D4 - Antagonism dynamics Flashcards

1
Q

Antagonists

A
  • Endogenous neurotransmitters can produce unwanted effects
    • Eg. Histamine causing hay fever
    • Histamine release from mast cells activates histamine receptors causing itch, secretions and nasal congestion - possible to inhibit these unwanted effects
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2
Q

Chemical antagonists

A
  • Bind directly with soluble agonists
    • Inhibit agonist induced effect
    • Monoclonal antibodies, soluble receptors - ‘biologicals’
      ○ Bind to protein agonists
      ○ Prevents the agonist from binding to and acting on the receptor
    • Eg. Infliximab (monoclonal antibody) and etanercept (soluble receptor)
      ○ Both neutralise pro inflammatory TNF- alpha
      ○ Prevents binding and activation of TNF receptors
      ○ Treats rheumatoid arthritis
      § Inflammatory condition driven by TNF alpha
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3
Q

Infliximab

A
  • Eg. Infliximab (monoclonal antibody) and etanercept (soluble receptor)
    ○ Both neutralise pro inflammatory TNF- alpha
    ○ Prevents binding and activation of TNF receptors
    ○ Treats rheumatoid arthritis
    § Inflammatory condition driven by TNF alpha
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4
Q

Monoclonal antibodies

A

○ Some work by binding to agonist eg. inflixamab
○ Others work by binding to the receptor to inhibit agonist binding
§ Dupilumab binds to IL-4 receptor, suppressing eczema and asthma
○ Binding involves weak ionic bonds, hydrogen bonds, van der walls forces
○ Large number of high affinity interactions makes binding irreversible
○ Majority of monoclonal antibodies used to treat cancer and inflammatory diseases eg. Eczema, asthma, rheumatoid arthritis

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5
Q

Competitive receptor antagonists

A
  • Compete with agonists for the same binding site on the receptor
    • Blocks effect induced by endogenous agonists
      ○ Neurotransmitters
      § Acetylcholine, noradrenaline
      ○ Hormones
      § adrenaline
      ○ Mediators
      § Histamine blocked by cetirizine - cetirizine competes with histamine for the same binding site - antihistamine drug
    Competitive antagonist
    ○ Relies on the fact that the agonist binding is reversible
    ○ Antagonist will occupy binding site
    ○ When the competitive antagonist leaves, the binding site is free again, the agonist can bind
    Which one (competitive antagonist or endogenous agonist) will mainly bind the receptor depends on
    ○ Relative concentration
    ○ Relative affinity
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6
Q

dose response curve for Competitive receptor antagonists

A

Dose response curve
○ Increasing concentration of the antagonist moves the graph to the right
○ Rightward shift is theoretically unlimited, and does not cause reduction in maximum response
○ In the presence of antagonist, you need more agonist to produce a response

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7
Q

increasing concentration of a competitive receptor antagonist

A

ncreasing concentration of the antagonist moves the graph to the right
○ Rightward shift is theoretically unlimited, and does not cause reduction in maximum response
○ In the presence of antagonist, you need more agonist to produce a response

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8
Q

Metoprolol and adrenaline in patients with angina

A

○ Competitive antagonism between adrenaline and metoprolol
○ angina
§ Coronary arteries can be clocked by atherosclerotic plaque
§ When exercising, adrenaline is released and causes increased heart rate
§ Heart requires more oxygen from the coronary arteries
§ If coronary arteries are blocked then the heart goes into oxygen debt - causes angina pain
○ Metoprolol (competitive antagonist for B1 receptor)
§ Metoprolol blocks binding of adrenaline
§ Occupies B1 receptor without activating it
§ Decreases chances of heart going into oxygen debt
§ Decreases anginal attack
§ Often referred to as a beta blocker medication

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9
Q

angina

A

§ Coronary arteries can be clocked by atherosclerotic plaque
§ When exercising, adrenaline is released and causes increased heart rate
§ Heart requires more oxygen from the coronary arteries
§ If coronary arteries are blocked then the heart goes into oxygen debt - causes angina pain

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10
Q

metoprolol

A

○ Metoprolol (competitive antagonist for B1 receptor)
§ Metoprolol blocks binding of adrenaline
§ Occupies B1 receptor without activating it
§ Decreases chances of heart going into oxygen debt
§ Decreases anginal attack
§ Often referred to as a beta blocker medication

Metoprolol 
	○ Same level of adrenaline does not cause the heart to work any harder 
	○ Full protection against an anginal episode 
	○ Moves dose response curve to the right without a decrease in maximum response 
	○ In a high level of exertion, more adrenaline is released 
		§ Can overcome some of the metoprolol block 
		§ Metoprolol will only give partial protection in high exertion 
		§ May have to increase the dose - but this has possibility of adverse effects
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11
Q

metoprolol dose response curve

A

○ Same level of adrenaline does not cause the heart to work any harder
○ Full protection against an anginal episode
○ Moves dose response curve to the right without a decrease in maximum response
○ In a high level of exertion, more adrenaline is released
§ Can overcome some of the metoprolol block
§ Metoprolol will only give partial protection in high exertion
§ May have to increase the dose - but this has possibility of adverse effects

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12
Q

Irreversible receptor antagonists

A
  • Irreversible (or slowly reversible) bond with binding site
    • Phenoxybenzamine (PBZ)
      ○ Forms a covalent bond with agonist binding site on the alpha adrenoceptor
      ○ Prevents adrenaline from binding it
      ○ When in an aqueous solution, phenoxybenzamine forms an aziridinium ion which is highly reactive
      ○ Ion binds to cysteine amino acid residue in binding site of alpha adrenoreceptor to form a covalent receptor adduct
      ○ Permanently bound - adrenaline can no longer activate the receptor
    Irreversible antagonist
    ○ Forms covalent bond with the receptor
    ○ The receptor can no longer be activated
    ○ Irreversible antagonist causes a reduction in the number of receptors
    ○ Effectively Decreases receptor density
    ○ Reduction in the maximum response produced by an agonist
    ○ Reduction in maximum response on the graph
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13
Q

iverversable receptor antagonists dose response curve effect

A

○ Irreversible antagonist causes a reduction in the number of receptors
○ Effectively Decreases receptor density
○ Reduction in the maximum response produced by an agonist
○ Reduction in maximum response on the graph

