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_Sem 1. ICCP NOTES > Lecture 10 > Flashcards

Lecture 10 Flashcards

1
Q

Drug potency

A

Governed by affinity and efficacy

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2
Q

Beta 1 adrenoreceptors and beta 2 adrenoreceptors - where are they found?

A

Beta 1 adrenoreceptors - heart

Beta 2 adrenoreceptors - Lungs

(‘1 heart, 2 lungs’)

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3
Q

How does relaxation occur in the lungs?

A
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4
Q

What happens when you stimulate the beta 2 adrenoreceptors?

A

Stimulating this receptor causes relaxation, we can target this recept as this inhibits contraction.

This is functional antagonism because: Reversal of the effects of a drug by an agent which, rather than acting at the same receptor, causes a response in the tissue or animal which opposes that induced by the drug. i.e. the drug causes relaxation, opposing the contraction that is occuring naturally.

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5
Q

The problem with stimulating all beta-adrenoreceptors?

A

If beta-adrenoreceptors are stimulated:

  • beta-2 adrenoreceptors in the lungs stimulated cause relaxation (think sympathetic - fight and flight)
  • beta-1 adrenoreceptors in the heart will also be stimulated, this causes increase force and rate of contraction (think sympathetic - fight and flight) BAD IN THIS EXAMPLE

Therefore, need to have drugs which are selective/specific, that only target the beta 2 adrenoreceptors in the airways

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6
Q

Meaning of selective/specific activation?

A
  • Selective: e.g. Drug preferientially activates beta-2 adrenoreceptors (but can activate other types of too)
  • Specific: only activates one type e.g. only activate beta-2 adrenoreceptors
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7
Q

How do we achieve selectivity/specificity?

A
  • Affinity: We can use affinity, e.g. lower Kd = higher affinity, e.g. if the drug has a higher affinity for beta-2 adrenoreceptors, more likely to bind to these, so more likely to act on them
  • Intrinsic efficacy: Ability to activate the receptor when bound e.g. the drug may have the same affinity for beta-1 and beta-2 adrenoreceptors, but may have higher efficacy for beta-2 adrenoreceptors when bound i.e. more likely to actually activate the receptor
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8
Q

How is sulbutamol selective for beta-2 adrenoreceptors?

A
  • Affinity is similar for beta-1 adrenoreceptors and beta-2 adrenoreceptors (little difference in affinities)
    Kd Beta-1 adrenoreceptors 20uM 20-fold
    Beta-2 adrenoreceptors 1uM (Beta-2 selective)
    ^^poor selectivity
  • EFFICACY: Much higher efficacy for beta-2 adrenoreceptors
  • Also, ROUTE OF ADMINSTRATION: inhaler form, delivering the drug straight to the lungs. If it was adminstered by drip (it can be!), it would have a greater affect on the heart (beta-1 adrenoreceptors), which is why it is better in inhaler form
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9
Q

How is salmeterol selective for beta-2 receptors?

A
  • AFFINITY: Much higher affinity for beta-2 adrenoreceptors (only selective based on affinity)
  • No selective efficacy
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10
Q

Why can’t inhalers always be used in an asthma attack?

A

If very severe, trachea is almost closed, not getting air in at all. Drug enters lung with the air, therefore, also won’t get air in.

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11
Q

What is the route of adminstering for salmeterol?

A

Inhaler

Salmeterol is insoluble so can’t be adminstered through the blood in drip form.

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12
Q

Recap - What would the affect of salbutomol be, if it is given by drip?

A

Higher efficacy for beta-2 adrenoreceptors (selectivity for beta-2 adrenoreceptors), but still affects beta-1 adrenoreceptors considerably…

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13
Q

Summary of salbutomal and salmeterol

A
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14
Q

Discuss ligand affinity, intrinsic efficacy and potency

A

For any ligand-receptor combination:

  • Affinity (strength of interaction) FIXED FOR A LIGAND AND THE RECEPTOR
  • Receptor -> active conformation (intrinsic efficacy) fixed FIXED FOR A LIGAND AND THE RECEPTOR
  • Potency – variable (cell/tissue-dependent factors affect efficacy) i.e. affected by number of receptors
    Think - the AR* form may be activated, but it is then up to the number of receptors for the response e.g. if very few receptors, get a small response, even if there is very high drug concentration around the receptors)
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15
Q

Relationship between agonist affinity and agonist potency GRAPH WITH NO SPARE RECEPTORS - ALL RECEPTORS USED

A
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16
Q

Meaning of spare receptors….

