- Email: [email protected]
Anticholinergic agents in asthma and COPD
European Journal of Pharmacology 533 (2006) 36 – 39 www.elsevier.com/locate/ejphar
Review
Anticholinergic agents in asthma and COPD Nicholas J. Gross ⁎ Stritch-Loyola School of Medicine, Voluntary Attending Physician, Hines VA Hospital, Chicago, IL, USA Accepted 12 December 2005 Available online 20 February 2006
Abstract Anticholinergic agents have important uses as bronchodilators for the treatment of obstructive airway diseases, both asthma and, more particularly, chronic obstructive pulmonary disease (COPD). Those in approved clinical use are synthetic quaternary ammonium congeners of atropine, and include ipratropium bromide, oxitropium bromide, and tiotropium bromide, each of which is very poorly absorbed when given by inhalation. Ipratropium and oxitropium have relatively short durations of action (4–8 h). They have been widely used for many years, either alone or in combination with short-acting beta-adrenergic agents such as albuterol and fenoterol, for both maintenance treatment of stable disease and for acute exacerbations of airway obstruction. Tiotropium, which was introduced in the early 2000s, has a duration of action of at least 1–2 days making it suitable for once-daily maintenance treatment of COPD. All of the above agents have a wide therapeutic margin and are safe and well tolerated by patients. © 2006 Elsevier B.V. All rights reserved. Keywords: Muscarinic receptor; Antimuscarinic agent; COPD (Chronic Obstructive Pulmonary disease); Asthma; Ipratropium; Tiotropium
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . Available agents . . . . . . . . . . . Clinical role and uses . . . . . . . . 3.1. Stable COPD . . . . . . . . . 3.2. Acute exacerbations of COPD 3.3. Stable asthma. . . . . . . . . 3.4. Acute severe asthma . . . . . 3.5. Pediatric airways disease . . . 4. Side-effects and adverse events . . . References . . . . . . . . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
1. Introduction Although naturally occurring anticholinergic alkaloids such as atropine and scopolamine have been used in traditional medical cultures for many years, these agents are well absorbed into the systemic circulation and thus have multiple systemic side-effects that limit their clinical usefulness. The discovery ⁎ NJ Gross, Bldg 1, Room E438, Hines VA Hospital, 5th Avenue and Roosevelt Road, Hines, IL, 60141, USA. Tel.: +708 202 2738; fax: +708 202 2319. E-mail address: [email protected]. 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.12.072
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
36 36 37 37 38 38 38 38 38 39
that synthetic quaternary congeners of atropine were very poorly absorbed but retained topical anticholinergic activity enabled the development of analogues of atropine such as ipratropium, oxitropium, and tiotropium bromides for clinical use as inhaled bronchodilators. In the last 2 decades, these agents have become important agents in the routine treatment of COPD but also for asthma in certain circumstances. 2. Available agents In most countries, ipratropium bromide is available as a metered-dose inhaler, as a dry powder inhalation, and as a
N.J. Gross / European Journal of Pharmacology 533 (2006) 36–39
nebulizable solution as Atrovent®. Because the original dose of ipratropium, 40 μg, is suboptimal for COPD (Gross et al., 1989), a double strength metered-dose inhaler form, Atrovent forte®, is also available in many countries outside the USA. Fixed combinations of ipratropium with albuterol (salbutamol) are also available in metered-dose inhaler form as Combivent® and in nebulizer form as DuoNeb®. In many countries but not in USA, metered-dose inhaler combinations of ipratropium with fenoterol are also available as DuoVent® and Berodual®. Oxitropium bromide is available by metered-dose inhaler in many countries outside USA as Oxivent®. The onset of action of both ipratropium and oxitropium is a little slower than that of beta-adrenergic agents such as albuterol, and peak bronchodilation may take 60–90 min to occur. The duration of action of ipratropium, both as monotherapy and as a combination, is 4–6 h; that of oxitropium is approximately 5–8 h. Tiotropium bromide is available as a dry powder inhaler in many countries including USA as Spiriva Handihaler®. A ‘soft mist’ form delivered by the Respimat® device is also available in some countries. The onset of action of tiotropium is relatively quite slow, but its duration of action is greater than 24 h—probably at least 48 h (Maesen et al., 1995). The pharmacokinetics of tiotropium make it uniquely well suited for use as a once-daily bronchodilator, but inappropriate for occasional use or for ‘rescue’ purposes. Fixed combinations of tiotropium and other classes of respiratory agents are not currently available. Each of these quaternary anticholinergic agents is functionally selective for muscarinic M1 and muscarinic M3 receptor subtypes, and tends to spare muscarinic M2 receptors by dissociating rapidly from the latter. The half-life of the tiotropium–muscarinic M3 receptor complex is 35 h compared with 0.3 h for ipratropium, consistent with its long duration of action (Disse et al., 1993; Haddad et al., 1994). Apart from tiotropium's somewhat slower and prolonged pharmacokinetics, the actions and side-effects of each of these agents are very similar. 3. Clinical role and uses 3.1. Stable COPD The major clinical use of inhaled anticholinergic agents is for the routine treatment of stable COPD. Several large multi-center long-term clinical studies in the 1980s compared ipratropium metered-dose inhaler with a β-adrenoreceptor agonist metereddose inhaler. These uniformly showed that the increase in Forced Expired Volume in 1 s (FEV1), the primary outcome of the studies, was at least as great and as prolonged with ipratropium as with a conventional β-adrenoreceptor agonist and sometimes more so (Gross, 1988; Lefcoe et al., 1982; Tashkin et al., 1986). Adverse effects were generally mild and included dry-mouth—a feature of all anticholinergic inhalations, and occasional cough. No tachyphylaxis has been observed with prolonged use. Subsequent short-term studies have shown that lung volumes, e.g. functional residual capacity and residual volume, are transiently decreased by anticholinergic agents, and inspiratory capacity tends to increase, indicating a reduction in the hyper-
37
