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Bronchodilators — Complete MD Exam Review

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1. Definition & Overview

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2. Classification

BRONCHODILATORS
│
├── β₂-Adrenoceptor Agonists
│   ├── SABA (Short-Acting β₂ Agonists) — onset <5 min, duration 4–6 h
│   │   ├── Salbutamol (Albuterol)  ← DRUG OF CHOICE for acute bronchospasm
│   │   ├── Terbutaline
│   │   └── Fenoterol
│   └── LABA (Long-Acting β₂ Agonists) — duration ≥12 h
│       ├── Salmeterol (12 h)
│       ├── Formoterol (12 h, rapid onset)
│       ├── Indacaterol (24 h)  ← COPD only
│       ├── Vilanterol (24 h)
│       └── Olodaterol (24 h)
│
├── Muscarinic Receptor Antagonists (Anticholinergics)
│   ├── SAMA (Short-Acting Muscarinic Antagonists) — duration 6–8 h
│   │   └── Ipratropium bromide
│   └── LAMA (Long-Acting Muscarinic Antagonists) — duration 12–24 h
│       ├── Tiotropium (24 h)  ← most widely used LAMA
│       ├── Aclidinium (12 h)
│       ├── Glycopyrronium / Glycopyrrolate (24 h)
│       └── Umeclidinium (24 h)
│
└── Methylxanthines (Phosphodiesterase Inhibitors)
    ├── Theophylline (oral/IV)
    └── Aminophylline (IV — theophylline + ethylenediamine)

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3. β₂-Adrenoceptor Agonists

Mechanism of Action

1. Bind Gs-protein–coupled β₂ receptors on bronchial smooth muscle
2. Activate adenylyl cyclase → ↑ cAMP → activate PKA (Protein Kinase A)
3. PKA phosphorylates myosin light chain kinase (MLCK) → inactivates it → smooth muscle relaxation (bronchodilation)
4. Additional effects:
   • Inhibit mast cell degranulation
   • Stimulate mucociliary clearance
   • Reduce microvascular leakage

Key Drugs — SABAs

Exam key: Salbutamol is the first-line rescue bronchodilator in asthma. Terbutaline SC is used in severe acute asthma if inhalation is not possible. Terbutaline also used as tocolytic (delays preterm labor by relaxing uterine smooth muscle).

Key Drugs — LABAs

Exam key: Salmeterol has SLOW onset — never use for acute attack. Formoterol has fast onset — used in MART (Maintenance And Reliever Therapy) in asthma. LABAs should always be combined with ICS in asthma (never as monotherapy — risk of asthma death: FDA Black Box Warning).

Adverse Effects of β₂ Agonists

Exam key: Hypokalemia is a classic exam viva point — β₂ agonists drive K⁺ intracellularly. SABAs used for acute severe asthma can worsen hypokalemia when combined with systemic steroids and nebulization. Monitor serum K⁺.

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4. Muscarinic Receptor Antagonists (Anticholinergics)

Mechanism of Action

1. Block M₃ muscarinic receptors on bronchial smooth muscle and submucosal glands
2. Normally, ACh from parasympathetic postganglionic fibers activates M₃ → Gq → ↑ IP₃/DAG → ↑ intracellular Ca²⁺ → bronchoconstriction + mucus secretion
3. Blocking M₃ → prevents bronchoconstriction, reduces mucus hypersecretion
4. Also block M₂ (presynaptic/autoreceptors) — M₂ blockade paradoxically increases ACh release, partially opposing bronchodilation (less relevant clinically with modern selective agents)

Tiotropium is more M₁/M₃ selective (dissociates quickly from M₂ but slowly from M₁/M₃ — "kinetic selectivity").

Key Drugs

Exam key: Ipratropium is preferred over SABAs in COPD acute exacerbation (AECOPD). In asthma, anticholinergics are add-on (not first-line). Tiotropium reduces COPD exacerbations and hospitalizations and improves quality of life (GOLD 2025, p. 92).

Adverse Effects of Anticholinergics

Contraindicated in: Closed-angle glaucoma (relative), BPH (relative), urinary retention.

