Pharmacotherapy of Bronchial Asthma and COPD

DEFINITION

1. DIFFERENCE TABLE: ASTHMA vs COPD

2. CLASSIFICATION OF ANTI-ASTHMATIC DRUGS

A. BRONCHODILATORS (Relieve bronchoconstriction)

• Short-Acting β2 Agonists (SABA): Salbutamol (albuterol), Terbutaline
• Long-Acting β2 Agonists (LABA): Salmeterol, Formoterol, Indacaterol (ultra-LABA)

• Short-Acting (SAMA): Ipratropium bromide
• Long-Acting (LAMA): Tiotropium, Aclidinium, Umeclidinium, Glycopyrrolate

• Theophylline, Aminophylline (IV)

B. ANTI-INFLAMMATORY DRUGS (Prevent/control airway inflammation)

• Inhaled Corticosteroids (ICS): Beclomethasone, Budesonide, Fluticasone, Mometasone
• Systemic Corticosteroids: Prednisolone, Methylprednisolone (for acute severe asthma)

• Montelukast, Zafirlukast

• Sodium Cromoglicate, Nedocromil sodium (mainly prophylactic)

C. BIOLOGICAL/TARGETED THERAPIES (for Severe Asthma)

D. PHOSPHODIESTERASE (PDE) INHIBITORS (mainly COPD)

3. MECHANISM OF ACTION

(A) Beta-2 Agonists (SABA/LABA)

• Selectively bind to β2-adrenergic receptors on bronchial smooth muscle
• Activate Gs protein → adenylyl cyclase → ↑cAMP → ↑PKA
• PKA phosphorylates myosin light chain kinase (MLCK) → inhibits MLCK activity
• Results in: smooth muscle relaxation → bronchodilation
• Additional effects: inhibit mast cell mediator release, reduce mucosal edema, improve mucociliary clearance
• SABAs (salbutamol) act within 5 minutes, duration 4-6 hours (rescue/reliever)
• LABAs (salmeterol, formoterol) have duration >12 hours (used as add-on to ICS) (Goodman & Gilman's, 14e)

(B) Anticholinergic Agents (SAMA/LAMA)

• Block muscarinic receptors (M1, M2, M3) in airway smooth muscle and glands
• M3 receptor blockade → inhibits ACh-mediated bronchoconstriction → bronchodilation
• Also reduce mucus secretion from submucosal glands
• Ipratropium (SAMA): onset 15 min, peak 1-2 hrs, duration 4-6 hrs
• Tiotropium (LAMA): kinetically selective - dissociates faster from M2 than M3 → preferred in COPD
• Duration of tiotropium: 24 hours (once daily dosing) (Katzung, 16e)

(C) Methylxanthines (Theophylline)

• Mechanism (multiple):
  1. Non-selective PDE inhibition → ↑cAMP and cGMP → bronchodilation
  2. Adenosine receptor antagonism → reduces bronchoconstriction
  3. Anti-inflammatory effects (histone deacetylase activation at low doses)
• Narrow therapeutic index: serum level 10-20 mcg/mL
• Now mainly used when ICS/LABA insufficient; also has mild anti-inflammatory effects

(D) Inhaled Corticosteroids (ICS)

• Enter the cell and bind to glucocorticoid receptors (GR) in the cytoplasm
• GR-steroid complex enters nucleus → binds to glucocorticoid response elements (GREs)
• Transcriptional effects:
  • Transactivation: induce anti-inflammatory proteins (e.g., lipocortin-1, IL-10)
  • Transrepression: inhibit pro-inflammatory transcription factors (NF-kB, AP-1)
• Net result: ↓ production of cytokines (IL-4, IL-5, IL-13), ↓ eosinophil recruitment, ↓ mucosal edema, ↓ mucus secretion
• ICS do not cause immediate bronchodilation - they reduce chronic inflammation (onset days-weeks)

(E) Leukotriene Receptor Antagonists (LTRAs)

