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BIOM30001 - Frontiers in Biomedicine > Lecture 19 - β2 adrenoceptor agonists - Risk and Reward > Flashcards

Lecture 19 - β2 adrenoceptor agonists - Risk and Reward Flashcards

1
Q

Describe the factors that contribute to obstructive respiratory disease

A
  1. Airway smooth muscle shortening (contraction)
    → narrowing of lumen
  2. Airway wall oedema
    → airway encroachment into lumen
  3. Mucous hyper secretion
    → occlusion of lumen
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2
Q

What is obstructive respiratory disease?

Give examples

Compare with restrictive respiratory disease

A

Obstructuve: Lung disease characterised by difficulty exhaling all the air from the lungs

FEV1 decreases, FEV1/FVC ratio decreases

Examples:
 • COPD
- Emphysema
- Chronic bronchitis
 • Asthma
 • Bronchiectasis
 • Cystic fibrosis

Restrictive: lung disease characterised by difficulty filling lungs upon inspiration

FEV1 and FVC equally reduced → ratio stays the same

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3
Q

List the mediators that control airway smooth muscle tone

A 
Contraction:
 • ACh
 • HA (histamine)
 • LTC4 (Leukotriene C4)
 • LTD4

Relaxation:
• Adrenaline
• PGE2 (Prostaglandin E2)
• PGI2

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4
Q

Which autonomic NS receptors are found on bronchial smooth muscle?

Which molecules bind these receptors?

A

β2 adrenoceptors

Agonists: adrenaline

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5
Q

Compare the sympathetic and parasympathetic neurotransmitters

A

Sympathetic:
• Pre-ganglionic: ACh released onto N2 receptors (nAChR)
• Post-panglionic: Adrenaline released onto α and β adrenoceptors

Parasympathetic:
• Pre-ganglionic: ACh released onto N2 receptors (nAChR)
• Post-ganglionic: ACh released onto mAChR

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6
Q

What class of receptor are adrenoceptors?

A

GPCR

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7
Q

Outline the various adrenoceptors

A

α:
α1 → smooth muscle contraction, vasoconstriction in the skin
α2 → smooth muscle contraction

β:
β1 → increased cardiac output (heart rate, force of contraction, conduction time)
β2 → smooth muscle relaxation = bronchodilation

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8
Q

Describe the signal-transduction pathway of adrenaline on β2 adrenoceptors

A
  1. Adrenaline binds β2 adrenoceptor on airway smooth muscle
  2. Gs
  3. AC
  4. cAMP activated
  5. cAMP activates PKA (protein kinase A)
  6. PKA inhibits of IP3R channel (Ca2+ channel on intracellular stores) and stimulates reuptake of Ca2+ by SERCA channels
  7. Decreased cytosolic Ca2+
  8. Less MLCK activation
  9. Smooth muscle relaxation
  10. Bronchodilation
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9
Q

What is MLCK?

A

Myosin light chain kinase

Adds phosphate to the myosin light chain to allow cross-bridge cycling and thus muscle contraction

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10
Q

Describe the effect of ACh on airway smooth muscle

A
  1. ACh binds GPRCs
  2. Activation of PLC
    →
  3. Ca2+ oscillations; activation of PKC and Rho kinase (inhibit MLC-phosphatase)
  4. Increased MLCK activity
  5. Phosphorylation of MLC
  6. Cross bridge cycling
  7. Smooth muscle contraction
  8. Bronchoconstriction
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11
Q

Compare the activity of PKA and PKC

A

PKA: activation of MLC-phosphatase → smooth muscle relaxation

PKC: inhibition of MLC-phosphatase → smooth muscle contraction

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12
Q

Describe some Long-acting β2-adrenoceptor agonists

A

Salmeterol: slow onset, 12 hrs duration

Formoterol: rapid onset, 12 hrs duration

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13
Q

Describe how β2-adrenoceptor agonists bring about smooth muscle relaxtion

A

Inhibition of:
• Ca2+ release
• PKC

Activation of:
• PKA → MLC-phosphatase activation
PKA → MLCK inhibition

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14
Q

Compare SABA and LABA

A

SABA: short acting β2-adrenoceptor agonists

LABA: long acting β2 adrenoceptor agonists

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15
Q

List some short acting β2-adrenoceptor agonists

Describe their features

AEs?

A

Salbutamol
Terbutaline

Rapid onset (2-5 mins)
Short lasting
β2-adrenoceptor selective

Adverse effects:
• Tachycardia
• Hypokalaemia
• Tremor

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16
Q

Which β2-adrenoceptor agonists are indicated for prophylaxis?

