Lecture 20 - The beta 2-adrenoceptor agonist: risk and reward

Question 1

Cold air causes..

Answer 1

an increase in smooth muscle responsiveness and hence, the airways narrow

Question 2

The airway will remodel over time - causing…

Answer 2

thickening in muscle - will now react too much to allergins in asthsma for instance

Question 3

What are the 3 ways of increased airway obstruction?

Answer 3

Airway smooth msucle shortening (narowing of lumen)

Bronchial wall oewdema (swelling, encroachment of lumen)

Mucus hypersecretion (occulision of lumen)

Question 4

What obstruction casues are targetted by relievers, controllers and preventers

Answer 4

Airway smooth msucle shortening and Bronchial wall oewdema

Question 5

Where do controllers act?

Answer 5

used chronically

again on the smooth msucle - reduce the liklihood of spasm

Question 6

What are the ‘preventor’ class of drugs

Answer 6

anti-inflammatory
used chronically

act on inflammatory cells to reduce the burden of mediators generated in the allergic reaction

Question 7

The contractile mechanism is regulated by…

Answer 7

intracellular calcium

Question 8

What are the mechanisms increasing free calcium

Answer 8

TRP chanels

voltage operated calcium chanels

pohospholipase C release, which triggers release of IP3, which then releases Ca from IC stores

Question 9

What are the mechanisms decreasingfree calcium

Answer 9

Plasma Ca2+ ATOase - extrusion (out of cell)

sarcoplasmic reticulum Ca2+ ATPase (SERCA) - pumps calcium back into internal stores

Question 10

The sets of release and reuptake Ca systems are able to generate waves of Ca through the smooth muscle cells, these waves trigger..

Answer 10

the contractile apparatus

Question 11

What triggers Ca2+ osscilations

Answer 11

Phospo-lipase C, signalling molecule associaed with GPCR

Question 12

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

Answer 12

Myosin Light Chain Kinase

Question 13

The Phospo-lipase C can also active which other enzymes

Answer 13

Rho kinase and protein kinase C

Question 14

Rho kinase and protein kinase C inhibit…

Answer 14

Myosin light chain phosphatase

this is the regulatory enzyme that turns off contraction, by removing phosphate from the Myosin light chain

Question 15

Hence the Rho kinase and protein kinase C signalls reinforce the …

Answer 15

original signal, by inhibiting the inhibition of actomyosin crossbridge formation and hence, contraction

Question 16

Protein kinase A, has influence which oppose…

Answer 16

the GPCR signalling mechanism

• inhibits Ca2+ ossilations
• stimulates Myosin light chain phosphatase

Question 17

Protein kinase A is targeted by

Answer 17

the beta-2-adrenoceptor

Question 18

How does B2-adrenoceptors agonists relax airway smooth muscle?

Answer 18

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)

Question 19

PKA inhibits the ip3R receptor, meaning…

Answer 19

Ca2+ cannot escapes the intracellular stores

Question 20

PKA also stimulates the re-uptake of Ca via..

Answer 20

SERCA pump - takes Ca out of cytoplasm and hence reduces the waves

Question 21

What are the key features of Short-acting B2-adrenoceptor agonists are relievers?

Answer 21

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

Question 22

What are the adverse effects of Short-acting B2-adrenoceptor agonists?

Answer 22

tachycardia, tremor, hypokalemia

Question 23

the controllers are used _____

Answer 23

prophylactic

12hrs duration - reduced the likelihood that the asthmatic would have their airways constrict enough to have symptoms

Question 24

The long-acting b2-adrenoceptors agonists (controllers) are now combined with ..

Answer 24

inhaled glucocorticoid in single actuator

reduces the likelihood of symptomes, no substantial anti-inflammatory action

Question 25

What is the history of b2-agonists and their associated mortality?

Answer 25

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

Question 26

Higher efficacy liekly to be an explanation to asthma exacerbations?

Answer 26

No, becuase some members of the class of drugs are actually partial agonsits

Question 27

true or False

Excessive use could be a explanation for current exacerbations

Answer 27

True

Question 28

The absence of b2-AR in mice models seems to..

Answer 28

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

Question 29

In a system with baseline stimulation of b2AR , you can see the effects of..

Answer 29

inverse agonists