Pharmacology of Asthma and COPD Drugs

Overview

• Asthma and COPD: Chronic lung diseases marked by inflammation and narrowing of the airways.
• Pathophysiology Distinctions: Though similar, asthma and COPD have distinct pathophysiological mechanisms.

Asthma Pathophysiology

• Key Player: Mast cells abundant in asthmatic airways.
• Activation Mechanism: Inhaled allergens activate sensitized mast cells via IgE, releasing bronchoconstrictor mediators.
• Cascade Effects: Allergens processed by dendritic cells release chemokines, attracting T helper 2 cells, which induce B cells to produce IgE antibodies.
• Key Mediators:
  • Histamine: Causes smooth muscle contraction via H1 receptors.
  • Leukotrienes (LTC4, LTD4, LTE4): Potent bronchoconstrictors activating CysLT1 receptors.
  • Adenosine: Activates A1 receptors, reducing cAMP leading to contraction.
• Neuronal Influence: Sympathetic fibers (epinephrine and norepinephrine) induce relaxation via β2-adrenergic receptors; parasympathetic fibers (acetylcholine) induce contraction via M3 receptors.

COPD Pathophysiology

• Key Player: Macrophages, not mast cells.
• Inflammation Initiation: Cigarette smoke and irritants activate alveolar macrophages and epithelial cells.
• Effects:
  • Neutrophils produce proteases, leading to mucus secretion and bronchitis.
  • Structural cell apoptosis by proteolytic enzymes leads to emphysema.
  • Chronic inflammation promotes fibroblast proliferation and pulmonary fibrosis.

Pharmacological Treatments

Beta-2 Adrenergic Agonists

• Mechanism: Increase cAMP levels causing smooth muscle relaxation.
• Types:
  • Short-acting (SABA): Albuterol, Levalbuterol.
  • Long-acting (LABA): Arformoterol, Formoterol, Vilanterol, Salmeterol.

Muscarinic Antagonists (Anticholinergics)

• Mechanism: Block acetylcholine on M3 receptors reducing intracellular calcium for muscle relaxation.
• Types:
  • Short-acting (SAMA): Ipratropium.
  • Long-acting (LAMA): Tiotropium, Aclidinium, Umeclidinium.

Leukotriene Modifiers

• Mechanism: Affect cysteinyl leukotrienes action.
• Function:
  • Block CysLT1 receptors: Montelukast, Zafirlukast.
  • Inhibit lipoxygenase: Zileuton.

Phosphodiesterase Inhibitors

• Theophylline: Non-selective inhibition, blocks adenosine A1 receptors and PDE activity.
• Roflumilast: Selective PDE-4 inhibition, more effective and safer than Theophylline.

Allergy-targeted Treatments

• Omalizumab: Monoclonal antibody binding free IgE, inhibiting mast cell activation.
• Antihistamines: Inhibit H1 receptors reducing histamine responses.

Corticosteroids

• Mechanism: Suppress inflammatory genes and activate anti-inflammatory genes.
• Effect on Cells:
  • Low doses inhibit histone acetyltransferase activity.
  • High doses bind glucocorticoid response elements activating anti-inflammatory proteins like annexin A1.
• Examples:
  • Inhaled: Beclomethasone, Budesonide, Ciclesonide, Fluticasone, Mometasone, Triamcinolone.
  • Oral: Dexamethasone, Methylprednisolone, Prednisone, Prednisolone.