein. G protein triggers adenylate cyclase to convert ATP to cAMP. cAMP triggers PKA to trigger smooth muscle relaxation which causes bronchodilation and lessens symptoms of asthma.

Question 25

How do type 3 drug receptors work? Enzyme-coupled receptors

Answer 25

Binding of drug to enzyme-linked receptor. Triggering of protein phosphorylation cascade which effects gene and protein synthesis to trigger cellular response.

Question 26

How do type 4 drug receptors work?

Answer 26

Receptor moves to nucleus when they bind to ligands and form a complex. Movement of receptor to nucleus allows for control of gene expression and leads to new protein synthesis which has a physiological response.

Question 27

Why do some individuals with asthma not respond to salbutamol?

Answer 27

Some people do not respond to β2 receptor agonists such as Salbutamol due to genetic differences in the molecular structure of their β2 receptors.

Question 28

What is refractoriness?

Answer 28

Loss of therapeutic efficacy in drugs

Question 29

How can drug receptor activity be altered?

Answer 29

1. Receptor desensitisation

2. Receptor down-regulation

Question 30

What is receptor desensitisation?

Answer 30

Loss of intrinsic activity of receptor complexes; short term.

Question 31

What is receptor down-regulation?

Answer 31

Loss of number of receptors from cell surface; longer term.