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Basic Pharmacology > 3. Agonists > Flashcards

3. Agonists Flashcards

1
Q

Define ‘agonist’

A

a ligand (neurotransmitter, hormone, drug) that combines with receptors to elicit a cellular response

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2
Q

General steps from an agonist to effect

A
  • receptor
  • agonist-receptor complex
  • action
  • effect
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3
Q

Steps of salbutamol to effect

A
  • B2-adrenoreceptor
  • salbutamol-b2 adrenoreceptor complex
  • increased cAMP
  • bronchodilation
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4
Q

Why is dose important?

A
  • all things are poison in the wrong dose as wouldn’t have effect if they didnt have poisonous qualities
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5
Q

Correct dose of aspirin

A

300-600 mg

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6
Q

Two types of dose-response curve?

A
  • concentration plotted against effect
  • semi-logarithmic plot of agonist concentration against percentage response
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7
Q

Shapes seen on dose-response curve

A
  • if not log its a half semi circle
  • if log used, its sigmoidal
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8
Q

Difference between dose and concentration given

A
  • dose is the initial given
  • concentration is the amount in the systemic circulation
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9
Q

2 types of dose-response relationships

A
  • graded
  • quantal
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10
Q

Explain graded dose-response relationships

A
  • response of a particular system
  • in isolated tissue, animal or patient
  • measured against agonist concentration
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11
Q

Explain quantal dose-response relationships

A
  • drug doses (agonist or antagonist)
  • required to produce a specified response determined in each member of a population
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12
Q

How does a log axis work?

A
  • each unit increase represents an exponential increase on previous value
  • base 10 logs are used for dose-response
  • 10 fold increase from one unit to the next (1 to 10 to 100
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13
Q

Why is a log used?

A

to make a concise graph

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14
Q

Why do we plot dose-response graphs?

A
  • allows estimation of Emax
  • and of dose required for 50% of Emax/EC50
  • allows determination of efficacy and potency
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15
Q

Define ‘Emax’

A

maximal response with highest concentration in system

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16
Q

Define ‘EC50’

A

concentration/dose required to produce 50% of maximal response

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17
Q

Define ‘potency’

A
  • the amount of drug needed to produce an effect
  • how well a drug binds, the signalling involved and effect recieved at the end
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18
Q

Define ‘affinity’

A

strength with which an agonist/drug binds to a receptor

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19
Q

Explain the two state hypothesis

A
  • when receptor is resting, when not occupied by agonist (drug or natural product) any basal activity is low
  • forms a complex when occupied and equilibrium state shifts - more likely here for receptor to be activated, more receptive to turning on signalling system
  • shows how likely it is that the receptor is active or inactive
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20
Q

What does R and R* mean?

A
  • rested
  • activated
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21
Q

Affinity is the ratio of …

A

how easy an agonist (drug or natural product) sticks vs comes off

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22
Q

Receptor saturation is easily/tough to measure/d but …

A
  • easily (with max number of binding sites Bmax)
  • difficult to get a measure of how avidly the drug binds (affinity/Kd)
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23
Q

How to find amount of specific binding sites?

A

total sites - non-specific

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24
Q

How to work out affinity?

A
  • use k1/k-1
  • k1 being the rate of association of agonist with receptor
  • k-1 being rate of AR complex dissociation
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25
Q

A high affinity drug means what?

A
  • much greater tendency to bind to receptor (much larger k1)
  • relative to dissociation from receptor (smaller k-1 value)
26
Q

Kd is what?

A

the equilibrium dissociation constant

27
Q

Define ‘Kd’

A
  • a physiochemical constant
  • the same for any given receptor and drug combo in tissue in any species (as long as receptor is the same)
28
Q

What does Kd tell us?

A
  • can be used to identify unknown receptor
  • used to quantitatively compare affinity of diff drugs on same receptor
29
Q

If we assume a direct relationship between receptor occupancy and response, what can we assume?

A

concentration of ligand at which 50% of the available receptors are occupied is Kd
- inverse relationship between Kd and affinity
- a lower Kd indicates a tighter ligand-receptor interaction (higher affinity)

30
Q

How to show inverse relationship between affinity and Kd?

A

affinity is k1/k-1
Kd is k-1/k1

31
Q

The lower the Kd, the greater the …

A

affinity

32
Q

Can you work out affinity from the dose-response relationship?

A
  • no
  • don’t know how many of the receptors are occupied
  • need to see % of receptors occupied
33
Q

True affinity can only be determined by …

A

binding dose relationships

34
Q

Potency depends on what 4 things?

