Asthma is a chronic airway hyperresponsiveness (with acute exacerbations), which is widespread all over the world in both children and adults. In most cases, it is in response to environmental stimuli. The main pathological changes are bronchospasm, edema, and mucosal plugging, and the symptoms are wheezing, cough, and breathlessness. Asthma therapy is directed against bronchospasms or inhibition of inflammation in general or their mediators such as leukotrienes. The most common drugs used are inhaled β2 agonists and inhaled corticosteroids.

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asthma inhaler

Image: “Asthma inhaler.” by NIAID. License: CC BY 2.0


Pathophysiology of Asthma

Asthma is a chronic inflammatory disease of the airway, involving airflow obstruction due to airway inflammation and bronchial hyperresponsiveness (manifesting as bronchoconstriction, edema, and mucus plugging).

A variety of stimuli can lead to the increased sensitivity of asthma, which is typically an IgE-mediated (type I) hypersensitivity reaction; however, non-atopic and drug-induced asthma is also possible. Symptoms include wheezing, breathlessness, cough particularly at night/early morning.

Pathology of chronic asthma additionally involves airway remodelling – airway wall thickening, membrane fibrosis, increase in size and number of mucous glands, and hypertrophy/hyperplasia of bronchial wall.

Asthma-attack-illustration

Image: “Figure A shows the location of the lungs and airways in the body. Figure B shows a cross-section of a normal airway. Figure C shows a cross-section of an airway during asthma symptoms.” by United States-National Institute of Health: National Heart, Lung, Blood Institute. License: Public Domain

The underlying pathophysiology is complex. The inflammatory mechanism is basically an exaggerated T2 cell response to normal environmental stimuli (e.g., pollen or dust). This leads to secretion of cytokines such as interleukins and IgE.

While interleukins themselves promote inflammation, IgE acts on mast cells to release other cytokines and inflammatory mediators.

Although the list of mediators is huge, the ones that are definitely implicated, and against which pharmacology can be successfully directed, are leukotrienes (bronchoconstriction, increased vascular permeability, mucus secretion) and acetylcholine (direct smooth muscle constriction). All this combined leads to the hypersensitivity reaction of asthma.

Exercise-induced asthma: an asthma attack that is triggered by (aerobic) exercise. It lasts several minutes.

Nocturnal asthma: marked worsening of asthma symptoms during sleep.

Antiasthmatic Drugs

Classification

Bronchodilators

  • β2 adrenergic agonists
  • Short-acting (mnemonics: ALT): Albuterol (Salbutamol), Levalbuterol, Terbutaline
  • Long-acting (mnemonics: FoSa): Formoterol, Salmeterol
  • Methylxanthines: Theophylline
  • Muscarinic antagonists: Ipratropium, Tiotropium

Anti-inflammatory agents

  • Mast cell stabilizers: Cromolyn, Nedocromil
  • Antibodies (immunoglobulin E, IgE)
  • Corticosteroids: Prednisone, Budesonide, Fluticasone, etc.

Leukotriene antagonists

  • Lipoxygenase inhibitors: Zileuton
  • Receptor inhibitors: Zafirlukast and Montelukast

