Mechanisms of Drug Action

Question 1

State the 4 types of drug antagonism.

Answer 1

Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism

Question 2

What is meant by ‘use dependency’ in terms of receptor blockade?

Answer 2

The more the tissue on which a drug is acting is being used (more active), the more effective the channel blocker will be.

Question 3

What is physiological antagonism?

Answer 3

When 2 drugs act on different receptors in the same tissue and have opposite effects
E.g. NA will bind to alpha-1 receptors and cause vasoconstriction, histamine will bind to histamine receptors and cause vasodilation

Question 4

What is chemical antagonism?

Answer 4

Interactions of drugs in solution. 1 negates the action of another
E.g. dimercaprol is a chelating agent that forms heavy metal complexes that are more easily excreted by the kidneys

Question 5

What is pharmacokinetic antagonism?

Answer 5

When 1 drug reduces the concentration of another drug at the site of its action
A drug may reduce the absorption, increase the metabolism or increase the excretion of the other drug

Question 6

Define drug tolerance.

Answer 6

Gradual decrease in responsiveness to a drug due to repeated administration of the drug

Question 7

What are the 5 main mechanisms of drug tolerance?

Answer 7

Loss of receptors 
Change in receptors
Pharmacokinetic factors  
Physiological adaptation  
Exhaustion of mediator stores

Question 8

Describe how exhaustion of mediator stores leads to drug tolerance

Answer 8

Occurs with amphetamines –they locate central NA neurones and bind to uptake transporters. Bind to vesicles, causing release of NA, increase NA in synaptic transmission.
Response diminishes with time as endogenous stores run out

Question 9

What are the 4 receptor families? Describe how their transmission varies.

Answer 9

Type 1 – ion channel linked receptors
Type 2 – G protein coupled receptors
Type 3 – tyrosine kinase linked  
Type 4 – intracellular steroid type  
They increase in transmission time from 1-4

Question 10

Describe the structure of type 1 receptors and give an example

Answer 10

Consists of 4 or 5 subunits, each with transmembrane alpha helices
e.g. nAChR, GABA A

Question 11

Describe the structure of type 2 receptors and give an example

Answer 11

Consists of 1 subunit with 7 transmembrane domains.

e.g. B1 adrenoceptors (heart)

Question 12

Describe the structure of type 3 receptors and give an example

Answer 12

Single protein with 1 transmembrane domain
Inside the cell there is an intracellular domain
When the agonist stimulates the receptor it activates the catalyst
e.g. insulin, growth factors

Question 13

Describe the structure of type 4 receptors and give an example

Answer 13

Steroid receptors that are found in the nucleus, change DNA transcription
e.g. steroids, thyroid hormones

Question 14

What is another name for the DNA binding domain of the steroid-receptor complex?

Answer 14

Zinc fingers

Question 15

How can we take advantage of use dependency?

Answer 15

Normal neurons fire at a quite low rate so LA’s have fairly limited effects.
Nociceptor neurons fire rapidly so their channels are open more, thus the LA can get inside the ion channel and block it more easily.

Question 16

Give an example of a drug that works by pharmacokinetic antagonism. How do these become an issue if given long term?

Answer 16

Barbiturates.
They are enzyme inducers- liver enzymes that metabolise barbiturates become upregulated, becomes an issue if we need to give them another drug that is metabolised by the same set of enzymes- need to increase dose

Question 17

Describe how loss of receptors leads to drug tolerance

Answer 17

Overstimulation can lead to endocytosis of receptors so there are fewer receptors available on the cell membrane

Question 18

Describe how change in receptors leads to drug tolerance

Answer 18

Conformational change in the receptors, they become desensitized, so a proportion of the receptors are no longer stimulated by the agonist

Question 19

Describe how pharmacokinetic factors lead to drug tolerance

Answer 19

Metabolism of the drug is increased after repeated use (e.g. alcohol, barbiturates)

Question 20

Describe how physiological adaptation leads to drug tolerance

Answer 20

Homeostatic responses to maintain a stable internal environment e.g. Antihypertensives reduce BP, homeostatic response slightly increases BP

Question 21

How can physiological adaptation causing drug tolerance be beneficial?

Answer 21

Contributes to tolerance of drug side effects