Role of muscarinic antagonist therapy in COPD

INTRODUCTION — Muscarinic antagonists (also known as anticholinergic agents) are effective bronchodilators used in the treatment of chronic obstructive pulmonary disease (COPD), used to alleviate dyspnea and improve exercise tolerance.

This topic will review the pharmacology of muscarinic antagonists and their role in the treatment of COPD. The management of acute exacerbations and the approach to the treatment of COPD are discussed separately. (See "COPD exacerbations: Management" and "Stable COPD: Initial pharmacologic management".)

HISTORY OF BELLADONNA ALKALOIDS — Pharmacologically active anticholinergic alkaloids exist in the roots, seeds, and leaves of a variety of belladonna plants [1]. The most important of these naturally occurring alkaloids are atropine and scopolamine.

Atropa belladonna, the deadly nightshade, contains mainly the alkaloid atropine. The same alkaloid is present in Datura stramonium, known as Jamestown or jimson weed, stinkweed, thorn-apple, and devil's apple. The alkaloid scopolamine (hyoscine) is found chiefly in the plants Hyoscyamus niger (henbane) and Scopolia carniolica.

The use of extracts from these plants for the relief of respiratory symptoms and bronchospasm originated thousands of years ago in India and was introduced into Western medicine by British colonists in the early 19th century [1]. Atropine was then isolated in a pure form by Mein in 1831. In 1867, Bezold and Bloebaum showed that atropine blocked the cardiac effects of vagal stimulation, and five years later Heidenhain found that it prevented salivary secretion produced by stimulation of the chorda tympani. In 1859, it was reported that a severe asthma attack was successfully treated by injecting atropine into the vagus nerve [2].

Smoke from the leaves of these plants became the preparation of choice for relief of bronchospasm; inhalational and systemic preparations of atropine were soon available for the treatment of asthma. With the introduction of ephedrine and epinephrine during the 20th century, the use of atropine and related substances for relief of bronchospasm declined. Anticholinergic therapy has again come to the forefront of bronchodilator therapy with the introduction of the synthetic quaternary derivatives of atropine, including ipratropium bromide and tiotropium bromide [1].

PHYSIOLOGY AND PHARMACOLOGY — The parasympathetic nervous system plays a major role in regulating bronchomotor tone. The bulk of autonomic nerves in the human airways are branches of the vagus nerve, whose efferent preganglionic fibers enter the lung at the hilum and travel along the airways into the lung [3]. A diverse set of stimuli can cause a reflex increase in parasympathetic activity that contributes to bronchoconstriction. Acetylcholine (ACh) is the endogenous neurotransmitter at cholinergic nerve endings, and its actions are mediated through nicotinic and muscarinic cholinergic receptors. The figure outlines the role of nicotinic and muscarinic receptors in cholinergic transmission in the airway (figure 1).

Nicotinic receptors — Nicotinic receptors are located on ganglionic neurons and are activated by ACh released from preganglionic vagal fibers (figure 1). These receptors are stimulated by nicotinic agonists and inhibited by nicotinic antagonists like hexamethonium. They are not significantly affected by currently available muscarinic antagonist medications [4].

Muscarinic receptors — Muscarinic receptors are found primarily on the autonomic effector cells that are innervated by postganglionic parasympathetic nerves. There are at least five subtypes of muscarinic receptors [5]. At least three of these are expressed in the lung (table 1) [5]:

●M1 receptors are present on peribronchial ganglion cells where the preganglionic nerves transmit signals to the postganglionic nerves

●M2 receptors are present on the postganglionic nerves

●M3 receptors are present on smooth muscle

M1 and M3 receptors mediate the parasympathetic bronchoconstrictive effect of the vagus nerve. Vagal fibers synapse and activate nicotinic and M1 muscarinic receptors in parasympathetic ganglia present in the airway wall. Short postganglionic fibers release ACh, which acts on M3 muscarinic receptors in airway smooth muscle. The submucosal glands are also innervated by parasympathetic neurons and have predominantly M3 receptors.

The activation of M1 and M3 receptors by ACh and its analogs stimulates secretion by tracheobronchial glands and causes bronchoconstriction. On the other hand, activation of M2 receptors limits further production of ACh and protects against parasympathetic-mediated bronchoconstriction [1,5]. Based upon this information, an ideal muscarinic antagonist for treating COPD would inhibit only the M1 and M3 receptors and spare the M2 receptors.

