Objectives

1. To discuss the differences in pathogenesis of the airway diseases asthma and COPD.
2. To o utline the differences in molecular structure of anticholinergic agents.
3. To u nderstand the physiology of cholinergic-induced bronchoconstriction and the mechanism of action for anticholinergic agents.
4. To d iscuss the differences in pharmacokinetics and pharmacodynamics of short-acting (ipratropium bromide) and long-acting (tiotropium) anticholinergic agents.
5. To r eview studies of the clinical efficacy and safety of short- and long-acting anticholinergic agents in COPD and asthma.

Key words: anticholinergics; asthma; COPD; ipratropium bromide; tiotropium

Abbreviations
BDI/TDI = Baseline Dyspnea Index/Transition Dyspnea Index; FRC = functional residual capacity; M₁ = muscarinic-1; M₂ = muscarinic-2; M₃ = muscarinic-3; SGRQ = St. George Respiratory Questionnaire

Asthma prevalence in the United States is estimated at approximately 30 million,¹ and COPD prevalence may be as high as 24 million based on the latest National Health and Nutrition Examination Survey III.¹ There are approximately 5,000 deaths attributed to asthma per year,² but more than 110,000 deaths associated with a diagnosis of COPD. Asthma and COPD are clinically defined airway disorders that individually have significant heterogeneity with regard to underlying pathogenesis and responses to therapy. The pathogenesis of asthma involves an airway infiltration predominated by CD4 lymphocytes, eosinophils, mast cells, and a host of other cells that generate an inflammatory milieu that is typically responsive to glucocorticosteroids. Neutrophils, CD-8 lymphocytes, and macrophages are predominant cell types in the chronic inflammation of COPD, and the consequent inflammatory cascade generated is usually considered to be relatively steroid unresponsive. For both conditions, the chronic inflammation can lead to structural changes referred to as airway remodeling. These changes are believed to be irreversible and cause gradually worsening airflow obstruction and reduced response to bronchodilators and glucocorticosteroids. Bronchodilators play a central role in symptomatic relief of acute bronchoconstriction in both conditions and are the primary maintenance therapy for COPD patients.^3,4 Asthmatics with any stage of persistent disease should be treated with inhaled glucocorticosteroids as their first line of control and maintenance, but the majority also benefit from use of a long-acting inhaled bronchodilator as part of their maintenance regimen.^2,4 We will review the role of anticholinergic agents in the treatment of airway disease, including a history of their use in treating airway diseases, the current understanding of their mechanism of action, and discussion of their indications, contraindications, and safety issues.

Historical Aspects

The medicinal properties of naturally occurring anticholinergic agents such as atropine, found in many plants in the tropics and temperate climates, have been recognized for centuries. There are reports from India dating from the 17th century that describe the use of Datura stramonium leaves for the treatment of asthma from the 17th century. This plant arrived in Europe by the 19th century via British colonialists and was used to treat a wide assortment of breathing disorders.⁵ The anticholinergic agents, such as atropine and scopolamine, are readily absorbed from the respiratory and GI tracts and have significant side effects. Newer synthesized agents, such as ipratropium bromide, oxitropium bromide, and tiotropium bromide, have similar but modified chemical structures compared with naturally occurring anticholinergics. These drugs have significantly reduced systemic absorption and, consequently, reduced side effects. Thus, they are used broadly in the treatment of airway diseases, particularly COPD, as we understand the importance of the parasympathetic pathway's role in controlling airway tone.⁶

Molecular Structure

Anticholinergic compounds are ammonium alkaloids. Naturally occurring compounds, such as atropine and scopolamine, are tertiary ammonium compounds with a 3-valent nitrogen atom, which renders them water and lipid soluble (Fig 1). As a result, they are well absorbed through the skin and mucous membranes and can cross the blood brain barrier, resulting in a variety of systemic effects. These are dose dependent and can include flushing of the skin, tachycardia, dry mouth, blurred vision, urinary retention, and mental effects, such as irritability and confusion. Ipratropium bromide, oxitropium bromide (not available in the United States), and tiotropium bromide are quaternary ammonium compounds with a charge at the 5-valent nitrogen atom that renders them water and lipid insoluble, and consequently these drugs have much lower systemic absorption (Fig 1). Thus, these synthetic compounds have much less potential for causing side effects, even at levels much higher than recommended doses.⁷