Individual antiasthmatic drugs

β2 adrenergic agonists

  • Act on the β2 adrenergic receptors on the smooth muscles of the bronchial tree (via the G protein–adenylylcyclase pathway) to induce relaxation
  1. Short-acting β2 agonists (e.g., Albuterol)
    • Onset of action: 5–30 min
    • Duration of action: 4–6 hours
    • Albuterol has a high first-pass metabolism (oral bioavailability, 50%)
    • Albuterol and levalbuterol are β2 selective. Albuterol has β2:β1 action ratio of approximately 650:1.
    • Route(s) of administration: inhalation, oral
    • Clinical uses:
      • Quick, symptomatic treatment for bronchospasm and acute bronchoconstriction
      • As an inhaler for asthma (attacks)
      • Oral β2 agonist therapy is reserved for those who cannot use inhalers or tolerate other drugs
    • Adverse effect/toxicity:
      • Because of high β2 selectivity, side effects due to α or β1 stimulation is minimal
      • Tachycardia, hyperglycemia, hypokalemia, and hypomagnesemia (minimized with intranasal administration)
      • β2-mediated skeletal muscle tremors
    • Contraindications:
      • Cardiovascular disorders
  2. Long-acting β2 agonists (e.g., Salmeterol)
    • Onset of action: slow (formoterol has a slightly faster onset of action than salmeterol)
    • Duration of action: approximately 12 hours
    • Salmeterol is highly β2 selective—β2:β1 action ratio = 50,000:1
    • Route(s) of administration: inhalation
    • Clinical uses:
      • Maintenance therapy
      • Nocturnal asthma
      • Round-the-clock bronchodilation (asthma prophylaxis)
    • Adverse effect/toxicity:
      • Tachycardia, hyperglycemia, hypokalemia, and hypomagnesemia (minimized with intranasal administration)
      • β2-mediated skeletal muscle tremors
    • Contraindications:
      • Monotherapy; should be only used in combination with inhaled corticosteroids
      • Tachyarrhythmias

Methylxanthines – Theophylline

  • Other methylxanthines include caffeine (coffee) and theobromine (cocoa)
  • Route(s) of administration: oral (prompt-release and slow-release formulations)
  • Mechanism of action:
    • Bronchodilation: this is achieved by two possible mechanisms: inhibition of phosphodiesterase), which degrades cyclic AMP (and other cyclic nucleotides), and blocking of adenosine receptors in the central nervous system and elsewhere.
  • Clinical uses:
  • Adverse effect/toxicity:
    • Gastrointestinal symptoms (nausea, vomiting), tremor, insomnia
    • At high doses: hypotension, cardiac arrhythmias, and seizures
    • Very high doses can be lethal
    • Beta blockers (e.g., esmolol) should be administered in cases of methylxanthine (theophylline) toxicity
  • Drug interactions:
    • Theophylline is metabolized by hepatic cytochrome P450. Therefore, drugs that inhibit this (e.g., erythromycin, fluoroquinolones, ketoconazole, antidepressants such as fluvoxamine and paroxetine, etc.) can increase blood theophylline levels
    • Increases renal clearance of lithium.
  • Contraindications:
    • To be used with caution in patients with neurological and cardiovascular conditions

Muscarinic antagonists – Ipratropium & Tiotropium

  • Ipratropium and tiotropium are a quaternary antimuscarinic agents for aerosol use; they have little systemic action
  • Tiotropium is longer-acting (duration of action: 24 hours)
  • Tiotropium has recently (September 2015) been approved for use in long-term maintenance treatment of asthma by the US FDA in people ages 12 and over
  • Route(s) of administration: aerosol
  • Mechanism of action:
    • Competitively block muscarinic receptors, thereby preventing vagal discharge-induced bronchoconstriction
    • On systemic administration (not approved), they act like other short-acting muscarinic antagonists
    • No effect on the inflammation involved in asthma
  • Clinical uses:
    • Some patients with asthma (to reverse bronchoconstriction)
    • Acute COPD episodes
    • COPD maintenance therapy – daily inhalation of tiotropium
  • Adverse effect/toxicity:
    • Little systemic effects, because poorly absorbed into the circulation
    • Minor atropine-like effects with high doses
  • Drug interactions:
    • Pramlintide (synergistic action with tiotropium for decreasing gastrointestinal motility)
  • Contraindications:
    • To be avoided or used with caution in patients with narrow-angle glaucoma and urinary retention as they can worsen these conditions
    • Tiotropium – lactose allergy and hypersensitivity to milk proteins (as milk proteins can be a part of the powder in the capsule)
    • Ipratropium – some cases of severe anaphylaxis have been reported in patients with allergy to soy and peanuts (due to soy lecithin as one of the ingredients).

