Lecture 19 - β2 adrenoceptor agonists - Risk and Reward Flashcards
Describe the factors that contribute to obstructive respiratory disease
- Airway smooth muscle shortening (contraction)
→ narrowing of lumen - Airway wall oedema
→ airway encroachment into lumen - Mucous hyper secretion
→ occlusion of lumen
What is obstructive respiratory disease?
Give examples
Compare with restrictive respiratory disease
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
List the mediators that control airway smooth muscle tone
Contraction: • ACh • HA (histamine) • LTC4 (Leukotriene C4) • LTD4
Relaxation:
• Adrenaline
• PGE2 (Prostaglandin E2)
• PGI2
Which autonomic NS receptors are found on bronchial smooth muscle?
Which molecules bind these receptors?
β2 adrenoceptors
Agonists: adrenaline
Compare the sympathetic and parasympathetic neurotransmitters
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
What class of receptor are adrenoceptors?
GPCR
Outline the various adrenoceptors
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
Describe the signal-transduction pathway of adrenaline on β2 adrenoceptors
- Adrenaline binds β2 adrenoceptor on airway smooth muscle
- Gs
- AC
- cAMP activated
- cAMP activates PKA (protein kinase A)
- PKA inhibits of IP3R channel (Ca2+ channel on intracellular stores) and stimulates reuptake of Ca2+ by SERCA channels
- Decreased cytosolic Ca2+
- Less MLCK activation
- Smooth muscle relaxation
- Bronchodilation
What is MLCK?
Myosin light chain kinase
Adds phosphate to the myosin light chain to allow cross-bridge cycling and thus muscle contraction
Describe the effect of ACh on airway smooth muscle
- ACh binds GPRCs
- Activation of PLC
→ - Ca2+ oscillations; activation of PKC and Rho kinase (inhibit MLC-phosphatase)
- Increased MLCK activity
- Phosphorylation of MLC
- Cross bridge cycling
- Smooth muscle contraction
- Bronchoconstriction
Compare the activity of PKA and PKC
PKA: activation of MLC-phosphatase → smooth muscle relaxation
PKC: inhibition of MLC-phosphatase → smooth muscle contraction
Describe some Long-acting β2-adrenoceptor agonists
Salmeterol: slow onset, 12 hrs duration
Formoterol: rapid onset, 12 hrs duration
Describe how β2-adrenoceptor agonists bring about smooth muscle relaxtion
Inhibition of:
• Ca2+ release
• PKC
Activation of:
• PKA → MLC-phosphatase activation
PKA → MLCK inhibition
Compare SABA and LABA
SABA: short acting β2-adrenoceptor agonists
LABA: long acting β2 adrenoceptor agonists
List some short acting β2-adrenoceptor agonists
Describe their features
AEs?
Salbutamol
Terbutaline
Rapid onset (2-5 mins) Short lasting β2-adrenoceptor selective
Adverse effects:
• Tachycardia
• Hypokalaemia
• Tremor
Which β2-adrenoceptor agonists are indicated for prophylaxis?
LABA
Describe the various β2-adrenoceptor agonists that have been used over the decades
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
Why might β2-adrenoceptor agonists be causing excess deaths in asthmatics?
- 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
Describe how inverse β2-adrenoceptor agonists can protect from murine ‘asthma’
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
Compare the following classes of drugs:
• Reliever
• Controller
• Preventer
Relievers:
• e.g. SABAs
• Used acutely to decrease bronchoconstriction
Controllers:
• e.g. LABAs
• Used prophylactically to achieve a background of bronchodilation
Preventers:
• Anti-inflammatories
What are IP3R and SERCA?
IP3R: Ca2+ release channel
SERCA: Ca2+ re-uptake channel
Compare neutral antagonists and inverse agonists
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%
Describe the results of the extensive meta-analysis mandated by the FDA into the safety of LABAs
Analysed mortality across many trials of individuals taking corticosteroids with and without LABAs
Results:
• Indicate an increase in mortality when taking LABAs
Describe the surprising results from studies in transgenic mice of airway obstruction
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