Atropine (the prototype of muscarinic receptor antagonists) prevents the effects of ACh by competitively blocking its binding to muscarinic receptors in the CNS, peripheral ganglia, and at neuroeffector sites on smooth muscle, cardiac muscle, and secretory glands [1]. Atropine inhibits secretions of the nose, mouth, pharynx, and bronchi and thus causes dryness of the mucous membranes of the respiratory tract. This action is especially marked if secretion is excessive and is the basis for the use of atropine and scopolamine in preanesthetic medication. This depression of mucous secretion and the inhibition of mucociliary clearance, however, are undesirable side effects of atropine in patients with airway disease [6].

Atropine is particularly effective against bronchoconstriction produced by parasympathomimetic drugs such as methacholine; it also partially antagonizes bronchoconstriction induced by histamine and bradykinin. In general, however, muscarinic receptor antagonists cause little blockade of the effects of ACh at nicotinic receptor sites. As a result, extremely high doses of atropine or related drugs are required to produce any degree of blockade of the predominantly nicotinic receptors at the neuromuscular junction [1].

Tertiary versus quaternary muscarinic antagonists — Quaternary ammonium drugs (such as ipratropium) are synthetic derivatives of the naturally occurring tertiary ammonium compounds (such as atropine) (figure 2).

The structure of the quaternary ammonium compounds (figure 2) renders them freely soluble in water but insoluble in lipids; it is therefore difficult for these compounds to cross biologic barriers that can be easily crossed by the tertiary ammonium compounds like atropine. Most of the pharmacologic properties that distinguish quaternary ammonium compounds from atropine are due to this feature [1,6]:

●The tertiary ammonium compounds are lipid-soluble, easily absorbed, and can cause significant side effects, including tachycardia, dry mouth, flushing of the skin, blurred vision, and mood changes

●Since compounds with a quaternary ammonium structure are poorly absorbed after oral administration, they cause fewer side effects

●Quaternary compounds generally exhibit a greater degree of nicotinic blocking activity and consequently are likely to interfere with neuromuscular transmission in doses that more closely approximate those that cause muscarinic block.

Ipratropium bromide produces effects similar to atropine when each agent is administered parenterally [1,6]. These include bronchodilation, tachycardia, and inhibition of salivary secretion. Unlike atropine, though, ipratropium lacks appreciable effect on the central nervous system (CNS), is poorly absorbed from the lungs or the gastrointestinal tract, and does not inhibit mucociliary clearance [1,6]. The use of ipratropium in patients with COPD therefore avoids the increased accumulation of lower airway secretions and the antagonism of beta-adrenergic agonist-induced enhancement of mucociliary clearance that is encountered with atropine.

Even when ipratropium bromide is administered in amounts many times the recommended dosage, little or no change occurs in heart rate, blood pressure, bladder function, intraocular pressure, or pupillary diameter [6]. This selectivity results from the very inefficient absorption of the drug from airway or gastrointestinal mucosa.

IPRATROPIUM — Ipratropium bromide (Atrovent) is available in a metered dose inhaler (MDI) form. Each actuation of the MDI provides 17 mcg of ipratropium bromide, and each canister contains 200 inhalations. Prior to initial use of the MDI formulation, the inhaler should be actuated into the air twice; this step should be repeated if the inhaler is not used for more than three days. A 0.02 percent solution for nebulized administration is also available.

Dose — The recommended dose from the MDI is two puffs four times daily, usually taken as needed. For patients with a COPD exacerbation requiring emergency department or hospital based care, ipratropium can be increased to a higher dose (eg, two inhalations every hour for two to three doses and then every two to four hours, or four inhalations every four hours), if response to the lower dose is insufficient [7].

Ipratropium can also be administered by nebulization. Ipratropium solution comes as 0.5 mg/2.5 mL (0.02 percent) vials that can be given by nebulization every four to six hours [6].

Efficacy — Ipratropium has been shown to alleviate dyspnea, increase exercise tolerance, and improve gas exchange in patients with COPD [8]. Ipratropium, however, does not have anti-inflammatory properties and does not alter the natural history of the disease in terms of lung function or mortality [8-10]. Tachyphylaxis to ipratropium has not been demonstrated, and thus its efficacy is not blunted over years of regular use [6].

