Pharmacotherapy of Bronchial Asthma and COPD

(M.Pharm | High Yield | 10 Marks Long Answer)

DEFINITIONS

1. DIFFERENCE TABLE: ASTHMA vs COPD

2. CLASSIFICATION OF ANTI-ASTHMATIC DRUGS

A. Bronchodilators (Reliever Drugs)

• Short-Acting Beta-2 Agonists (SABAs): Salbutamol (albuterol), Terbutaline
• Long-Acting Beta-2 Agonists (LABAs): Salmeterol, Formoterol

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

• Theophylline, Aminophylline

B. Anti-Inflammatory Drugs (Controller/Preventer Drugs)

• Inhaled Corticosteroids (ICS): Beclomethasone, Budesonide, Fluticasone
• Systemic: Prednisolone, Hydrocortisone (for severe attacks)

• Montelukast, Zafirlukast

• Sodium cromoglycate (Cromolyn sodium), Nedocromil sodium

• Roflumilast

C. Biological/Targeted Therapies (for Severe Asthma)

• Anti-IgE: Omalizumab
• Anti-IL-5: Mepolizumab, Reslizumab
• Anti-IL-4/IL-13: Dupilumab

3. MECHANISM OF ACTION

Beta-2 Agonists

• Activate beta-2 adrenergic receptors (Gs-coupled) on airway smooth muscle
• Activate adenylyl cyclase → increase cAMP → activate PKA → phosphorylate MLCK (myosin light chain kinase)
• Result: Relaxation of bronchial smooth muscle → bronchodilation
• SABAs act within 3-5 minutes, last 4-6 hours (rescue use)
• LABAs last ~12 hours (maintenance use)

Anticholinergics

• Block muscarinic M3 receptors on airway smooth muscle and glands
• Prevent bronchoconstriction caused by acetylcholine (vagal reflex)
• Reduce excessive mucus secretion
• Tiotropium (LAMA) has 24-hour duration, ideal for COPD

Methylxanthines (Theophylline)

• Inhibit phosphodiesterase (PDE) → increase cAMP and cGMP → bronchodilation
• Also block adenosine receptors (A1 and A2) on bronchial smooth muscle
• Additional anti-inflammatory effects at low doses
• Narrow therapeutic index (therapeutic range: 10-20 mcg/mL)

Inhaled Corticosteroids (ICS)

• Bind to intracellular glucocorticoid receptors (GR)
• Drug-receptor complex enters nucleus → activates anti-inflammatory genes (lipocortin-1), suppresses pro-inflammatory genes (cytokines, COX-2, iNOS)
• Reduce eosinophilic inflammation, decrease mucus hypersecretion, reduce airway hyperresponsiveness
• Do NOT cause immediate bronchodilation - work over days to weeks

Leukotriene Receptor Antagonists (LTRAs)

• Leukotrienes (LTC4, LTD4, LTE4) are potent bronchoconstrictor mediators derived from arachidonic acid via 5-lipoxygenase pathway
• Montelukast and Zafirlukast block cysteinyl leukotriene (CysLT1) receptors on bronchial smooth muscle
• Result: Prevent bronchoconstriction, reduce mucosal edema, decrease mucus secretion, reduce eosinophil recruitment

Mast Cell Stabilizers

• Stabilize mast cell membranes → prevent degranulation
• Inhibit release of histamine, leukotrienes, and other inflammatory mediators
• Inhibit both early and late phase allergic response
• Only preventive - no use in acute attacks

Roflumilast (PDE-4 Inhibitor)

• Selectively inhibits PDE-4 → increases cAMP in inflammatory cells (neutrophils, macrophages)
• Reduces neutrophilic inflammation (predominant in COPD)
• Oral tablet, used to reduce COPD exacerbation frequency

4. PHARMACOTHERAPY OF ASTHMA

Step 1 - Mild Intermittent Asthma

• Reliever: SABA (salbutamol) as needed (PRN)
• Preferred: Low-dose ICS/formoterol as needed (GINA 2024 AIR therapy)

