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Pharmacology > Receptor theory > Flashcards

Receptor theory Flashcards

1
Q

What is KD?

A

Dissociation constant - measure if affinity. Concentration of ligand the binds to 50% of the receptors. The smaller the KD = the higher the affinity

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2
Q

Relationship between KD and affinity?

A

Smaller KD = higher affinity

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3
Q

What is the Ki value?

A

Concentration of competing ligand required to displace 50% of the specific binding of radioligand

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4
Q

What affects Ki values?

A

the assay conditions and dependent on the concentration of ligand

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5
Q

relationship between affinity and Ki?

A

Highest affinity has the lowest Ki value

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6
Q

why are higher affinities desired?

A

If there is a better affinity for the receptor - it means you need less of the drug for an effect - less chance of S/E and less damage to the organs

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7
Q

What is an agonist?

A

bind to receptors and Activate them to initiate a response

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8
Q

Define EC50

A

Concentration of drug that causes half the maximal effect produced by the drug (agonist) - measure of potency

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9
Q

Define antagonist

A

Drug that binds to a receptor but does not activate it - zero efficacy. Blocks the action of the agonis & competes for receptor binding.

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10
Q

Define IC50

A

Concentration of antagonist to inhibit 50% of the agonist response. Sometimes it can be an over or underestimation depending on the concentration of the agonist present.

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11
Q

what information does the IC50 NOT provide?

A

NO info on the mechanism e.g. if it is competitive, reversible, non competitive etc

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12
Q

Dose ratio equation?

A

EC50 + [antagonist] / EC50 of control

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13
Q

What happens to the agonist in presence of an antagonist ?

A

We need more agonist (higher conc) to produce the same response as it would be without the antagonist present - log curve shifts to the right. Dose ratio >1
This is called competitive surmountable antagonism

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14
Q

What happens when we add more competitive surmountable antagonist?

A

Reduces the amount of receptor-agonist complex and thus less effect.

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15
Q

what does surmountable mean?

A

increase in antagonist pushes equilibrium to get less agonist effect

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16
Q

In the presence of what type of antagonist will you eventually get the agonist maximal response?

A

Competitive surmountable antagonist

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17
Q

Define dose ratio

A

The fold increase in agonist concentration that is needed to evoke a given response (normally EC50) in the presence of an antagonist

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18
Q

What does antagonist do to the dose ratio?

A

Increases it

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19
Q

What does a dose ratio of 2 mean?

A

Twice as much agonist is required to produce the same response

20
Q

What does a straight line = 1 on schild plot show?

A

we have a competitive antagonist, it also gives us the log KB

21
Q

Define KB

A

The concentration of antagonist that binds to 50% of receptors - a measure of affinity

22
Q

Relationship between KB and affinity, and PKB and affinity (antagonist)

A

The lower theKB = higher the affinity of antagonist.
PKB is the negative of KB so the higher the PKB = higher the affinity.

PKB = -logKB

23
Q

how do you calculate PKB?

A

-logKB

24
Q

What is PKB also referred to as?

A

The PA2 value - measure of affinity & potency.

The concentration of antagonist required to produce an agonist dose ratio of 2.

25
Q

Give an example of a competitive antagonist

A

Candesartan - anti-hypertensive/heart failure - an antagonist of angiotensin II = reduce peripheral resistance - vasodilation

26
Q

When is the PKB/PA2 value only a valid measure of affinity?

A

ONLY if the antagonist is competitive and reversible (slope = 1 schild)

27
Q

2 types of insurmountable antagonism

A

Irreversible

Allosteric

28
Q

Insurmountable antagonism Definition

A

In the presence of antagonist, no matter how much agonist you add, you will NEVER elicit the maximum response

29
Q

what is non-competitive allosteric antagonism?

A

Bind to different site - form another complex to prevent receptor from causing an effect. Have free agonists and thus less complex being formed and less effect.

30
Q

Compare competitive and non-competitive antagonism

A

Competitive competes for receptor sites, more sites occupied and less effect.
Whereas non - just binds to a different site and changes conformation to reduce the agonist complex

31
Q

2 types of irreversible antagonism

A

competitive - compete for same binding site.

Non competitive - lock receptor into irreversible state

32
Q

are irreversible antagonists used clinically?

A

Not really, some antibody based biologics that lock receptor but no small molecule drugs.
Most drugs can target ENZYMES as irreversible inhibitors (suicide inhibitors ) e.g aspirin but not receptors.

33
Q

3 things that bioassays tell us about antagonists?

A

Type of antagonism e.g competitive/surmountable, non competitive, insurmountable? if it is insurmountable then implications e.g could overdose with anticoagulants

Dissociation constant= affinity for competitive antagonists - KB

drug effects

34
Q

Define efficacy

A

The ability of a drug to activate a receptor and cause a. response - response is dependent on amount of receptors occupied.

35
Q

What is a partial agonist?

A

Some agonists cannot evoke the maximal response that a tissue can produce = lower Emax
Full agonist = 1
Partial agonist = <1

36
Q

what is potency based on?

A

EC50 value

37
Q

Why doesn’t receptor occupancy theory explain partial agonists?

A

A full agonist causes a near maximum response at 50% occupancy of receptors (e. g phenylephrine at a-1 adrenoceptors). However, partial agonists can never cause max response even at 100% occupancy. The theory does not explain partial agonists as receptors occupied at the same extent. This - the response can’t be directly proportional to stimulus

38
Q

How does intrinsic activity explain partial agonists? - modified occupancy theory

A

Response is governed by occupancy and efficacy.
Intrinsic efficacy factor (beta) determines drug type e.g
B = 1 - full agonist
B = <1 partial agonist
B = 0 antagonist

39
Q

Advantages of partial agonists as drugs

A
  • submaximal tissue response - does not stimulate fully the system
  • Less desensitisation
  • can also act as competitive inhibitors of full agonists
40
Q

Drug that is a partial agonist

A

Buprenorphine - For opioid dependence and pain relief (Temgesic)
Partial agonist at opioid receptors - don’t get full response desensitisation

41
Q

what is the theory of receptor reserve?

A

Maximal response can be obtained with submaximal occupation - irreversible agonism - the agonist can still produce max response even if occupancy is only 50% - meaning there must be a reserve of spare receptors

42
Q

is receptor reserve advantageous?

A

It means that there are large responses at lower concentrations of the drug meaning there could be less chance of S/E

43
Q

What is furchgott modification?

A

Effect of drug - Response (=f - receptor number, occupancy, efficacy). It depends on 2 tissue factors (transduction, receptor number), and 2 drug factors (occupancy/affinity, intrinsic efficacy).

44
Q

What are inverse agonists?

A

drug that produces the opposite response to the agonist

45
Q

What is the difference between antagonists and inverse agonists?

A

antagonists - block the action of agonists - neutral effect on receptor

Inverse = block the actions of agonists but ALSO suppress agonist-independent activity.

46
Q

What are 4 drug classifications?

A

Agonist - drug binds to receptor & produce response
Partial agonist - produces an effect LESS than the maximum
Antagonist - binds but does not cause activation
Inverse agonist - produces opposite response to agonist, blocks agonist and suppresses agonist independent activity.

Pharmacology (3 decks)

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