Mechanisms of Drug Action

Question 1

State the four types of drug antagonism.

Answer 1

Receptor blockade
Physiological antagonism
Chemical antagonism
Pharmacokinetic antagonism

Question 2

What is receptor blockade?

Answer 2

The binding of an antagonist to a receptor, thereby preventing the binding of an agonist to that receptor

Question 3

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

Answer 3

This refers to ion channel blockers
The more the tissue on which a drug is acting is being used (i.e. the more active they are), the more effective the blocker will be

Question 4

Give an example of ‘use dependency’.

Answer 4

Normal neurones fire at a relatively low rate so if you put local anaesthetic on them there will be fairly limited effects BUT nociceptor neurones fire rapidly (respond to ‘danger signals’) so their ion channels are open more often meaning that the local anaesthetic can get inside the ion channel (VGSC) and block it more easily

Question 5

What is physiological antagonism?

Answer 5

When two drugs act on different receptors in the same tissue and have opposite effects

Question 6

Give an example of physiological antagonism.

Answer 6

Noradrenaline will bind to alpha-1 receptors and cause vasoconstriction, histamine will bind to histamine receptors and cause vasodilation - so if they are co-administered they will cancel out each others’ effects

Question 7

What is chemical antagonism?

Answer 7

Interactions of drugs in solution - the antagonist reduces the concentration of the agonist in the solution by forming a chemical complex so the effect of the agonist on the tissue is reduced (once bound to the antagonist, it can no longer interact with the tissue and exert its effect)

Question 8

Give an example of chemical antagonism.

Answer 8

Dimercaprol is a chelating agent that forms heavy metal complexes (with e.g. lead, mercury) that are more easily excreted by the kidneys
This is useful for things like lead poisoning (here lead is the ‘agonist’ – would interact with tissues to have a harmful effect so the antagonist binds to the agonist and prevents it from exerting its effect)

Question 9

What is pharmacokinetic antagonism?

Answer 9

When one drug reduces the concentration of another drug at the site of its action (i.e. there is less of the other drug present where at its target site; e.g. for TCA’s the target site would be the brain)
A drug may reduce the absorption, increase the metabolism (in this case breakdown) or increase the excretion of the other drug

Question 10

Give an example of pharmacokinetic antagonism.

Answer 10

If we repeatedly administer barbiturates, we increase the production of microsomal enzymes in the liver, so if we administer another drug that is metabolised by the same enzymes then it is going to be metabolised more quickly and its effect will be reduced (as there will be less of that drug present at its target site at one time to cause an effect)

Question 11

Define drug tolerance.

Answer 11

Gradual decrease in responsiveness to a drug due to repeated administration of the drug (over days/weeks)
EXAMPLE: benzodiazepines

Question 12

What are the five main mechanisms of drug tolerance?

Answer 12

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

Question 13

Describe how pharmacokinetic factors lead to tolerance.

Answer 13

Metabolism of the drug increases when it is given repeatedly over a period of time (i.e. drug is broken down more)
EXAMPLE: barbiturates and alcohol – these drugs induce enzymes and as more enzymes are induced, they end up breaking down the drug, so less drug reaches its target site

Question 14

Describe how loss of receptors lead to tolerance.

Answer 14

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

Question 15

Describe how change in receptors lead to tolerance.

Answer 15

Chronic stimulation makes the receptors undergo a conformational change so that they are desensitised, so a proportion of the receptors are no longer effective

Question 16

Describe how exhaustion of mediator stores lead to tolerance.

Answer 16

EXAMPLE: amphetamines
Amphetamine is a CNS stimulant - it gets into the blood steam, crosses the BBB, gets into the brain and it acts on the noradrenergic neurones in the brain
Amphetamine binds to the uptake 1 protein and gets taken into the central noradrenaline synthesis system
Therefore, it enters the gets packaged into the NA vesicles (like NT recycling), which leads to NA being forced out of their vesicles and released into the synaptic cleft
If you take a second dose of amphetamine after the first, you’ll get a less severe response because you would have exhausted the NA stores - there is no more NA to be released unless it undergoes de novo synthesis (which takes time)

Question 17

Describe how physiological adaption stores lead to tolerance.

Answer 17

Sort of like a homeostatic response to maintain a stable internal environment
EXAMPLE: drug used to treat hypertension
Because a hypertensive patient’s normal BP is at a higher ‘set point’ than a healthy person’s, the homeostatic response to the drug would be to increase the BP a little bit to try and get closer to that hypertensive ‘set point’
This process can also lead to tolerance to side effects

Question 18

How does physiological adaption lead to tolerance to side effects?

Answer 18

Tolerance to side effects means that if you continue taking a drug which is giving you certain side effects for a period of time, the side effects could disappear
This could be due to the body adapting to whatever process by which the drug was causing the side effects in the first place

Question 19

What are the four receptor families?

Answer 19

Type 1 – ionotropic (ion channel-linked)
Type 2 – metabotropic (G-protein coupled)
Type 3 – tyrosine kinase-linked
Type 4 – intracellular steroid type

Question 20

Describe how the transmission of the 4 different receptor types varies.

Answer 20

Speed of transmission increases from type 1 to type 4
Type 1 (ionotropic) - milliseconds
Type 2 (G-protein-linked) - seconds
Type 3 (tyrosine kinase-linked) - minutes
Type 4 (intracellular) - hours

Question 21

Give an example for the 4 receptor types.

Answer 21

Type 1 (ionotropic) - nicotinic ACh and GABA receptor
Type 2 (G-protein-linked) - β1 adrenoceptor in heart
Type 3 (tyrosine kinase-linked) - insulin and growth factor receptors
Type 4 (intracellular) - steroid and thyroid hormone receptors

Question 22

Describe the structure of type 1 receptors.

Answer 22

Consists of 4 or 5 subunits
Has transmembrane sections (alpha helices) as its defining feature
There is an external binding domain (i.e. the receptor part) that will stimulate and open the ion channel

Question 24

Describe the structure of type 2 receptors.

Answer 24

Consists of 1 subunit but with 7 transmembrane domains

Question 25

Describe the structure of type 3 receptors.

Answer 25

Single subunit with 1 transmembrane domain, an extracellular binding domain and an intracellular catalytic domain

Question 25

Describe the structure of type 4 receptors.

Answer 25

These are steroid receptors that are found in the nucleus (or cytoplasm but then enters nucleus anyway)

Question 26

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

Answer 26

Zinc fingers

Question 27

How do type 2 receptors work?

Answer 27

When you stimulate a type 2 receptor, the G-protein coupling domain within the receptor becomes activated
The G-protein has to bind to this domain before it can mediate a response which makes responses much slower than ionotropic receptors
NOTE:
Metabotropic means that the cellular response to the ligand (first messenger) is mediated by a second messenger (e.g. cAMP)

Question 28

How do type 3 receptors work?

Answer 28

When the agonist stimulates the receptor at the extracellular (binding) domain, it stimulates the kinase activity of the receptor within the intracellular (catalytic) domain leading to phosphorylation of amino acids in that domain → initiates intracellular signalling cascade

Question 29

How do type 4 receptors work?

Answer 29

When the receptor gets stimulated the receptor unfolds to expose the zinc fingers leading to DNA binding and transcription regulation (i.e. they act like transcription factors)