Asthma Drugs

Overview

• Therapeutic strategies for treating asthma include:
  • decreasing inflammation
  • increasing sympathetic tone
• There are 7 families of drugs that are commonly used:
  • corticosteroids
  • β-agonists
  • muscarinic antagonists
  • methylxanthines
  • cromolyn
  • antileukotrienes
  • omalizumab

Corticosteroids

• Inhaled corticosteroids are first line therapy for chronic asthma 
• Examples
  • mometasone
  • fluticasone 
  • budesonide
  • beclomethasone
  • triamcinolone
  • flunisolide
• Mechanism
  • inhibiting the synthesis of virtually all cytokines
  • upregulating expression of beta-adrenergic receptors 
  • inactivating NF-κB  
    • NF-κB is the transcription factor that induces the production of TNF-α and other inflammatory agents
• Toxicity
  • oral candidiasis 
• use spacers or post-inhalation mouth rinse to prevent 

β₂-agonists

• Drugs
  • short acting — used for breakthrough symptoms and during acute exacerbation
    • albuterol 
      • known internationally as salbutamol
    • levalbuterol 
    • Others used much less commonly
      • terbutaline
      • metaproterenol (β₂, minor β₁)
      • isoproterenol (nonselective)
        • tachycardia
        • may lead to cardiac death
  • long acting — used for maintenance in combination with inhaled corticosteroid (never without)
    • salmeterol 
      • tremors, arrhythmia
    • formoterol 
• Mechanism
  • β₂ receptors are activated on bronchial smooth muscle to achieve bronchodilation
• stimulation of adenylate cyclase leading to closing of calcium channels and ultimately the relaxation of smooth muscles

Methylxanthines

• Drugs
  • theophylline (rarely used)
• Mechanism
  • inhibition of phosphodiesterase leading to decreased cAMP hydrolysis
    • causes bronchodilation
  • metabolized by P-450
  • blocks actions of adenosine
• Toxicity
  • seizures 
  • narrow therapeutic index
  • nausea/vomiting
• arrhythmia

Muscarinic antagonists

• Drugs
  • ipratropium  
  • tiotropium
• Mechanism
  • competitive inhibition of muscarinic receptors 
    • prevents bronchoconstriction
• Also used for COPD
• toxicity includes anticholinergic effects such as urinary retention 

Cromolyn

• Prophylaxis only!
  • ineffective during an acute asthma attack
• Mechanism
  • prevents release of mediators from mast cells
• Toxicity
• rare

Antileukotrienes

• Drugs
  • zileuton
    • 5-lipoxygenase pathway inhibitor
      • blocks conversion of arachidonic acid to leukotrienes 
  • zafirlukast, montelukast
    • blocks leukotriene receptors
• particularly effective in aspirin-induced asthma 

Omalizumab

• Clinical use
  • severe uncontrolled asthma with elevated IgE
    • symptoms and activity refractory to standard therapies and oral glucocorticoids
• Mechanism
  • anti-IgE antibody  
    • inhibits action of IgE with inflammatory cells 
  • asthma can be caused by uncontrollably high IgE response