Mast cell stabilizers – Cromolyn & Nedocromil

  • Nedocromil is no longer available in the US
  • Route(s) of administration: aerosol, oral
  • Mechanism of action:
    • Unknown; possibly a decrease in the release of asthma inflammation mediators, e.g., leukotrienes, histamine, interleukins, etc. perhaps by interfering with chloride channel; possible inhibition of chemotaxis of inflammatory cells
    • No bronchodilation
    • Prevent allergy-induced bronchoconstriction
  • Clinical uses:
    • Asthma (but the use is on the decline in the U.S.), but ineffective during an asthma attack (as bronchoconstriction has already occurred)
    • Oral cromolyn can, to an extent, prevent food allergy
    • Topical administration to the conjunctiva (allergic conjunctivitis) and nasopharynx also has some allergy-prevention effects (e.g., hay fever, allergic rhinitis)
  • Adverse effect/toxicity:
    • Cough and airway irritation with aerosol
    • As they are generally insoluble, even high doses lead to very small systemic levels, and are very rapidly excreted
  • Contraindications:
    • Hypersensitivity
    • Acute asthma (as they cannot reverse bronchospasm, only prevent it)

IgE antibodies (Omalizumab)

  • Omalizumab is a monoclonal antibody
  • Very expensive
  • Route(s) of administration: parenteral (intravenous or subcutaneous)
  • Mechanism of action:
    • Selectively binds to IgE; decreases binding of IgE to its receptor on mast cells and basophils – thus, it prevents mast cell degranulation and subsequent release of inflammatory mediators, thereby decreasing the allergic response
  • Clinical uses:
    • Asthma prophylaxis and to reduce asthma exacerbation (administration for 10 weeks significantly reduces IgE levels, bronchospastic responses to antigen, and asthma severity, as well as reduces corticosteroid requirement)
    • Generally, reserved for refractory patients with positive skin tests or raised IgE levels and those with frequent exacerbations (requiring hospitalization)
  • Adverse effect/toxicity:
    • Minor injection site effects
  • Contraindications:
    • Known hypersensitivity to the drug

(Inhaled) Corticosteroids

  • Corticosteroids (particularly systemic administration) have many uses and side effects, but this section will focus mainly on inhaled corticosteroids.
  • Route(s) of administration: inhalation – surface-active corticosteroids (e.g., beclomethasone, budesonide, dexamethasone, flunisolide, fluticasone, mometasone), oral (prednisone)
  • Mechanism of action:
    • They induce their antiinflammatory action by inhibiting the release of arachidonic acid (via phospholipase A2 inhibition)
    • Decrease airway mucosal edema, capillary permeability, leukotriene release
    • Regular, long-term use (several months) leads to reduced airway hyperresponsiveness
  • Clinical uses:
    • Inhaled corticosteroids – drug of choice (very effective) for long-term control of asthma, e.g., persistent asthma
    • Inhaled corticosteroids + short course of oral corticosteroids – severe persistent asthma
    • Systemic corticosteroids – severe chronic asthma, acute severe asthma attack, status asthmaticus
    • Systemic corticosteroids – COPD exacerbation
  • Adverse effect/toxicity:
    • Inhaled corticosteroids have much fewer systemic adverse effects. Local side effects include hoarseness and dysphonia.
    • Long-term administration in children can affect growth, adrenal function, and bone mass
    • Long-term high doses can lead to adrenal insufficiency in both children and adults and cataract in adults
  • Drug interactions:
    • Caution is required with coadministration of CYP3A4 inhibitors such ketoconazole, itraconazole, and ritonavir as this can increase the risk of adrenal insufficiency.

