Bronchodilators

Bronchodilators are a critical class of medications used primarily to manage respiratory disorders characterized by reversible or partially reversible airway obstruction. Their primary role is to relax bronchial smooth muscle, thereby dilating the airways and facilitating easier breathing. These agents are the cornerstone of therapy in diseases such as asthma, chronic obstructive pulmonary disease (COPD), and other pulmonary conditions with bronchospasm.

---

1. Classification of Bronchodilators

Bronchodilators are categorized based on their pharmacological targets and duration of action:

A. Beta-2 Adrenergic Agonists

• Short-acting beta-2 agonists (SABAs)

• Long-acting beta-2 agonists (LABAs)

B. Anticholinergics (Muscarinic Antagonists)

• Short-acting muscarinic antagonists (SAMAs)

• Long-acting muscarinic antagonists (LAMAs)

C. Methylxanthines

• Non-selective phosphodiesterase inhibitors

D. Combination Bronchodilators

• LABA + LAMA

• SABA + SAMA

• Bronchodilator + Inhaled corticosteroid (ICS)

---

2. Beta-2 Adrenergic Agonists

Mechanism of Action:
Beta-2 agonists bind to beta-2 adrenergic receptors on bronchial smooth muscle, activating adenylate cyclase, increasing cyclic AMP (cAMP), and resulting in smooth muscle relaxation.

Short-Acting Beta-2 Agonists (SABAs):

• Onset: 1–5 minutes

• Duration: 4–6 hours

• Used for acute relief of bronchospasm ("rescue inhalers")

Examples:

• Salbutamol (Albuterol) – Ventolin, ProAir

• Levalbuterol – Xopenex

• Terbutaline

• Fenoterol (available in certain countries)

Long-Acting Beta-2 Agonists (LABAs):

• Onset: 15 minutes to 2 hours

• Duration: ≥12 hours

• Maintenance therapy for asthma (in combination) and COPD

Examples:

• Salmeterol – Serevent

• Formoterol – Foradil, Oxeze

• Indacaterol – Arcapta Neohaler

• Olodaterol – Striverdi Respimat

• Vilanterol – used only in combination products

---

3. Anticholinergics (Muscarinic Antagonists)

Mechanism of Action:
These agents competitively inhibit acetylcholine at muscarinic receptors (primarily M3) in bronchial smooth muscle, preventing bronchoconstriction.

Short-Acting Muscarinic Antagonists (SAMAs):

• Duration: 6–8 hours

• Used in combination with SABAs for acute COPD exacerbations

Examples:

• Ipratropium bromide – Atrovent

Long-Acting Muscarinic Antagonists (LAMAs):

• Duration: ≥24 hours

• Maintenance therapy in COPD, increasingly used in asthma

Examples:

• Tiotropium – Spiriva

• Glycopyrronium – Seebri

• Aclidinium – Tudorza Pressair

• Umeclidinium – Incruse Ellipta

• Revefenacin – Yupelri (nebulized LAMA)

---

4. Methylxanthines

Mechanism of Action:
Inhibit phosphodiesterase, increasing cAMP, and also antagonize adenosine receptors, promoting bronchodilation. These drugs also have mild anti-inflammatory properties.

Examples:

• Theophylline

• Aminophylline

Notes:

• Narrow therapeutic index

• Requires serum level monitoring

• Usage has declined due to side effects and drug interactions

---

5. Combination Bronchodilators

A. SABA + SAMA

• Salbutamol + Ipratropium – Combivent Respimat, DuoNeb

• Used for acute bronchospasm in COPD

B. LABA + LAMA

• Indacaterol + Glycopyrronium – Ultibro

• Vilanterol + Umeclidinium – Anoro Ellipta

• Formoterol + Aclidinium – Duaklir Genuair

C. LABA + ICS

• Salmeterol + Fluticasone – Seretide, Advair

• Formoterol + Budesonide – Symbicort

• Vilanterol + Fluticasone furoate – Breo Ellipta

D. Triple Combinations (LABA + LAMA + ICS)

• Fluticasone + Umeclidinium + Vilanterol – Trelegy Ellipta

• For patients with frequent exacerbations and severe COPD

---

6. Clinical Indications

A. Asthma

• SABAs for rescue therapy

• LABAs only in combination with ICS

• LAMAs in severe asthma not controlled with ICS + LABA

• Theophylline as adjunct (less common)

