lecture 20: the beta 2-adrenoceptor agonist: risk and reward Flashcards
How does the burden of disease drive frontiers?
- worldwide deaths attributed to:
- lower respiratory infections (3rd): 3.5 million (6.1%)
- COPD (4th): 3.3 million (5.8%)
- trachea/broncus/lung cancer (6th): 1.4 million (2.4%)
- tuberculosis (7th): 1.3 million (2.4%)
- DALYs (disability adjusted life years) lost worldwide:
- lower respiratory infections (1st): 79 million (5.4%)
- COPD (7th): 33 million (2.3%)
- Tuberculosis (8th): 29 million (2.0%)
- trachea/bronchus/lung cancer: 13 million (0.9%)
- lung health is worsening in terms of its impact
What happens when airways are exposed to triggers?
- e.g. cold air or allergen in a person with atopy
- airway narrowing
- acute inflammation → typically takes a little more time to evolve than the acute spasm of the muscle
- in ongoing asthma there is also an infiltration of the airway with inflammatory cell types e.g. T cells (TH2), eosinophils → can trigger structural changes → airway remodelling
- narrows to easily and too much
- multiple parallel intersecting processes rather than a linear pathology
![](https://s3.amazonaws.com/brainscape-prod/system/cm/117/833/563/a_image_thumb.png?1659437941)
What contributes to airway obstruction?
- airway smooth muscle shortening (narrowing of lumen)
- relievers (used to relieve a perceived need of relief of spasm), controllers (used chronically to control/diminish likelihood of spasm), preventers (chronic use with the aim of reducing inflammatory cell activation)
- bronchial wall oedema (swelling - enroachment on lumen)
- preventers
- mucus hypersecretion ( occlusion of lumen)
- preventers
What is the balance between mediators and airway smooth muscle?
- balance between constrictor and dilatory mediators on that smooth muscle
- functional antagonism
- contraction
- ACh
- HA
- LTC4
- LTD4
- relaxation
- PGE2
- PGI2
- Adrenaline
- B2-selective adrenoceptor agonists
What is airway smooth muscle contraction?
- lung slice
- area as the percentage of the initial area over time
- able to induce pretty considerable narrowing
![](https://s3.amazonaws.com/brainscape-prod/system/cm/117/835/604/a_image_thumb.png?1659437941)
What is the contractile mechanism?
- regulation of intracellular calcium
- mechanisms increasing free [calcium]
- TRP channels
- voltage operated calcium channels
- phospholipase C/inositol trisphosphate (IP3)
- release from intracellular stores
- mechanisms decreasing free [calcium]
- plasma Ca2+ ATPase-extrusion
- sarcoplasmic reticulum Ca2+ ATPase (SERCA)
- uptake into internal stores
- these processes make waves
What is airway smooth muscle relaxation?
- relationship between contraction and frequency of waves
- histamine causes spikes of calcium fluorescence
- formoterol causes a decreases in calcium waves → causes a concentration related decrease in spikes of calcium, decrease in frequency → relaxes
- long acting beta-agonists
- long duration of action
- given twice
- background level of bronchodilator effect
- measure of [Ca2+] vs time
![](https://s3.amazonaws.com/brainscape-prod/system/cm/117/836/106/a_image_thumb.png?1659437941)
What are the molecular mechanism by which the contractile operatus is operated?
- g protein coupled receptor
- Gq (g protein)
- couples through to phospholipase C
- able to generate inosotil trisphosphate → triggers calcium oscillations
- calcium oscillations trigger myosin light chain kinase → phosphorylates myosin light chain (MLC) → confers on the actin/myosin filaments their ATPase activity which allows them to slide over each other and shorten → contraction
- calcium dependent process
- PLC is able to activate protein kinase C and rho kinase
- these two systems impinge on the myosin light chain phoshpatase → regulatory enzyme tending to turn off the stimulus for contraction by removing phosphate from the phosphorylated myosin light chain
- so as well as stimulation there are pathways inhibiting an inhibitory influence → reinforce the original stimulus
- PKA has influences that oppose the influences of the GPCR (targeted by B2 adrenoceptor
- contractile agonists work through Gq coupled GPCR (each agonist has its own receptor, highly selective agonists working through separate receptors)
![](https://s3.amazonaws.com/brainscape-prod/system/cm/117/915/136/a_image_thumb.png?1659437961)
How do B2-adrenoceptor agonists relax airway smooth muscle?
