Drugs affecting airway structure and function Flashcards Preview

Cardiovascular & Respiratory Pharmacology (Karen) > Drugs affecting airway structure and function > Flashcards

Flashcards in Drugs affecting airway structure and function Deck (30)
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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
  • 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
16
Q

terbutaline

A
  • SABA
  • mainstay of acute bronchodilator therapy in asthma
17
Q

What are the key features of SABAs?

A
  • 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
18
Q

What are the adverse effects of SABAs?

A
  • tachycardia
  • tremor
  • hypokalemia
  • increased morbidity and mortality with regular use (use only as required)
  • variable degrees of efficacy
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
20
Q

What dictates the duration of SABAs?

A
  • 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
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
  • together this causes bronchodilation
23
Q

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

A

functional antogonism to the bronchoconstriction

24
Q

Which drugs are controllers in asthma?

A
  • long-acting beta2-aR agonists (LABAs)
  • e.g. salmeterol, formoterol, indacaterol
25
Q

salmeterol

A
  • slow-onset LABA
  • duration ~12 hours
  • given twice daily
26
Q

formoterol

A
  • rapid-onset LABA
  • duration ~12 hours
  • given twice daily
27
Q

indacaterol

A
  • rapid-onset LABA
  • duration ~24 hours
  • given once daily
28
Q

What is the function of LABAs?

A
  • used as controllers to provide a background bronchodilator tone
  • this reduces likelhood of asthmatic symptoms
29
Q

What is the key information about LABAs?

A
  • 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
30
Q

What are LAMAs?

A
  • 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