A

Don’t need to occupy these extra receptors for the same response.

However, having spare receptors allows higher potency (more sensitive), at a lower concentration, able to reach Emax

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17
Q

Relationship between agonist affinity and agonist potency

A
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18
Q

The concept of spare-receptors exist because…

A

Exist because of:
• amplification in the signal transduction pathway (activation of 1 G protein receptor, will activate many G protein -> these activate many effector molecules etc…)
• response limited by a post-receptor event (e.g. a cell can only contract so much or a cell can only secrete so much etc…)

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19
Q
A
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20
Q
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21
Q

Why have spare receptors? (if it doesn’t appear to need them?)

A

Spare receptors increase sensitivity/potency ie. - allow responses at low concentrations of agonist

agonist sensitivity (and therefore agonist potency)

…but can also influence the maximal response

Receptor number therefore influences agonist sensitivity and therefore, agonist potency

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22
Q

Draw a graph with curve lines showing number of receptors and response (some lines with spare receptors, line with exact number of receptors and line with less than the number of receptors that is required for maximal response)

A
23
Q

Is the receptor number fixed, if not, what does this mean?

A

Number of receptors change according to the local environment

Receptor numbers are not fixed:
• tend to increase (more receptors) with low activity (up-regulation)
• tend to decrease (lower receptors) with high activity (down-regulation)

Up-regulation and down-regulation occurs due to:
- physiological, pathological or drug-induced changes

24
Q

What can down-regulation of the number of receptors cause for the effect of drugs?

A

For drugs this can contribute to tolerance and withdrawal symptoms

If taking lots of drugs, causes the receptors to become highly active so they down regulate = reduce in number (tissues have become less sensitive) = start developing tolerance, as then need to take a higher dose (to increase the conc. around them) for the same effect

25
Q
A
26
Q

Are all agonists equal at the same receptors?

A

Ligands have…
• Different affinities
• Different efficacies

27
Q

What are partial receptors?

A

Partial agonists are ligands that evoke responses that are lower than the maximal response of a full agonist (ie. they have lower Emax values and therefore lower intrinsic activity).

Irrespective of the amount of ligand added, do not get a full response. (not the receptor number that will allow a full response)

28
Q

How to calculate EC50 for partial agonist?

A

50% of its response (not of the full agonist)

29
Q

Concentration-response curve showing full agonist and partial agonist (explaination of each part of the curve)

A
30
Q

Compared to full agonists, partial agonists have lower….

A

Lower intrinsic efficacy

31
Q

What is intrinsic acivity?

A

The maximal possible effect that can be produced by a drug

32
Q

Draw a graph (concentration-response curve) with lots of different curves on showing intrinsic activity…

A

A and B curves - these ligands have the same intrinsic activity - same magnitude of response

33
Q

Partial agonism is dependent on ligand type… but also receptor number

A

Shows that increasing the number of receptors (e.g. up-regulation), changes a partial agonist into a ful agonist

This shows that the agonist being a partial or full agonist will change according to the receptor and the environemnt (i.e. if up-regulation or down-regulation has occurred)

34
Q

Opiods

A
35
Q

Why can buprenorphine inhibit the effect of heroin

A
  • has a higher affinity than herion
  • partial agaonist - so will give a smaller response than herion, less likely to lead to respiratory depression.
  • Therefore, it is used more to block the receptor from heroin, it can be refered to as a MIXED AGONIST/ANTAGONIST
36
Q
A
37
Q

Spare receptors - clearing up spare receptors (REALLY IMPORTANT TO UNDERSTAND AND REALISE THIS…)

A
38
Q

What are the two types of antagonism?

A

Can be achieved by:
1. Antagonism of a cellular/tissue event being mediated by one mechanism by another mechanism (FUNCTIONAL ANTAGONISM). Functional antagonism - works at a different effector, but it causes an effector which opposes what is happening e.g. sulbutamol

  1. Antagonism of the action of an agonist AT ITS RECEPTOR using a ligand (ANTAGONIST).
39
Q

What the are three types of antagonism?