A

LABA

17
Q

Describe the various β2-adrenoceptor agonists that have been used over the decades

A

60’s: Isoprenaline
• Excess deaths observed:
• Non-selective: agonist for both β1 and β2-ADR
• Lead to adverse cardiovascular effects

80’s: Fenoterol
• Still saw excess mortality
• Very high efficacy
• It’s a SABA, so tolerance was probably occurring, so people were upping their doses

90’s: LABA introduction
• Appeared to be reduced deaths due to asthma

00’s: Salmeterol
• Excess deaths reported
• Resolution in symptoms, so individuals did not take the inhaled corticosteroids
• The underlying chronic inflammation may have been the cause of these excess deaths

18
Q

Why might β2-adrenoceptor agonists be causing excess deaths in asthmatics?

A
  • Chance observations
  • Lack of selectivity (isoprenaline)
  • High efficacy (fenoterol)
  • Excessive usage (all)
  • Innapropriate reliance on controller/reliever, and not taking preventers (inhaled corticosteroids)

• β2-adrenoceptor dysfunction

19
Q

Describe how inverse β2-adrenoceptor agonists can protect from murine ‘asthma’

A

Experimental design:
• WT and β2-ADR KO mice
• Both mice challenged with an allergen with and without treatment with Nadolol (a β2-ADR inverse agonist)
• Inflammatory response in airway monitored

Results:
• WT mice, when challenged with the allergen, develop an inflammatory response in epithelium: formation of goblet cells and mucous secretion
• β2-ADR KO mice do not develop this inflammatory response
• When Nadolol is administered to the mice, the WT do not develop the inflammatory response when challenged by the allergen
• In the KO mouse, there is no difference (i.e. still no inflammatory response)

Implication:
• Empty β2-ADRs play a causative role in the inflammatory component of murine asthma
• β2-ADR inverse agonists protect against this murine asthma
• β2-ADR plays a more complex role in the airways than simply bringing about smooth muscle relaxation and thus bronchodilation

20
Q

Compare the following classes of drugs:
• Reliever
• Controller
• Preventer

A

Relievers:
• e.g. SABAs
• Used acutely to decrease bronchoconstriction

Controllers:
• e.g. LABAs
• Used prophylactically to achieve a background of bronchodilation

Preventers:
• Anti-inflammatories

21
Q

What are IP3R and SERCA?

A

IP3R: Ca2+ release channel

SERCA: Ca2+ re-uptake channel

22
Q

Compare neutral antagonists and inverse agonists

A

Neutral antagonist:
• Receptor activity is at basal level
• i.e. Efficacy is 0%

Inverse agonist:
• Decreases receptor activity below basal level
• (By stabilising the inactive form of the receptor, and preventing it from coupling with the G protein)
• i.e. Efficacy is <0%

NB Efficacy of a full agonist: 100%

23
Q

Describe the results of the extensive meta-analysis mandated by the FDA into the safety of LABAs

A

Analysed mortality across many trials of individuals taking corticosteroids with and without LABAs

Results:
• Indicate an increase in mortality when taking LABAs

24
Q

Describe the surprising results from studies in transgenic mice of airway obstruction

A

β2-ADR -/- mice showed less airway obstruction that WT mice

Furthermore, mice that over express β2-ADR had increased obstruction of airways compared to WT mice when exposed to ACh

This is the opposite of what would be expected, and the activation of β2-ADRs brings about smooth muscle relaxation

25
Q

What is the effect of ACh on the airways?

A

Smooth muscle contraction

Acts through mAChR

(Parasympathetic NS)

26
Q

Explain the model for the various responses elicited by agonists, neutral antagonists and inverse agonists on B2-ADRs

A

The empty receptor has some baseline activity, indicated by production of cAMP

A neutral agonist will not change the activity of the receptor, thus there will not be a change in the amount of cAMP produced

Full agonists greatly increase the amount of cAMP produced

Inverse agonists decrease the amount of cAMP produced

27
Q

Describe the recent trial of Nadolol in asthmatic humans

A

Nadolol: non-selective B-ADR inverse agonist (i.e. a beta blocker)

Design:
• Individuals with asthma were given increasing doses of Nadolol
• PC20 (dose of contractile agonists: MCh, Histamine, required to decrease FEV1 by 20%) was measured

NB: the greater the PC20, the less ‘asthmatic’ the airways (i.e. the more drug required to decrease FEV1)

Results:
• Nadolol resulted in an increase in PC20 in the airways
• i.e. The airways of the individuals with asthma became less hyper-responsive to contractile agonists such as Methacholine and Histamine when they were taking Nadolol

BIOM30001 - Frontiers in Biomedicine (35 decks)

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