Mechanism of Action

The submucosa of human airways, both upper and lower, contain afferent irritant receptors and nociceptive C fibers that can be triggered to fire by a wide assortment of stimuli, including many irritant gases (ie, cigarette smoke), aerosols, particles, cold dry air, mechanical irritation, and various specific mediators.⁸ Once stimulated, the C fibers transfer the impulse through vagal afferents up to vagal nuclei in the brainstem and then down through vagal efferents to the larger airways that receive vagal innervation (Fig 2). Parasympathetic cholinergic efferents supply most of the autonomic innervation to the human airways. They synapse in peribronchial ganglia with short postganglionic nerves that have muscarinic-1 (M₁) receptors. These neurons in turn release acetylcholine that stimulates muscarinic-3 (M₃) receptors found on smooth muscle and submucosal glands. This leads to bronchoconstriction and mucous gland secretion and increased ciliary beat frequency. This reflex arc likely contributes to bronchospastic events that both asthmatic and COPD patients experience when exposed to various environmental triggers. Muscarinic-2 (M₂) receptors are located on the distal terminus of the short postganglionic fibers and have an autoreceptor function of feedback inhibition to shut down acetylcholine release from postganglionic fibers. These receptors play an important role in down-regulating the release of acetylcholine in the synapses with M₃ receptors on smooth muscle and consequently limit the amount of bronchoconstriction. There is also evidence to suggest that basal cholinergic tone is increased in asthma⁹ and COPD,⁸ leading to tonic relative bronchoconstriction that contributes to the chronic persistent airflow limitation found in these disorders.

Figure 2. Mechanism of action of anticholinergic agents. Three muscarinic receptor subtypes have been identified in human airways. Postsynaptic M₁ receptor stimulation in peribronchial parasympathetic ganglia facilitate neurotransmission and enhance the reflex cholinergic-induced bronchoconstriction induced by stimulation of M₃ receptors located on the smooth muscle of airways. Blockade at M₁ and M₃ receptors by anticholinergic agents inhibits bronchoconstriction. M₂ receptors are located on the presynaptic distal terminus of the postganglionic nerve and provide feedback inhibition of further acetylcholine release into the neuromuscular junction, thus down-regulating the degree of cholinergic-induced bronchoconstriction. Tiotropium preferentially binds to M₁ and M₃ receptors, thus accentuating its bronchodilating effects with minimum impact from the countereffects of anticholinergic agent blockade of M₂ receptors.

Anticholinergic agents compete with acetylcholine for these various muscarinic receptors and block bronchoconstriction and mucous gland secretion. Because cholinergic stimulation is only one of many contributing factors leading to bronchoconstriction, anticholinergics can only partially reverse the airflow obstruction of COPD and asthma. Furthermore, as outlined above, anticholinergic blockade of the M₂ receptors may actually promote further bronchoconstriction because of their feedback inhibition role. Unfortunately, most anticholinergic agents have no selectivity when it comes to stimulating M₁, M₂, or M₃ receptors. Tiotropium, a congener of ipratropium bromide, has been reported to bind avidly to M₁ and M₃ receptors while dissociating rapidly from M₂ receptors, thus having a relative selectivity that promotes bronchodilation.⁷ The anticholinergic agents can partially reverse the bronchoconstriction that occurs in asthma and COPD, but they have no or minimal known effect on leukotrienes and other components or mechanisms of airway inflammation. For these reasons, their greatest role and indication has been as a primary bronchodilator in the treatment of COPD. Moreover, from the above discussion it is evident that there are reasonable grounds to consider that anticholinergic agents may have some role complementary to β-agonists in the treatment of at least a subset of patients with asthma and COPD.