inflation commonly associated with chronic airways obstruction (Gross and Skorodin, 1984b). However, the effects of long-term ipratropium use on clinically relevant outcomes such as exercise tolerance, quality of life and the frequency of acute exacerbations of COPD tended to be modest and often of doubtful clinical significance. The Lung Health Study, a large 5 year study in mild to moderate COPD, showed that regular ipratropium use had no effect on the rate of decline of lung function over time (Anthonisen et al., 1994). Thus short-acting anticholinergic agents can be regarded solely as symptomatic treatment for COPD. Fixed combinations of ipratropium with a β-adrenoreceptor agonist, e.g. Combivent, consistently provide greater increases in FEV1 at peak but little or no prolongation of bronchodilation than either of its individual components. Importantly, the combinations are also well tolerated by patients and there is no increase in adverse effects over those with the single agents (Petty, 1994; Gross et al., 1998). Ipratropium and oxitropium and the fixed combinations of ipratropium and a β-adrenoreceptor agonist, given 2–4 times daily, are approved and recommended by many current guidelines as options for first-line regular therapy for stable COPD of all degrees of severity (Celli and MacNee, 2004). Tiotropium bromide differs from ipratropium and oxitropium principally in its slower onset but much longer duration of action (Gross, 2004). Following single doses, the FEV1 increases to a peak over 3–4 h and declines very slowly over the next 1–2 days (Maesen et al., 1995). Consequently, the FEV1 remains above baseline and above that of placebo 24 h after administration. When used on a regular once-daily basis, both the pre-bronchodilator (trough) FEV1 and 3 h post-bronchodilator FEV1 increase daily over the first several days of treatment (Casaburi et al., 2002). These features of tiotropium suggest that it should not be used for the short-term relief of dyspnoea, nor for occasional or intermittent use, but that it is uniquely suitable as regular once-daily therapy of stable COPD. In head-to-head trials, tiotropium taken once daily resulted in statistically greater increases in trough and peak FEV1 and area under the curve than either ipratropium given 4-times daily or salmeterol given twice daily (Vincken et al., 2002; Brusasco et al., 2003). Clinically relevant outcomes such as dyspnoea index, exercise tolerance, and frequency of acute exacerbations were numerically but not always statistically better with tiotropium than with salmeterol. Importantly, measures of quality of life (health status) with regular tiotropium use consistently improved by an amount that is believed to signify clinical benefit. Compared to conventional treatment alone, regular use of tiotropium reduced the frequency of acute exacerbations by 20–25% (Casaburi et al., 2002; Vincken et al., 2002; Brusasco et al., 2003; Niewoehner et al., 2004). Some of the 1 year studies suggest that regular use of tiotropium may decrease the rate of decline of lung function in COPD (Casaburi et al., 2002) but this has not been established. A long-term study of this possibility is underway at present. Tiotropium DPI, once daily, is approved and recommended by many current guidelines as an option for first-line therapy for stable COPD of all degrees of severity.
38
N.J. Gross / European Journal of Pharmacology 533 (2006) 36–39
3.2. Acute exacerbations of COPD Comparative studies of bronchodilator options in the initial treatment of these serious events do not show any advantage for the use of an anticholinergic agent over a quick-acting β-adrenoreceptor agonist such as salbutamol alone. Nor have they shown that an agent such as ipratropium consistently adds to the bronchodilation achieved by a β-adrenoreceptor agonist alone in acute exacerbations of COPD (Rebuck et al., 1987). Nevertheless, current guidelines recommend that if a prompt response to a β-adrenoreceptor agonist does not occur, an anticholinergic agent should be added (Celli and MacNee, 2004; GOLD, 2003). In practice, it is common to initiate treatment with the combination and this seems appropriate as acute exacerbations may be life-threatening and the addition of ipratropium is unlikely to significantly increase the occurrence of adverse effects or cost. Tiotropium has not been studied for acute exacerbations of COPD and should not be used as monotherapy for this condition. However when patients are already receiving it, it should be continued through the exacerbation in addition to the above therapy, in order to maintain the accumulated benefit of its regular use referred to above. The concomitant use of tiotropium and ipratropium has raised the theoretical concern that the benefit of tiotropium may be jeopardized if ipratropium molecules were to occupy muscarinic receptors and thus prevent the access of tiotropium molecules to these sites. This concern seems misplaced in that the half-life of the ipratropium–muscarinic M3 receptor complex is 2 orders of magnitude shorter that that of the tiotropium–muscarinic M3 receptor complex (Disse et al., 1993). Thus, even if both agents were given simultaneously in usual doses, it is very likely that any muscarinic M3 receptors that happened to become occupied by ipratropium would nevertheless become available to tiotropium molecules within an hour and remain occupied by tiotropium molecules for days thereafter. Both ipratropium and tiotropium have very wide therapeutic margins, nor have any unfavorable interactions between these 2 agents been reported, so it is unlikely that adverse events would be more common when both are used concomitantly. In clinical studies, when patients are receiving tiotropium ipratropium provides almost no increment in bronchodilation, so the only consideration with their concomitant use is that the addition of ipratropium is of little benefit and could possibly be discontinued with some cost savings. 3.3. Stable asthma Numerous studies have compared short-acting anticholinergic agents with a variety of short-acting β-adrenoreceptor agonists for the regular treatment of stable asthma (Ruffin et al., 1977). Almost uniformly, these reports show that ipratropium results in less bronchodilation than a short-acting β-adrenoreceptor agonist in asthmatic patients. As in COPD, the onset of action of the anticholinergic agent is somewhat slower than that of the β-adrenoreceptor agonist, while its duration of action may be 1–2 h longer. No anticholinergic agent has been approved for use in asthma in the USA. Despite this, there is considerable variation in responsiveness to an anticholinergic agent among asthmatic
