Therapeutics in Asthma and COPD

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Therapeutics in Asthma and COPD
2013-02-07 01:02:59
Pulmonary II

Tx of Asthma and COPD
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  1. Asthma
    potential drug targets
    Primary factors:  smooth muscle spasm, bronchial wall edema, hypersecretionand mucousplugs secondary secondaryto to

    • Cellular targets: airway inflammation: 
    • 1. Mast cells and other inflammator
    • 2. Bronchial smooth muscle cells.
    • 3. Mucus-producing cells. y cells (e. y(g, g. , eosino p phils ) )

    • Neural factors (especially for "nonspecific bronchial hyperreactivity"):
    • 1. Vagal reflexes
    • 2. CNS contribution

    Multiple chemical mediators are targets but it is unclear which is/are most important:  leukotrienes, 5HT, histamine as "early" mediators in asthma while for "late" asthmatic reactions (postantigen), these include cytokines from Th2 lymphs (e.g., IL-4, -5, -9, -13 and GM-CSF)

    Other initiator targets: infection, IgE, environmental antigens and irritants
  2. Autonomic nerve involvement in bronchial constriction/dilation
    • Imbalance of Gs and Gq:
    • -M3 receptor is Gq --> increases intracellular Ca2+: Bronchoconstricts
    • -Beta 2 receptor is Gs --> increases intracellular cAMP: Bronchodilates
  3. Asthma
    Cellular and non-cellular mediators
    • -Mast cells
    • -Eosinophils
    • -Other (smooth muscle hypertrophy and hyperplasia and glandular hyperplasia); collagen deposition

    • Preformed mediators (stored in mast cell, immediately released):
    • -Histamine
    • -Heparin
    • -Proteases (Contributes to bradykinin formation)
    • -PLA22

    • Lipid-derived (minutes)
    • -PAF, PGD2
    • Cytokines (hours)
    • -Interleukins that activate and attract neutrophils, eosinophils, and T cells

  4. Principles of Asthma treatment
    • 1. Relax bronchial smooth muscle (relievers symptoms) Bronchodilators
    • 2. Prevent/treat inflammation (Controllers that treat underlying inflammatory processes) Anti-inflammatory

    • - Inhaled medications provide local administration of the drug;
    • - Oral medications have doses ~20x that of inhaled; more systemic side effects
  5. Asthma 
    • Bronchodilators:
    • -Short and long acting β2-agonists (SABA and LABA)
    • -Cyclic nucleotide phosphodiesterase (PDE) inhibitors (nonselective  and PDE4-selective inhibitor, especially for COPD)
    • -Anticholinergic (muscarinic antagonist) 

    • Anti-inflammatory:
    • Corticosteroids 
    • - Leukotriene modifiers
    • - Cromolyn and nedocromil 
    • - Anti-IgEantibodies
  6. Asthma and COPD
    current treatment
    • "stepped care"
    • -inhaled corticosteroids (ICS); inhibit allergic inflammation
    • -Short acting and long acting beta 2 agonists

    • No therapy is curative

    • Beta 2 adrenergic agonists 
    • -mast cells (decrease mediator release)
    • -decrease plasma exudation
    • -decrease cholinergic neurotranmission
    • -increase mucociliary clearance
    • -rapid desensitization (neutrophils, eosinophils, T cells)
    • -Type II pneumocyte (increase surfactant)

    • M3- muscarinic cholinergic antagonists:
    • -slower and longer acting than beta agonists
    • -anticholinergic side effects
    • -Approved only for COPD; especially those on beta blockers

    • Corticosteroids (glucocorticoids)
    • -inhibit pro-inflammatory cell recruitment and production of pro-inflammatory cytokines
    • -may decrease airway remodelling
    • -alter transcritpion of genes relevant to asthma and COPD

    • GC: side effects
    • Glaucoma
    • Lunacy (Psychotic)
    • Ulcers (Peptic)
    • Cushing syndrome
    • Osteo (porosis and -malacia)
    • Cataracts
    • Opportunistic infections
    • Retention of sodium and water
    • Telangiectasias
    • Insulin resistance
    • Cause muscle weakness
    • grOwth retardation
    • by growth hormone Inhibition
    • Delayed wound healing
    • Suppress hypothalamic-pituitary-adrenal axis

    • Anti-leukotriene therapy:

    • Zileuton (LT synthesis inhibitor)
    • Zafirlukast (LT receptor blocker)
    • Montelukast (LTD4 receptor antagonist)