Ipratropium bromide has been shown to provide bronchodilation via the mechanisms outlined above, as well as being bronchoprotective against bronchospastic agents such as methacholine and acetylcholine.⁸ Interestingly, anticholinergics are only partially protective against such agents as histamine, bradykinin, or prostaglandin F₂α and not protective at all against mediators such as leukotrienes or serotonin.⁸

Considering the effects of atropine on depressing mucociliary clearance, one would anticipate that synthetic anticholinergic agents would have the same potential to retard mucociliary clearance, but studies that have examined this question have not shown any significant effects by ipratropium or tiotropium on mucociliary clearance.⁸

Pharmacokinetics/Dynamics

Ipratropium bromide has an onset of action within 1 to 3 min and a peak effect 1.5 to 2 h after dosing. The duration of action is generally about 4 h. Studies have shown that about 15% of each dose reaches the lower airways. Tiotropium causes a relatively slower improvement in FEV₁ but reaches a peak between 1 and 3 h and is sustained for >24 h owing to its very long dissociation half-life of >34 h, vs ipratropium bromide's dissociation half-life of approximately 15 min⁸ (Table 1). There is an observable dip in lung function 16 to 24 h after dosing, but this is related to natural circadian rhythms that are not abolished by anticholinergic agents.¹⁰

Clinical Studies

COPD: Assessing Response to Bronchodilators

The gold standard for assessment of efficacy of therapeutic interventions for the treatment of airway diseases has been assessment of the FEV₁. Studies by Hogg and colleagues¹¹ have demonstrated the importance of the small airways in the pathogenesis of COPD. Measurement of FEV₁ reflects flow through larger airways and not the smaller bronchioles that are typically involved in COPD. This may help explain why assessment of bronchodilator response by measurement of changes in FEV₁ is insensitive to detecting true physiologic benefits from bronchodilators in patients with COPD.⁴ Many COPD experts now recommend that other physiologic and clinical parameters be measured to assess the response to treatment interventions. Improvements in FVC and inspiratory capacity and reductions in functional residual capacity (FRC) lead to reduced dynamic hyperinflation during exercise and improved exercise tolerance.

Other useful outcomes to consider in the treatment of COPD include reduction in the cardinal symptoms of COPD, including shortness of breath, cough, chest tightness, and wheezing. There are now standardized scales to assess dyspnea, such as the Baseline Dyspnea Index/Transition Dyspnea Index (BDI/TDI) developed by Mahler and colleagues.¹² The TDI represents the change in baseline scores, with a maximum change of -9 or +9 possible; a 1-unit change indicates a clinically relevant worsening (negative) or improvement (positive). The St. George Respiratory Questionnaire (SGRQ) assesses overall quality of life and health status using a 100-point scale; lower scores represent improved health status. A change of the total score by more than 4 points up or down correlates to a clinically significant worsening or improvement, respectively.

Reduction in the need for rescue inhalers is also used as an outcome to reflect improved control of the disease. In the United States, more than $32 billion is spent on treatment of COPD, and more than 75% of that money is spent on treatment of acute exacerbations³; hence, another important outcome to judge the efficacy of treatment is whether an agent is able to reduce exacerbation rates. It is no longer considered sufficient to judge response to therapy on the basis of improvements in FEV₁ alone. Newer studies are taking these additional parameters into consideration as primary outcomes when judging response to therapy for COPD patients.