- beta agonists couple through B2-adrenoceptors
- coupled to a stimulatory g-protein → Gs
- Gs activates adenolatecyclase (AC)
- increase in cAMP → activates PKA
- PKA reduces calcium wave frequency
- activates SERCA and inhibits IP3 receptors
- IP3R will open calcium stores allowing Ca2+ into the cytoplasm → inhibited by PKA
- stimulates reuptake of calcium by the SERCA
- i.e. decreases rate of release and increases rate of reuptake → reduced cytoplasmic Ca2+ → less MLCK activation → relaxation
![](https://s3.amazonaws.com/brainscape-prod/system/cm/117/916/199/a_image_thumb.png?1659437961)
What are relievers?
- short-acting b2-adrenoceptor agonists
- short-acting:
- salbutamol, terbutaline (SABA)
- mainstay of acute bronchodilator therapy
- key features:
- short acting agents: rapid (2-5 min) onset
- B2-selective (very important)
- adverse effects:
- tachychardia
- tremor
- hypokalemia
- other features:
- variable degrees of efficacy (important??)
- tolerance (measurable - may be important)
What are controllers?
- long-acting Beta2-adrenoceptor agonists
- salmeterol - slow onset, 12 hrs duration
- formoterol - rapid onset, 12 hrs duration
- indicated for prophylaxis
- combined with inhaled glucocorticoid in single actuator
- reduce likelihood of symptoms
- no substantial anti-inflammatory action
- introduced into clinical use in late 1990s
- long duration changed nature of use
What is the Beta2-agonist saga?
- 60s Isoprenaline - excess mortality, non-selective, CVS?
- late 90s Fenoterol in NZ - excess mortality, high efficacy, marketed for more severe asthma
- 90s: LABA - introduction closely monitored
- noughties - SMART - salmeterol multi-centre asthma research trial: asthma deaths increased from 0.45 to 1.98 per 1000 patient years - Black box warning and further trials
- meta-analysis suggets that there is an increase in mortality in those patients on LABAs cf those not on
![](https://s3.amazonaws.com/brainscape-prod/system/cm/118/126/377/a_image_thumb.png?1659438169)
What ares plausible explanations for what might be happening with the beta agonists?
- chance observations (probably not)
- lack of selectivity - isoprenaline, adrenaline (doesn’t offer explanation for more recent data)
- high efficacy - fenoterol (unlikely to be the explanation, some are partial agonists)
- excessive usage - all (may be a feature in each of the studies, difficult to measure)
- inappropriate reliance on reliever/controller - inadequate anti-inflammatory treatment (sense that the disease is under control but underlying inflammation is advancing unchecked)
- beta-2 adrenoceptor dysfunction: intrinsic/acquired
What are some surprising insights into the beta-agonist function?
- studies in transgenic mice
- some are beta-adrenoceptor deficient
- would expect that removal would make airway obstruction worse
- actually saw less airway obstruction
- when the muscle is taken ex-vivo from the mouse - less contraction seen
- different set: over expression of beta-2
- contrary to expectation
- the contractile apparatus is more active with over-expression of beta-2 ADR
- an inverse beta2-agonist PROTECTS against murine “asthma”
- NAD (nadolol, an inverse agonist at beta2-adrenoceptors)
- mice b2-ADR-/-
- less mucus production
- non-selective
- signalling from empty beta2-adrenoceptors facilitates asthma phenotype in mice
- inverse agonists stop signally from ‘empty’ receptors
![](https://s3.amazonaws.com/brainscape-prod/system/cm/118/127/169/a_image_thumb.png?1659438171)
What does the inverse agonist do?
- inverse agonist able to change the activity of the receptor
- manifests as decrease in cAMP
- system where there is some baseline stimulation you can see effects of inverse agonist
- a two state model where Ra can form spontaneously in sufficient amount to cause significant cAMP increase
- the inverse agonist decreases Ra by stabilising the pool of Ri which does not couple to AC
![](https://s3.amazonaws.com/brainscape-prod/system/cm/118/127/560/a_image_thumb.png?1659438171)