Asthma Medications

Overview

• Asthma is a lung condition characterized by:
  • Airway hyperresponsiveness (due to release of mediators, e.g., histamine)
  • Variable airway obstruction (due to bronchoconstriction and inflammation)
  • Airway inflammation (due to recruitment of inflammatory cells)
• Goals of asthma management:
  • Preventing/reversing bronchoconstriction:
    • β-agonists (e.g., albuterol)
    • Methylxanthines (e.g., theophylline)
    • Muscarinic agonists (e.g., ipratropium)
  • Preventing mast cell degranulation:
    • Anti-IgE (immunoglobulin E) monoclonal antibodies (e.g., omalizumab)
    • Chromones or cromoglycates (e.g., cromolyn)
  • Preventing the release of inflammatory mediators:
    • Corticosteroids
    • Antileukotrienes (e.g., montelukast, zafirlukast, zileuton)
    • Antibodies (e.g., mepolizumab)

Bronchodilators: β2-Agonists

Types and administration

• SABA: 
  • Albuterol (inhalation, oral)
  • Levalbuterol (inhalation)
  • Terbutaline (oral, intravenous (IV))
• LABA:
  • Salmeterol (inhalation)
  • Formoterol (inhalation)
  • Vilanterol (inhalation)

Mechanism of action and effects

• Drug binds the β-2 receptor.
• Effect: stimulates cAMP in smooth muscle cells → smooth muscle relaxation → dilation of bronchioles
• SABA: duration of 4–6 hours and onset within 5 minutes
• LABA: duration of up to 12 hours

Clinical uses

• SABA:
  • Rapidly acting bronchodilator, used in acute asthma exacerbation 
  • Oral form not recommended for acute exacerbation (longer onset of action, less effective bronchodilation)
• LABA: 
  • Used only with inhaled corticosteroids, not as a monotherapy
  • Combined inhaled CS and LABA (low-dose inhaled CS-formoterol): can be used as acute symptom reliever (Global Initiative for Asthma guidelines)
  • Used for exercise-induced bronchoconstriction and prevention of nocturnal symptoms

Side effects

• β2-mediated skeletal muscle tremors (most common side effect)
• Other effects: 
  • Tachycardia (cardiac β receptor stimulation)
  • Hyperglycemia
  • Hypokalemia

Precautions

• Use with caution in cardiovascular disease (arrhythmia, heart failure, coronary artery disease).
• May increase glucose in diabetics
• May elevate intraocular pressure in glaucoma

Bronchodilators: Muscarinic Antagonists

Types and administration

• SAMA: ipratropium bromide (inhalation)
• LAMA: tiotropium bromide (inhalation)

Mechanism of action and effects

• Competitively block muscarinic receptors, thereby preventing vagal-induced bronchoconstriction
• ↓ cyclic guanosine monophosphate (cGMP) → ↓ smooth muscle contraction and ↓ mucus secretion
• No anti-inflammatory effect

Clinical uses

• Less effective than β2-agonists for acute exacerbation but with additive benefit
• Long-term maintenance treatment in children > 6 years of age and adults with severe symptomatic asthma uncontrolled with inhaled CS
• Also used in chronic obstructive pulmonary disease

Side effects

• Few systemic effects because of poor absorption into the circulation
• Minor atropine-like effects with high doses

Precautions

• Use with caution in patients with narrow-angle glaucoma (can increase intraocular pressure).
• Bladder neck obstruction/prostatic hyperplasia (may cause urinary retention)

Bronchodilators: Methylxanthines

Types and administration

• Theophylline (oral, IV)
• Theobromine (found in cocoa) and caffeine (found in coffee) are also methylxanthines.

Mechanism of action and effects

• Blockage of receptors for adenosine (which provokes smooth muscle contraction and histamine release) 
• Inhibition of phosphodiesterase (which degrades cyclic adenosine monophosphate (cAMP)) → smooth muscle relaxation
• Overall, results in bronchodilation and reduced inflammation

Clinical uses

• Nonpreferred alternative for asthma that is uncontrolled with inhaled CS
• Decreases exacerbations; has similar effect as increasing the dosage of the inhaled CS
• Modest anti-inflammatory action
• Narrow therapeutic index and serum concentration must be monitored regularly.
• Despite disadvantages, theophylline is used in some countries due to low cost.