Ipratropium Bromide in the Treatment of COPD

Numerous studies have demonstrated ipratropium bromide's ability to improve FEV₁ and reduce dyspnea in patients with COPD.⁸ While β-agonists are known to be more potent bronchodilators than anticholinergics in asthma, anticholinergic agents appear to have at least equal potency and prolonged duration of action compared with β-agonists in COPD.¹³ As noted above, ipratropium bromide lasts only about 4 to 6 h and therefore it requires dosing four or more times per day. Ipratropium bromide is generally taken in two puffs per dose, but there is a dose-response relationship and there are likely many patients who will have optimum bronchodilator response with four or more puffs per dose period.⁸ Petty¹⁴ has shown there to be a benefit of using short-acting ipratropium bromide with albuterol in a combined formulation, which improves FEV₁ better than either agent individually. Combining these agents provides for the quick-onset bronchodilation of the β-agonist agent, the prolonged duration of action of the ipratropium bromide component, and the superior combined bronchodilating effects during the intermediate period without any additional side effects. This combined formulation has been very popular as a maintenance treatment and rescue formulation for COPD, although the US Food and Drug Administration has not actually granted an indication for rescue-inhaler use of the combination.

For acute exacerbations of COPD, use of both adrenergic agents (because of their rapid onset of action) and short-acting anticholinergics (because of their additive bronchodilator effect) is recommended.⁴

Tiotropium in Treatment of COPD

As outlined above, tiotropium has a prolonged dissociation constant providing sustained bronchodilation for >24 h and is purported to have a selectivity for M₁ and M₃ receptors that mediate smooth muscle contraction.⁷ Once-a-day dosing has great appeal as far as improving compliance. Dose-response studies using 10 to 80 µg of tiotropium demonstrated that all doses tested were relatively similar in their ability to provide sustained bronchodilation for >24 h and 18 µg has been chosen as the optimum dose formulation.⁷ The trough FEV₁ , defined as the FEV₁ 23 to 24 h after the last dose, increased over the first few days of administration by as much as 0.19 L (18% above initial baseline) in one study,¹⁵ demonstrating that there is sustained bronchodilation that can be maintained around the clock. Peak action of tiotropium occurs after 8 days of therapy¹⁵ (Fig 3). A study by Tashkin and Kesten¹⁶ indicated that the response on the first day of therapy did not predict the long-term response to therapy with tiotropium. Tiotropium has also been shown to be bronchoprotective against methacholine-induced bronchospasm for up to 48 h after a standard 18-µg dose.¹⁷ Studies have shown tiotropium to also provide statistically significant improvement in trough FEV₁ plus FVC and to reduce the requirements for rescue albuterol compared with ipratropium.^18,19

Figure 3. Peak effect of tiotropium noted after 8 days of therapy. As a result of tiotropium's duration of action of >24 h, baseline FEV 1 before drug administration is elevated after day 1 and peaks at day 8. Adapted with permission from Vincken et al.¹⁹

Moderate-to-severe COPD is frequently associated with significant hyperinflation that leads to stretch and compromise of the respiratory muscles and significantly increases the work of breathing. Reduction in hyperinflation frequently leads to reduced dyspnea and greater exercise tolerance. Bronchodilators can reduce hyperinflation by allowing for greater emptying and reductions in FRC or thoracic gas volume and increased inspiratory capacity. Celli et al²⁰ have shown that after 4 weeks of treatment, patients treated with tiotropium had reductions in FRC and improved inspiratory capacity vs placebo. O'Donnell and colleagues²¹ demonstrated that compared with placebo, tiotropium reduced hyperinflation and allowed for greater tidal volume recruitment during exercise on a constant work rate cycle ergometer, leading to a 21% improvement in endurance time and improved dyspnea index scores.

Boehringer Ingelheim Pharmaceuticals sponsored four studies that were published in major peer-reviewed journals that provide significant information regarding the efficacy of tiotropium in the treatment of COPD (Table 2). Casaburi et al¹⁸ studied 921 patients to compare tiotropium 18 µg daily vs placebo in a randomized controlled trial lasting 1 year. Vincken et al¹⁹ studied 535 patients randomly assigned to receive either tiotropium 18 µg once a day or ipratropium 40 µg qid in a randomized, double-blind, double-dummy study for 1 year. Donahue et al²² studied tiotropium 18 µg via dry powder inhaler vs salmeterol 50 µg bid via metered-dose inhaler in a randomized, double-blind, double-dummy trial for 6 months. Brusasco and colleagues²³ compared 1,207 patients receiving tiotropium or salmeterol or placebo in a randomized, double-blind, double-dummy trial for 6 months.

