Drugs affecting airway structure and function

Question 1

What causes the inflammation in asthma?

Answer 1

• 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)

Question 2

What is the pathogenesis of airway obstruction in asthma?

Answer 2

• 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

Question 3

What do relievers target?

Answer 3

• airway smooth muscle shortening
  
  • reduce lumen narrowing (initial asthma response)

Question 4

What do controllers target?

Answer 4

• airway smooth muscle shortening to reduce lumenal narrowing
• give consistent bronchodilation

Question 5

What do preventers target?

Answer 5

• 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

Question 6

Why is exhalation more difficult than inhalation in asthma?

Answer 6

• 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

Question 7

What is the contractile mechanism of airway smooth muscle?

Answer 7

• 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

Question 8

How is the contractile mechanism of airway smooth muscle regulated?

Answer 8

• 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+

Question 9

What are the mediators of airway smooth muscle?

Answer 9

• 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
• PGE2 and PGI2 are made locally
  
  • activate receptors coupled to cAMP to cause relaxation of muscle

Question 10

How is airway smooth muscle tone regulated?

Answer 10

• 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

Question 11

What are the remodelling outcomes in asthma?

Answer 11

• 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

Question 12

How is degree of obstruction in asthma measured clinically?

Answer 12

• FEV1
  
  • reduced in asthmatic
  • can be improved w/bronchodilator (reversible obstruction)
    
    • residual decrement with bronchodilator can be indicative of irreversible obstruction and severe asthma

Question 13

How is airway responsiveness measured in asthma?

Answer 13

• 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!

Question 14

What drug acts as an asthma reliever?

Answer 14

short-acting beta2-aR agonists (SABA)

e.g. salbutamol, terbutaline

Question 15

salbutamol

Answer 15

• SABA (short-acting beta2-aR agonist)
• mainstay of acute bronchodilator therapy in asthma

Question 16

terbutaline

Answer 16

• SABA
• mainstay of acute bronchodilator therapy in asthma

Question 17

What are the key features of SABAs?

Answer 17

• e.g. salbutamol, terbutaline
• mainstay of acute bronchodilator therapy
• short acting agents (2-5min onset)
• beta2 selective
• partial agonists (variable efficacy)
  
  • full agonists lead to tolerance, desensitization of receptors

Question 18

What are the adverse effects of SABAs?

Answer 18

• tachycardia
• tremor
• hypokalemia
• increased morbidity and mortality with regular use (use only as required)
• variable degrees of efficacy

Question 19

How are SABAs administered?

Answer 19

• 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

Question 20

What dictates the duration of SABAs?

Answer 20

• action is at the lung
• dictated by rate at which blood perfusing the bronchiolar tissue is able to remove it from the smooth muscle and airways by its diffusion
• it is then metabolised
• tf related to lung perfusion kinetics rather than metabolism

Question 21

How do b2-aR agonists relax airway smooth muscle?

Answer 21

• 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

Question 22

How do SABAs influence the mechanism of airway smooth muscle tone?

Answer 22

• 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
• together this causes bronchodilation

Question 23

What is the benefit conferred by long and short acting beta agonists?

Answer 23

functional antogonism to the bronchoconstriction

Question 24

Which drugs are controllers in asthma?

Answer 24

• long-acting beta2-aR agonists (LABAs)
• e.g. salmeterol, formoterol, indacaterol

Question 25

salmeterol

Answer 25

• slow-onset LABA
• duration ~12 hours
• given twice daily

Question 26

formoterol

Answer 26

• rapid-onset LABA
• duration ~12 hours
• given twice daily

Question 27

indacaterol

Answer 27

• rapid-onset LABA
• duration ~24 hours
• given once daily

Question 28

What is the function of LABAs?

Answer 28

• used as controllers to provide a background bronchodilator tone
• this reduces likelhood of asthmatic symptoms

Question 29

What is the key information about LABAs?

Answer 29

• reduce number of exacerbations of asthma
  
  • no evidence of anti-inflammatory effect, however
• indicated for prophylaxis only
• combined with inhaled glucocorticoids in a single actuator (for anti-inflammatory tx concurrently, ie decrease mediator release)
  
  • monotherapy associated with increased mortality/morbidity
• tolerance does occur, may or may not be clinically relevant
• similar mechanism to SABAs
  
  • persist for longer due to lipophilicity and tf ability to integrate into the membrane of cells & persist around the receptors
• may cause increased mortality in asthma, but not in COPD

Question 30

What are LAMAs?

Answer 30

• long-acting muscarinic antagonist
• e.g. ipratropium bromide, tiotropium bromide
• give less bronchodilation than b2-agonists
• act on muscarinic receptors in ASM that are activated by ACh
  
  • act specifically on the cholinergic pathway of bronchoconstriction
• more effective in COPD than asthma
• used in combo with LABAs