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14
Q
  • Phenoxybenzamine (PBZ)
A

○ Forms a covalent bond with agonist binding site on the alpha adrenoceptor
○ Prevents adrenaline from binding it
○ When in an aqueous solution, phenoxybenzamine forms an aziridinium ion which is highly reactive
○ Ion binds to cysteine amino acid residue in binding site of alpha adrenoreceptor to form a covalent receptor adduct
○ Permanently bound - adrenaline can no longer activate the receptor
○ Lacks selectivity for alpha adrenoceptors - rarely used clinically
§ Also blocks muscarinic - adverse side effects

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15
Q

Allosteric antagonists

A
  • Bind to different binding site and causes a conformational change
    • Reduces affinity or efficacy of the agonist for the receptor
    • Do not compete with the agonist for the binding site
    • Interaction with agonist and antagonist happens through the receptor - not at the same binding site
    • Also called negative allosteric modulators (NAMS)
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16
Q

NAMS that decrease affinity

A

○ Clinical drugs most commonly decrease affinity not efficacy
○ Binding sites
§ Agonist - authosteric binding site
§ Separate binding site for the NAM - allosteric binding site
○ When the NAM binds to the site
§ Causes a change in the authosteric binding site such that the affinity for the agonist is reduced
§ Authosteric site has a lower affinity for the agonist - high agonist concentration is required for the same effect

Binding of NAMS is also reversible 
	○ When it leaves the receptor, normal activation can be achieved at normal activations again
17
Q

Dose response curve

A

○ NAMS cause dose dependant antagonism
○ Antagonism is limited
§ Because Allosteric site can be saturated/fully occupied
○ Moves dose response curve to the right
§ rightward movement is limited because the effect is limited
□ Unlike in competitive antagonist where rightward movement is unlimited
§ Called the ceiling effect
□ Associated with fewer side effects
□ Less likely to cause excessive blockage produced by other antagonists esp. irreversible

18
Q

○ Maraviroc

A

§ decreases affinity for HIV-1 for CCR5 and decreases viral entry
§ Entry of HIV to CD4+ cells requires binding of portion of HIV (GP120) to a chemokine receptor (CCR5) on CD4+ cells
§ Component of the virus GP120 binds to CCR5 - causes viral entry
§ Negative allosteric modulator at the CCR5 receptor
□ Binds to CCR5 receptor on CD4+ cell
□ Reduces affinity for GP120 component of the HIV
□ Disrupts binding of viral to cell - decreases viral entry

19
Q

NAMS that decrease efficacy

A

○ Also exist NAMS that decrease agonist efficacy (instead of affinity)
§ not used clinically yet

20
Q

PAMS - positive allosteric modulators

A

○ Also exist PAMS - positive allosteric modulators which increase affinity
§ Eg. Benzodiazepines increase affinity at the GABA receptor for GABA

21
Q

Inhibitors of intracellular signalling

A

• Inhibit pathway that link the activated receptor to the cellular effect
• Have widespread effects and side effects
○ Because any receptors and cell types share intracellular signalling pathways - lacking selectively
• Some cells uniquely express signalling molecules - may be specifically targeted
• Eg. BCR-Abl enzyme is uniquely expressed by leukaemic cells
○ Inhibited by Imatinib
○ Binds to and inhibits the function of the enzyme - decreases the viability of the leukaemic cell
§ Used in treatment of chronic myeloid leukaemia

22
Q

BCR-Abl enzyme

A

BCR-Abl enzyme is uniquely expressed by leukaemic cells
○ Inhibited by Imatinib
○ Binds to and inhibits the function of the enzyme - decreases the viability of the leukaemic cell
§ Used in treatment of chronic myeloid leukaemia

23
Q

Functional/ physiological antagonists

A
  • (Technically agonists)
    • Activate receptors to produce opposing effects within the same cell
    • Eg. During anaphylactic reaction
      ○ Promotes the release of histamine from degranulating mast cell which binds to H1 receptor on the surface of airway smooth muscle cells which increase intracellular calcium levels promoting contraction of smooth muscle
      ○ Airways narrow causing breathing difficulty
      ○ EpiPen - contains solution of adrenaline
      § Adrenaline binds to B2 adrenoceptors on the surface of airway smooth muscle cells (same cells that express histamine receptor)
      § Causes an increase in cyclic amp levels - promotes relaxation of airway smooth muscle cells - opposes contraction by histamine
    • Adrenaline is a functional antagonist of histamine induced contraction
      ○ Both are agonists but induce opposite effect
      ○ Cause opposite effects in the same cell
24
Q

Functional/ physiological antagonists dose response curve

A

Dose response curve
○ Cause dose dependant but limited antagonism
○ Receptors can be saturated
○ Limit to the extent of antagonism
○ Rightward shift of histamine curve
§ Histamine is less able to produce smooth muscle airway contraction

25
Q

epi pen

A

○ EpiPen - contains solution of adrenaline
§ Adrenaline binds to B2 adrenoceptors on the surface of airway smooth muscle cells (same cells that express histamine receptor)
§ Causes an increase in cyclic amp levels - promotes relaxation of airway smooth muscle cells - opposes contraction by histamine