A

Block the effects of agonists ie. prevent receptor activation by agonists

  1. Reversible competitive antagonism (commonest and most important in therapeutics) BINDS AT THE ACTIVE SITE
  2. Irreversible competitive antagonism BINDS AT THE ACTIVE SITE
  3. Non-competitive antagonism (generally allosteric – can even work post-receptor) BINDS ELSEWHERE - NOT AT THE ACTIVE SITE
40
Q
  1. Reversible competitive antagonism relies on a dynamic equilibrium between ligands and receptors
A

Works as ligands associate and disociate

41
Q

What is IC50?

A

IC5O gives an indication of antagonist affinity but influenced by [antagonist] AND strength of stimulus (i.e. [agonist])

Concentration of ligand that gives us 50% inhibition

42
Q

Response vs antagonist concentration curve

A

Greater [antagonist] = greater inhibition

43
Q

Is competitive antagonists surmountable or non-surmountable

A

Increasing agonist - leads to all receptors then occupying by the agonist

44
Q

Reversible competitive antagonists cause of parallel shift to the right of the agonist concentration-response curve

A

Agonist curve shift - shifts to the right as it is having to compete with the antagonist -> but if we increase the concentration of the agonist enough, we can outcompete the reversible antagonist - so can still get a full response

more of the right the curve is = the higher the affinity the reversible competitive antagonist has (as agonist has to be in higher concentration)

45
Q

Give an example of a competitive antagonist and how and why it works, draw a graph to show this

A

Naloxone - high affinity, competitive antagonist at μopioid receptors
Can compete with opiods like herion

  • high affinity means it will compete effectively with other opioids (e.g. heroin) for receptors
  • reversal of opioid-mediated respiratory depression
46
Q
  1. Irreversible competitive antagonism occurs when the antionist disscoaites slowly or not at all
A

Non-surmountable - does not matter how much agonist we add, the agonist will never compete with the antagonist

47
Q

Graph to show irrevesible competitive antagonists

A

on y axis - increasing concentration

48
Q

Example of an irreversible competitive antagonist

A

Pheochromocytoma (this is a type of tumour in adrenal chromaffin cells)
drugs e.g. phenoxybenzamine – this is a non-selective irreversible a1-adrenoceptor blocker used in hypertensive episodes in pheochromocytoma

49
Q
  1. Non-competitive antagonist
A

(acts like an irreversible antagonist - can’t always tell the difference on a graph)
binds to the allosteric site (not the active site/orthosteric site where the natural ligand binds)

50
Q

Allosteric sites binding

A
51
Q

Give an example of a non-competitive antagonist

A

Allosteric compounds for GPCRs just emerging in the clinic – inhibitors and activators (Allosteric drugs already common at some molecular targets)

Maraviroc - Negative allosteric modulator (NAM) of chemokine receptor 5 (CCR5) Used by HIV to enter cells. - Used in AIDS.

Allosteric compounds more established in other areas eg. ion channels and enzymes – positive AND negative effects

52
Q

Recap - description of the three types of antagonists

A
  1. Reversible competitive antagonism Takes place at the same binding site as the endogenous ligand(s) (orthosteric site). Interaction is by relatively weak (non-covalent) bonding
  2. Irreversible competitive antagonism Takes place at the same binding site as the endogenous ligand(s) (orthosteric site). Irreversible interaction reflects high affinity with very slow dissociation – may be covalent binding.
  3. Non-competitive antagonism Binding occurs at separate allosteric site - no competition for orthosteric site access. Interaction can be either low or high affinity and could include non-covalent or covalent bonding
53
Q

Recap of drugs covered:

  • Naloxone
  • Buprenorphine
  • Sulbutamol
  • Salmeterol
  • Phenoxybenzamine
  • Maraviroc
A
  • Naloxone - reversible antagonist (higher affinity than herion)
  • Buprenorphine - partial agonist (higher affinity and lower Bmax than heroin)
  • Sulbutamol - agonist but works using functional antagonism
  • Salmeterol - agonist
  • Phenoxybenzamine - irreversible antagonist
  • Maraviroc - non-competitive antagonist

_Sem 1. ICCP NOTES (13 decks)

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