3. 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

what is a receptor blockade?

Answer 2

it is an antagonist binding to a receptor and preventing the binding of an agonist

Question 3

what does the term ‘use dependency’ relating to receptor blockage mean?

Answer 3

the more the tissue on which the drug is acting is being used, the more effective this type of blocker will be (usually because the binding site is within the ion channel)

Question 4

give an example of ‘use dependency’ in action

Answer 4

local anaesthetics work by binding to the inside of ion channels after they are open. nociceptor neurones fire rapidly and generate APs rapidly so ion channels are open more often. LAs therefore have a selective action on these pain conducting neurones

Question 5

what is physiological antagonism?

Answer 5

two drugs act at different receptors to have opposite effects in the same tissue

Question 6

how do NA and histamine display physiological antagonism?

Answer 6

NA on the vasculature binds to adrenoreceptors (antagonises a1) and causes vasoconstriction, histamine acts on different receptors (antagonises h1) and causes vasodilation

Question 7

what is chemical antagonism?

Answer 7

interaction of drugs in solution

Question 8

how does dimercaprol display chemical antagonism?

Answer 8

it is a chelating agent

it forms heavy metal complexes which are rapidly excreted by the kidneys which is useful for things such as lead poisoning because it binds and antagonises the lead and allows its rapid excretion

Question 9

what is pharmacokinetic antagonism?

Answer 9

when one drug reduces the concentration of the other drug at the site of its action - a drug may reduce the absorption, increase the metabolism or increase the excretion of a co-administered drug

Question 10

how do barbiturate drugs display pharmacokinetic antagonism?

Answer 10

they are enzyme inducers

repeated administration increases production of microsomal enzymes in the liver. if you administer another drug that is metabolised by the same enzymes it will be metabolised more quickly and its effect will be reduced, so a greater concentration needs to be administered

Question 11

what is drug tolerance? give an example of a drug that is tolerated

Answer 11

gradual decrease in responsiveness to a drug with repeated administration

e.g. benzodiazepines for epilepsy

Question 12

what 5 factors underlie tolerance to drugs?

Answer 12

1. pharmacokinetic factors
2. loss of receptors
3. change in receptors
4. exhaustion of mediator stores
5. physiological adaption

Question 13

explain what is meant by pharmacokinetic factors in terms of drug tolerance

Answer 13

metabolism of the drug increases when it is given repeatedly over a period of time due to an increase in metabolising enzymes in the liver (e.g. alcohol)

Question 14

explain what is meant by loss of receptors in terms of drug tolerance

Answer 14

the cell takes receptors off its membrane via membrane endocytosis so there are fewer available on the cell surface -> receptor down-regulation (e.g. b1 adrenoreceptors on cardiomyocytes)

Question 15

explain what is meant by exhaustion of mediator stores in terms of drug tolerance

Answer 15

a less severe response occurring after another dose due to stores of the mediator being used up

Question 16

give an example of a substance that causes exhaustion of mediator stores

Answer 16

amphetamines (CNS stimulant)

it gets into the bloodstream, crosses the BBB and gets into the brain -> it acts on noradrenergic neurones and binds to uptake protein 1 to get into the central NA synthesis system -> it acts on NA in vesicles and you get a big increase in NA production -> a second dose gives a less severe response because NA stores are exhausted

Question 17

explain what is meant by physiological adaption in terms of drug tolerance

Answer 17

the body attempts to maintain a stable internal environment (like a homeostatic response)

usually a tolerance to drug side effects rather than tolerance to the drug

Question 18

what are the 4 types of receptors based on molecular structure and signal transduction systems?

Answer 18

1. ion channel-linked receptors (ionotropic receptors)
2. G-protein coupled receptors
3. kinase-linked type
4. intracellular steroid type receptors

Question 19

describe the functional properties of ion channel-linked receptors

Answer 19

location: membrane
effector: channel
coupling: direct
examples: nAChR, GABAa receptor

mediate very fast responses

Question 20

describe the functional properties of G-protein receptors

Answer 20

location: membrane
effector: enzyme or channel
coupling: G-protein
examples: mAChR, adrenoceptors

mediate slower responses

Question 21

describe the functional properties of kinase-linked receptors

Answer 21

location: membrane
effector: enzyme
coupling: direct
examples: insulin receptor, growth factor and cytokine receptors

result in the phosphorylation of intracellular proteins

Question 22

describe the functional properties of intracellular steroid type receptors

Answer 22

location: intracellular
effector: gene transcription
coupling: via DNA
examples: steroid/thyroid receptors

have to pass through the cell membrane and access the nucleus before it can have an effect

Question 23

describe the structural properties of ion channel-linked receptors

Answer 23

• 4/5 subunits
• transmembrane sections (a-helices)
• external binding domain that will bind the agonist and open the ion channel

Question 24

describe the structural properties of G-protein coupled receptors

Answer 24

• metabotropic (2nd messenger mechanism)

- 1 subunit, 7 transmembrane domains (7 a-helices)

Question 25

describe the structural properties of kinase-linked receptors

Answer 25

• single protein, 1 transmembrane domain (single a-helix)
• inside the cell there is an intracellular domain
• when the agonist stimulates the receptor it activates the catalyst inside the cell and stimulates the kinase activity of the receptor -> phosphorylation of proteins

Question 26

describe the structural properties of steroid receptors

Answer 26

• found in the nucleus
• the DNA binding domains are called zinc fingers
• receptor stimulation leads to DNA binding and increase in transcription