The Lung Health Study prospectively evaluated the effect of smoking cessation with or without ipratropium therapy on the decline of lung function in 5887 male and female smokers with COPD [9]. In this landmark study, ipratropium was chosen as the bronchodilator of choice because of its low frequency of side effects, relatively long duration of action, and demonstrated bronchodilator efficacy in patients with COPD [6,9,11]. Results were as follows:

●The regular use of inhaled ipratropium bromide (two puffs three times daily from a metered dose inhaler) produced an increase in FEV₁ that was evident at the end of the first year. This relative improvement was maintained for the succeeding four years (figure 3).

●The improvement in lung function appeared to reverse within a few weeks of stopping the ipratropium.

These results reflect the relatively short term, pharmacologically mediated change in lung function attributable to the bronchodilator, and support the use of bronchodilators for symptomatic benefit, including relief of dyspnea and improvement in exercise tolerance. By comparison, no treatment is needed in asymptomatic patients, as therapy does not alter the natural history of the disorder.

Ipratropium versus beta-agonists — In COPD, ipratropium has been shown to be superior to the beta-adrenergic agonists in both short- and long-term studies. As an example, in a multicenter, randomized trial of 260 patients with COPD but no asthma or atopy, ipratropium was more potent at its peak effect and was longer acting than metaproterenol [11] (figure 4). Similar findings were also reported for nebulized ipratropium bromide [12]. In addition, some studies have shown that ipratropium bromide produced significant bronchodilation in patients who did not respond to inhaled sympathomimetics [12].

Ipratropium therapy may also result in an improvement in the quality of life of patients with COPD. In a multicenter, randomized trial of 223 patients with COPD, the efficacy of nebulized ipratropium (500 mcg) was compared to nebulized albuterol (2.5 mg) (each taken three times daily for up to 83 days) [13]. Although clinical improvement was noted in both groups, the ipratropium bromide group had a greater symptomatic benefit and scored higher on quality of life questionnaires.

Although the side effects of inhaled beta-2 agonists are generally minor, they may produce troublesome tremor in the dosages required to produce bronchodilation in COPD. In addition, beta-2 agonist use in patients with COPD may be accompanied by pulmonary vasodilation, which may worsen ventilation-perfusion matching and result in a slight fall in arterial PaO2 [14]. The beneficial effects of ipratropium bromide combined with its minimal side effects make this agent the preferred bronchodilator for COPD in the ambulatory setting.

Fewer studies are available in acute exacerbations of COPD. (See "COPD exacerbations: Management".)

Combination therapy — The administration of a combination of antimuscarinic and beta-agonist agents generally results in greater bronchodilation than does the administration of single agents in patients with COPD [15,16]. As an example, one crossover trial of 863 patients found that combination therapy with nebulized ipratropium-albuterol resulted in a peak forced expiratory volume in one second (FEV₁) that was 24 percent higher than that achieved by albuterol alone, and 37 percent greater than that achieved with ipratropium monotherapy [16]. In patients with COPD, this combination offers a potential therapeutic advantage over albuterol alone without a risk of increased side effects. (See "Stable COPD: Initial pharmacologic management", section on 'Use of dual bronchodilator therapy'.)

Often the agents are administered in a fixed combination, such as the ipratropium-albuterol soft mist inhaler, one inhalation four times a day. Patients may take additional inhalations as required; however, the total number of inhalations should not exceed six in 24 hours. When ipratropium and albuterol are given separately, there is little evidence to indicate in which sequence to give the two drugs and whether they should be given in immediate sequence or should be separated by an interval [6].

Several physiologic reasons exist for the potential benefit of combination therapy with ipratropium and a beta-agonist:

●Muscarinic antagonists act predominantly on the proximal large airways, while sympathomimetics act on the more distal small airways.

●The two classes of medications cause bronchodilation via different mechanisms: Beta-agonists are thought to cause bronchodilation by directly acting on muscle, and ipratropium causes bronchodilation by reducing cholinergic tone.

●Coadministration of adrenergic and muscarinic antagonists provides the rapid onset of action of the former and the sustained activity of the latter; their combined effect is present at intermediate times.

TIOTROPIUM — Tiotropium (figure 2) is a long-acting muscarinic antagonist (LAMA) with M1 and M3 selectivity (table 1) (see 'Muscarinic receptors' above) [17,18]. Tiotropium binds to all three muscarinic receptors, but it comes off the M2 receptor rather rapidly without affecting the inhibition of M1 and M3 receptors. Tiotropium may therefore have a theoretical advantage over ipratropium bromide since inhibition of the M2 receptor would have a bronchoconstrictive effect.

