Drugs Used in Bronchial Asthma & COPD

Asthma and COPD pharmacology is one of the most reliably tested areas in NEET PG Pharmacology, sitting at the intersection of autacoids, autonomic drugs and clinical respiratory medicine. The key is to know each drug class by its receptor target, route, onset/duration, and exact clinical niche (reliever vs controller), plus the few high-yield toxicities (theophylline, LABA monotherapy, ICS local effects).

Classification of Anti-asthma Drugs

Drugs are broadly divided into bronchodilators (relievers) and anti-inflammatory/controllers.

Category	Class	Examples
Bronchodilators	Beta-2 agonists (SABA/LABA)	Salbutamol, terbutaline; salmeterol, formoterol, indacaterol
	Methylxanthines	Theophylline, aminophylline, doxofylline
	Anticholinergics (SAMA/LAMA)	Ipratropium; tiotropium, glycopyrronium, umeclidinium
Anti-inflammatory	Inhaled corticosteroids (ICS)	Budesonide, beclomethasone, fluticasone, ciclesonide
	Leukotriene modifiers	Montelukast, zafirlukast (antagonists); zileuton (5-LOX inhibitor)
	Mast cell stabilisers	Sodium cromoglycate, nedocromil
Biologicals	Anti-IgE	Omalizumab
	Anti-IL-5	Mepolizumab, reslizumab, benralizumab
	Anti-IL-4/13	Dupilumab

High-yield: Relievers act on bronchial smooth muscle (bronchodilation); controllers act on the underlying inflammation. The single most important controller is the inhaled corticosteroid.

Beta-2 Adrenergic Agonists

These are the cornerstone bronchodilators. They stimulate β2 receptors → activate adenylyl cyclase → ↑cAMP → bronchial smooth muscle relaxation. β2 receptors also stabilise mast cells, enhance mucociliary clearance and reduce microvascular leak.

Short-acting β2 agonists (SABA)

• Salbutamol (albuterol) and terbutaline are the prototypes.
• Onset within 5 minutes, duration 4-6 hours.
• Drug of choice for acute bronchospasm / relief of acute symptoms and for exercise-induced asthma (pre-exercise).
• Route: inhaled (MDI/nebuliser) preferred; oral and parenteral cause more systemic effects.

Long-acting β2 agonists (LABA)

• Salmeterol (slow onset, ~30 min; not for rescue) and formoterol (rapid onset, can double as reliever).
• Duration ~12 hours; indacaterol, vilanterol, olodaterol are ultra-LABAs (24 h, once daily, used in COPD).
• Salmeterol is a partial agonist and is highly lipophilic, anchoring in the membrane (the "exosite/exoreceptor" theory explains its long action).

High-yield: LABA must NEVER be used as monotherapy in asthma — it increases asthma-related deaths (SMART/SALSA trials). Always combine with an ICS. In COPD, LABA monotherapy is acceptable.

Adverse effects of β2 agonists: tremor (β2 on skeletal muscle — most common), tachycardia/palpitation (β1 + reflex), hypokalaemia (β2 drives K⁺ intracellularly — basis for use in hyperkalaemia), hyperglycaemia, restlessness, and tolerance/down-regulation on chronic use.

High-yield: Salbutamol nebulisation is used off-label to treat hyperkalaemia because β2 stimulation shifts K⁺ into cells.

Inhaled Corticosteroids (ICS)

ICS are the most effective controllers and the backbone of long-term asthma therapy. They bind cytoplasmic glucocorticoid receptors → ↑transcription of anti-inflammatory genes (lipocortin/annexin-1, which inhibits phospholipase A2) and trans-repression of pro-inflammatory genes (NF-κB), reducing eosinophils, cytokines and airway hyper-responsiveness.

• Examples: budesonide, beclomethasone, fluticasone, ciclesonide, mometasone.
• Ciclesonide is a prodrug activated by esterases in the lung → minimal oropharyngeal effects.
• Budesonide is preferred in pregnancy (best safety data).

Local adverse effects: oropharyngeal candidiasis (thrush) and dysphonia/hoarseness — minimised by using a spacer and rinsing the mouth after use. Systemic effects (high dose, chronic): adrenal suppression, growth retardation in children (usually small, catch-up occurs), osteoporosis, cataract, easy bruising.