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5. Methylxanthines

Mechanism of Action

1. Non-selective PDE (phosphodiesterase) inhibition → ↓ breakdown of cAMP and cGMP → smooth muscle relaxation (bronchodilation)
2. Adenosine receptor antagonism (A₁, A₂) → bronchodilation, CNS stimulation
3. Stimulate respiratory center (medullary) → useful in apnea of prematurity (caffeine/theophylline)
4. Anti-inflammatory effects at low doses (histone deacetylase activation)
5. Improve diaphragm contractility

Key Drugs

Theophylline — Pharmacokinetics (Exam-Critical)

• Narrow therapeutic index: therapeutic range = 10–20 mg/L
  • < 10 mg/L: subtherapeutic

  • 20 mg/L: toxic

• Hepatic metabolism (CYP1A2)
• Half-life: ~8–9 h (adults); shortened by smoking, rifampicin, phenytoin, carbamazepine; prolonged by cimetidine, erythromycin, ciprofloxacin, heart failure, liver disease, old age

Drug Interactions — Theophylline

Adverse Effects of Theophylline (Dose-Related)

Exam key: Convulsions and arrhythmias are life-threatening toxicity features. Aminophylline IV = theophylline + ethylenediamine (20x more soluble). Loading dose of aminophylline is NOT given if patient is already on oral theophylline (risk of toxicity).

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6. Combination Bronchodilators

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7. Bronchodilators in Asthma vs. COPD

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8. Special Situations — Exam Pearls

Acute Severe Asthma

• Nebulized salbutamol (2.5–5 mg) — continuous/repeated
• Ipratropium added to SABA in severe/life-threatening asthma (synergistic)
• IV aminophylline if refractory (load 5 mg/kg over 20–30 min unless on oral theophylline)
• IV magnesium sulfate (smooth muscle relaxant, alternative bronchodilator)
• IV salbutamol if no response to inhaled therapy

COPD Exacerbation (AECOPD)

• Increase dose/frequency of SABA and SAMA (ipratropium)
• SABA > SAMA for speed; combine both for additive effect
• Add systemic corticosteroids (5 days prednisolone 40 mg)
• Controlled oxygen therapy

Pregnancy

• Salbutamol: safe (Category C; widely used)
• Terbutaline: used as tocolytic (not long-term tocolysis after 48 h)
• Theophylline: can be used (monitor levels; lower protein binding in pregnancy)
• Ipratropium: probably safe; limited data

Apnea of Prematurity

• Caffeine citrate — preferred over theophylline (better safety profile, wider therapeutic index)
• Mechanism: adenosine antagonism + respiratory center stimulation

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9. Magnesium Sulfate (Adjunct Bronchodilator)

• Mechanism: Ca²⁺ antagonist → smooth muscle relaxation (bronchodilation); inhibits ACh and histamine release
• Use: IV MgSO₄ 1.2–2 g over 20 min in severe/life-threatening asthma not responding to initial therapy
• Exam key: Not a classic bronchodilator but acts as one clinically; BTS/SIGN guidelines include it in stepwise asthma management

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10. Inhaler Devices — High-Yield

Exam key: DPIs require high inspiratory flow — not suitable for acute severe asthma (weak inspiratory effort). Nebulizers are used in acute severe asthma and very young/elderly patients.

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11. Quick Recall Summary Table

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12. Top Exam Viva Points

1. Salbutamol causes hypokalemia — via β₂-mediated K⁺ shift into cells (not renal loss)
2. Salmeterol must never be used alone in asthma — FDA Black Box Warning; always combine with ICS
3. Salmeterol has slow onset (15–20 min) — never for acute rescue; Formoterol has fast onset
4. Ipratropium preferred in COPD over SABAs in some guidelines; both combined in exacerbations
5. Theophylline has narrow therapeutic index (10–20 mg/L); CYP1A2 interactions critical
6. Aminophylline = theophylline + ethylenediamine; do NOT give loading dose if already on oral theophylline
7. Tiotropium — kinetic selectivity: slow dissociation from M₁/M₃, fast from M₂
8. Magnesium sulfate — bronchodilator for severe/life-threatening asthma (IV)
9. Terbutaline SC — used when salbutamol inhalation not possible; also used as tocolytic
10. Caffeine preferred over theophylline in apnea of prematurity (wider therapeutic index)
11. LABAs are safe as monotherapy in COPD but contraindicated as monotherapy in asthma
12. Smoking induces CYP1A2 → decreases theophylline levels → smokers need higher doses

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