patients, a few responding as well to it as to an adrenergic. It has been reported that older patients (Ullah et al., 1981) and those with intrinsic asthma (Jolobe, 1984) are most likely to respond favorably to anticholinergic agents. However, clinically useful responses to an anticholinergic agent have been reported in some asthmatic children aged 10–18 (Vichyanond et al., 1990). In general, it has not been possible to predict reliably which asthmatics will obtain benefit from ipratropium other by an individual trial (Brown et al., 1984). For those rare asthmatic patients who cannot tolerate the adverse effects that a β-adrenoreceptor agonist may produce, ipratropium may be a useful alternative bronchodilator. Similarly, ipratropium may be useful in treating asthma of psychogenic origin (Rebuck and Marcus, 1979) and the bronchospasm induced by inadvertent use of a β2-adrenoreceptor antagonist (De Vries, 1975). The role of tiotropium has not been studied in asthma. 3.4. Acute severe asthma Although short-acting β-adrenoreceptor agonists are the bronchodilators of choice in the initial management of acute severe asthma, several studies (Rebuck et al., 1987) and a metaanalysis (Stoodley et al., 1999) suggest that the inclusion of ipratropium in the initial treatment of these serious events may provide greater and more rapid improvement in lung function and may avoid prolonged emergency room treatments and hospitalization. Current guidelines recommend that ipratropium, usually by nebulization, be added when the response to initial treatments with a short-acting β-adrenoreceptor agonist alone is “less than complete” or “poor” (www.ginaasthma.com). In practice, it is common for the combination of salbutamol and ipratropium to be given routinely as initial treatment for episodes of acute severe asthma, at least for the first few treatments. As explained above (in Acute exacerbations of COPD) this seems appropriate. 3.5. Pediatric airways disease For pediatric asthma, both stable and acute forms, the role of ipratropium is similar to that in adults. Although studies with adequate statistical power or long duration in children are lacking, adult doses have been used without adverse effects in children down to 4 years of age (Warner et al., 1989; Hargreave et al., 1990). As in adults, its role in the treatment of asthma is limited. Again, the role of tiotropium has not been studied in pediatric asthma. There are occasional reports of the use of ipratropium in other pediatric diseases such as cystic fibrosis, viral bronchiolitis, exercise-induced asthma, and broncho-pulmonary dysplasia. Although these reports sometimes suggest a benefit from its use, the body of evidence is insufficient to make any recommendation in these conditions. 4. Side-effects and adverse events Being very poorly absorbed, currently approved inhaled anticholinergic agents have a very wide therapeutic margin and are very well tolerated, even in rare instances when massive
N.J. Gross / European Journal of Pharmacology 533 (2006) 36–39
doses have accidentally been given (Gross and Skorodin, 1985). In normal clinical use, dryness of the mouth is a common side effect of all agents in this class but is rarely sufficiently severe for the patient to discontinue use. Bad taste is an occasional complaint, as is a brief coughing spell shortly after inhalation. One serious but rare idiosyncratic effect is paradoxical bronchospasm whose mechanism is unknown (Beasley et al., 1998; Boucher et al., 1992). It has been reported to occur in perhaps 0.3% of patients following use of any of the above anticholinergic bronchodilators. The drug should be discontinued in patients who experience wheezing, chest tightness and worsening of dyspnoea within an hour of the inhalation. Ipratropium was extensively studied for possible adverse effects on mucociliary clearance from the lungs, urinary outflow, and increased intraocular pressure, well known side-effects of atropine (Gross and Skorodin, 1984a). These were found not to be problems with inhaled ipratropium, nor have they been found with oxitropium or tiotropium. However, if any of these agents are inadvertently placed directly onto the eye, they can cause dilatation of the pupil and blurred vision, which may be prolonged in the case of tiotropium, and possibly precipitate acute glaucoma. Situations where this might occur include actuation of the pressure driven metered-dose aerosol with the eyes open, or delivery of a nebulized solution through a face mask that has not been carefully fitted, or when a patient handles the used capsule of an anticholinergic agent delivered as a dry powder inhaler Care should be taken to avoid these situations. References Anthonisen, N.R., Connett, J.E., Kiley, J.P., 1994. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 272, 1497–1505. Beasley, R., Fishwick, D., Miles, J.F., 1998. Preservatives in nebulizer solutions: risks without benefit. Pharmacotherapy 18, 130–139. Boucher, M., Roy, M.T., Henderson, J., 1992. Possible association of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann. Pharmacother. 26, 772–774. Brown, I.G., Chan, C.S., Kelly, 1984. Assessment of the clinical usefulness of nebulised ipratropium bromide in patients with chronic airflow limitation. Thorax 39, 272–276. Brusasco, V., Hodder, R., Mitravilles, M., Korducki, L., Towse, L., Kesten, S., 2003. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 58, 399–404. Casaburi, R., Mahler, D.A., Jones, P.W., et al., 2002. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur. Respir. J. 19, 217–224. Celli, B.R., MacNee, W., 2004. Standards for the diagnosis and treatment of patients with COPD; a summary of the ATS/ERS position paper. Eur. Respir. J. 23, 932–946. De Vries, K., 1975. The protective effect of inhaled Sch1000 MDI on bronchoconstriction induced by serotonin, histamine, acetylcholine and propanaolol. Postgrad. Med. J. 51, 106 (Suppl). Disse, B., Reichl, R., Speck, G., et al., 1993. Ba 679 BR, a novel long-acting anticholinergic bronchodilator. Life Sci. 52, 537–544. GOLD, The Global Initiative for Chronic Obstructive Lung Disease, 2003. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2003 update. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute.