High-yield: The classic exam pairing — patient on inhaled steroid develops oral thrush/hoarse voice → answer is use a spacer and rinse mouth. Steroids do NOT relieve acute bronchospasm immediately; their benefit takes hours.

Methylxanthines (Theophylline)

Theophylline, aminophylline (theophylline-ethylenediamine, IV form) and doxofylline.

Mechanisms (multiple):

1. Non-selective phosphodiesterase (PDE) inhibition → ↑cAMP and cGMP → bronchodilation.
2. Adenosine receptor (A1/A2) antagonism → bronchodilation; also explains some cardiac/CNS effects.
3. At low doses, activation of histone deacetylase (HDAC) → anti-inflammatory effect and restoration of corticosteroid sensitivity (relevant in COPD).

Other actions: CNS stimulation, diuresis, positive inotropy/chronotropy, increased diaphragmatic contractility, gastric acid secretion.

High-yield: Theophylline has a narrow therapeutic index (therapeutic plasma level 10-20 µg/mL); it requires therapeutic drug monitoring.

Toxicity (often when level >20 µg/mL): nausea, vomiting, headache, insomnia → at higher levels seizures (often refractory) and cardiac arrhythmias (can be fatal, may precede GI symptoms in chronic toxicity).

Metabolism — CYP1A2 (the most exam-relevant pharmacokinetic point):

Increase theophylline levels (inhibitors / ↓clearance)	Decrease theophylline levels (inducers / ↑clearance)
Cimetidine, ciprofloxacin (fluoroquinolones), erythromycin/clarithromycin, oral contraceptives, fluvoxamine	Rifampicin, phenytoin, carbamazepine, smoking, charcoal-broiled meat, phenobarbitone
Heart failure, liver disease, fever, viral infection	—

High-yield: A patient stabilised on theophylline who stops smoking has a fall in CYP1A2 induction → rising theophylline levels → toxicity. Conversely, ciprofloxacin + theophylline is a classic interaction causing toxicity/seizures.

Doxofylline: a newer xanthine with weaker adenosine antagonism → fewer cardiac and CNS adverse effects.

Anticholinergics (Antimuscarinics)

Block M3 receptors on airway smooth muscle and submucosal glands → reduce vagally mediated bronchoconstriction and secretions. They are more useful in COPD (where cholinergic tone dominates) than in asthma.

Drug	Type	Duration	Notes
Ipratropium	SAMA	4-6 h	Quaternary; add-on in acute severe asthma & COPD; DOC bronchodilator in β-blocker-induced bronchospasm
Tiotropium	LAMA	24 h	M3-selective (kinetic selectivity); once daily; mainstay of COPD
Glycopyrronium, umeclidinium, aclidinium	LAMA	12-24 h	COPD maintenance

High-yield: Tiotropium dissociates slowly from M3 (and M1) but rapidly from M2 → effective "kinetic" M3 selectivity, allowing once-daily dosing.

Adverse effects (minimal as inhaled, quaternary): dry mouth, metallic taste; caution in glaucoma (avoid nebulised mist near eyes) and bladder outflow obstruction/BPH. Paradoxical bronchospasm rarely.

Leukotriene Modifiers

Cysteinyl leukotrienes (LTC4, LTD4, LTE4) cause bronchoconstriction, mucus secretion and eosinophil recruitment.

• Montelukast, zafirlukast — competitive CysLT1 receptor antagonists (oral, once daily for montelukast).
• Zileuton — 5-lipoxygenase inhibitor (blocks leukotriene synthesis); hepatotoxic, needs LFT monitoring.

Best uses: aspirin-induced (NSAID-exacerbated) asthma, exercise-induced asthma, and asthma with allergic rhinitis; useful add-on/steroid-sparing in mild persistent asthma, especially in children where inhaler technique is poor.

High-yield: Montelukast is the drug of choice add-on for aspirin-sensitive asthma (Samter's triad: asthma + nasal polyps + aspirin sensitivity). Watch for neuropsychiatric adverse effects (mood changes, nightmares — FDA boxed warning) and rarely Churg-Strauss/EGPA unmasking.

