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Toxicology and Pharmacology > Drug Mechanism of action one > Flashcards

Drug Mechanism of action one Flashcards

1
Q

Describe the structure of ligand gated ion channel receptors

A

Oligomeric assembly of subunits around a pore

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2
Q

Describe the strucure of GPCR

A

Monomeric structure of seven transmembrane domains

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3
Q

Describe the structure of tryosine kinase receptors

A

Single transmembrane helix with extracellular receptors and intergrated intracellular kinase (enzyme) domain

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4
Q

Describe the structure of nuclear receptor

A

Monomeric structure with seperate receptor and DNA binding domains

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5
Q

Describe the tyrosine kinase receptor

A

Extracellular receptor linked with an intracellular kinase domain (enzyme)

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6
Q

How do tyrosine kinase receptors work?

A

Ligand binds, Protein undergoes conformational change and autophosphorylates itself. The the intracellular kinase enzyme phosphorylate the tyrosine residues of intracellular target proteins

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7
Q

What ligands bind to tyrosine kinase receptors?

A

Cytokines, Growth hormones, Certain hormones

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8
Q

What is the example of tyrosine kinase receptor we look at?

A

Vascular Endothelial Growth Factor Receptors

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9
Q

What is the function of Vascular Endothelial Growth Factor Receptors?

A

Essential for angiogenesis during development, pregnancy (placenta), wound healing

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10
Q

When else is Vascular Endothelial Growth Factor Receptors important?

A

During pathophysiological conditions such as rheumatoid athritis and cancer, CV disease.

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11
Q

What is the specific Vascular Endothelial Growth Factor Receptors we look at?

A

VEGFR2

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12
Q

Though most tyrosine kinase receptors are monomeric structures in the case of VEGFR2 what has occured?

A

Dimerisation (two units together)

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13
Q

Describe the process that occurs when the ligand binds to VEGFR2

A

Ligand binds
Conformational change
Autophosphorylation of tyrosine residues and cytoplasmic domain.
This in turn can now phosphorylate (usually phosphorylation cascades) many target proteins mediating many biological processes such as:

Endothelial cell survivial
Endothelial cell proliferation
Endothelial cell migration
NO and PGI2 production
Increased vascular permeability
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14
Q

What are the resultant biological outcomes of VEGFR2 activation?

A 
Endothelial cell survivial
Endothelial cell proliferation
Endothelial cell migration
NO and PGI2 production
Increased vascular permeability
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15
Q

With VEGFR2 describe the exact cascade that results in increased gene transcription

A

Receptor activation leads to autophosphorylation, then, phosphorylation of:

Phospholipase C Y (gamma)
Which hydrolyses PIP2 to DAG and IP3
DAG activates PKC (phosphorylates)
PKC (phosphorylates) Raf which Phosphorylates MEK which phosphorylates ERK

ERK activation leads to increased gene transcription

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16
Q

What drugs could target VEGF pathways?

A

Angiogensis inhibitors used in Cancer (watching for CV effects)

and

Angiogenesis stimulators used in Wound healing, Placental development etc.

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17
Q

Is the tyrosine kinase receptor pathway fast or slow?

A

Slow, it doesnt need to be fast as cell proliferation does not need to be isntantaneous

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18
Q

What sort of interactions does a ligand have with a receptor?

A

Van der waals
Hydrogen bonds
Ionic bonds
Covalent bonds

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19
Q

List the types of bonds ligands have with receptors from strongest to weakest

A

Van der waals (weakest)
Hydrogen bonds
Ionic bonds
Covalent bonds (essentially irreversible)

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20
Q

What is the affinity constant?

A

The affinity constant (Kd) is defined as the concentratioon of ligand present when the fractional occupany of receptors is 50%

21
Q

What is affinity?

A

The affinity is the attraction a drug/molecule has for a specific receptor

22
Q

Whats the relationship between Kd, Affinity and Fractional Occupany (FO)

A

The higher the affinity of a drug is the lower the concentration is for a given level of fractional occupany. This also means lower Kd value for a drug. I.e Less drug more binding.

23
Q

What is the difference between affinity and biological response?

A

Affinity measures the concentration of a drug at a given receptor occupany.

Biological response measures concentration of a drug to produce a given response.

24
Q

Why is a concentration response curve not reliable?

