4. Antagonists

Question 1

Steps of antagonist to effect

Answer 1

• receptor
• antagonist-receptor complex
• effect

Question 2

Explain steps of propranolol to effect

Answer 2

• on beta-adrenoreceptor
• propranolol-beta-adrenoreceptor complex
• decreased blood pressure

Question 3

3 classes of antagonist

Answer 3

• chemical
• physiological
• pharmacological

Question 4

Explain ‘chemical antagonists’

Answer 4

• binding of two agents to render active drug inactive
• commonly called chelating agents
• example is protamine binds/sequesters heparin

Question 5

Explain physiological antagonists

Answer 5

• two agents with opposite effects cancelling each other out
• e.g glucocorticoids and insulin

Question 6

Explain pharmacological antagonists

Answer 6

• binds to receptor
• blocks normal action of agonist on receptor responses

Question 7

Antagonists can be receptor or non-receptor. 2 types of non-receptor antagonists are …

Answer 7

• chemical
• physiological

Question 8

Explain how non-receptor antagonists work

Answer 8

• doesn’t bind to same receptor as agonist but inhibits ability of agonist to initiate response
• this occurs by inhibiting agonist directly by inhibiting a downstream molecule in activation pathway or activating pathway that opposes agonist
• chemical ones inactivate agonist before it’s opportunity to act e.g chem neutralisation
• physiological ones cause physiological effect opposite to that induced by agonist

Question 9

Receptor antagonists can have … binding or … binding and both of these can be … or …

Answer 9

• allosteric
• active site
• reversible or irreversible

Question 10

A reversible active site binding antagonist is …
What happens here?

Answer 10

• competitive
• action of agonist will come back when antagonist is lost
• adding more agonist gives it more chance of binding and vice versa

Question 11

Reversible and irreversible allosteric binding antagonists are non-comp/comp?

Answer 11

non-comp
(all are non-comp except reversible active site binding)

Question 12

Pure antagonists alone have what effect when binding to receptor?

Answer 12

no action

Question 13

What kind of efficacy do antagonists have?

Answer 13

none
AR* for antagonists doesn’t exist

Question 14

How do competitive active site antagonists work?

Answer 14

• binds and prevents agonist action but can be overcome with increased agonist conc
• causes parallel shift to right of agonist-response curve

Question 15

How do non-competitive active site antagonists work?

Answer 15

• binds and form irreversible covalent bonds with receptor
• causes parallel shift right of agonist-response curve AND reduced maximal asymptote

Question 16

How do non-competitive allosteric antagonists work?

Answer 16

• signal transduction rather than receptor effects
• downstream responses are blocked e.g calcium ion influx
• reduces slope and maximum of dose response curve

Question 17

How does an agonist curve look with a competitive antagonist?
Why?

Answer 17

• same form but displaced to the right
• same maximal response
• linear portion of curves are parallel
• because comp antagonist binds reversibly with receptor, gives rise to antagonism which can be overcome by increased conc of agonist

Question 18

Equation for dose ratio

Answer 18

agonist +antagonist EC50 (x)/agonist EC50 (y)

Question 19

What is the Schild equation?

Answer 19

r-1 = [B]/Kb

r is dose ratio
B is antagonist conc
Kb - antagonist dissocation constant

Question 20

What do pA2 values describe?
When does it work?

Answer 20

the activity of a receptor antagonist in simple numbers
pA2 = -logKb
- only works if relationship is linear and slope of Schild plot is 1/a comp antagonist

Question 21

Implications of comp antagonists on clinic

Answer 21

• extent of agonist inhibition depends on conc of competing antagonist (varies in response to normal physical activity as well as disease states)
• extent of inhibition depends on antagonist’s conc (inter individual diffs in metabolism or clearance influence plasma concs)

Question 22

How does the agonist curve look with an irreversible antagonist?
Why?

Answer 22

• don’t have same form and reduced maximal response
• ant binds irreversibly to receptor and gives rise to antagonism which cannot be overcome by increased conc of agonist

Question 23

Irreversible antagonism on a concentration response graph

Answer 23

• increased EC50
• duration of effect related to receptor turnover
• receptor reserves allow parallel shift to right

Question 24

Weak partial agonists are also …

Answer 24

irreversible antagonists

Question 25

Which is most common? Competitive or irreversible antagonism?

Answer 25

competitive

Question 26

Examples of competitive antagonists

Answer 26

• cimetidine at H2 receptor
• tamoxifen at oestrogen receptor

Question 27

Examples of irreversible antagonists

Answer 27

phenoxybenzamine at alpha1 adrenoreceptor

Question 28

Why are reversible inhibitors advantageous?

Answer 28

• once inhibited, receptor has to be regenerated
• extreme situations can be avoided
• receptor exists for a reason in the first place and don’t want to remove function completely

Question 29

How does a non-comp antagonist work?

Answer 29

• blocks signal transduction events
• inhibit agonist action by stopping something that signals outside
• no physical blockage
• reduces slope and maximal effect
• e.g nifedipine blocks calcium ion influc

Question 30

Define ‘therapeutic window/index’

Answer 30

proportion of unwanted effects of all effects like sickness or headache

Question 31

Equation for risk:benefit ratio

Answer 31

TD50/ED50
or
LD50/ED50

Question 32

What does it mean to have a small or large therapeutic window?

Answer 32

• large means concentration we need to give desired effect is much lower than conc where we see unwanted effects
• small means the gap is smaller and it’s easier to get side effects

Question 33

Example of drug with small or large TI

Answer 33

small is warfarin
large is penicillin