Anticholinergic Treatment in Airways Diseases

Acute and chronic airways diseases represent a large proportion of the inpatient and outpatient population continuously under the care of pulmonary physicians and primary healthcare providers. This review article aims to analyze the available literature regarding the use of anti-cholinergic medication in airways diseases. For the purposes of this paper, a comprehensive review of the role of anti-cholinergics in the two most common airways diseases (ie, chronic obstructive pulmonary disease [COPD] and asthma) is outlined (Table 1). In addition, the use of anti-cholinergic bronchodilators in less common airways disorders, such as bronchiectasis and bronchiolitis in children, is briefly described.

Anticholinergic alkaloids, such as atropine, exist in nature in the roots, seeds, and leaves of a variety of belladonna plants. Extracts from these plants have been used for thousands of years in India for the relief of bronchoconstriction and other respiratory symptoms. British colonists introduced this concept to Western medicine during the early 19th century. Atropine was isolated in a pure form for the first time in 1831, and in 1859 it was reported that a severe asthma attack was successfully treated by injecting atropine into the vagus nerve.

The parasympathetic motor system is the primary regulator of bronchomotor tone. Parasympathetic activity causes bronchial smooth muscle constriction and the release of mucus into the airways lumen. These actions are mediated through muscarinic (M) and nicotinic receptors, both of which are present in lung tissue. Currently available aerosolized anti-cholinergic medications primarily target M receptors, hence their alternative name of antimuscarinics. There are three types of M receptors present in the lung (M1, M2, and M3). Stimulation of M1 and M3 receptors mediate the parasympathetic bronchoconstrictive effect. In contrast, M2 receptors, positioned on the postganglionic parasympathetic nerves, inhibit acetylcholine release, protecting against parasympathetic-mediated bronchoconstriction. Therefore, an ideal anticholinergic would inhibit the M1 and M3 receptor, and spare the M2 receptor.

Ipratropium bromide and tiotropium bromide are the two currently commercially available anticholinergic aerosolized agents used in Europe and the USA (Table 1). They are quaternary ammonium synthetic derivatives of naturally occurring tertiary ammonium compounds. The systemic effects of tertiary ammonium compounds (eg, atropine) administration, such as tachycardia, blurred vision, dry mouth, gastrointestinal upset, are easily remembered with the aid of the mnemonic “hot as a hare, blind as a bat, dry as a bone, red as a beet, and mad as a hatter”. The quaternary compounds are insoluble in lipids and are therefore associated with few systemic side-effects even at high doses due to negligible passage through biological barriers. Side effects include dry mouth (6%-16%), urinary retention, nausea (~3%), constipation (<10%), and headache (~3%). Tachycardia and atrial fibrillation have also been reported. They should be used with caution in patients with prostatic hyperplasia and those susceptible to angle-closure glaucoma.

Incorporating once-daily dose administration is an important strategy to improve compliance in patients with COPD. Aclidinium bromide and OrM3 (an oral M3-selective anticholinergic agent) are two novel long-acting beta2-adrenergic receptor (LABA) agents, prescribed on a once-daily basis, currently under evaluation. Safety studies are ongoing for the inhaled agent  aclidinium and appear favourable. OrM3 has been studied in an oral preparation and was not superior to inhaled ipratropium in a small 6-week study of 412 patients with COPD. There are many other LABA agents under early investigation.

Other inhaled anticholinergic agents, such as oxitropium bromide and flutropium bromide, have not gained widespread use. After initial reports suggested a longer mode of action than ipratropium, oxitropium bromide, another quaternary ammonium compound, became widely available in the 1990s. Subsequent studies, however, did not show any difference in maximal response with ipratropium and its use is now minimal and availability limited. Flutropium bromide was initially promoted as having both bronchodilator and anti-allergy properties through animal research; however, after studies showed no benefit over ipratropium in humans, it is not currently available in the USA and Europe.



Robert A. Flynn · Deirdre A. Glynn · Marcus P. Kennedy. Adv Ther (2009) 26(10):908-919.

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