A

It is not strictly proportional,

  • Considerable amplification may occur i.e low level of receptor occupany may cause full biological response
  • Many factors downstream of receptor binding may interact to produce the final response
25
Q

What can be determined from a concentration response curve?

A

EC50 (The 50% effective concentration fo a drug)

Emax (max effective concentration)

26
Q

What is potency?

A

The EC50 of a agonist

Concentration that produces 50% of the maximal response

27
Q

What is the relationship of potency and EC50?

A

The more potent a drug the lower the EC50

28
Q

Does the EC50 describe the antagonist potency?

A

NO this is more complicated - however similar principles hold

29
Q

What is the difference between Potency and Affinity?

A

Affinity is the measure of FO for a drug at a given concentration. Higher affinity means lower concentration of drug produces higher FO.

Potency is a measure of the drugs EC50. How much drug is required to produce 50% maximal effect.

Affinity doesnt = potency.

A drug may have high affinity but produce low biological response for that tissue. Or it may be very potent but have low affinity.

30
Q

What is Efficacy?

A

The Ability of a drug to bind to a receptor and induce change in the receptors action. Measured by Emax.

31
Q

Are receptors in a Off/on state?

A

No, some receptors have a basal level.

32
Q

What is the result of having receptors at a basal level?

A

We have reverse agonists designed to turn off this basal level of activity

33
Q

In relation to efficacy what are the three categories of drugs?

A

Agonist - positive efficacy, increases cellular response
Inverse agonist - negative efficacy, turns off cellular response.

Antagonist - Blocks receptors, keepings its basal cellular response.

34
Q

What is an example in which an inverse agonist would be used?

A

Precocious puberty: The thyroid receptors are activated at a basal level with no ligand present at all, however we do not want their basal rate, so we use a inverse agonist to block them

35
Q

Does an agonist produce the full response?

A

No, we grade agonism based on what we have observed today as the full response (moving target)

A partial agonist cannot induce full response even at maximal receptor occupancy. Only a full agonist can do so.

36
Q

What is a partial agonist?

A

A drug that cannot induce full biological response even at full receptor occupancy

37
Q

If you LOG the x axis of a concentration, FO/Response hyperbole the resulting graph is

A

Sigmoidal

38
Q

What is the maximal effect of a drug determined by?

A

Efficacy and tissue properties

39
Q

If the maximal effect of a drug is determined by tissue properties, what does this imply?

A

Drugs have different maximal response in different tissues

40
Q

In terms of Affinity, Efficacy etc, how would an antagonist be described as?

A

They have affinity, but no efficacy. As it does not change the action of the receptor/ cellular response

41
Q

How are antagonists defined?

A

How they bind to receptors

42
Q

What are the categories of antagonism binding?

A

Reversible Competitive Antagonism

Irreversible Antagonism

43
Q

What is reversible competitive antagonism?

A

Bind to the receptor in a reversible manner to compete directly with agonist binding.

44
Q

What can be observed on a response concentration graph for agonist and reversible competitive antagonist binding?

A

As the concentration of reversible competitive antagonist increases, the concentration of agonist must increase to produce a full response.

I.e a maximal biological response can occur in the presence or reversible competitive antagonism providing the concentration of agonist is sufficient. It can out compete the antagonist.

45
Q

How does a irreversible antagonist bind to a receptor?

A

Covalent bonding. New receptors must be formed to re-establish the previous level of function

46
Q

On a concentration response curve for an agonist, in the presence of irreversible antagonist, what occurs?

A

The maximal response of the agonist is diminished.

However this tends only to occur at high levels of irreversible antagonist because of potency - how a little bit of drug can produce a large response, there is no need for full receptor occupancy.

47
Q

Describe the equilibrium shift between receptors on and off in the presence of different drug efficacy..

A

No ligand = equilibrium favors receptors off

Full agonist = equilibrium strongly shifts to receptors on

Partial agonist = slight equilibrium to receptors on

Antagonist = no shift in equilibrium

Inverse agonist = shift in equilibrium to receptors off

48
Q

Describe the difference between Affinity, Potency and Efficacy:

A

Affinity is a measure of a drugs FO at a given concentration

Potency is the EC50 of a drug. How much drug it takes to produce 50% of known maximal response

Efficacy is the ability of a drug to bind to a receptor and change its action. E max.

Toxicology and Pharmacology (32 decks)

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