Mast Cell Stabilisers

Sodium cromoglycate (cromolyn) and nedocromil inhibit mast cell degranulation. Used only prophylactically (no role in acute attack), now largely obsolete but historically useful in children and in exercise/allergen-induced asthma. Safe, minimal systemic effects.

Biological Therapies (Severe Asthma)

Reserved for severe, uncontrolled asthma despite high-dose ICS + LABA, phenotype-directed:

Biological	Target	Phenotype
Omalizumab	Anti-IgE (binds free IgE, ↓FcεRI)	Severe allergic asthma; ↑total serum IgE, sensitised to perennial allergen
Mepolizumab, reslizumab	Anti-IL-5	Eosinophilic asthma (↑blood eosinophils)
Benralizumab	Anti-IL-5Rα	Eosinophilic asthma
Dupilumab	Anti-IL-4Rα (blocks IL-4 & IL-13)	Type-2 high, eosinophilic / steroid-dependent; also atopic dermatitis
Tezepelumab	Anti-TSLP	Broad severe asthma

High-yield: Omalizumab (subcutaneous) is the prototype anti-IgE; dose is based on body weight and baseline serum IgE. Risk of anaphylaxis → observe after dosing.

Stepwise Management of Chronic Asthma (GINA-based)

The major paradigm shift: SABA-only treatment is no longer recommended because of risk; every patient should receive ICS-containing therapy.

Preferred reliever across steps → low-dose ICS-formoterol (anti-inflammatory reliever, AIR).

Track 1 (preferred) flow:

1. Step 1-2: As-needed low-dose ICS-formoterol.
2. Step 3: Low-dose maintenance ICS-formoterol + as-needed ICS-formoterol (MART — Maintenance And Reliever Therapy).
3. Step 4: Medium-dose maintenance ICS-formoterol (MART).
4. Step 5: Add-on LAMA (e.g., tiotropium) and refer for phenotyping → biologicals; consider high-dose ICS.

Stepwise logic: ICS-formoterol reliever → add maintenance ICS-formoterol → ↑ICS dose → add LAMA → biologicals.

High-yield: Formoterol is the LABA used in MART because of its rapid onset (acts as reliever) — salmeterol cannot be used this way. Oral corticosteroids are the last resort (chronic) due to systemic toxicity.

Acute Severe Asthma (Status Asthmaticus)

Approach: Oxygen (target SpO2 93-95%) → nebulised SABA (salbutamol) ± ipratropium → systemic corticosteroids early (oral prednisolone or IV hydrocortisone) → IV magnesium sulphate if severe/poor response → consider IV salbutamol/aminophylline, escalate to ventilation.

High-yield: IV magnesium sulphate is the additional drug in acute severe/life-threatening asthma not responding to initial nebulisation. Systemic steroids reduce mortality and relapse but take ~4-6 h to act — give early.

COPD Pharmacotherapy

COPD differs from asthma: airflow limitation is largely irreversible, neutrophilic, less steroid-responsive, and bronchodilators (LABA/LAMA) are the foundation.

Stable COPD (GOLD groups):

• Group A: a bronchodilator (LABA or LAMA).
• Group B: LABA + LAMA combination.
• Group E (exacerbations): LABA + LAMA; add ICS if blood eosinophils ≥300/µL (triple therapy LABA+LAMA+ICS).

High-yield: In COPD, ICS is added based on blood eosinophil count (≥300 favours ICS; <100 argues against). LAMA (tiotropium) is the most effective single maintenance class. ICS in COPD increases pneumonia risk.

Other COPD-specific drugs:

• Roflumilast — selective PDE-4 inhibitor; oral; reduces exacerbations in severe COPD with chronic bronchitis and frequent exacerbations. Adverse: diarrhoea, weight loss, nausea, psychiatric effects.
• Mucolytics: N-acetylcysteine, carbocysteine, erdosteine.
• Azithromycin (long-term, low-dose) to reduce exacerbations in selected patients.

Acute COPD exacerbation flow:

1. Controlled oxygen (target SpO2 88-92% — avoid CO2 retention).
2. Short-acting bronchodilators: salbutamol + ipratropium nebulised.
3. Systemic corticosteroids (e.g., prednisolone 40 mg × 5 days).
4. Antibiotics if increased sputum purulence/volume/dyspnoea (Anthonisen criteria) — amoxicillin-clavulanate, macrolide, or doxycycline.
5. NIV (BiPAP) for hypercapnic respiratory failure (pH < 7.35).

