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
What is the effect of ACh on the airways?
Smooth muscle contraction
Acts through mAChR
(Parasympathetic NS)
Explain the model for the various responses elicited by agonists, neutral antagonists and inverse agonists on B2-ADRs
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
Describe the recent trial of Nadolol in asthmatic humans
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
