Lecture 20 - The beta 2-adrenoceptor agonist: risk and reward Flashcards
Cold air causes..
an increase in smooth muscle responsiveness and hence, the airways narrow
The airway will remodel over time - causing…
thickening in muscle - will now react too much to allergins in asthsma for instance
What are the 3 ways of increased airway obstruction?
Airway smooth msucle shortening (narowing of lumen)
Bronchial wall oewdema (swelling, encroachment of lumen)
Mucus hypersecretion (occulision of lumen)
What obstruction casues are targetted by relievers, controllers and preventers
Airway smooth msucle shortening and Bronchial wall oewdema
Where do controllers act?
used chronically
again on the smooth msucle - reduce the liklihood of spasm
What are the ‘preventor’ class of drugs
anti-inflammatory
used chronically
act on inflammatory cells to reduce the burden of mediators generated in the allergic reaction
The contractile mechanism is regulated by…
intracellular calcium
What are the mechanisms increasing free calcium
TRP chanels
voltage operated calcium chanels
pohospholipase C release, which triggers release of IP3, which then releases Ca from IC stores
What are the mechanisms decreasingfree calcium
Plasma Ca2+ ATOase - extrusion (out of cell)
sarcoplasmic reticulum Ca2+ ATPase (SERCA) - pumps calcium back into internal stores
The sets of release and reuptake Ca systems are able to generate waves of Ca through the smooth muscle cells, these waves trigger..
the contractile apparatus
What triggers Ca2+ osscilations
Phospo-lipase C, signalling molecule associaed with GPCR
The Ca2+ osscillations actives ____ ___ _____ _____,
which then phosphorylates the Myosin light chain, which the confers on the actin filaments the ATPase activity which allows then to slide over each other and shorten (muscle contraction
Myosin Light Chain Kinase
The Phospo-lipase C can also active which other enzymes
Rho kinase and protein kinase C
Rho kinase and protein kinase C inhibit…
Myosin light chain phosphatase
this is the regulatory enzyme that turns off contraction, by removing phosphate from the Myosin light chain
Hence the Rho kinase and protein kinase C signalls reinforce the …
original signal, by inhibiting the inhibition of actomyosin crossbridge formation and hence, contraction
Protein kinase A, has influence which oppose…
the GPCR signalling mechanism
- inhibits Ca2+ ossilations
- stimulates Myosin light chain phosphatase
Protein kinase A is targeted by
the beta-2-adrenoceptor
How does B2-adrenoceptors agonists relax airway smooth muscle?
Couple though b2-atrnoceptors, couples to Gs protein which actives adenolate cyclase
Adenolate cyclase casues an increase in cAMP, which acivates PROTEIN KINASE A (which inhibits the calcium waves)
PKA inhibits the ip3R receptor, meaning…
Ca2+ cannot escapes the intracellular stores
PKA also stimulates the re-uptake of Ca via..
SERCA pump - takes Ca out of cytoplasm and hence reduces the waves
What are the key features of Short-acting B2-adrenoceptor agonists are relievers?
Short acting agents, mainstay of acute bronchodilator therapy
rapid (2-5min) onset, B2-selective (very important)
Variable degrees of efficacy, could be imporatnt in the evelpoment of tolerance
What are the adverse effects of Short-acting B2-adrenoceptor agonists?
tachycardia, tremor, hypokalemia
the controllers are used _____
prophylactic
12hrs duration - reduced the likelihood that the asthmatic would have their airways constrict enough to have symptoms
The long-acting b2-adrenoceptors agonists (controllers) are now combined with ..
inhaled glucocorticoid in single actuator
reduces the likelihood of symptomes, no substantial anti-inflammatory action
What is the history of b2-agonists and their associated mortality?
60s - Isoprenaline -excess mortailty (lack of selectivity, targetted CVS )
Late 80s - Fenoterol in NZ - excess mortality, asthma deaths in particular
90s LABA (long acting Beta-agonists) - was closely monitored. reduced the exacerbations of asthma
00s - SMART trial - suggested issues
Higher efficacy liekly to be an explanation to asthma exacerbations?
No, becuase some members of the class of drugs are actually partial agonsits
true or False
Excessive use could be a explanation for current exacerbations
True
The absence of b2-AR in mice models seems to..
interfere with the acquisition of the allergic component
There may be some signalling from the empty b2-AR, in some cell types this could be adverse, by create the right environment of the allergic asthma
In a system with baseline stimulation of b2AR , you can see the effects of..
inverse agonists
