D3 - agonism dynamics Flashcards

1
Q

Pharmacodynamics

A

how drugs can bind to a drug target and how this produces a therapeutic response

- Impact of drug binding on the target 
- Impact of drug binding on cell response
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2
Q

How drugs bind to drug targets

A
  • 99% of drugs used bind to drug target
    ○ Typically reversible - can dissociate again
    • Receptors
      ○ Recognise presence of hormone, drug, neurotransmitter, mediator, drug
      ○ Transduce binding signal to downstream signalling pathway to produce a change in cellular activity
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3
Q

B1 adrenoceptors

A

○ In cell membrane of cardiac cells
○ Recognise adrenaline and noradrenaline
○ Changes intracellular calcium levels
○ Increase heart rate and contractility

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4
Q

Receptors

A
  • Receptors are proteins
    ○ Large
    ○ Typically >300 amino acids in length that have small cavities for drug binding
    ○ Have small cavities for drug binding - binding site
    ○ Arrangement of amino acids and functional groups
    ○ Binding site and drug have
    § complimentary 3 dimensional shapes
    § chemical forces of attraction
    □ Typically weak chemical forces - hydrogen bonds, ionic bonds, van der walls
    □ Covalent bonds rarely involved
    ○ When a drug comes into close proximity to the binding site - drug becomes activated because of existence of chemical forces of attraction between it and the binding site
    ○ Drug will bind to binding site depending on
    § 3 dimensional fit
    § existence of chemical forces - hydrogen bonds, ionic bonds, van der waals forces
    ○ Binding reflects affinity
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5
Q

Affinity

A

○ Tendency of a drug to bind to it’s drug target
○ Affinity depends upon
§ complimentary chemical forces
§ Complimentary three dimensional shapes
○ Without affinity, drugs don’t bind - don’t work

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6
Q

Strength of chemical forces varies based on

A
  • Type of bond involved in binding
    ○ Van der walls - weak
    ○ Hydrogen - slightly stronger
    ○ Ionic bonds - stronger still
    ○ All much weaker than covalent bonds
    • Distance between receptor and drug
      ○ Inverse relationship between distance and strength of binding
      § most acute for van der walls forces
      □ Strength of wan der walls forces dissipates quickly as distance is increased
      ○ Less acute for ionic bonds
      § Still exists inverse relationship of distance and strength
      ○ Good 3 dimensional fit will minimise the distance between the drug and it’s target
    • Total number of bonds involved
      ○ More bonds -> stronger the binding
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7
Q

Affinity enables drug binding

A

How much drug binding depends upon drug concentration
- Binding is reversible
- Drug-drug target complex can dissociate again
- Equilibrium
- Law of mass action
○ As the concentration of drug is increased, equilibrium is forced to the right
§ Greater fraction of targets is bound by the drug
○ Fraction of target bound by the drug is dependant on
§ concentration of drug
§ affinity of drug for the receptor - Ka value
- Drug/(drug + Ka) = fraction of target bound by drug

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8
Q
  • Law of mass action
A

○ As the concentration of drug is increased, equilibrium is forced to the right
§ Greater fraction of targets is bound by the drug
○ Fraction of target bound by the drug is dependant on
§ concentration of drug
§ affinity of drug for the receptor - Ka value

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9
Q

Ka value

A
  • The concentration of drug occupying 50% of receptors
    • Measure of affinity of the drug for the receptor
    • Equilibrium dissociation constant
    • Measure of affinity of the drug for the drug target
    • Measure of the concentration of the drug at which 50% of the drug target is bound
    • Inverse relationship between the size of the Ka and the affinity
      ○ Low Ka value indicates high affinity
      ○ Only high affinity drugs bind at low concentrations
    • Constant value for a given drug/drug target pair
      ○ Relative term - will be different with different drug pairs
      ○ Difference in Ka value can explain
      § Why drugs vary in potency
      § Why drugs have selectivity
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10
Q

Inverse relationship between the size of the Ka and the affinity

A

○ Low Ka value indicates high affinity
○ Only high affinity drugs bind at low concentrations
- Constant value for a given drug/drug target pair
○ Relative term - will be different with different drug pairs
○ Difference in Ka value can explain
§ Why drugs vary in potency
§ Why drugs have selectivity

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11
Q

Saturation

A
  • Almost all receptors are bound by the drug

- Increasing concentration of the drug wont cause significant increase in the fraction of receptors bound by the drug

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12
Q

Drugs that activate drug targets

A

○ agonists
○ Eg. Adrenaline binds and activates beta-1 adrenoceptor causing increase in intracellular calcium levels and increase in heart rate and contractility

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13
Q

Agonist binding

A
  • When an agonist is in the vicinity of the receptor it can bind to the site and induce a conformational change affecting the rest of the receptor
    • Activation of the receptor so that it can bind to and activate down stream signalling pathways
    • Agonists have affinity enable binding to receptor - also posses efficacy
      ○ Efficacy
      Ability to activate receptor
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14
Q

Efficacy at G protein coupled receptors - ability to activate the receptor

A
  • B2 receptor is a G-protein coupled receptor
    ○ A single protein that fold to form 7 transmembrane regions spanning the cell membrane creating a barrel structure in the cell membrane
    ○ The binding site is a third of the way down the barrel-like structure
    ○ One of the transmembrane domain helixes moves (number 6) to generate a binding pocket for the G protein
    ○ When activated - a binding pocket is created which can be occupied by a g protein
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15
Q

High efficacy agonists

A
  • Cause a high level of receptor activation

* Called full agonists

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16
Q

low efficacy agonists

A
  • Cause less receptor activation
    • Cause smaller effects within cells
    • Partial agonists
17
Q

Antagonists

A
  • bind to receptors but don’t activate them

- Have affinity but no efficacy

18
Q

Magnitude of effect

A
  • Magnitude of effect produced by an agonist dependant on
    ○ Concentration of an agonist
    ○ Affinity of the agonist for the receptor
    ○ Efficacy
    • Magnitude of an effect also depend on cell dependant factors
      ○ Number/density of receptors
      ○ Existence and efficiency of coupling of signalling pathways between activated receptor and end effect
    • Decrease in receptor density is associated with a decrease of effect
    • Factors leading to decrease density
      ○ Disease
      § Myasthenia gravis - autoimmune disease where autoantibodies reduce the number of nicotinic acetyl choline receptor on skeletal muscle cells
      § Skeletal muscle cells are less responsive to acetyl choline - muscle weakness
      ○ Drugs
      § Irreversible antagonists
      ○ Gene silencing techniques
19
Q

Dose-response relationship

A
  • Relationship between agonist concentration and effect
    • Plot of agonist concentration against effect
      ○ Non-linear with a plateau region
20
Q
  • Log concentration
A

○ Sigmoidal dose response curve
○ Linear portion in the middle
§ Used to estimate factors including agonist potency

21
Q

Potency reflects relationship between concentration and effect

A
  • Measured using EC50 value (effective concentration 50)

○ Concentration of the value that produces 50% of it’s maximum possible effect

22
Q

EC50 value (effective concentration 50)

A

○ Concentration of the value that produces 50% of it’s maximum possible effect

23
Q

EC50 value depends on

A

○ affinity of the agonist for the receptor
○ Its efficacy
○ Cell dependant parameters eg. Receptor density
- Increasing any of the parameters will lead to a decrease in EC50 value
○ Movement of dose-response curve to the left
- Measure of potency - not the same as the Ka value
○ Ka value is just a measure of the affinity
- EC value is dependant on Ka value but is also dependant on other parameters