The dry powder preparation is administered via a capsule inhaler device (HandiHaler), 18 mcg once daily (picture 1). The soft mist preparation (Respimat) is administered as two inhalations of 2.5 mcg (5 mcg total) once daily (picture 2 and table 2). Depending on the country, one or both of these inhaler types may be available.

Tiotropium is longer acting than ipratropium and allows a more convenient dosing schedule for patients with COPD [19-21]. One study randomized 288 patients with severe COPD to receive either tiotropium once per day or ipratropium four times per day [22]. Significantly greater bronchodilation was achieved and significantly less albuterol was used in the tiotropium group.

Continuous therapy with tiotropium appears to be well tolerated and is associated with decreased dyspnea, improved quality of life, fewer acute exacerbations, a reduction in hyperinflation, and improved overnight arterial oxygen saturation compared to placebo [23-31]. A meta-analysis of 22 trials with 23,309 participants found that tiotropium therapy resulted in a significantly improved mean quality of life (mean difference [MD] -2.89, 95% CI -3.35 to -2.44) and significantly reduced the number of participants suffering from exacerbations (OR 0.78, 95% CI 0.70-0.87) [30]. In this analysis, the number needed to treat to benefit (NNTB) was 16 to prevent one exacerbation. Tiotropium also reduced exacerbations leading to hospitalization but no significant difference was found for hospitalization of any cause or mortality.

The lack of an immediate bronchodilator response to tiotropium does not correlate with the results of extended therapy. This was demonstrated in a large randomized controlled trial comparing one year of therapy with tiotropium to placebo [32]. The presence or absence of a bronchodilator response on the first day of treatment did not predict long-term outcome, and patients treated with tiotropium had improved spirometry and less subjective dyspnea than control patients regardless of the response to the first dose.

In a systematic review that compared tiotropium with ipratropium in patients with COPD (n = 1073), tiotropium was associated with improved lung function, fewer hospitalizations, fewer exacerbations of COPD, and improved quality of life [33]. This observation supports guideline recommendations for use of a long-acting bronchodilator in patients whose symptoms are not controlled with intermittent use of a short-acting bronchodilator.

Tiotropium, like ipratropium, appears to provide superior bronchodilation and improvements in dyspnea when compared with long-acting beta-agonists in patients with stable disease [34-36]. This was demonstrated in a large three-armed trial comparing tiotropium with the long-acting beta-agonist salmeterol and placebo in over 1200 patients with COPD. Therapy with tiotropium resulted in a significant delay in the time until first exacerbation, and fewer exacerbations per year, than treatment with salmeterol or placebo [35].

Over the long-term, tiotropium improves lung function and quality of life, and also decreases the risk of exacerbations, but does not reduce the rate of decline in forced expiratory volume in one second (FEV₁) [37]. This was demonstrated in a randomized four year trial, Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT), which compared inhaled tiotropium to placebo. Patients were allowed to take other respiratory medications, as needed. (See 'Potential risks' below.)

A further analysis of the UPLIFT trial found that the benefit of tiotropium (relative to placebo) on pre and post bronchodilator FEV1, exacerbation risk, and quality of life was present irrespective of smoking status, although the magnitude of the benefit varied among current smokers, intermittent smokers, and continuing ex-smokers [38].

UMECLIDINIUM — Umeclidinium is a long-acting muscarinic antagonist (LAMA) that acts preferentially on the muscarinic M3 receptor, similar to tiotropium. Bronchodilation peaks at three hours after a dose and is sustained for 24 hours [39]. The long duration of action is attributable, at least in part, to prolonged residence of the molecule on the M3 receptor.

In a 28 day randomized trial, three once daily doses of umeclidinium (125 mcg, 250 mcg, 500 mcg) were compared with placebo [39]. All three doses of umeclidinium significantly increased trough forced expiratory volume in one second (FEV₁) (150 to 160 mL) at 24 hours after the last dose on days 2, 14, 28, and 29, and also reduced rescue salbutamol (albuterol) use during the study. Overall, adverse events in the 125 mcg and 250 mcg groups were not different from placebo, but were increased in the 500 mcg group. Cough and headache were increased in frequency at the higher doses.

Umeclidinium is available in a combination inhaler, umeclidinium-vilanterol (62.5 mcg/25 mcg), that is approved for use in COPD. The umeclidinium dose in this inhaler is lower than that used in the dose-ranging study described above. (See "Stable COPD: Initial pharmacologic management", section on 'Long-acting muscarinic antagonists'.)

