Category:Bronchodilators

A bronchodilator is a medicine that relaxes the smooth muscle of the bronchi and bronchioles, widening the airway lumen and reducing the airflow resistance of the lower respiratory tract. The category is the pharmacological foundation of the management of asthma and chronic obstructive pulmonary disease (COPD), the two principal obstructive airway diseases, and includes the beta-2 adrenergic agonists, the antimuscarinics used inhalationally, and the methylxanthines.

The first bronchodilator medicine was a herbal preparation. The leaves of the Datura stramonium plant, smoked as a "stramonium cigarette", were known in the early nineteenth century to relieve asthmatic wheezing; the active principles were the antimuscarinic alkaloids atropine and hyoscyamine. The clinical use of inhaled antimuscarinics has therefore an unusual continuity from herbal medicine to the present-day metered-dose inhaler. The adrenergic side of the category opened with the isolation of adrenaline (epinephrine) by Jokichi Takamine in 1900 and the subsequent demonstration by Solomon Solis-Cohen that subcutaneous adrenaline relieved acute asthmatic attacks within minutes. Adrenaline was a non-selective adrenergic agonist, producing tachycardia and tremor and elevation of blood pressure as much as bronchodilation, and the pharmacological history of the next sixty years was the progressive separation of the bronchial-smooth-muscle effect from the cardiac one.

The first selective beta-adrenergic agonist was isoproterenol (isoprenaline), introduced in 1940. Isoproterenol activated both beta-1 and beta-2 receptors and so was selective relative to adrenaline but not within the beta family. The decisive insight came from Robert Furchgott and from Raymond Ahlquist: in 1948 Ahlquist proposed the alpha/beta classification of adrenergic receptors, and in the 1960s the recognition that beta-1 mediated cardiac stimulation and beta-2 mediated smooth-muscle relaxation (bronchial, uterine, vascular) led the pharmacologist David Jack's team at Allen and Hanburys (later Glaxo) to develop the first beta-2 selective agent. Salbutamol (albuterol in the United States), introduced in 1968, provided substantial bronchodilation with substantially less tachycardia than isoproterenol and became the prototype of the short-acting beta-2 agonist (SABA) class.^[1] Albuterol (Ventolin) became and has remained the standard rescue inhaler for the acute relief of bronchospasm.

The long-acting beta-2 agonists arrived in the early 1990s. Salmeterol (Glaxo, 1990) and formoterol (1986 in Europe, 2001 in the United States) provided 12-hour bronchodilation and enabled twice-daily maintenance therapy; the once-daily indacaterol, olodaterol, and vilanterol followed in the 2010s. The Salmeterol Multicenter Asthma Research Trial (SMART) in 2006 raised the concern that long-acting beta-agonist monotherapy might increase asthma-related death, leading to a black-box warning and the establishment of the standing principle that a LABA in asthma must be combined with an inhaled corticosteroid; in COPD, where there is no allergic-airway component, LABA monotherapy has not shown the same signal.^[2]

The inhaled antimuscarinics returned with a quaternary-amine modification that prevented systemic absorption from the airway. Ipratropium bromide (Boehringer Ingelheim, 1976), a quaternary derivative of atropine, was the first inhaled muscarinic antagonist; it provided 6-to-8-hour bronchodilation as a short-acting agent. The long-acting muscarinic antagonist tiotropium (Boehringer Ingelheim, 2002), with its slow off-rate from the M3 receptor, gave once-daily dosing; aclidinium, umeclidinium, and glycopyrronium followed. The LAMAs are now first-line maintenance therapy in COPD and increasingly used as add-on in moderate-to-severe asthma. The combination of a LABA and a LAMA in a single inhaler (umeclidinium/vilanterol, glycopyrronium/indacaterol, tiotropium/olodaterol, others) has become the standard maintenance regimen in moderate COPD; the triple combination of LABA, LAMA, and inhaled corticosteroid (the so-called single-inhaler triple therapy, including fluticasone/umeclidinium/vilanterol and budesonide/glycopyrronium/formoterol) is now the standard for severe COPD with exacerbations and for severe asthma not controlled on dual therapy.

