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PHARMACOTHERAPY OF BRONCHIAL ASTHMA AND COPD

Complete High-Yield Answer for M.Pharm University Exam

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PART A - LONG ANSWER (10 Marks)

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Q. Discuss the Pharmacotherapy of Bronchial Asthma and COPD. Classify Anti-Asthmatic Drugs and Explain Their Mechanism of Action, Therapeutic Uses, and Adverse Effects.

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1. INTRODUCTION

• Relieve bronchospasm (bronchodilators)
• Reduce airway inflammation (anti-inflammatory drugs)
• Prevent exacerbations
• Improve quality of life

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2. CLASSIFICATION OF ANTI-ASTHMATIC DRUGS

A. BRONCHODILATORS

• Short-Acting (SABA): Salbutamol (Albuterol), Terbutaline, Metaproterenol
• Long-Acting (LABA): Salmeterol, Formoterol, Vilanterol

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

• Theophylline, Aminophylline

B. ANTI-INFLAMMATORY DRUGS

• Inhaled (ICS): Beclomethasone, Budesonide, Fluticasone, Mometasone, Ciclesonide
• Systemic: Prednisone, Methylprednisolone, Hydrocortisone

• Cromolyn Sodium (Sodium Cromoglycate), Nedocromil

• Leukotriene Receptor Antagonists (LTRA): Montelukast, Zafirlukast
• 5-Lipoxygenase Inhibitor: Zileuton

C. TARGETED / BIOLOGIC THERAPY

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3. MECHANISM OF ACTION, USES & ADVERSE EFFECTS

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A. BETA-2 AGONISTS (beta2-agonists)

• Activate beta-2 adrenergic receptors on airway smooth muscle
• These are G-protein coupled receptors that activate adenylyl cyclase
• This increases intracellular cyclic AMP (cAMP)
• cAMP activates protein kinase A (PKA), which causes relaxation of smooth muscle → bronchodilation
• Also stabilize mast cells (minor role)

• Onset: within 3-5 minutes by inhalation
• Duration: 4-6 hours
• Route: MDI (metered dose inhaler), nebulizer, oral

• First-line drug for acute bronchospasm in asthma (drug of choice)
• Rescue therapy during acute attacks
• Prevention of exercise-induced bronchoconstriction
• Drug of choice in acute exacerbations of COPD

• Duration: ~12 hours
• Used as maintenance therapy - NOT for acute attacks
• Salmeterol has slow onset - only preventive
• Formoterol has faster onset - can be used as reliever too
• Always combined with ICS in asthma (never used alone - risk of fatal attacks)

• Tremor (fine skeletal muscle tremor) - most common
• Tachycardia, palpitations
• Hypokalemia (at high doses)
• Headache
• Arrhythmias (overdose)
• Regular use of SABA alone (without ICS) - associated with increased asthma mortality

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B. MUSCARINIC ANTAGONISTS (Anticholinergics)

• Block muscarinic (M1, M2, M3) receptors in the airways
• Prevent acetylcholine (ACh)-mediated bronchoconstriction
• Reduce mucus secretion
• LAMAs (e.g., tiotropium) selectively dissociate from M2 receptors - preserving the feedback inhibition of ACh release - making them more effective and longer acting

• Ipratropium (SAMA): 6-8 hours duration, via MDI or nebulizer
• Tiotropium (LAMA): 24 hours duration, once daily inhalation
• Umeclidinium, Glycopyrrolate, Aclidinium: other LAMAs

• Ipratropium: Alternative bronchodilator in asthma (especially for patients intolerant to beta-agonists); additive effect with salbutamol in severe acute attacks
• Tiotropium/LAMAs: First-line maintenance therapy in COPD (reduces exacerbations and improves exercise capacity); can be added to ICS + LABA in severe asthma

• Dry mouth (most common)
• Urinary retention (in elderly with BPH)
• Constipation
• Blurred vision (if sprayed into eyes)
• Long-term: concern for increased risk of dementia with advancing age
• Note: Short-acting and long-acting anticholinergics should NOT be combined (additive side effects)

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C. METHYLXANTHINES (Theophylline)

• Inhibits phosphodiesterase (PDE) enzyme → prevents breakdown of cAMP → bronchodilation
• Adenosine receptor antagonism
• At low doses: also has anti-inflammatory effects

• Alternative add-on therapy when ICS + LABA is inadequate
• Oral formulation - useful in patients who cannot use inhalers
• IV Aminophylline - used in severe acute asthma and COPD exacerbations

