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• Asthma


  Common disease characterized by airway inflammation and episodic, reversible bronchospasm with severe shortness of breath
• COPD (Chronic Obstructive Pulmonary Disease)


  Characterized by airflow limitation that is less reversible than in asthma and usually follows a progressive course

  
• Many of the drugs used in asthma are also effective in COPD
• Drugs useful in classic allergic asthma


  • Bronchodilators (smooth muscle relaxants)
  • Anti-inflammatory
• Bronchodilators


  • Sympathomimetics: especially β2-selective agonists
  • Muscarinic antagonists
  • Methylxanthines
  • Leukotriene receptor blockers
• Anti-inflammatory


  • Corticosteroids
  • Mast cell stabilizers
  • Anti-IgE antibodies
  • Leukotriene antagonists
• Pathophysiology of Asthma


  1. Release of mediators from IgE-sensitized mast cells and other cells

  2. Early response: bronchoconstriction and increased secretions

  3. Late response: inflammation

  4. Chronic inflammation leads to bronchial hyperreactivity
• Pathophysiology of COPD


  1. Associated with neutrophilic inflammation

  2. Permanent structural damage to airways and parenchyma

  3. Exacerbation often triggered by upper respiratory infection

  4. Occurs mainly in older patients, especially long-term smokers

  5. Poorly reversible with bronchodilators, less responsive to corticosteroids than asthma

  
• Beta adrenoceptor agonist (sympathomimetics)


  Selective β2-agonists used to reverse asthmatic bronchoconstriction
• Selective direct-acting β2-agonists


  • Short-acting: albuterol (salbutamol), terbutaline, metaproterenol
  • Long-acting: salmeterol, formoterol, indacaterol, vilanterol
• Mechanism of action of β2-agonists


  Stimulate adenylyl cyclase (via the β2-adrenoceptor-Gs-coupling protein-adenylyl cyclase pathway) and increase cyclic adenosine monophosphate (cAMP) in smooth muscle cells, leading to bronchodilation
• β2-agonists have no anti-inflammatory effects
• Therapeutic uses of β2-agonists


  • Sympathomimetics are first-line therapy in acute asthma
  • Short-acting β2-agonists are drugs of choice for acute bronchospasm
  • Short-acting not effective for prophylaxis
  • Long-acting agents used for prophylaxis
  • Long-acting not used for acute episodes
  • Long-acting drugs increase asthma mortality but are useful adjunctive therapy with corticosteroids
  • Many patients with COPD also benefit
• Adverse effects of β2-agonists


  • Skeletal muscle tremor
  • Significant β1-agonist effects at high doses
  • Tachycardia
  • Arrhythmias and tremor with excessive use
  • Tolerance and tachyphylaxis with prolonged use of short-acting
  • Increased risk in patients with COPD and concurrent cardiac disease
• Methylxanthines


  Purine derivatives found in plants, provide stimulant effects in beverages like coffee, tea, and cocoa
• Theophylline


  The only methylxanthine important in the treatment of asthma and COPD
• Mechanism of action of methylxanthines


  Non-selective phosphodiesterase (PDE) inhibitor, increasing cAMP; also inhibit adenosine receptors leading to cardiac and CNS stimulant effects
• Therapeutic uses of methylxanthines


  • Major use is in asthma and COPD
  • Slow-release theophylline for control of nocturnal asthma
  • Aminophylline for intravenous administration
  • Pentoxifylline for intermittent claudication
  • Other effects: CNS stimulation, cardiac stimulation, vasodilation, diuresis, increased GI motility
• Adverse effects of methylxanthines


  • GIT distress
  • Tremor
  • Insomnia
  • Severe nausea, vomiting, hypotension, arrhythmias, seizures in overdose
  • Beta blockers useful in reversing severe cardiovascular toxicity
  • Drug interactions due to high protein binding
• Muscarinic antagonists


  Competitively block muscarinic M3 receptors in the airways, preventing bronchoconstriction mediated by vagal discharge
• Muscarinic antagonists


  • Ipratropium
  • Tiotropium, aclidinium, umeclidinium, glycopyrrolate
• Muscarinic antagonists have no effect on the chronic inflammatory aspects of asthma
• Therapeutic uses of muscarinic antagonists


  • Useful in 1/3 to 2/3 of asthmatic patients, less potent than β2 agonists
  • More effective and less toxic than β2 agonists in COPD
• Adverse effects of muscarinic antagonists


  • Minor atropine-like effects like dry mouth at high doses
  • Do not cause tremor or arrhythmias unlike β2 agonists
• Corticosteroids


  Potentially beneficial in severe asthma, inhaled corticosteroids are common first-line therapy for moderate to severe asthma
• Inhaled corticosteroids


  • Beclomethasone
• Muscarinic antagonists


  • Reverse bronchoconstriction in some asthma patients (especially children) and in many patients with COPD
  • Have no effect on the chronic inflammatory aspects of asthma
  • Less potent than B2 agonist
• All corticosteroids are potentially beneficial in severe asthma
• Leukotriene antagonists are not as effective as corticosteroids in severe asthma
• Leukotriene Receptor Blockers (Montelukast,Zafirlukast)


  • Block LTD4 and LTE4 leukotriene receptors
  • Orally active
  • Effective in preventing exercise, antigen and aspirin-induced bronchospasm
  • Not recommended for acute episodes of asthma
  • Adverse effect is generally low
  • Rarely may cause eosinophilic granulomatosis with polyangiitis (EGPA)
• Lipoxygenase Inhibitor (Zileuton)


  • Selective inhibitor of 5-lipoxygenase, a key enzyme in the conversion of arachidonic acid to leukotrienes
  • Orally active
  • Effective in preventing exercise, aspirin, and antigen-induced bronchospasm
  • Adverse effect: occasional elevation of liver enzymes, and this drug is therefore less popular than the receptor blockers
• Cromolyn & nedocromil


  Unusually insoluble chemicals, so even massive doses given orally or by aerosol result in minimal systemic blood levels
• Omalizumab


  • A humanized murine monoclonal antibody to human IgE
  • Inhibits the binding of IgE and thus inhibits mast cell degranulation
  • Prevents activation of trigger antigens of asthma and subsequent release of inflammatory mediators
  • Approved for the prophylactic management of severe asthma
  • Very expensive and must be administered parenterally
• Other antibodies


  • Benralizumab, which targets the IL5 receptor
  • Mepolizumab and reslizumab, which target interleukin IL-5 itself