Side effects

• Gastrointestinal symptoms (nausea, vomiting), tremor, headache
• Toxic doses: hypotension, cardiac arrhythmias, seizures, and possibly death

Precautions

• Limited use due to significant side effects and life-threatening toxicity
• Use with caution in patients with seizures, cardiac arrhythmias, hepatic impairment, peptic ulcer disease, and hyperthyroidism.

Corticosteroids

Types and administration

• Inhaled corticosteroids (ICS): beclomethasone, budesonide, fluticasone, mometasone, triamcinolone  
• Systemic corticosteroids:
  • Oral CS: prednisone, prednisolone 
  • IV CS: hydrocortisone, methylprednisolone

Mechanism of action and effects

• Blocks the release of arachidonic acid (via phospholipase A2 inhibition), consequently halting the release of inflammatory mediators
• Effects: 
  • ↓ airway hyperresponsiveness
  • ↓ airway mucosal edema
  • ↓ capillary permeability
  • ↓ leukotriene release

Clinical uses

• ICS: generally, the most effective anti-inflammatory agent for the treatment of asthma
• Drug of choice for long-term control of persistent asthma
• Short-term oral CS treatment (< 7 days) of acute severe exacerbations
• Tapering required if oral CS > 2 weeks

Side effects

• ICS:
  • Less severe and fewer than those of systemic CS
  • Local effects:
    • Dysphonia: less common with devices that produce smaller-sized particles 
    • Thrush: can be avoided by a large-volume spacer with metered-dose inhalers (MDIs); rinsing of the oropharynx and spacer after inhalation also helps
  • Much less common:
    • Deceleration of growth velocity in children
    • Adrenal suppression
    • Cataracts
• Systemic CS side effects: adrenal suppression, weight gain, diabetes, hypertension, immune suppression, osteoporosis, and depression

Antileukotriene Agents

Types and administration

• Leukotriene receptor antagonists (LTRAs): zafirlukast, montelukast (oral)
• 5-lipoxygenase inhibitor: zileuton (oral)

Mechanism of action and effects

• Zileuton: selective inhibition of 5-lipoxygenase (thus preventing conversion of arachidonic acid to leukotrienes)
• Zafirlukast and montelukast: inhibit leukotriene (LT)-D4 receptors and LTE4 receptors
• Effects (by targeting leukotriene): 
  • ↓ smooth airway contraction
  • ↓ vascular permeability and mucus secretion
  • Reduced activation of inflammatory cells

Clinical uses

• Exercise-induced bronchospasm
• Mild persistent asthma + allergic rhinitis
• Asthma and aspirin-exacerbated respiratory disease
• Additive benefit for moderate-to-severe persistent asthma
• Considered in patients with difficulty with compliance or inhaler technique (e.g., children)

Side effects

• Common: headaches, fatigue, dyspepsia 
• Neuropsychiatric adverse effects: behavior and mood-related changes (especially montelukast) 
• Zafirlukast and zileuton: 
  • Potentially hepatotoxic, requiring liver function test monitoring
  • Drug interactions (including increased warfarin effect)
• Eosinophilic granulomatous polyangiitis can develop when antileukotrienes are given to patients with steroid-dependent asthma.

Precautions

• Zafirlukast and zileuton: 
  • Contraindicated in liver disease/hepatic impairment
  • Monitor for mood and behavioral changes
• Montelukast: 
  • Monitor for mood and behavioral changes
  • Contains phenylalanine (not recommended for patients with phenylketonuria)

Mast Cell Stabilizers (Chromones)

Types and administration

• Cromolyn (nebulization)
• Nedocromil (not available for asthma treatment in the United States)

Mechanism of action and effects

• Prevents the degranulation of mast cells, thereby preventing local inflammation 
• Prevents early and late inflammatory effects

Clinical uses

• For prevention of exercise-induced bronchospasm 
• Alternative long-term asthma maintenance therapy
• Less effective and more expensive than CS
• Rarely used (metered-dose inhaler not available in the United States)

Side effects

• Throat irritation
• No significant toxicity due to minimal systemic absorption

Antibodies: Anti-IgE

Type(s) and administration

Omalizumab (subcutaneous)

Mechanism of action and effects

• Monoclonal antibody that binds circulating IgE
• IgE plays a central role in immediate bronchoconstriction and the influx of inflammatory cells.