Lipoxygenase inhibitor – Zileuton

  • Less effective than corticosteroids in severe asthma
  • Route(s) of administration: oral
  • Mechanism of action:
    • Selective inhibition of 5-lipoxygenase; this inhibits the conversion of arachidonic acid to leukotrienes
  • Clinical uses:
    • Prevention of exercise- and antigen-induced bronchospasm
    • Aspirin allergy (i.e., aspirin-induced bronchospasm)
    • Prophylaxis and chronic treatment of asthma – but liver toxicity and availability of other safer drugs have reduced this use
  • Adverse effect/toxicity:
    • Liver toxicity – elevation of liver enzymes
  • Drug interactions:
    • Zileuton is a cytochrome P450 3A4 inhibitor and a substrate for 1A2, so it may increase the levels of drugs that are metabolized by those pathways, e.g., terfenadine, theophylline, cisapride, etc. and careful monitoring is required.
  • Contraindications:
    • Liver dysfunction

Leukotriene receptor inhibitors – Zafirlukast and Montelukast

  • Less effective than corticosteroids in severe asthma
  • Route(s) of administration: oral
  • Mechanism of action:
    • Inhibit LTD4, as well as LTE4, leukotriene receptors
  • Clinical uses:
    • Prevention of aspirin-, exercise-, and antigen-induced bronchospasm
    • Because they can be taken orally, they are used frequently in children (over 6 years of age) who have low compliance with inhalers. Also, montelukast can be taken irrespective of meals and only once a day.
  • Adverse effect/toxicity:
    • Usually well tolerated
    • Rarely, Churg–Strauss syndrome (systemic vasculitis with asthma, pulmonary infiltrates, and eosinophilia) is reported, but the association seems coincidental as it is usually due to unmasking of the syndrome when corticosteroids are withdrawn.
    • Rarely, allergic granulomatous angiitis
  • Drug interactions:
    • Zafirlukast may increase prothrombin time, especially in combination with warfarin
  • Contraindications:
    • Acute asthma
    • Severe hepatic impairment

Choice of Treatment Based On the Type of Asthma

Form Treatment
Mild episodic  asthma Inhaled short-acting β2 agonist at the onset of the asthmatic episode; no prophylaxis (Step 1)
Seasonal  asthma Regular inhaled corticosteroids from 3–4 before to 3–4 weeks after the anticipated seasonal attack
Mild chronic asthma with occasional exacerbations Regular inhaled low-dose corticosteroid + Inhaled short-acting β2 agonist at the onset of the episode (Step 2)
Moderate asthma with frequent exacerbations Regular inhaled low-dose corticosteroid + Regular inhaled long-acting β2 agonist (Step 3)

+ Inhaled short-acting β2 agonist at the onset of the episode

Alternatives: Zafirlukast, Montelukast, Theophylline

Severe asthma Regular inhaled high-dose corticosteroid + Regular inhaled long-acting β2 agonist + Additional treatment with one of the following:Leukotriene antagonist or sustained release theophylline or oral β2 agonist or inhaled ipratropium (Step 4)

+ Inhaled short-acting β2 agonist at the onset of the episode

If not controlled, oral steroid therapy (Step 5)

Review Questions on Antiasthmatic Drugs

The correct answers can be found below the references.

1. Which of the following antiasthmatic drugs is not available in an aerosol form?

  1. Ipratropium
  2. Salbutamol
  3. Fluticasone
  4. Montelukast
  5. None of the above

2. An 11-year-old boy was diagnosed with asthma, and was prescribed an inhaled antiasthmatic drug. However, he could not use the inhaler well and was switched to an oral antiasthmatic. Two weeks later, the boy presented again with low-grade fever, cough and breathlessness, ankle edema with a rash, polyarthralgia, numbness over fingers and heels, and general malaise. C-reactive protein and eosinophil count were elevated. Which of the following antiasthmatic drugs could most likely be responsible?

  1. Montelukast
  2. Prednisone
  3. Theophylline
  4. Salmeterol
  5. Beclomethasone

3. A patient with chronic obstructive pulmonary disease is prescribed slow-release theophylline. Theophylline is a methylxanthine antiasthmatic that has many interactions. Which of the following will have to be ruled out in order to require no change in theophylline dosage?

  1. History of congenital heart surgery with cardiopulmonary bypass
  2. Concomitant ketoconazole use
  3. Concomitant salmeterol use
  4. History of neurological disease
  5. Concomitant zileuton use
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