ACLIDINIUM — Aclidinium bromide is a long-acting muscarinic antagonist (LAMA) that selectively inhibits the M3 muscarinic receptor [40-43]. Aclidinium is longer acting than ipratropium, but shorter acting than tiotropium. It is administered via a dry powder inhaler (Tudorza Pressair) at a dose of 400 mcg twice daily (picture 1). It was initially developed as a once daily medication, but further study showed better efficacy with the twice daily dosing schedule. (See 'Muscarinic receptors' above.)

Support for the use of aclidinium in stable chronic obstructive pulmonary disease (COPD) comes from several trials:

●In a 24-week trial, patients with COPD and moderate to severe airflow limitation (forced expiratory volume in one second [FEV₁] <80 percent predicted) were randomly assigned to twice-daily aclidinium (200 mcg or 400 mcg) or placebo [40]. Significant improvements in trough and peak FEV₁were noted with both doses of aclidinium and peak FEV₁ improvements in week 24 were comparable with day one. Health status assessed by questionnaire and dyspnea also improved relative to placebo.

●In a small trial, aclidinium 400 mcg twice daily was compared with tiotropium 18 mcg once daily [44]. With both medications, improvements in FEV₁ were greater than with placebo but not significantly different from each other.

●In an unpublished trial, aclidinium 400 mcg twice daily was compared with the long-acting beta-agonist formoterol 12 mcg twice daily in patients with COPD and moderate to severe airflow limitation (FEV₁ <80 percent) [45]. The trough and peak FEV₁ values were not significantly different between these groups.

Larger studies with longer treatment durations are needed to provide meaningful comparisons between aclidinium, tiotropium, and the long-acting beta-agonists [46].

Aclidinium is not appropriate for acute relief of dyspnea due to bronchoconstriction and has not been studied in subjects younger than 18.

The most common adverse effects (with a frequency greater than placebo) in clinical trials were headache (6.6 versus 5 percent), nasopharyngitis (5.5 versus 3.9 percent), and cough (3 versus 2.2 percent) [45]. Anticholinergic side effects, such as urinary retention, dry mouth, and constipation, were not different from placebo in clinical trials including 2717 patients on twice daily dosing regimens [40,45].

GLYCOPYRRONIUM — Glycopyrronium, known by the generic name glycopyrrolate in the United States, is a long-acting muscarinic antagonist (LAMA) that selectively inhibits muscarinic receptors in bronchial smooth muscle with greater affinity for M1 and M3 than M2 [47]. (See 'Muscarinic receptors' above.)

Glycopyrronium is administered via dry powder inhaler, one capsule for inhalation (50 mcg/capsule) once daily in Canada and Europe.

Depending on the country, the dose is variably expressed as the glycopyrronium or glycopyrrolate base or bromide salt (table 3). Evidence in favor of efficacy in COPD includes the following:

●In a 26 week trial, 822 subjects with moderate-to-severe chronic obstructive pulmonary disease (COPD) were randomly assigned to glycopyrronium 50 micrograms by oral inhalation once daily or placebo [48]. The trough forced expiratory volume in one second (FEV₁), assessed at 12 weeks, was significantly higher (least squares mean treatment difference of 108 mL) in the glycopyrronium group. Three patients in the glycopyrronium group had serious atrial fibrillation (AF) events, although two had a prior history of AF. No patients on placebo had AF.

●In a 52 week trial, 1086 subjects with moderate-to-severe COPD were randomly assigned to once daily inhaled glycopyrronium, placebo, or open label tiotropium 18 micrograms [49]. At week 12, the trough FEV₁ was increased over placebo by 97 mL (95% CI 64.6-130.2) with glycopyrronium and 83 mL (95% CI 45.6-121.4) with tiotropium. Glycopyrronium was also associated with significant improvement in dyspnea and reduction in exacerbations relative to placebo. AF occurred in four patients (0.8 percent) in the glycopyrronium group and none in the placebo or tiotropium groups.

Additional, larger studies are needed to ascertain the safety of long-term inhaled glycopyrronium and to provide meaningful efficacy and safety comparisons with the other long-acting muscarinic antagonists and long-acting beta-agonists.

The most commonly reported adverse effects with inhaled glycopyrronium are dry mouth (2 percent of glycopyrronium recipients versus 1 percent of placebo), urinary tract infection (1.77 versus 1.87 percent), and constipation (1 versus 1.5 percent) [47]. In a trial that compared glycopyrronium with tiotropium, dry mouth was slightly more common with inhaled glycopyrronium than tiotropium, but urinary infection was slightly more common with tiotropium than glycopyrronium [49].

