Drugs affecting airway structure and function Flashcards
1
Q
What causes the inflammation in asthma?
A
- eosinophils infiltrate airway within and beneath the epithelium
- release toxic proteins that lead to epithelial loss
- tf air space constituents have increased acces to underlying nerves
- nerves become hyperactive due to cytokine chemoattractants (IL-5, GM-CSF, eotaxin)
2
Q
What is the pathogenesis of airway obstruction in asthma?
A
- allergen acticates macros, DCs, mast cells (acutely), some neutrophils in subsets
- eosinophils cause epithelial damage and shedding
- exposed sensory nerves trigger cough reflex and SM constriction
- cysLTs and histamines increase vascular leak
- plasma components leak out (complement, coagulation components)
- leak causes bronchial swelling
- stimulation of mucous glands contributes to obstruction
3
Q
What do relievers target?
A
- airway smooth muscle shortening
- reduce lumen narrowing (initial asthma response)
4
Q
What do controllers target?
A
- airway smooth muscle shortening to reduce lumenal narrowing
- give consistent bronchodilation
5
Q
What do preventers target?
A
- e.g. glucocorticoids
- initial reaction of airway smooth muscle shortening causing lumenal narrowing
- bronchial wall oedema and mucous hypersecretion
- these are difficult to reverse acutely
- occur in response to the inflammatory mediators
- these are reduced by anti-inflammatory effects of preventers (decreased mast cell activation and cytokine production)
- decrease likelihood of these mast cell and cytokine responses
6
Q
Why is exhalation more difficult than inhalation in asthma?
A
- on exhalation, the alveolar sacs empty
- this unloads the tethering muscle, causing it to contract more quickly
- favours collapse of the airways
- increases airway resistance
- tf expiratory wheeze
7
Q
What is the contractile mechanism of airway smooth muscle?
A
- Ca2+ binds to calmodulin
- activates myosin light chain kinase
- MLC phosphorylated
- binds actin, forms actomyosin complex
- activates actomyosin ATPase
- cross-bridges between actin and myosin break and reform
- causes cell to contract
- criss-crossing of fibres yields a ‘squashing’ of muscle
8
Q
How is the contractile mechanism of airway smooth muscle regulated?
A
- not so much by voltage operated Ca2+ channels as in vascular SM
- most of intracellular Ca2+ increase is by activation of PLC and inositol triphosphate (IP3) released from intracellular stores
- free Ca2+ is decreased by:
- plasma Ca2+ ATPase - extrusion across plasma membrane to the ECF
- sarcoplasmic reticulum Ca2+ ATPase (SERCA) - uptake into internal stores
- both serve to reduce contractile influence of Ca2+
9
Q
What are the mediators of airway smooth muscle?
A
- constrictory inputs via ACh acting on muscarinic M3 receptors (cholinergic nerve activity)
- histamine and mast cell degranulation
- LTC4, LTD4 generated by activated cells; cause contraction
- opposed by endogenous influence on airway muscle:
-
there is no direct sympathetic innervation of ASM
- tf beta2-aRs in ASM are stimulated by endogeous products like adrenaline
- receptor occupation is usually low
-
there is no direct sympathetic innervation of ASM
- opposed by endogenous influence on airway muscle:
- PGE2 and PGI2 are made locally
- activate receptors coupled to cAMP to cause relaxation of muscle
10
Q
How is airway smooth muscle tone regulated?
A
- oscillations in intracellular Ca2+ stimulate myosin light chain activation and contraction
- +Ca2+ increases contraction
- protein kinase A (coupled to cAMP) activates myosin light chain phosphatase that dephosphorylates MLC-P back to MLC, causing relaxation of the smooth muscle
- MLC phosphatase activity is inhibited by Rho kinase and protein kinase C
- decreased activity leads to prolonged contraction
- tf contractile agonists have 3 points of intersection with this mechanism:
- increased frequency of Ca2+ oscillations
- activation of Rho Kinase and PKC
- these make the mechanism more sensitive to Ca2+ and tf lower levels will eleicit the same level of constriction
11
Q
What are the remodelling outcomes in asthma?
A
- chronic inflammation drives:
- fibrosis (stiffening) of the airway - limits response to deep inspiration (opens airways)
- increased volume of smooth muscle
- abnormal activation by constriction mediators exacerbated by hypertrophy
- increased velocity of SM spasm
- results in epithelial damage:
- thickening of BM, collagen
- separation of epithelium from BM
- injury followed by repair that is not proportional leads to scarring
12
Q
How is degree of obstruction in asthma measured clinically?
A
- FEV1
- reduced in asthmatic
- can be improved w/bronchodilator (reversible obstruction)
- residual decrement with bronchodilator can be indicative of irreversible obstruction and severe asthma
13
Q
How is airway responsiveness measured in asthma?
A
- exposure to increasing concentrations of histamine or methacholine
- normal individuals may have ~20% fall in FEV1
- mild asthma is shifted left of this = mild hyper-responsiveness that plateaus
- discontinued in severe asthma because there is no plateau; airways can close completely because they narrow more easily!
14
Q
What drug acts as an asthma reliever?
A
short-acting beta2-aR agonists (SABA)
e.g. salbutamol, terbutaline
15
Q
salbutamol
A
- SABA (short-acting beta2-aR agonist)
- mainstay of acute bronchodilator therapy in asthma
19
Q
How are SABAs administered?
A
- metered dose inhalers or nebulisers
- designed to deposit drugs at site of action (eg airways) with assistance of an aerosol to maximize absorption and prevent systemic effects of being swallowed
- swallowed portion is metabolised through the GIT and liver (first-pass), some active drug enters the systemic circulation
21
Q
How do b2-aR agonists relax airway smooth muscle?
A
- couple to the G protein, activating adenyly cyclase and cAMP/PKA
- PKA then:
- increases activity of SERCA (+rate of Ca2+ taken out of cytoplasm and into SR)
- inhibits operation of IP3R (phosphorylation), reducing activity of the ion channel and tf Ca2+ release from the SR
- overall, there is a decrease in intracellular Ca2+, reducing the oscillations and tf activation of MLC and contraction of ASM
22
Q
How do SABAs influence the mechanism of airway smooth muscle tone?
A
- SABA binds to b2-aR, couples G protein, activates adenylyl cyclase and cAMP
- cAMP activation increases PKA activity and tf MLC phosphatase activity
- this dephosphorylates MLC-P to relaxed MLC
- cAMP activates SERCA and inhibits IP3R to promote Ca2+ uptake from the cytoplasm into the SR, decreasing intracellular Ca2+
- this decreases Ca2+ oscillations and tf MLC kinase activity that promotes contraction (can also directly phosphorylate MLC kinase to decrease its activity)
- these actions can be increased by contractile agonists
- this decreases Ca2+ oscillations and tf MLC kinase activity that promotes contraction (can also directly phosphorylate MLC kinase to decrease its activity)
- cAMP activation increases PKA activity and tf MLC phosphatase activity
- together this causes bronchodilation