Casaburi et al¹⁸ demonstrated that compared with placebo, tiotropium reduced wheezing and shortness of breath but not cough or chest tightness when using a severity score from 0 to 3. In the studies comparing tiotropium and placebo, there was a statistically significant improvement in the TDI,^18,19,22 whereas similar findings were found in one of the two studies that compared it with salmeterol²² but not the other.²³

Tiotropium caused a significant improvement in the SGRQ score (a reduction of 4 or more points) compared with placebo^18,22,23 or ipratropium.¹⁹ Compared with salmeterol, tiotropium achieved a clinically relevant drop in SGRQ (ie, a >4-point drop), whereas salmeterol did not, but the difference between the two was not statistically significant.²² The Medical Outcomes Study Short Form-36 measures general health status rather than respiratory health specifically. In trials comparing tiotropium with placebo¹⁸ and ipratropium,¹⁹ tiotropium showed statistically significant improvement in the domains of role physical and physical health summary compared with the control agent.

Casaburi et al¹⁸ and Vinken et al¹⁹ reported that tiotropium could reduce exacerbations by 14 to 24% vs placebo and ipratropium, respectively.

Asthma

Ipratropium Bromide in Treatment of Chronic Asthma

Currently in the United States, the Food and Drug Administration has not approved ipratropium bromide in the treatment of asthma. However, there are theoretical as well as clinical data to suggest that in a subset of asthmatic patients, typically those with more severe disease, that ipratropium bromide provides an additional improvement in FEV₁ over and above that produced by short-acting b -agonists.²⁴ Currently available β-agonists have a quicker onset of action and superior bronchodilation than ipratropium in asthmatics and therefore are the drugs of choice for rescue short-acting bronchodilation in the vast majority of asthma patients; short-acting anticholinergics should be considered only as an add-on for those with suboptimal responses to β-agonists alone.⁸ The underlying reasons for the reduced response to anticholinergics in asthmatics vs COPD patients is not completely understood but likely relates to multiple factors, including the nature of the inflammatory response in asthma. There is evidence that adrenergic agents inhibit both the release of and the smooth-muscle contraction resulting from mediators such as histamine and leukotrienes that have an important role in the bronchoconstrictive response in asthma (but not in COPD). There is also less airway remodeling in the airways of many mild and moderate asthmatics that likely allows for a more profound response to b -agonists; more severe asthmatics demonstrate a reduced β-agonist response vs milder asthmatics.

Interestingly, a recent Cochrane analysis involving a systematic literature review concluded that the quality of studies that examined the comparison of albuterol alone vs in combination with ipratropium bromide was quite poor, but that the evidence that was available for review did not provide justification for the routine use of anticholinergics as add-on treatment for asthma not controlled with standard therapy.²⁵ Nevertheless, there are likely still patients with significant airflow obstruction that is not completely reversible who warrant an empiric trial with an anticholinergic agent to document whether they achieve any added benefit in regard to symptom control and improvements in FEV₁.

Tiotropium in Asthma

To date, there has been little study of the use of tiotropium in asthma. However, one study demonstrated that tiotropium was bronchoprotective against methacholine for up to 48 h.¹⁷

Safety

As noted above, with minimal systemic absorption there are minimal side effects from the topical inhaled anticholinergics. Dryness of the mouth is the only consistent side effect noted^18,19 (Table 3). There are no known major drug interactions. Ipratropium bromide should not be used with tiotropium as they will compete for the same receptors and reduce the effectiveness of tiotropium. Patients with narrow-angle glaucoma, prostatic hypertophy, bladder neck obstruction, or renal impairment should use anticholinergic drugs with caution. Experience with tiotropium is limited but studies to date have demonstrated side-effect profiles similar to ipratropium; dry mouth was the only major reported adverse event and it was slightly more common than with ipratropium (12.1% vs 6.1%, respectively; p=0.03, Fisher's exact test).¹⁹

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