39
Gross, N.J., 1988. Ipratropium bromide. N. Engl. J. Med. 319, 486–494. Gross, N.J., 2004. Tiotropium bromide. Chest 126, 1946–1953. Gross, N.J., Skorodin, M.S., 1984a. Anticholinergic, antimuscarinic bronchodilators. Am. Rev. Respir. Dis. 129, 856–870. Gross, N.J., Skorodin, M.S., 1984b. Role of the parasympathetic system in airway obstruction due to emphysema. N. Engl. J. Med. 311, 421–425. Gross, N.J., Skorodin, M.S., 1985. Massive overdose of atropine methonitrate with only slight untoward effects. Lancet 2, 386. Gross, N.J., Petty, T.L., Friedman, M., et al., 1989. Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study. Am. Rev. Respir. Dis. 139, 1188–1191. Gross, N., Tashkin, D., Miller, R., et al., 1998. Inhalation by nebulization of albuterol–ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group. Respiration 65, 354–362. Haddad, E.B., Mak, J.C., Barnes, P.J., 1994. Characterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: radioligand binding and autoradiographic mapping. Mol. Pharmacol. 45, 899–907. Hargreave, F.E., Dolovich, J., Newhouse, M.T., 1990. The assessment and treatment of asthma: a conference report. J. Allergy Clin. Immunol. 85, 1098–1111. Jolobe, O.M., 1984. Asthma vs. non-specific reversible airflow obstruction: clinical features and responsiveness to anticholinergic drugs. Respiration 45, 237–242. Lefcoe, N.M., Toogood, J.H., Blennerhassett, G., et al., 1982. The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis. A double-blind single dose study. Chest 82, 300–305. Maesen, F.P., Smeets, J.J., Sledsens, et al., 1995. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group. Eur. Respir. J. 8, 1506–1513. Niewoehner, D., Rice, K., Cote, C., et al., 2004. Reduced COPD exacerbations and associated health care utilization with once-daily tiotropium in the VA medical system. Am. J. Respir. Crit. Care Med. 169, A207. Petty, T.L., 1994. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest 105, 1411–1419. Rebuck, A.S., Marcus, H.I., 1979. Sch1000 in psychogenic asthma. Scand. J. Respir. Dis. 103, 186–190 (Suppl). Rebuck, A.S., Chapman, K.R., Abboud, R., et al., 1987. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am. J. Med. 82, 59–64. Ruffin, R.E., Fitzgerald, J.D., Rebuck, A.S., 1977. A comparison of the bronchodilator activity of Sch 1000 and salbutamol. J. Allergy Clin. Immunol. 59, 136–141. Stoodley, R.G., Aaron, S.D., Dales, R.E., 1999. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a meta-analysis of randomized clinical trials. Ann. Emerg. Med. 34, 8–18. Tashkin, D.P., Ashutosh, K., Bleecker, E.R., 1986. Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study. Am. J. Med. 81, 81–90. Ullah, M.I., Newman, G.B., Saunders, K.B., 1981. Influence of age on response to ipratropium and salbutamol in asthma. Thorax 36, 523–529. Vichyanond, P., Sladek, W.A., Sur, S., et al., 1990. Efficacy of atropine methylnitrate alone and in combination with albuterol in children with asthma. Chest 98, 637–642. Vincken, W., van Noord, J.A., Greenhorst, A.P., et al., 2002. Dutch/Belgian tiotropium study group. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur. Respir. J. 19, 209–216. Warner, J.O., Gotz, M., Landau, L.I., et al., 1989. Management of asthma: a consensus statement. 64, 1065–1079.