Clinical use

• For persistently uncontrolled allergic asthma despite high-dose ICS and ≥ 1 other controller(s)
• For patients with:
  • Age ≥ 6 years
  • An elevated IgE level (30–700 IU/mL)
  • Positive allergen skin test or specific IgE tests to a perennial allergen
• Reduces CS requirements

Side effects

• Urticaria, injection site reaction
• Headache

Precautions

• Anaphylaxis/severe hypersensitivity reaction is a contraindication.
• Monitor for parasitic infections (helminth).
• Cerebrovascular events have been reported.

Antibodies: Anti-IL-5 and Anti-IL-5 Receptor

Types and administration

• Mepolizumab (subcutaneous)
• Reslizumab (intravenous)
• Benralizumab (subcutaneous)

Mechanism of action and effects

• IL-5 is a pro-eosinophilic cytokine contributing to eosinophilic inflammation.
• Mepolizumab, reslizumab: monoclonal antibody to IL-5
• Benralizumab: cytotoxic monoclonal antibody against IL-5 receptor alpha

Clinical use

• For severe eosinophilic asthma
• Mepolizumab: 
  • For blood eosinophil count ≥ 300 cells/μL
  • Patient age: > 12 years
• Reslizumab: 
  • For blood eosinophil count ≥ 400 cells/μL 
  • Patient age: > 18 years
• Benralizumab: 
  • For blood eosinophil count ≥ 300 cells/μL
  • Patient age: > 12 years

Side effects

• Mepolizumab: herpes zoster (may give varicella vaccine ≥ 1 month before)
• Reslizumab: oropharyngeal pain
• Benralizumab: headache, pharyngitis

Precautions

• Anaphylaxis/severe hypersensitivity reaction is a contraindication.
• Helminth infection needs to be treated prior to initiation.

Antibodies: Anti-IL-4 Receptor

Types and administration

• Dupilumab (subcutaneous)

Mechanism of action and effects

• Blocks IL-4 receptor
• Through receptor blockage, IL-4 and IL-13 with other cytokines are inhibited.

Clinical use

• For severe eosinophilic asthma or oral-steroid asthma
• Inadequately controlled asthma with eosinophil count ≥ 150 cells/μL 
• Patient age: > 12 years
• Other uses: atopic dermatitis, rhinosinusitis with nasal polyposis

Side effects

• Injection site reaction
• Transient eosinophilia

Precautions

• Anaphylaxis/severe hypersensitivity reaction is a contraindication.
• Monitor for eosinophilia and vasculitis.
• May cause worsening eye symptoms (conjunctivitis and keratitis)
• Helminth infection needs to be treated prior to initiation.

Clinical Relevance

Asthma medications are also used for the following conditions:

• Chronic obstructive pulmonary disease (COPD): a common chronic disease of the airways characterized by airflow limitation. Obstructive inflammation is noted in the small airways, lung parenchyma, and pulmonary vasculature. Patients usually present with dyspnea and chronic cough. Bronchodilators and corticosteroids are part of the regimen for treating COPD.
• Eosinophilic granulomatous polyangiitis (EGPA): vasculitis characterized by necrotizing granulomas, eosinophilia, and eosinophilic tissue infiltration. The vasculitis affects small- and medium-sized arteries. Multiple organs can be affected, including the pulmonary, renal, gastrointestinal, cardiovascular, and nervous system. Among the treatments is mepolizumab.
• Allergic rhinitis: a condition characterized by rhinorrhea, sneezing, and itching of nose, eyes, and palate. Allergens trigger an allergic nasal response where nasal mast cells release histamine and other mediators. Corticosteroid nasal sprays are commonly prescribed. Other less-used therapies available include cromolyn nasal spray, ipratropium nasal spray, and montelukast.