High-yield: COPD target SpO2 is 88-92% (controlled O2) versus asthma 93-95%. Systemic steroid course in COPD exacerbation is short (5 days, no taper needed).

Key Differentials / Comparisons

Feature	Asthma	COPD
Reversibility	Largely reversible	Largely irreversible
Inflammation	Eosinophilic, CD4/Th2	Neutrophilic, CD8
Steroid response	Good	Poor/variable (eosinophil-guided)
Foundation drug	ICS (controller)	LAMA/LABA (bronchodilator)
O2 target in acute	93-95%	88-92%
Onset/age	Younger, atopic	Older, smoker

Recently asked / exam angle

• Mechanism MCQs: salmeterol = LABA (never monotherapy in asthma); formoterol = rapid-onset LABA used in MART; ciclesonide = ICS prodrug; zileuton = 5-LOX inhibitor; montelukast = CysLT1 antagonist; roflumilast = PDE-4 inhibitor; tiotropium = LAMA (M3 kinetic selectivity).
• Theophylline is a perennial favourite: narrow therapeutic index (10-20 µg/mL), CYP1A2 metabolism, smoking cessation/ciprofloxacin/cimetidine raising levels → seizures.
• Aspirin-sensitive asthma → leukotriene antagonist (montelukast); Samter's triad.
• Drug for β-blocker-induced bronchospasm = ipratropium (β2 agonists ineffective when β receptors blocked).
• IV magnesium sulphate in acute severe asthma.
• Eosinophil-guided ICS in COPD; ICS → pneumonia risk.
• ICS adverse effect → oral candidiasis/dysphonia; management = spacer + mouth rinse; budesonide safest in pregnancy.
• Omalizumab = anti-IgE; mepolizumab/benralizumab = anti-IL-5; dupilumab = anti-IL-4Rα.

Mnemonic — Theophylline level raisers "CCC-E-OF": Cimetidine, Ciprofloxacin, Clarithromycin/erythromycin, Erythromycin, Oral contraceptives, Fluvoxamine (and liver disease/CHF). Inducers = RSP: Rifampicin, Smoking, Phenytoin/phenobarbitone/carbamazepine.

Rapid revision

1. Salbutamol (SABA) = drug of choice for acute relief; onset 5 min, lasts 4-6 h; causes tremor, tachycardia, hypokalaemia (used in hyperkalaemia).
2. Salmeterol = slow-onset LABA (not rescue); formoterol = rapid-onset LABA used in MART.
3. LABA monotherapy is contraindicated in asthma — always pair with ICS.
4. ICS = most effective controller; local effects = thrush + hoarseness → spacer + rinse; budesonide safest in pregnancy; ciclesonide is a lung-activated prodrug.
5. Theophylline: PDE inhibitor + adenosine antagonist + HDAC activator; narrow TI 10-20 µg/mL; CYP1A2; toxicity = vomiting, seizures, arrhythmias.
6. Smoking cessation, ciprofloxacin, cimetidine raise theophylline; rifampicin & smoking lower it.
7. Ipratropium = SAMA, DOC for β-blocker-induced bronchospasm; tiotropium = LAMA, COPD mainstay (M3 kinetic selectivity).
8. Montelukast = CysLT1 antagonist, best for aspirin-sensitive & exercise-induced asthma; watch neuropsychiatric effects; zileuton = 5-LOX inhibitor (hepatotoxic).
9. Acute severe asthma: O2 (93-95%) → SABA+ipratropium nebs → early systemic steroid → IV MgSO4.
10. COPD: bronchodilators (LABA/LAMA) are foundation; add ICS if eosinophils ≥300/µL; ICS raises pneumonia risk; O2 target 88-92%.
11. Roflumilast = PDE-4 inhibitor for severe COPD with chronic bronchitis/exacerbations.
12. Biologicals: omalizumab (anti-IgE), mepolizumab/benralizumab (anti-IL-5), dupilumab (anti-IL-4Rα), tezepelumab (anti-TSLP).