Step 2 - Mild Persistent Asthma

• Low-dose ICS (beclomethasone 100-200 mcg/day) + SABA PRN
• Alternative: Montelukast (LTRA) as add-on or alternative to ICS

Step 3 - Moderate Persistent Asthma

• Low-dose ICS + LABA (e.g., Fluticasone/Salmeterol combination inhaler)
• Alternatively: Medium-dose ICS alone

Step 4 - Severe Persistent Asthma

• Medium to high-dose ICS + LABA
• Add Tiotropium (LAMA) as third bronchodilator
• Consider Montelukast as add-on

Step 5 - Very Severe / Uncontrolled

• High-dose ICS + LABA + Tiotropium
• Add Oral corticosteroids (minimum effective dose)
• Biologic therapy: Omalizumab (anti-IgE), Mepolizumab (anti-IL-5) for eligible patients

Acute Severe Asthma / Status Asthmaticus Management

1. High-flow oxygen (target SpO2 93-95%)
2. Nebulized SABA (salbutamol 2.5-5 mg) every 20 minutes
3. Ipratropium bromide nebulization (add-on for severe attacks)
4. IV/oral systemic corticosteroids (prednisolone 40-50 mg/day for 5-7 days)
5. IV Magnesium sulfate (bronchodilator, for severe refractory cases)
6. IV Aminophylline (if no response to above)
7. Heliox mixture and mechanical ventilation in life-threatening cases

5. PHARMACOTHERAPY OF COPD

Non-Pharmacological (Always First)

• Smoking cessation - single most effective intervention
• Pulmonary rehabilitation and exercise
• Vaccination (influenza yearly, pneumococcal)
• Oxygen therapy for chronic hypoxia (PaO2 <55 mmHg)

Pharmacological - Stepwise

• SABA or SAMA (short-acting bronchodilator as needed)

• LAMA (tiotropium) or LABA (salmeterol/formoterol)
• If symptoms persist: LAMA + LABA combination

• LAMA preferred (tiotropium reduces exacerbations better than LABA alone)

• LAMA + LABA combination as initial therapy
• If eosinophils >300 cells/μL: Add ICS
• Roflumilast: Add if FEV1 <50% + chronic bronchitis + frequent exacerbations
• Azithromycin: Prophylactic antibiotic for frequent exacerbators (especially ex-smokers)

Management of COPD Exacerbations (AECOPD)

1. Short-acting bronchodilators (SABA + SAMA nebulized)
2. Systemic corticosteroids: Prednisolone 30-40 mg for 5 days
3. Antibiotics: Amoxicillin/Doxycycline/Azithromycin (if purulent sputum or signs of infection)
4. Controlled oxygen (target SpO2 88-92%)
5. Non-Invasive Ventilation (NIV/BiPAP) if hypercapnic respiratory failure
6. Mechanical ventilation if life-threatening

6. ADVERSE EFFECTS

Beta-2 Agonists

• Tremor (skeletal muscle stimulation)
• Tachycardia and palpitations (beta-1 spillover)
• Hypokalemia (K+ shift into cells)
• Headache
• Long-term LABA use in asthma: May increase mortality if used without ICS

Anticholinergics (Ipratropium/Tiotropium)

• Dry mouth (most common)
• Urinary retention (in prostatic hyperplasia)
• Constipation
• Blurred vision (if sprayed in eyes)
• Avoid in glaucoma patients

Theophylline (Narrow Therapeutic Index!)