REVEFENACIN — Revefenacin is a long-acting muscarinic antagonist (LAMA) with broad affinity for all muscarinic receptors M1 to M5; it exerts its bronchodilating effects through prolonged attachment to the M3 receptor on airways smooth muscle [50,51]. Revefenacin is approved by the US Food and Drug Administration (FDA) for maintenance treatment of chronic obstructive pulmonary disease (COPD) at a once daily dose of 175 mcg/3 mL, administered via a standard jet nebulizer [52]. It is not indicated for relief of acute bronchoconstriction. Given the time needed for a nebulizer treatment (>8 minutes), this medication is typically reserved for patients who have difficulty with the technique of soft mist or dry powder formulations of the other LAMAs.

In two randomized trials that included 395 patients with moderate to severe COPD (mean forced expiratory volume in one second [FEV₁] 55 percent of predicted), revefenacin 175 mcg increased mean FEV₁ from baseline to trough at day 85 by 146 mL (95% CI 103.7 to 188.8 mL) and 147 mL (95% CI 97 to 197.1 mL) [52-54]. In the placebo groups, approximately 37 percent were also taking a long-acting beta-agonist (LABA) or inhaled glucocorticoid/LABA.

Use of revefenacin should be avoided in patients with hepatic impairment and has not been studied in patients with endstage renal disease. Revefenacin can exacerbate narrow angle glaucoma and worsen urinary retention.

COMBINATION LAMA-LABA — A number of single inhaler preparations are available combining long-acting muscarinic antagonists (LAMA) and long-acting beta-agonists (LABA). These agents are discussed separately. (See "Stable COPD: Initial pharmacologic management", section on 'Use of dual bronchodilator therapy' and "Stable COPD: Follow-up pharmacologic management".)

OTHER AGENTS — Several additional quaternary muscarinic antagonists are being evaluated for a potential role in the treatment of patients with chronic obstructive pulmonary disease (COPD):

●Oxitropium bromide (Ba 253 Br) is an effective muscarinic antagonist bronchodilator that inhibits all three muscarinic airway receptors. It may be a more potent bronchodilator than ipratropium at lower doses, but there is no difference in maximal response between the two [55].

●Telenzepine is an experimental M1-selective muscarinic receptor antagonist that has been found to improve lung function in patients with nocturnal asthma but not in those with COPD [56,57].

●Tiquizium is another experimental antimuscarinic agent that inhibits all three muscarinic receptor subtypes. It has been shown to be an effective bronchodilator in both animals and humans [58].

POTENTIAL RISKS — Systemic absorption of ipratropium and the long-acting muscarinic antagonists (LAMA) from the mouth and gastrointestinal tract is low, although some absorption from the lung does occur. Systemic bioavailability of tiotropium is estimated to be about 20 to 25 percent, while bioavailability of aclidinium is less than 5 percent [59,60].

Cardiovascular effects — Despite the minimal impact of ipratropium and long-acting muscarinic antagonists (LAMAs) on heart rate and blood pressure, concern has been raised regarding possible adverse cardiovascular effects of these agents in patients with COPD [37,61-65]. Conflicting findings have been reported in randomized trials and meta-analyses [37,61-64,66-68].

Evidence against a significant adverse cardiovascular impact comes from three large randomized trials that adjudicated adverse cardiovascular events:

●The Understanding Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial randomized 5993 patients to either tiotropium or placebo in addition to other, unrestricted respiratory medications for four years. A significantly lower rate of cardiac adverse events was found in the tiotropium group (RR 0.84 [95% CI 0.73-0.98]) [37]. Cardiac mortality was also decreased in the tiotropium group (HR 0.86 [95% CI 0.75-0.99]) [69].

●The risk of cardiovascular events was further examined using the clinical trial safety database for tiotropium, which monitored 19,545 patients with moderate to severe COPD (including the UPLIFT data), who were randomly assigned to tiotropium or placebo in a total of 30 trials [68]. No increase in all-cause mortality, cardiovascular mortality, or cardiovascular events was found in the tiotropium group.

●In the randomized ASCENT trial that included 3589 subjects with moderate to very severe COPD and a history of cardiovascular disease or two atherothrombotic risk factors, the risk of a major adverse cardiovascular event during the three years of the trial was not significantly different between the aclidinium and placebo groups (3.9 versus 4.2 percent, HR 0.89, 1-sided 97.5% CI 0-1.23) [70]. Approximately 60 percent of subjects were taking an inhaled glucocorticoid and a LABA.