• Leukotrienes (LTC4, LTD4, LTE4) are released from mast cells, eosinophils, and basophils
• They cause: bronchoconstriction, mucosal edema, mucus hypersecretion
• Montelukast / Zafirlukast selectively block CysLT1 receptors on airway smooth muscle
• Result: prevent leukotriene-induced bronchoconstriction, reduce eosinophilic inflammation
• Useful in aspirin-sensitive asthma, exercise-induced asthma, asthma + allergic rhinitis
• Oral, once daily (montelukast: 10 mg adults, 5 mg children 6-14 yrs)

(F) Mast Cell Stabilizers (Cromoglicate, Nedocromil)

• Inhibit chloride channels on mast cells → prevent mast cell degranulation
• Block early and late phase allergic responses
• Only prophylactic - no bronchodilator effect; taken 4x daily
• Now mainly used in children and exercise-induced asthma

(G) Anti-IgE (Omalizumab)

• Binds free circulating IgE → prevents IgE binding to FcεRI receptors on mast cells
• ↓ mast cell activation → ↓ inflammatory mediator release
• Used in moderate-to-severe allergic asthma inadequately controlled by ICS + LABA
• Requires positive skin prick test/RAST and serum IgE within specified range
• Given subcutaneously every 2-4 weeks

4. PHARMACOTHERAPY OF ASTHMA

Stepwise Management (GINA Guidelines):

• Reliever: SABA (salbutamol) as needed
• Symptoms <2 days/week, no nighttime symptoms

• Controller: Low-dose ICS (budesonide 200-400 mcg/day OR fluticasone 100-250 mcg/day)
• Reliever: SABA as needed
• Alternative: LTRA (montelukast) if ICS not tolerated

• Low-dose ICS + LABA (preferred: budesonide/formoterol combination)
• Alternative: Medium-dose ICS alone, or Low-dose ICS + LTRA

• Medium-to-high dose ICS + LABA
• Add-on: Tiotropium, LTRA, or low-dose theophylline

• High-dose ICS + LABA + biological therapy (Omalizumab, Mepolizumab, Dupilumab, Tezepelumab)
• Add oral corticosteroids (lowest possible dose)

Acute Severe Asthma (Status Asthmaticus):

• Oxygen supplementation (maintain SpO2 ≥94%)
• Nebulized salbutamol (2.5-5 mg q20 min, continuous if needed)
• IV/oral prednisolone (40-50 mg/day) or IV methylprednisolone
• Ipratropium bromide nebulization (add-on to SABA)
• IV aminophylline or magnesium sulphate (for refractory cases)
• ICU/intubation if respiratory failure develops

5. PHARMACOTHERAPY OF COPD

GOLD Classification (by FEV1 % predicted):

• GOLD 1 (Mild): FEV1 ≥80%
• GOLD 2 (Moderate): FEV1 50-79%
• GOLD 3 (Severe): FEV1 30-49%
• GOLD 4 (Very Severe): FEV1 <30%

Stepwise Treatment:

• A bronchodilator (either SAMA or SABA as needed)
• Preferred: LAMA (tiotropium) OR LABA

• LAMA + LABA combination (preferred dual bronchodilation)
• Example: Tiotropium + Salmeterol, or Umeclidinium + Vilanterol (single inhaler)

• LAMA alone (tiotropium preferred - reduces exacerbation frequency)

• LAMA + LABA (first choice)
• If eosinophils ≥300 cells/μL: add ICS → triple therapy (ICS + LABA + LAMA)
• If FEV1 <50% + chronic bronchitis + frequent exacerbations: add Roflumilast (PDE4 inhibitor)
• Low-dose theophylline as add-on if needed

Additional COPD Therapies:

• Oxygen therapy (long-term, if PaO2 <55 mmHg)
• Pulmonary rehabilitation (exercise training, education)
• Vaccinations - Annual influenza, pneumococcal vaccine
• Mucolytics - N-acetylcysteine, carbocisteine (reduce mucus viscosity)
• Alpha-1 antitrypsin augmentation (for hereditary emphysema)
• Surgical options - Lung volume reduction surgery, lung transplant (severe cases)