Review
Anticholinergic agents in asthma and COPD Nicholas J. Gross ⁎ Stritch-Loyola School of Medicine, Voluntary Attending Physician, Hines VA Hospital, Chicago, IL, USA Accepted 12 December 2005 Available online 20 February 2006
Abstract Anticholinergic agents have important uses as bronchodilators for the treatment of obstructive airway diseases, both asthma and, more particularly, chronic obstructive pulmonary disease (COPD). Those in approved clinical use are synthetic quaternary ammonium congeners of atropine, and include ipratropium bromide, oxitropium bromide, and tiotropium bromide, each of which is very poorly absorbed when given by inhalation. Ipratropium and oxitropium have relatively short durations of action (4–8 h). They have been widely used for many years, either alone or in combination with short-acting beta-adrenergic agents such as albuterol and fenoterol, for both maintenance treatment of stable disease and for acute exacerbations of airway obstruction. Tiotropium, which was introduced in the early 2000s, has a duration of action of at least 1–2 days making it suitable for once-daily maintenance treatment of COPD. All of the above agents have a wide therapeutic margin and are safe and well tolerated by patients. © 2006 Elsevier B.V. All rights reserved. Keywords: Muscarinic receptor; Antimuscarinic agent; COPD (Chronic Obstructive Pulmonary disease); Asthma; Ipratropium; Tiotropium
Contents 1. 2. 3.
Introduction . . . . . . . . . . . . . Available agents . . . . . . . . . . . Clinical role and uses . . . . . . . . 3.1. Stable COPD . . . . . . . . . 3.2. Acute exacerbations of COPD 3.3. Stable asthma. . . . . . . . . 3.4. Acute severe asthma . . . . . 3.5. Pediatric airways disease . . . 4. Side-effects and adverse events . . . References . . . . . . . . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
1. Introduction Although naturally occurring anticholinergic alkaloids such as atropine and scopolamine have been used in traditional medical cultures for many years, these agents are well absorbed into the systemic circulation and thus have multiple systemic side-effects that limit their clinical usefulness. The discovery ⁎ NJ Gross, Bldg 1, Room E438, Hines VA Hospital, 5th Avenue and Roosevelt Road, Hines, IL, 60141, USA. Tel.: +708 202 2738; fax: +708 202 2319. E-mail address: [email protected]. 0014-2999/$ - see front matter © 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2005.12.072
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
. . . . . . . . . .
36 36 37 37 38 38 38 38 38 39
that synthetic quaternary congeners of atropine were very poorly absorbed but retained topical anticholinergic activity enabled the development of analogues of atropine such as ipratropium, oxitropium, and tiotropium bromides for clinical use as inhaled bronchodilators. In the last 2 decades, these agents have become important agents in the routine treatment of COPD but also for asthma in certain circumstances. 2. Available agents In most countries, ipratropium bromide is available as a metered-dose inhaler, as a dry powder inhalation, and as a
N.J. Gross / European Journal of Pharmacology 533 (2006) 36–39
nebulizable solution as Atrovent®. Because the original dose of ipratropium, 40 μg, is suboptimal for COPD (Gross et al., 1989), a double strength metered-dose inhaler form, Atrovent forte®, is also available in many countries outside the USA. Fixed combinations of ipratropium with albuterol (salbutamol) are also available in metered-dose inhaler form as Combivent® and in nebulizer form as DuoNeb®. In many countries but not in USA, metered-dose inhaler combinations of ipratropium with fenoterol are also available as DuoVent® and Berodual®. Oxitropium bromide is available by metered-dose inhaler in many countries outside USA as Oxivent®. The onset of action of both ipratropium and oxitropium is a little slower than that of beta-adrenergic agents such as albuterol, and peak bronchodilation may take 60–90 min to occur. The duration of action of ipratropium, both as monotherapy and as a combination, is 4–6 h; that of oxitropium is approximately 5–8 h. Tiotropium bromide is available as a dry powder inhaler in many countries including USA as Spiriva Handihaler®. A ‘soft mist’ form delivered by the Respimat® device is also available in some countries. The onset of action of tiotropium is relatively quite slow, but its duration of action is greater than 24 h—probably at least 48 h (Maesen et al., 1995). The pharmacokinetics of tiotropium make it uniquely well suited for use as a once-daily bronchodilator, but inappropriate for occasional use or for ‘rescue’ purposes. Fixed combinations of tiotropium and other classes of respiratory agents are not currently available. Each of these quaternary anticholinergic agents is functionally selective for muscarinic M1 and muscarinic M3 receptor subtypes, and tends to spare muscarinic M2 receptors by dissociating rapidly from the latter. The half-life of the tiotropium–muscarinic M3 receptor complex is 35 h compared with 0.3 h for ipratropium, consistent with its long duration of action (Disse et al., 1993; Haddad et al., 1994). Apart from tiotropium's somewhat slower and prolonged pharmacokinetics, the actions and side-effects of each of these agents are very similar. 3. Clinical role and uses 3.1. Stable COPD The major clinical use of inhaled anticholinergic agents is for the routine treatment of stable COPD. Several large multi-center long-term clinical studies in the 1980s compared ipratropium metered-dose inhaler with a β-adrenoreceptor agonist metereddose inhaler. These uniformly showed that the increase in Forced Expired Volume in 1 s (FEV1), the primary outcome of the studies, was at least as great and as prolonged with ipratropium as with a conventional β-adrenoreceptor agonist and sometimes more so (Gross, 1988; Lefcoe et al., 1982; Tashkin et al., 1986). Adverse effects were generally mild and included dry-mouth—a feature of all anticholinergic inhalations, and occasional cough. No tachyphylaxis has been observed with prolonged use. Subsequent short-term studies have shown that lung volumes, e.g. functional residual capacity and residual volume, are transiently decreased by anticholinergic agents, and inspiratory capacity tends to increase, indicating a reduction in the hyper-
37