• Nausea, vomiting, diarrhea (GI effects)
• Headache, insomnia, irritability (CNS)
• Tachycardia, arrhythmias (cardiovascular)
• Seizures (toxicity)
• Therapeutic drug monitoring required (plasma level: 10-20 mcg/mL)

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D. INHALED CORTICOSTEROIDS (ICS)

• Enter the cell and bind to intracellular glucocorticoid receptors (GR)
• GR-drug complex enters nucleus and modulates gene transcription
• Transrepression: Suppresses NF-kB → reduces production of pro-inflammatory cytokines (IL-4, IL-5, TNF-alpha), reduces eosinophil recruitment
• Transactivation: Increases synthesis of anti-inflammatory proteins (lipocortin)
• Overall: Reduces airway edema, mucus secretion, and bronchial hyperresponsiveness
• Also potentiate the effects of beta-2 agonists (upregulate beta-2 receptors)

• Most effective anti-inflammatory agents in asthma
• First-line for persistent asthma (mild to severe)
• Used in COPD patients with two or more exacerbations per year (combined with LABA)
• Reduce frequency and severity of exacerbations

• Local (common): Oral candidiasis (thrush), dysphonia (hoarse voice), cough
• Systemic (with high doses/prolonged use): HPA axis suppression, osteoporosis, growth retardation in children, skin thinning, cataracts
• Spacer device use and mouth rinsing after use reduces local side effects

• Used for acute severe asthma attacks (0.5 mg/kg every 6-12 hours)
• Short courses to control exacerbations
• Chronic use only when other drugs fail - due to significant systemic side effects

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E. LEUKOTRIENE ANTAGONISTS

• Block CysLT1 receptors (cysteinyl leukotriene receptors) in airway smooth muscle
• Prevent bronchoconstriction, reduce mucus hypersecretion and eosinophilic inflammation

• Inhibits the enzyme 5-lipoxygenase (5-LOX)
• Blocks the synthesis of all leukotrienes (both CysLTs and LTB4)

• Alternative to ICS in mild persistent asthma (especially children)
• Very effective in aspirin-induced asthma
• Useful in asthma with concurrent allergic rhinitis (montelukast treats both)
• Prevention of exercise-induced bronchoconstriction
• Add-on to ICS when asthma is not well controlled
• Oral administration - advantage over inhalers (better compliance in children)

• Montelukast: Generally well tolerated; associated with neuropsychiatric effects (depression, suicidal ideation) - FDA black box warning
• Zafirlukast: Headache, GI upset; rare liver toxicity; inhibits CYP2C9
• Zileuton: Hepatotoxicity (elevates liver enzymes in 3% of patients); inhibits CYP1A2; requires liver function monitoring

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F. MAST CELL STABILIZERS

• Cromolyn sodium inhibits mast cell degranulation
• Prevents release of histamine, leukotrienes, and other mediators
• Also inhibits neuronal reflexes that cause bronchoconstriction

• Mild asthma, especially in children (when ICS side effects are a concern)
• Prevention of exercise-induced and allergen-induced bronchoconstriction
• Must be given 2-4 times daily (by nebulization only)

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G. TARGETED / BIOLOGIC THERAPY

• Monoclonal antibody against the Fc portion of IgE
• Prevents IgE binding to mast cells and basophils
• Used in moderate-to-severe allergic asthma not controlled by ICS + LABA
• Subcutaneous injection every 2-4 weeks
• Adverse effect: Anaphylaxis (0.2% incidence)

• Reduce eosinophilic inflammation
• Used in severe eosinophilic asthma with blood eosinophils ≥300/µL
• Reduce exacerbations by ~50%

• Used in moderate-to-severe eosinophilic asthma
• Also used in chronic OCS-dependent severe asthma

• Newest biologic; no biomarker requirement
• Used in severe asthma regardless of eosinophil count

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4. DIFFERENTIATION: BRONCHIAL ASTHMA vs COPD

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5. PHARMACOTHERAPY OF COPD

A. GOALS OF TREATMENT

• Relieve symptoms (dyspnea, cough)
• Improve exercise tolerance
• Prevent and manage exacerbations
• Reduce mortality

B. STABLE COPD MANAGEMENT (Stepwise)

• Short-acting bronchodilators as needed: SABA (salbutamol) or SAMA (ipratropium)

• Long-acting bronchodilator (choose one):
  • LAMA (e.g., Tiotropium) - preferred first choice (reduces exacerbations + improves exercise capacity)
  • LABA (e.g., Salmeterol, Formoterol)
  • LAMA + LABA combination if needed