Management of Acute COPD Exacerbation:

• Controlled O2 (target SpO2 88-92%)
• Nebulized ipratropium + salbutamol (SAMA + SABA combination)
• Systemic corticosteroids - Prednisolone 40 mg/day for 5 days
• Antibiotics (if purulent sputum/infection: amoxicillin, azithromycin, or doxycycline)
• Non-invasive ventilation (BiPAP) if pH <7.35 with hypercapnia
• IV aminophylline if bronchospasm refractory

6. ADVERSE EFFECTS

7. TREATMENT FLOWCHART

ASTHMA - Stepwise Treatment

ASTHMA DIAGNOSIS CONFIRMED
(episodic wheeze, ↓FEV1, reversible obstruction)
           ↓
    STEP 1 (Intermittent)
    → SABA as needed (Salbutamol)
           ↓ (if not controlled)
    STEP 2 (Mild Persistent)
    → Low-dose ICS + SABA PRN
    (Alternative: LTRA - Montelukast)
           ↓ (if not controlled)
    STEP 3 (Moderate Persistent)
    → Low/Medium-dose ICS + LABA
    (Budesonide + Formoterol)
           ↓ (if not controlled)
    STEP 4 (Severe Persistent)
    → Medium/High-dose ICS + LABA
    + Tiotropium / LTRA / Theophylline
           ↓ (if not controlled)
    STEP 5 (Very Severe)
    → High-dose ICS + LABA
    + Biological Therapy
    (Omalizumab / Mepolizumab / Dupilumab)
    ± Oral Corticosteroids (low dose)

    *** ACUTE ATTACK: Nebulized SABA + O2
        + IV Corticosteroid + Ipratropium ***

COPD - Management Based on GOLD Groups

COPD DIAGNOSIS CONFIRMED
(FEV1/FVC <0.70, history of smoking, irreversible obstruction)
           ↓
    GOLD GROUP A
    → Single Bronchodilator (SABA or LAMA PRN)
           ↓
    GOLD GROUP B
    → LAMA + LABA (Dual bronchodilation)
           ↓
    GOLD GROUP C
    → LAMA alone (Tiotropium preferred)
           ↓
    GOLD GROUP D (High risk exacerbations)
    → LAMA + LABA first choice
    → If eosinophils ≥300: Add ICS (Triple therapy)
    → If FEV1 <50% + chronic bronchitis:
      Add Roflumilast (PDE4 inhibitor)
           ↓
    ALL GROUPS: 
    O2 therapy (if PaO2 <55 mmHg)
    + Pulmonary rehabilitation
    + Vaccination (influenza, pneumococcal)
    + Smoking cessation

    *** ACUTE EXACERBATION: SAMA+SABA nebulized
        + Systemic steroids + Antibiotics ± BiPAP ***

CONCLUSION

Bronchodilators (β2-agonists, anticholinergics, methylxanthines) provide immediate symptom relief by relaxing airway smooth muscle, while anti-inflammatory drugs (inhaled corticosteroids, leukotriene antagonists, biologicals) address the underlying airway inflammation to achieve long-term disease control and prevent exacerbations - making the combination of both essential in managing asthma and COPD effectively.

QUICK REVISION TABLE - Key Drugs at a Glance

• For 10-mark question: Write all 8 sections above with headings - examiner rewards structured answers
• For 5-mark question on Classification: Write the full drug class tree (A, B, C, D groups) with 2-3 examples each
• For 5-mark COPD: Focus on GOLD groups A-D with specific drug combinations
• For 5-mark β2-agonists: SABA vs LABA comparison + cAMP mechanism + SABAs as relievers only
• For 5-mark Corticosteroids: ICS mechanism (GR → GRE) + transrepression of NF-kB + adverse effects table
• For 5-mark LTRAs: Montelukast MOA (CysLT1 blockade) + uses (exercise-induced, aspirin-sensitive) + neuropsychiatric SE