B. Chronic Obstructive Pulmonary Disease (COPD)

• First-line: LAMA or LABA

• Dual therapy for moderate/severe COPD

• SABA/SAMA for acute relief

C. Other Indications

• Acute bronchitis with bronchospasm

• Exercise-induced bronchospasm (prevention)

• Anaphylaxis (as part of management with epinephrine)

• Bronchiolitis (off-label, controversial use)

---

7. Dosage and Administration

Dosages vary by agent and formulation:

Salbutamol (Albuterol):

• MDI: 100 mcg per actuation

• Typical dose: 1–2 puffs every 4–6 hours PRN

• Nebulized: 2.5 mg every 4–6 hours PRN

Ipratropium:

• MDI: 20 mcg per actuation

• Dose: 2 puffs 4 times daily

Tiotropium:

• DPI: 18 mcg once daily

• Respimat: 2.5 mcg or 5 mcg once daily

Theophylline:

• Dose individualized based on serum levels

• Typical range: 5–15 mcg/mL therapeutic window

---

8. Contraindications

Absolute:

• Hypersensitivity to the specific drug or formulation components

Relative:

• Beta-2 agonists:

  • Tachyarrhythmias

  • Uncontrolled hypertension

• Anticholinergics:

  • Narrow-angle glaucoma

  • Urinary retention

• Theophylline:

  • Peptic ulcer disease

  • Seizure disorders (unless controlled)

---

9. Adverse Effects

Beta-2 Agonists:

• Tremor

• Tachycardia

• Palpitations

• Hypokalemia

• Headache

• Paradoxical bronchospasm (rare)

Anticholinergics:

• Dry mouth

• Urinary retention

• Glaucoma exacerbation (with improper inhaler use)

• Constipation

Methylxanthines:

• Nausea/vomiting

• Insomnia

• Seizures (high levels)

• Arrhythmias

• GI upset

---

10. Precautions

• Monitor potassium levels with high-dose SABA use

• Caution in patients with cardiovascular disease

• Inhaler technique must be reviewed regularly

• MDI and DPI require patient education

• Nebulized therapy has increased systemic absorption

• Elderly patients may be more susceptible to side effects

---

11. Drug Interactions

Beta-2 Agonists:

• Enhanced hypokalemia with:

  • Diuretics

  • Corticosteroids

  • Theophylline

• Beta-blockers antagonize effects

Anticholinergics:

• Additive anticholinergic burden with:

  • Tricyclic antidepressants

  • Antihistamines

Theophylline:

• Metabolized by CYP1A2:

  • Inhibitors (e.g., ciprofloxacin, cimetidine) ↑ levels

  • Inducers (e.g., phenytoin, rifampin) ↓ levels

• Synergistic toxicity with beta-agonists

---

12. Formulations and Devices

Bronchodilators are available in multiple delivery systems:

• Metered-dose inhalers (MDI)

• Dry powder inhalers (DPI)

• Soft mist inhalers (SMI)

• Nebulizer solutions

• Oral tablets (theophylline)

• Parenteral (IV aminophylline – rarely used)

Choice of device is patient-dependent and influenced by:

• Age

• Cognitive status

• Coordination

• Inspiratory flow capability

• Disease severity

---

13. Clinical Guidelines

Global Initiative for Asthma (GINA) 2024 Recommendations:

• No longer recommend SABA-only treatment

• Stepwise approach using ICS + LABA

• Emphasizes symptom control and exacerbation prevention

Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2024 Recommendations:

• Initial therapy based on symptoms (mMRC, CAT scores)

• LAMA preferred for dyspnea

• LABA + LAMA for frequent exacerbators

• ICS reserved for patients with eosinophilic inflammation or asthma overlap

---

14. Summary of Key Bronchodilators

Class	Generic Name	Brand Names	Duration	Notes
SABA	Salbutamol (Albuterol)	Ventolin, ProAir	4–6 hours	First-line rescue therapy
SAMA	Ipratropium	Atrovent	6–8 hours	Often used with SABA in COPD
LABA	Salmeterol	Serevent	12 hours	Maintenance only, not for monotherapy in asthma
LABA	Formoterol	Foradil, Symbicort	12 hours	Rapid onset, suitable for SMART
LAMA	Tiotropium	Spiriva	≥24 hours	Maintenance therapy in COPD, asthma
Methylxanthine	Theophylline	Theo-Dur, Uniphyl	Variable	Narrow therapeutic index