Evidence suggesting increased cardiovascular adverse effects includes the following:

●In a meta-analysis of 17 randomized trials enrolling nearly 15,000 patients, but not including the UPLIFT or ASCENT trials, the use of ipratropium or tiotropium for more than 30 days significantly increased the risk of myocardial infarction (RR 1.53 [95% CI, 1.05 to 2.23]) and cardiovascular death (RR 1.80 [95% CI, 1.17 to 2.77]) [61]. However, the trials did not have prespecified and adjudicated cardiovascular endpoints.

●The potential effect of ipratropium on cardiovascular events was examined in a cohort study of 82,717 United States veterans with COPD who were followed from 1999 to 2002 [67]. The hazard ratio for cardiovascular events among patients who had four or fewer 30-day prescriptions for ipratropium was 1.40 [95% CI 1.30-1.51], and the hazard ratio among those with more than four 30 day prescriptions was 1.23 [95% CI 1.13-1.36]. The case cohort design results in several limitations on the interpretation of the findings.

Further data on the safety of ipratropium bromide are needed from randomized trials in which cardiovascular endpoints are specifically sought and defined. In the meantime, we continue to advise an individualized assessment of potential cardiovascular risk against the known benefits of inhaled muscarinic antagonists (eg, reduced frequency of exacerbations, fewer hospitalizations, and improved dyspnea).

Mortality — Tiotropium is available as a dry powder inhaler (Spiriva HandiHaler) or a soft mist inhaler (Spiriva Respimat), depending upon the geographic location. A systematic review raised concern about a possible increase in mortality associated with the tiotropium soft mist inhaler in patients with COPD [71]. A follow-up meta-analysis that included the UPLIFT trial described above was reassuring in terms of the safety of tiotropium by dry powder inhaler; fewer deaths occurred in the tiotropium dry powder inhaler group (Peto OR 0.92, 95% CI 0.80-1.05) than in the placebo group (yearly rate 2.8 percent) [30]. In contrast, there were more deaths in the tiotropium soft mist inhaler subgroup analysis (Peto OR 1.47, 95% CI 1.04-2.08) than with placebo (yearly rate 1.8 percent). However, methodologic concerns, such as uneven study discontinuation rates, limited the conclusions that could be drawn.

Subsequently, the TIOtropium Safety and Performance In Respimat (TIOSPIR) trial has provided the most reassuring data. In this trial, 17,135 patients with COPD were randomly assigned to Respimat 2.5 or 5 mcg/day or dry powder inhaler 18 mcg/day [72]. After a mean follow-up of 2.3 years, the risk of mortality did not differ in the Respimat groups; the hazard ratios were (HR 1.00, 95% CI 0.87-1.14) and (HR 0.96, 95% CI 0.84-1.09) for the 2.5 and 5 mcg doses of Respimat versus the dry powder inhaler. While patients with cardiac arrhythmia, ischemic heart disease, and coronary heart disease were included, those with unstable cardiovascular conditions (class III or IV heart failure, myocardial infarction in the prior six months, unstable or life-threatening arrhythmias that required an intervention or change in drug therapy within 12 months), or moderate or severe renal failure were excluded [73]. Thus, the safety of the tiotropium soft mist inhaler in these latter groups has not been determined.

Acute urinary retention — Systemic absorption of inhaled muscarinic antagonists has the potential to increase the risk of acute urinary retention in susceptible patients such as those with benign prostatic hypertrophy (BPH) or lower urinary tract symptoms [62,74-76]. Studies addressing this concern have yielded conflicting results.

Studies suggesting an increased risk of urinary retention include the following:

●In a pooled analysis of 19 randomized trials, the relative risk of symptoms of urinary retention was 10.93 (95% CI 1.26-94.88) [62]. However, the severity of the urinary symptoms was not delineated.

●A nested case control study of 565,073 older adults with COPD examined the risk of acute urinary retention associated with use of inhaled muscarinic antagonists [74]. Among men with BPH, the likelihood of acute urinary retention was greater in those taking an inhaled muscarinic antagonist (OR 1.81, 95% CI 1.46-2.24) and further increased among those taking both short and long-acting muscarinic antagonists compared with monotherapy (OR 1.84, 95% CI 1.25-2.71) or nonusers (2.69, 1.93-3.76).

