Pharm 2 - Mechanisms of Drug Action

Question 1

What are the 4 types of Drug antagonism?

Answer 1

1. Receptor blockade
2. Physiological antagonism
3. Chemical antagonism
4. Pharmacokinetic antagonism

Question 2

Explain how receptor blockade works

Answer 2

Antagonist binds to the receptor and prevents agonist from binding

Question 3

Receptor blockade involves “use dependency”. What is this

Answer 3

Receptor blockade is more effective against more active tissues. This applies to ion channel blockers

Question 4

What form of drug antagonism does local anaesthetic use?

Answer 4

Receptor blockade (nociceptor neurones fire at a faster rate than normal neurones)

Question 5

How does local anaesthetic work?

Answer 5

Binds on the inside of ion channels after they open

Question 6

Explain how physiological antagonism works

Answer 6

When 2 drugs act on different receptors to bring about opposing effects on the same tissue

e.g. NA acts on vasculature and causes vasoconstriction. If histamine is coadminstered, it acts on different receptors and causes vasodilation. Net effect = antagonistic effects on BP

Question 7

Explain how chemical antagonism works.

Answer 7

When drugs interact in solution.

e.g. giving dimercaprol (chelating agent) - this forms heavy metal complexes, which are rapidly excreted by the kidney. Very useful for things like lead poisoning

Question 8

Describe how pharmacokinetic antagonism works

Answer 8

When one drug decreases the concentration of another drug at its site of action.

i.e. drug A decreases absorption / increases metabolism / increases excretion of drug B

Question 9

What must you be careful of with pharmacokinetic antagonism?

Answer 9

Not to administer a drug that interferes with another drug

e.g. barbiturates increase the concentration of microsomal enzymes –> must ensure that the administered drug isn’t metabolised by microsomal enzymes

Question 10

Define drug tolerance

Answer 10

Gradual decrease in responsiveness to a drug with repeated administration

Question 11

Give 5 causes of drug tolerance

Answer 11

1. Pharmacokinetic factors
2. Loss of receptors
3. Change in receptors
4. Exhaustion of mediator stores
5. Physiological adaptation

Question 12

Explain how pharmacokinetic factors can cause drug tolerance

Answer 12

Drug metabolism increases over repeated administration

Question 13

Give examples of drugs that induce tolerance due to pharmacokinetic factors

Answer 13

Alcohol and barbiturates

Question 14

Explain how loss of receptors can cause drug tolerance

Answer 14

Receptor downregulation occurs.

Repeated stimulation by agonist –> cell endocytoses receptors —> cell loses receptors

Question 15

Give an example of a type of receptor susceptible to receptor downregulation

Answer 15

B-adrenoreceptors

Question 16

How can a change in the receptors induce drug tolerance

Answer 16

Receptor desensitisation occurs due to a conformational change in receptors - renders a proportion of receptors ineffective.

Occurs when there is continued stimulation of receptors

Question 17

Give an example of a receptor that can change due to repeated stimulation

Answer 17

NAChR at NMJ

Question 18

Explain how exhaustion of mediator stores can cause drug tolerance

Answer 18

e.g. amphetamines –> taken up into brain, and acts on noradrenergic neurones in the brain.

Amphetamines taken up into presynaptic terminals via uptake 1, causes NA efflux from vesicles into cytoplasm and then into synaptic cleft. Lots of NA in synaptic cleft which causes the euphoria. Second dose of amphetamines shortly after first dose won’t work because NA stores exhausted, no more NA is present in the presynaptic nerve terminals to be released.

Question 19

Describe how physiological adaptation can cause drug tolerance

Answer 19

Physiological adaptation is a homeostatic-esque response, whereby the body is trying to maintain a stable internal environment

Question 20

Name the 4 receptor type families

Answer 20

1. Ionotropic receptor
2. G-protein coupled
3. Tyrosine-Kinase ined receptor
4. Intracellular steroid type receptor

Question 21

Rank the receptors in terms of how fast they are

Answer 21

1. Ionotropic receptor (ms)
2. G protein coupled receptor (seconds)
3. Tyrosine-kinase linked receptor (minutes)
4. Intracellular steroid type receptor (hours)

Question 22

Give an example of a type 1 receptor (ionotropic receptor)

Answer 22

NAChR or GABA

Question 23

Give an example of a type 2 receptor (G protein coupled)

Answer 23

MAChR / B-1 receptors in the heart

Question 24

Give an example of a tyrosine kinase linked receptor

Answer 24

Insulin receptors & GF receptors

Question 25

Through what mechanism do tyrosine-kinase linked receptors work?

Answer 25

Via intracellular protein phosphorylation

Question 26

How are intracellular steroid type receptors activated?

Answer 26

Via steroids and thyroid hormones - used in DNA transcription

Question 27

Why do intracellular steroid type receptors take the longest time to work?

Answer 27

The drug must pass the cell membrane and enter the nucleus

Question 28

How many subunits does the ionotropic receptor have?

Answer 28

4/5 subunits - consisting of transmembrane sections that have an external binding domain

Question 29

How many subunits does the G protein coupled receptor have?

Answer 29

1 subunit

7 TM domains (alpha helices)

Question 30

How many TM domains does the tyrosine kinase linked receptor have?

Answer 30

1

Question 31

How is protein phosphorylation achieved in tyrosine kinase linked receptors?

Answer 31

The tyrosine kinase linked receptor has an intracellular catalytic domain which is activated when the agonist stimulates the receptor

Question 32

Which type receptor has DNA binding domain of “zinc fingers”

Answer 32

Intracellular steroid receptor

Question 33

What do the Zn fingers do?

Answer 33

When the intracellular steroid receptor is stimulated, the Zn fingers are uncovered which enables DNA binding and transcription