inflation commonly associated with chronic airways obstruction (Gross and Skorodin, 1984b). However, the effects of long-term ipratropium use on clinically relevant outcomes such as exercise tolerance, quality of life and the frequency of acute exacerbations of COPD tended to be modest and often of doubtful clinical significance. The Lung Health Study, a large 5 year study in mild to moderate COPD, showed that regular ipratropium use had no effect on the rate of decline of lung function over time (Anthonisen et al., 1994). Thus short-acting anticholinergic agents can be regarded solely as symptomatic treatment for COPD. Fixed combinations of ipratropium with a β-adrenoreceptor agonist, e.g. Combivent, consistently provide greater increases in FEV1 at peak but little or no prolongation of bronchodilation than either of its individual components. Importantly, the combinations are also well tolerated by patients and there is no increase in adverse effects over those with the single agents (Petty, 1994; Gross et al., 1998). Ipratropium and oxitropium and the fixed combinations of ipratropium and a β-adrenoreceptor agonist, given 2–4 times daily, are approved and recommended by many current guidelines as options for first-line regular therapy for stable COPD of all degrees of severity (Celli and MacNee, 2004). Tiotropium bromide differs from ipratropium and oxitropium principally in its slower onset but much longer duration of action (Gross, 2004). Following single doses, the FEV1 increases to a peak over 3–4 h and declines very slowly over the next 1–2 days (Maesen et al., 1995). Consequently, the FEV1 remains above baseline and above that of placebo 24 h after administration. When used on a regular once-daily basis, both the pre-bronchodilator (trough) FEV1 and 3 h post-bronchodilator FEV1 increase daily over the first several days of treatment (Casaburi et al., 2002). These features of tiotropium suggest that it should not be used for the short-term relief of dyspnoea, nor for occasional or intermittent use, but that it is uniquely suitable as regular once-daily therapy of stable COPD. In head-to-head trials, tiotropium taken once daily resulted in statistically greater increases in trough and peak FEV1 and area under the curve than either ipratropium given 4-times daily or salmeterol given twice daily (Vincken et al., 2002; Brusasco et al., 2003). Clinically relevant outcomes such as dyspnoea index, exercise tolerance, and frequency of acute exacerbations were numerically but not always statistically better with tiotropium than with salmeterol. Importantly, measures of quality of life (health status) with regular tiotropium use consistently improved by an amount that is believed to signify clinical benefit. Compared to conventional treatment alone, regular use of tiotropium reduced the frequency of acute exacerbations by 20–25% (Casaburi et al., 2002; Vincken et al., 2002; Brusasco et al., 2003; Niewoehner et al., 2004). Some of the 1 year studies suggest that regular use of tiotropium may decrease the rate of decline of lung function in COPD (Casaburi et al., 2002) but this has not been established. A long-term study of this possibility is underway at present. Tiotropium DPI, once daily, is approved and recommended by many current guidelines as an option for first-line therapy for stable COPD of all degrees of severity.
38
N.J. Gross / European Journal of Pharmacology 533 (2006) 36–39
3.2. Acute exacerbations of COPD Comparative studies of bronchodilator options in the initial treatment of these serious events do not show any advantage for the use of an anticholinergic agent over a quick-acting β-adrenoreceptor agonist such as salbutamol alone. Nor have they shown that an agent such as ipratropium consistently adds to the bronchodilation achieved by a β-adrenoreceptor agonist alone in acute exacerbations of COPD (Rebuck et al., 1987). Nevertheless, current guidelines recommend that if a prompt response to a β-adrenoreceptor agonist does not occur, an anticholinergic agent should be added (Celli and MacNee, 2004; GOLD, 2003). In practice, it is common to initiate treatment with the combination and this seems appropriate as acute exacerbations may be life-threatening and the addition of ipratropium is unlikely to significantly increase the occurrence of adverse effects or cost. Tiotropium has not been studied for acute exacerbations of COPD and should not be used as monotherapy for this condition. However when patients are already receiving it, it should be continued through the exacerbation in addition to the above therapy, in order to maintain the accumulated benefit of its regular use referred to above. The concomitant use of tiotropium and ipratropium has raised the theoretical concern that the benefit of tiotropium may be jeopardized if ipratropium molecules were to occupy muscarinic receptors and thus prevent the access of tiotropium molecules to these sites. This concern seems misplaced in that the half-life of the ipratropium–muscarinic M3 receptor complex is 2 orders of magnitude shorter that that of the tiotropium–muscarinic M3 receptor complex (Disse et al., 1993). Thus, even if both agents were given simultaneously in usual doses, it is very likely that any muscarinic M3 receptors that happened to become occupied by ipratropium would nevertheless become available to tiotropium molecules within an hour and remain occupied by tiotropium molecules for days thereafter. Both ipratropium and tiotropium have very wide therapeutic margins, nor have any unfavorable interactions between these 2 agents been reported, so it is unlikely that adverse events would be more common when both are used concomitantly. In clinical studies, when patients are receiving tiotropium ipratropium provides almost no increment in bronchodilation, so the only consideration with their concomitant use is that the addition of ipratropium is of little benefit and could possibly be discontinued with some cost savings. 3.3. Stable asthma Numerous studies have compared short-acting anticholinergic agents with a variety of short-acting β-adrenoreceptor agonists for the regular treatment of stable asthma (Ruffin et al., 1977). Almost uniformly, these reports show that ipratropium results in less bronchodilation than a short-acting β-adrenoreceptor agonist in asthmatic patients. As in COPD, the onset of action of the anticholinergic agent is somewhat slower than that of the β-adrenoreceptor agonist, while its duration of action may be 1–2 h longer. No anticholinergic agent has been approved for use in asthma in the USA. Despite this, there is considerable variation in responsiveness to an anticholinergic agent among asthmatic