• LAMA + LABA + ICS (triple therapy)
• ICS is added when: FEV1 <50% of predicted AND patient has ≥2 exacerbations/year
• ICS alone is not recommended in COPD (unlike asthma)

• Daily oral Azithromycin (macrolide antibiotic with anti-inflammatory properties) - reduces exacerbation frequency
• Phosphodiesterase-4 (PDE-4) inhibitor: Roflumilast - oral, reduces exacerbations in severe COPD with chronic bronchitis phenotype

C. ACUTE EXACERBATIONS OF COPD

• Oxygen therapy (controlled, to maintain SpO2 88-92%)
• Nebulized Salbutamol + Ipratropium (additive bronchodilation)
• Systemic Corticosteroids (Prednisolone 30-40 mg orally for 5 days or IV Methylprednisolone)
• Antibiotics (because exacerbations often involve bacterial infection):
  • Beta-lactams, Doxycycline, Azithromycin
  • Target: Haemophilus influenzae (most common COPD pathogen)
• Assisted ventilation (NIV/BiPAP) if severe respiratory failure

D. DIFFERENCES FROM ASTHMA MANAGEMENT

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PART B - SHORT ANSWER (5 Marks)

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1. CLASSIFICATION OF ANTI-ASTHMATIC DRUGS

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2. PHARMACOTHERAPY OF COPD (5 Marks)

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3. LEUKOTRIENE ANTAGONISTS (5 Marks)

1. Montelukast / Zafirlukast - CysLT1 receptor antagonists
   • Block leukotriene binding at receptor level
   • Taken orally (montelukast once daily at night)
2. Zileuton - 5-Lipoxygenase inhibitor
   • Blocks leukotriene synthesis entirely
   • Oral, twice daily (extended release)

• Mild persistent asthma (alternative to ICS)
• Aspirin-exacerbated respiratory disease (AERD) - very effective
• Allergic rhinitis with asthma (montelukast treats both)
• Exercise-induced asthma
• Add-on therapy when ICS alone is insufficient

• Montelukast: Neuropsychiatric effects - anxiety, depression, suicidal ideation (black box warning)
• Zafirlukast: Hepatotoxicity, headache, CYP2C9 inhibitor
• Zileuton: Hepatotoxicity (monitor LFTs), CYP1A2 inhibitor

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4. BETA-2 AGONISTS IN ASTHMA (5 Marks)

• SABAs: Salbutamol, Terbutaline, Metaproterenol (duration 4-6 hrs)
• LABAs: Salmeterol, Formoterol, Vilanterol (duration 12-24 hrs)

• SABAs: Rescue therapy for acute attacks and exercise-induced bronchoconstriction (drug of choice)
• LABAs: Maintenance therapy, always combined with ICS (never alone in asthma)
• LABA + ICS combination (e.g., Salmeterol + Fluticasone): For moderate-to-severe persistent asthma

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5. CORTICOSTEROIDS IN ASTHMA (5 Marks)

1. Inhaled (ICS): Beclomethasone, Budesonide, Fluticasone, Mometasone, Ciclesonide
2. Systemic: Prednisolone, Methylprednisolone, Hydrocortisone

• Bind to intracellular glucocorticoid receptors
• GR-drug complex acts on DNA
• Suppress NF-kB pathway → reduce IL-4, IL-5, TNF-alpha, eosinophil recruitment
• Reduce airway edema, mucus, and bronchial hyperresponsiveness
• Upregulate beta-2 receptors → potentiate bronchodilator response

• ICS: First-line anti-inflammatory treatment for all patients with persistent asthma
• ICS + LABA: For moderate-to-severe asthma
• Systemic CS: Acute severe attacks (short courses); severe refractory asthma

• Local (ICS): Oral candidiasis, dysphonia - prevented by spacer + mouth rinsing
• Systemic (high-dose or prolonged ICS): HPA axis suppression, osteoporosis, growth retardation in children, cataracts, skin atrophy
• Systemic CS: Cushing's syndrome, peptic ulcer, hyperglycemia, immunosuppression, osteoporosis

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QUICK REVISION TABLE: DRUG SUMMARY

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Exam Tips:

• Always start with a brief introduction (2-3 lines) and a classification table
• For mechanism questions, always draw the pathway (beta2 → Gs → adenylyl cyclase → cAMP → PKA → muscle relaxation)
• In differentiation questions, use a table format - easy to write, clear to read
• For 10-mark questions, spend ~3 marks on classification, 5 marks on mechanism/uses/ADRs, 2 marks on management steps
• For 5-mark short answers, write concise points under clear headings - no long paragraphs needed