●A separate nested case-control study of 22,579 patients with COPD found an increased risk of acute urinary retention among those on inhaled muscarinic antagonists (adjusted odds ratio 1.40, 95% CI 0.99-1.98) compared with non-users [75]. The risk associated with ipratropium did not appear different from that associated with tiotropium.

On the other hand, reassuring data comes from these studies:

●The UPLIFT trial that randomly assigned approximately 6000 patients with COPD to tiotropium or placebo for four years included patients with BPH whose symptoms were controlled with treatment [37]. Urinary retention occurred more often in the tiotropium group than placebo (rate ratio 1.65, 95% CI 0.92-2.93), but the difference was not statistically significant [77].

●Among 25 patients with COPD and BPH, use of tiotropium for months was not associated with any cases of acute urinary retention nor urinary parameters such as maximal flow rate (Q-max), average flow rate (Q-ave), postvoid residual urine volume (PVR), or bladder voiding efficiency (BVE) [78].

●Clinical trials with aclidinium have not noted an increased risk of acute urinary retention. (See 'Aclidinium' above.)

We are cautious when initiating inhaled muscarinic antagonists in patients with known BPH and advise patients to report any changes in urinary function.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic obstructive pulmonary disease".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Chronic obstructive pulmonary disease (COPD) (Beyond the Basics)" and "Patient education: Chronic obstructive pulmonary disease (COPD) treatments (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Parasympathetic activity regulates bronchomotor tone via the vagus nerve. Impulses from the vagus nerve lead to secretion of acetylcholine, which in turn acts through nicotinic and muscarinic cholinergic receptors on airway smooth muscle and tracheobronchial submucosal glands. (See 'Physiology and pharmacology' above.)

●The muscarinic receptors M1 and M3 on airway smooth muscle cells mediate the parasympathetic bronchoconstrictive effect of the vagus nerve (figure 1). M2 receptors are located on postganglionic nerves; activation of M2 receptors limits further production of acetylcholine and protects against bronchoconstriction mediated via the parasympathetic nerves. Theoretically, blocking M1 and M3 without M2 would optimize the bronchodilator effect. (See 'Physiology and pharmacology' above.)

●The inhaled muscarinic antagonists (also known as anticholinergic agents) interrupt vagal-induced bronchoconstriction. Ipratropium bromide is an inhaled quaternary ammonium that blocks all three muscarinic receptors (M1, M2, M3). Tiotropium bromide and other long-acting muscarinic antagonists (LAMAs) predominantly block the M1 and M3 receptors (table 1). (See 'Physiology and pharmacology' above.)

●For patients with COPD, ipratropium is superior to the beta-adrenergic agonists in both short- and long-term studies of acute bronchodilation and in long-term improvement in dyspnea and quality of life (figure 4). (See 'Ipratropium' above.)

●When used in COPD, the combination of ipratropium-albuterol provides greater bronchodilation than either agent used alone. (See 'Combination therapy' above.)

●Tiotropium, a dry powder inhaler, is more long-acting than ipratropium, but does not have an acute bronchodilating effect. Nonetheless, in COPD, it provides superior long-term bronchodilation compared with ipratropium. It also reduces the frequency of exacerbations and hospitalizations, and improves dyspnea when compared with long-acting beta-agonists. (See 'Tiotropium' above.)

●Aclidinium, administered by dry powder inhaler, is more long-acting than ipratropium, but shorter acting than tiotropium. At a dose of 400 mcg twice daily, it improves pulmonary function, health status, and dyspnea relative to placebo. Glycopyrronium (table 3), umeclidinium (in combination with vilanterol), and revefenacin (175 mcg/day by nebulization) are additional long-acting muscarinic antagonists (LAMAs) approved for maintenance treatment of COPD. (See 'Umeclidinium' above and 'Aclidinium' above and 'Glycopyrronium' above and 'Revefenacin' above.)

●Despite the minimal impact of ipratropium and tiotropium on heart rate and blood pressure, data are conflicting regarding possible adverse cardiovascular effects of these agents in patients with COPD. Based on available data, we believe that the potential for cardiovascular risk is extremely small and should be balanced against the known benefits. (See 'Potential risks' above.)

●Integration of muscarinic antagonists into the management of COPD is discussed in greater detail separately. (See "Stable COPD: Initial pharmacologic management" and "Stable COPD: Follow-up pharmacologic management" and "COPD exacerbations: Management".)