patients, a few responding as well to it as to an adrenergic. It has been reported that older patients (Ullah et al., 1981) and those with intrinsic asthma (Jolobe, 1984) are most likely to respond favorably to anticholinergic agents. However, clinically useful responses to an anticholinergic agent have been reported in some asthmatic children aged 10–18 (Vichyanond et al., 1990). In general, it has not been possible to predict reliably which asthmatics will obtain benefit from ipratropium other by an individual trial (Brown et al., 1984). For those rare asthmatic patients who cannot tolerate the adverse effects that a β-adrenoreceptor agonist may produce, ipratropium may be a useful alternative bronchodilator. Similarly, ipratropium may be useful in treating asthma of psychogenic origin (Rebuck and Marcus, 1979) and the bronchospasm induced by inadvertent use of a β2-adrenoreceptor antagonist (De Vries, 1975). The role of tiotropium has not been studied in asthma. 3.4. Acute severe asthma Although short-acting β-adrenoreceptor agonists are the bronchodilators of choice in the initial management of acute severe asthma, several studies (Rebuck et al., 1987) and a metaanalysis (Stoodley et al., 1999) suggest that the inclusion of ipratropium in the initial treatment of these serious events may provide greater and more rapid improvement in lung function and may avoid prolonged emergency room treatments and hospitalization. Current guidelines recommend that ipratropium, usually by nebulization, be added when the response to initial treatments with a short-acting β-adrenoreceptor agonist alone is “less than complete” or “poor” (www.ginaasthma.com). In practice, it is common for the combination of salbutamol and ipratropium to be given routinely as initial treatment for episodes of acute severe asthma, at least for the first few treatments. As explained above (in Acute exacerbations of COPD) this seems appropriate. 3.5. Pediatric airways disease For pediatric asthma, both stable and acute forms, the role of ipratropium is similar to that in adults. Although studies with adequate statistical power or long duration in children are lacking, adult doses have been used without adverse effects in children down to 4 years of age (Warner et al., 1989; Hargreave et al., 1990). As in adults, its role in the treatment of asthma is limited. Again, the role of tiotropium has not been studied in pediatric asthma. There are occasional reports of the use of ipratropium in other pediatric diseases such as cystic fibrosis, viral bronchiolitis, exercise-induced asthma, and broncho-pulmonary dysplasia. Although these reports sometimes suggest a benefit from its use, the body of evidence is insufficient to make any recommendation in these conditions. 4. Side-effects and adverse events Being very poorly absorbed, currently approved inhaled anticholinergic agents have a very wide therapeutic margin and are very well tolerated, even in rare instances when massive
N.J. Gross / European Journal of Pharmacology 533 (2006) 36–39
doses have accidentally been given (Gross and Skorodin, 1985). In normal clinical use, dryness of the mouth is a common side effect of all agents in this class but is rarely sufficiently severe for the patient to discontinue use. Bad taste is an occasional complaint, as is a brief coughing spell shortly after inhalation. One serious but rare idiosyncratic effect is paradoxical bronchospasm whose mechanism is unknown (Beasley et al., 1998; Boucher et al., 1992). It has been reported to occur in perhaps 0.3% of patients following use of any of the above anticholinergic bronchodilators. The drug should be discontinued in patients who experience wheezing, chest tightness and worsening of dyspnoea within an hour of the inhalation. Ipratropium was extensively studied for possible adverse effects on mucociliary clearance from the lungs, urinary outflow, and increased intraocular pressure, well known side-effects of atropine (Gross and Skorodin, 1984a). These were found not to be problems with inhaled ipratropium, nor have they been found with oxitropium or tiotropium. However, if any of these agents are inadvertently placed directly onto the eye, they can cause dilatation of the pupil and blurred vision, which may be prolonged in the case of tiotropium, and possibly precipitate acute glaucoma. Situations where this might occur include actuation of the pressure driven metered-dose aerosol with the eyes open, or delivery of a nebulized solution through a face mask that has not been carefully fitted, or when a patient handles the used capsule of an anticholinergic agent delivered as a dry powder inhaler Care should be taken to avoid these situations. References Anthonisen, N.R., Connett, J.E., Kiley, J.P., 1994. Effects of smoking intervention and the use of an inhaled anticholinergic bronchodilator on the rate of decline of FEV1. The Lung Health Study. JAMA 272, 1497–1505. Beasley, R., Fishwick, D., Miles, J.F., 1998. Preservatives in nebulizer solutions: risks without benefit. Pharmacotherapy 18, 130–139. Boucher, M., Roy, M.T., Henderson, J., 1992. Possible association of benzalkonium chloride in nebulizer solutions with respiratory arrest. Ann. Pharmacother. 26, 772–774. Brown, I.G., Chan, C.S., Kelly, 1984. Assessment of the clinical usefulness of nebulised ipratropium bromide in patients with chronic airflow limitation. Thorax 39, 272–276. Brusasco, V., Hodder, R., Mitravilles, M., Korducki, L., Towse, L., Kesten, S., 2003. Health outcomes following treatment for six months with once daily tiotropium compared with twice daily salmeterol in patients with COPD. Thorax 58, 399–404. Casaburi, R., Mahler, D.A., Jones, P.W., et al., 2002. A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease. Eur. Respir. J. 19, 217–224. Celli, B.R., MacNee, W., 2004. Standards for the diagnosis and treatment of patients with COPD; a summary of the ATS/ERS position paper. Eur. Respir. J. 23, 932–946. De Vries, K., 1975. The protective effect of inhaled Sch1000 MDI on bronchoconstriction induced by serotonin, histamine, acetylcholine and propanaolol. Postgrad. Med. J. 51, 106 (Suppl). Disse, B., Reichl, R., Speck, G., et al., 1993. Ba 679 BR, a novel long-acting anticholinergic bronchodilator. Life Sci. 52, 537–544. GOLD, The Global Initiative for Chronic Obstructive Lung Disease, 2003. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, 2003 update. Bethesda, MD: National Institutes of Health, National Heart, Lung, and Blood Institute.