A
  • affinity
  • efficacy
  • receptor density
  • efficiency of stimulus-response mechanisms used
35
Q

Define ‘potency’

A

the amount of drug needed to produce given effect
- found at EC50

36
Q

The lower the EC50, the greater the …

A

potency

37
Q

Agonists with high potency tend to have …

A

high affinity

38
Q

If there is a linear relationship between receptor occupation and biological effect, then what?

A

Kd and EC50 are equal
- meaning 50% receptro occupation means 50% effect

39
Q

Explain spare receptors/receptor reserves

A
  • if linear relationship between receptor occupation and biological effect, EC50 and Kd are equal
  • but many receptors can amplify signal duration and intensity
  • so only a fraction of total receptors for a specific ligand have to be occupied to elicit maximum response from cell
  • these systems are said to have spare receptors
40
Q

When an agonist binds to a receptor, this induces what?

A

a conformational change that sets off a chain of biochemical events called ‘an action’

41
Q

Define ‘efficacy’

A
  • the ability of an agonist to activate a receptor i.e evoke an action at cellular level
  • determined by receptor-effector system
  • refers to maximum effect an agonist can produce regardless of dose
42
Q

A full agonist has … efficacy and a partial agonist has … efficacy

A

high
low

43
Q

In a full agonist with high efficacy, … is very likely.
Explain

A
  • AR*
  • produce a maximum response while occupying only a small % of receptors available
  • may only occupy 1 or 2 in CNS
44
Q

In a partial agonist with low efficacy, … is less likely. Explain

A

AR*
- unable to produce a maximum response even when occupying all available receptors

45
Q

In a full agonist, the maximum response produced corresponds to …

A

maximum response a tissue can give

46
Q

Define ‘partial agonist’

A
  • a ligand that combines receptors to elicit maximum response
  • which falls short of maximal response the system is capable of producing
47
Q

List 3 partial agonists

A
  • varenicline
  • tamoxifen
  • aripiprazole
48
Q

Role of varenicline

A
  • nicotine receptor partial agonist
  • for smoking cessation
49
Q

Role of tamoxifen

A
  • estrogen receptor partial agonist
  • for use in estrogen dependent breast cancer
50
Q

Role of aripiprazole

A
  • antipsychotic
  • partial agonists at selected dopamine receptors
51
Q

Why are partial agonists good sometimes?

A
  • encourage endogenous reactions but reduced response
  • don’t inhibit natural response
  • can lower chances of breast cancer for example without completely stopping estrogen production
52
Q

What’s the new data showing a link between partial and full agonists?

A
  • suggests receptor operated ion channels like nAChR and GlyR
  • channels can open and close equally as well in response to either PA or FA
53
Q

What evidence is noted that shows two state model is maybe too simple?

A
  • shows receptor can only work in AR and AR*
  • new evidence suggests receptors can activate in absence of ligands i.e R* or change state depending on GPCR function
  • ternary complex model (four active states
54
Q

Explain inverse agonists

A
  • have higher affinity for AR state than AR*
  • shown in many classical competitive antagonists like cimetidine for H2 and atropine (M)
  • around 85% of competitive antagonists are actually inverse agonists
55
Q

Why are inverse agonists not antagonists?

A
  • binds to low level activity receptor and turns down the activity
  • doesn’t block it so not an antagonist
56
Q

Example of an inverse agonist

A
  • Beta-carbolines on GABAa receptors
  • anxiogenic rather than anxiolytic
57
Q

How do benzodiazepines act as allosteric modulators?

A
  • act on GABAa receptors
  • drug has own unique binding sites, they bind together so can’t block GABA binding site
  • increases Ka for GABA
  • increases efficacy of GABA
  • increases chloride ions that come through channel
58
Q

Explain positive allosteric modulators

A
  • not active alone but increase affinity and/or efficacy of endogenouds agonists
  • e.g diazepam, propofal, isoflurane
59
Q

Explain negative allosteric modulators

A
  • not active alone but decrease affinity and /or efficacy of endogenous agonists
  • e.g mGluR5 dipraglurant
60
Q

Define ‘desensitisation of receptors’

A

effect of drug reduces continual/repeated administration
- called tachyphylaxis

61
Q

Contributing factors to densentisisation of receptors

A
  • conformational changes in receptor
  • internalisation of receptors
  • depletion of mediators
  • altered drug metabolism
  • other physiological/homeostatic responses

Basic Pharmacology (16 decks)

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