The methylxanthines (theophylline, aminophylline) are the older oral bronchodilators, derivatives of the natural xanthine caffeine that acts through phosphodiesterase inhibition and adenosine-receptor antagonism. Their narrow therapeutic window (serum levels above 20 mg/L produce nausea, headache, tachyarrhythmia, and seizure), substantial interaction profile (multiple CYP isoforms), and modest bronchodilator effect have progressively narrowed their use to selected patients with refractory disease. Roflumilast (Daxas, 2010), an oral PDE4 inhibitor, is an inflammation-modifying medicine in severe COPD rather than a bronchodilator in the conventional sense, but is collected here for its closely related pharmacology.

The pharmacology of the contemporary inhaled bronchodilator is shaped, more than any other class, by the device through which the medicine is delivered. The pressurised metered-dose inhaler (developed by Riker Laboratories in 1956 and the first practical handheld aerosol medicine), the dry-powder inhaler (Spinhaler 1971, Turbuhaler 1988, Diskus 2000), the soft-mist Respimat inhaler, and the nebuliser each deliver a different fraction of the labelled dose to the lung depending on patient inhalation technique. The substantial fraction of clinical "treatment failure" in obstructive airway disease is, on close examination, failure of device technique rather than failure of the medicine, and patient education in inhaler use is part of the clinical pharmacology of this category in a way it is not for any other.

By mechanism:

• Beta-2 adrenergic agonists (beta-2 agonists):
  • Short-acting (SABA, 4-6 hour duration): albuterol (salbutamol), levalbuterol, terbutaline; pirbuterol (largely discontinued)
  • Long-acting (LABA, 12-hour duration): salmeterol, formoterol
  • Ultra-long-acting (24-hour duration): indacaterol, olodaterol, vilanterol
• Inhaled antimuscarinics (also indexed under antimuscarinics):
  • Short-acting (SAMA): ipratropium
  • Long-acting (LAMA, long-acting muscarinic antagonists): tiotropium, aclidinium, umeclidinium, glycopyrronium
• Methylxanthines (oral, intravenous): theophylline, aminophylline
• Fixed-dose inhaled combinations:
  • LABA+ICS: salmeterol/fluticasone, formoterol/budesonide, vilanterol/fluticasone furoate, formoterol/mometasone
  • LABA+LAMA: umeclidinium/vilanterol, glycopyrronium/indacaterol, tiotropium/olodaterol, aclidinium/formoterol
  • Triple (ICS+LABA+LAMA): fluticasone furoate/umeclidinium/vilanterol, budesonide/glycopyrronium/formoterol
• Phosphodiesterase-4 inhibitor (anti-inflammatory rather than bronchodilator): roflumilast

The boundary of this category is "medicine whose principal action is relaxation of bronchial smooth muscle to widen the airway." The inhaled corticosteroids, although fundamental to asthma and COPD maintenance, are not bronchodilators by mechanism (they act on the airway inflammation rather than on the smooth muscle) and are collected separately under inhaled corticosteroids and corticosteroids. The leukotriene receptor antagonists (montelukast, zafirlukast) modify airway inflammation and tone but are not direct bronchodilators; they are collected under antiasthmatic agents. The mast cell stabilisers (cromolyn, nedocromil) are also antiasthmatic but not bronchodilator. The biologics for severe asthma (omalizumab, mepolizumab, dupilumab, tezepelumab) modify the underlying inflammatory phenotype rather than the airway tone and are not bronchodilators.

This category page is an encyclopedia article about its subject. The actual index of medicines belonging to the category is generated automatically by the wiki engine, from category-membership declarations on the individual medicine pages, and appears at the foot of the page below the references.