39
Gross, N.J., 1988. Ipratropium bromide. N. Engl. J. Med. 319, 486–494. Gross, N.J., 2004. Tiotropium bromide. Chest 126, 1946–1953. Gross, N.J., Skorodin, M.S., 1984a. Anticholinergic, antimuscarinic bronchodilators. Am. Rev. Respir. Dis. 129, 856–870. Gross, N.J., Skorodin, M.S., 1984b. Role of the parasympathetic system in airway obstruction due to emphysema. N. Engl. J. Med. 311, 421–425. Gross, N.J., Skorodin, M.S., 1985. Massive overdose of atropine methonitrate with only slight untoward effects. Lancet 2, 386. Gross, N.J., Petty, T.L., Friedman, M., et al., 1989. Dose response to ipratropium as a nebulized solution in patients with chronic obstructive pulmonary disease. A three-center study. Am. Rev. Respir. Dis. 139, 1188–1191. Gross, N., Tashkin, D., Miller, R., et al., 1998. Inhalation by nebulization of albuterol–ipratropium combination (Dey combination) is superior to either agent alone in the treatment of chronic obstructive pulmonary disease. Dey Combination Solution Study Group. Respiration 65, 354–362. Haddad, E.B., Mak, J.C., Barnes, P.J., 1994. Characterization of [3H]Ba 679 BR, a slowly dissociating muscarinic antagonist, in human lung: radioligand binding and autoradiographic mapping. Mol. Pharmacol. 45, 899–907. Hargreave, F.E., Dolovich, J., Newhouse, M.T., 1990. The assessment and treatment of asthma: a conference report. J. Allergy Clin. Immunol. 85, 1098–1111. Jolobe, O.M., 1984. Asthma vs. non-specific reversible airflow obstruction: clinical features and responsiveness to anticholinergic drugs. Respiration 45, 237–242. Lefcoe, N.M., Toogood, J.H., Blennerhassett, G., et al., 1982. The addition of an aerosol anticholinergic to an oral beta agonist plus theophylline in asthma and bronchitis. A double-blind single dose study. Chest 82, 300–305. Maesen, F.P., Smeets, J.J., Sledsens, et al., 1995. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group. Eur. Respir. J. 8, 1506–1513. Niewoehner, D., Rice, K., Cote, C., et al., 2004. Reduced COPD exacerbations and associated health care utilization with once-daily tiotropium in the VA medical system. Am. J. Respir. Crit. Care Med. 169, A207. Petty, T.L., 1994. In chronic obstructive pulmonary disease, a combination of ipratropium and albuterol is more effective than either agent alone. An 85day multicenter trial. COMBIVENT Inhalation Aerosol Study Group. Chest 105, 1411–1419. Rebuck, A.S., Marcus, H.I., 1979. Sch1000 in psychogenic asthma. Scand. J. Respir. Dis. 103, 186–190 (Suppl). Rebuck, A.S., Chapman, K.R., Abboud, R., et al., 1987. Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am. J. Med. 82, 59–64. Ruffin, R.E., Fitzgerald, J.D., Rebuck, A.S., 1977. A comparison of the bronchodilator activity of Sch 1000 and salbutamol. J. Allergy Clin. Immunol. 59, 136–141. Stoodley, R.G., Aaron, S.D., Dales, R.E., 1999. The role of ipratropium bromide in the emergency management of acute asthma exacerbation: a meta-analysis of randomized clinical trials. Ann. Emerg. Med. 34, 8–18. Tashkin, D.P., Ashutosh, K., Bleecker, E.R., 1986. Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study. Am. J. Med. 81, 81–90. Ullah, M.I., Newman, G.B., Saunders, K.B., 1981. Influence of age on response to ipratropium and salbutamol in asthma. Thorax 36, 523–529. Vichyanond, P., Sladek, W.A., Sur, S., et al., 1990. Efficacy of atropine methylnitrate alone and in combination with albuterol in children with asthma. Chest 98, 637–642. Vincken, W., van Noord, J.A., Greenhorst, A.P., et al., 2002. Dutch/Belgian tiotropium study group. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur. Respir. J. 19, 209–216. Warner, J.O., Gotz, M., Landau, L.I., et al., 1989. Management of asthma: a consensus statement. 64, 1065–1079.