• Nausea, vomiting, abdominal discomfort (early signs of toxicity)
• Seizures (serious toxicity)
• Cardiac arrhythmias (at high levels)
• Tachycardia, insomnia
• Interactions: Clearance increased by smoking, rifampicin; decreased by erythromycin, cimetidine, ciprofloxacin

Inhaled Corticosteroids

• Oropharyngeal candidiasis (thrush) - rinse mouth after use
• Dysphonia (hoarseness of voice)
• Long-term systemic effects (high doses): Osteoporosis, adrenal suppression, cataracts
• Increased risk of pneumonia (especially in COPD patients)

Systemic Corticosteroids

• Hypertension, hyperglycemia
• Weight gain, Cushingoid features
• Peptic ulcer, osteoporosis
• Adrenal suppression with long-term use

Leukotriene Antagonists (Montelukast)

• Generally well tolerated
• Headache, GI disturbances
• Neuropsychiatric effects: Depression, suicidal ideation (FDA black box warning)
• Churg-Strauss syndrome (rare - eosinophilic granulomatosis, if corticosteroids being tapered)

Mast Cell Stabilizers

• Very safe profile
• Mild cough/throat irritation
• Bronchospasm (paradoxical, rare)

Roflumilast

• Nausea, diarrhea, weight loss
• Headache, insomnia
• Neuropsychiatric effects (depression) - caution required

7. SIMPLE TREATMENT FLOWCHART

ASTHMA MANAGEMENT (GINA Stepwise)
=========================================
         Patient with Asthma
                 |
         Assess Severity
                 |
    ┌────────────┼──────────────┐
    |            |              |
 Step 1       Step 2-3       Step 4-5
(Intermittent) (Persistent)  (Severe)
    |            |              |
SABA PRN     Low ICS +     Medium/High ICS
             SABA PRN      + LABA + LAMA
                           + Biologics if needed
                 |
        Not Controlled? → Step Up
        Well Controlled for 3 months? → Step Down


COPD MANAGEMENT (GOLD Groups)
=========================================
      Patient with COPD
             |
     Diagnose: FEV1/FVC < 0.7
     Classify: GOLD Groups A/B/C/D
             |
    ┌─────────────────────┐
    |                     |
GROUP A/B           GROUP C/D
(Low Risk)         (High Risk)
    |                     |
Short BD or         LAMA + LABA
LAMA or LABA            |
                 If exacerbations persist:
                 + ICS (if eos >300)
                 + Roflumilast
                 + Azithromycin

         ↓ At all stages ↓
  Smoking cessation + Pulmonary rehab
  + Vaccination + Oxygen if indicated

5-MARK SHORT ANSWERS (Quick Reference)

Classification of Anti-Asthmatic Drugs

• Bronchodilators: SABAs, LABAs, SAMAs, LAMAs, Theophylline
• Anti-Inflammatory: ICS, Systemic corticosteroids, LTRAs, Mast cell stabilizers, PDE-4 inhibitors
• Biologics: Omalizumab, Mepolizumab, Dupilumab

Pharmacotherapy of COPD

Leukotriene Antagonists

• Drugs: Montelukast, Zafirlukast, Pranlukast
• MOA: Block CysLT1 receptors → prevent LTD4/LTC4 mediated bronchoconstriction, mucus secretion, and eosinophil recruitment
• Uses: Mild persistent asthma (alternative to ICS), exercise-induced asthma, aspirin-exacerbated respiratory disease (AERD), allergic rhinitis with asthma
• ADR: Neuropsychiatric effects (FDA black box), Churg-Strauss syndrome (rare)

Beta-2 Agonists in Asthma

• MOA: Beta-2 receptor → ↑cAMP → relaxation of smooth muscle → bronchodilation
• SABAs (Salbutamol): Rescue therapy, onset 3-5 min, duration 4-6 hrs
• LABAs (Salmeterol, Formoterol): Maintenance therapy, 12-hr duration - never use alone in asthma (only with ICS)
• ADR: Tremor, tachycardia, hypokalemia

Corticosteroids in Asthma

• MOA: Bind GR → suppress cytokines/eosinophilic inflammation → reduce airway hyperresponsiveness
• ICS (Budesonide, Fluticasone): First-line controller drugs, local action, minimal systemic ADR
• Systemic (Prednisolone): For severe/acute exacerbations
• ADR (ICS): Oral candidiasis, dysphonia, osteoporosis (long-term high dose)

CONCLUSION