Lung (1990) Suppl:295-303
The Role of Anticholinergic Bronchodilators in Adult Asthma and Chronic Obstructive Pulmonary Disease K. R. Chapman Division of Respiratory Medicine, Toronto Western Hospital and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Abstract. Our renewed interest in anticholinergic bronchodilator therapy has been sparked by the development of safe yet effective quaternary anticholinergic compounds including ipratropium bromide, oxitropium and atropine methonitrate. These agents offer gradual and sustained bronchodilatation to patients with asthma and to patients with COPD. However, their role in the maintenance treatment of these two diseases differs significantly. In asthma, the anticholinergic drugs have useful additive properties when used with adrenergic drugs or theophylline. They may be a particularly useful component of combination regimens in patients with disease of more than mild severity and in older patients. The combination of inhaled adrenergic and anticholinergic drugs is also useful in the acute setting for acute exacerbations of asthma. In chronic obstructive lung disease, the anticholinergic compounds offer greater bronchodilatation than adrenergic drugs for the majority of patients. Thus, the inhaled anticholinergic drugs may be considered as useful initial choices in the chronic maintenance therapy of COPD.
Key words: Quaternary anticholinergic--Asthma--COPD. Introduction
Our present interest in antichohnergic bronchodilators represents the rediscovery and refinement of a form of therapy that is centuries old. Ayurvedic medical literature confirms that atropine-containing botanicals such as Datura stramonium were smoked for centuries in India for a variety of medicinal purposes including the relief of dyspnea [1]. Stramonium therapy was introduced to
Offprint requests to: Dr. K. R. Chapman, Suite 4-011, Edith Cavell Wing, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada.
296
K.R. Chapman
Western medicine at the turn of the nineteenth century and by mid-century, Salter's Treatise on A s t h m a listed stramonium as one of the truly effective remedies in this disorder. However, stramonium was not without hazard. Salter noted potent anticholinergic systemic side effects following the unpredictable absorption of the active alkaloid, atropine. Although atropine cigarettes and atropine-containing asthma powders were available well into the middle of the twentieth century, their use became infrequent after the introduction of adrenergic agents. Our renewed interest in anticholinergic bronchodilator therapy has been sparked by the development of safe yet effective quaternary anticholinergic compounds including ipratropium bromide, oxitropium, flutropium, atropine methonitrate and others [2]. These quaternary derivatives of atropine retain the bronchodilator properties of the parent compound atropine but are dissimilar in that they are poorly absorbed across biologic membranes. Thus, these agents are effective bronchodilators when given by inhalation but are essentially free of significant extrapulmonary side effects. This combination of safety and efficacy has prompted us to review our treatment strategies for asthma and chronic obstructive lung disease. Most of the data reviewed below concern the most widely studied and widely available of these compounds, ipratropium bromide.
Asthma
Anticholinergic bronchodilators have taught us the importance of distinguishing between asthma and chronic obstructive lung disease when devising our treatment regimens. Anticholinergic and adrenergic bronchodilators have different relative potencies between these disease states. Stable A s t h m a
Numerous studies have examined the bronchodilator potency of quaternary anticholinergics given by metered-dose inhaler to stable ambulatory asthma sufferers and have reported similar results [2-5]. Typically, ipratropium bromide bronchodilates more gradually than fl2-adrenergic agents such as salbutamol, fenoterol, and terbutaline (see Fig. 1). It produces 50% of its bronchodilator effect in 3 rain, 80% in 30 min, and its maximal effect in 1-2 h [3]. The compound is bound more strongly to cholinergic receptors than atropine so that its bronchodilator effects are better sustained. When ipratropium is compared to fl2-adrenergics in asthma, the adrenergic agents show superior bronchodilatation in the first 2-3 h postadministration. The combination of ipratropium and various fl2-agonists has been studied extensively. The combination produces greater bronchodilatation than either agent used singly [4-7]. This additive effect is demonstrable even when supramaximal doses of the adrenergic are given. Anticholinergic bronchodilators may also be combined effectively with theophylline. In a double-blind trial, Wolkove et al. examined the bronchodila-
Anticholinergic Bronchodilators
297
SALBUTAMOL SchlO00. . . . -
8OO[ . ~ . ~
,/
-
Fig. 1. Legend represents mean values for increase in FEV~ above baseline in 25 asthmatic patients after administration of salbutamol and ipratropium. Vertical bars indicate --. SE. Asterisks indicate significant differences between treatment groups: p < 0.05 (reproduced with permission from [4, 18, 24]).
z
O
30
60
gO 120
180
240
300
360
T I M E (minutes)
420
480
200pg S~lbutamol
ASTHMATICS
~ I+F+T c~ E~
°,i
O6
r,1 ,
1 L, the combina-
Anticholinergic Bronchodilators
299
0.7
A
0.6 0.5 _1
,,=
0.4 0.3 0.2 0.1 I
0
45 TIME
9tO
Fig. 3. For 138 patients with acute exacerbations of asthma, mean increase in FEVt above baseline after inhalation of ipratropium (triangles), fenoterol (open circles), or the combination (solid circles). Bars represent plus or minus one standard error [18].
(MIN)
tion regimen was superior to either monotherapy within each group. The bronchodilator advantage of combination nebulizer therapy over monotherapy was more evident in the more severely ill subset of asthmatics, those with initial FEV1 - 1 L; that is, patients in greatest need benefited most from the combination anticholinergic/adrenergic approach. Higgins et al. have recently extended these observations by confirming the superiority of combined salbutamol and ipratropium inhalations when compared to salbutamol inhalations alone in the first 4 h of emergency room asthma therapy [19]. All patients in their study received intravenous corticosteroids. The additive effect of anticholinergic bronchodilators in acute asthma is not the result of suboptimal adrenergic dosing. Two studies of acute asthma, one in adults and one in children, have shown that nebulized ipratropium bromide produces improvements in airflow unobtainable with additional doses of sympathomimetic [20, 21].
Chronic Obstructive Pulmonary Disease The role of anticholinergic bronchodilators in COPD contrasts sharply with their role in asthma. In the former disease, the anticholinergic bronchodilators offer greater relief of airflow limitation and hyperinflation than adrenergic agents. Using an acute bronchodilator challenge, Poppius and Salorrine were among the first to demonstrate the bronchodilator superiority of ipratropium to salbutamol [22]. In a much larger multicenter trial of maintenance therapy in COPD, Tashkin et al. showed that ipratropium's bronchoditator advantage over metaproterienol was evident on the first day of therapy and was unchanged after 3 months of continuous treatment [23]. Contrasting the bronchodilator effects of ipratropium and salbutamol in COPD, Braun et al. confirmed the superiority of the anticholinergic agent and pointed out that ipratropium's superiority was most evident when FEVl was low and there was a long history
300
K. R. Chapman
1.325 -
1.225
- ....
..
: 1.1751.125-
..............
~___
1.0751.025-
...................
0.975
.
.
.
0.250.5 1
• ...............................
2 Time
3 After Treatment,
,i
Fig. 4. In COPD, mean forced expiratory volume in 1 s (FEV0 in response to ipratropium (solid line), salbutamol (dashed line), and placebo (dotted line) [24].
i h
of cigarette smoking [24]. Anticholinergics have also been found more potent bronchodilators than oral theophylline in the treatment of COPD [25]. This bronchodilator superiority of anticholinergic versus adrenergic agents in COPD may lead to the erroneous impression that patients with chronic bronchitis and emphysema are uniquely sensitive to anticholinergic drugs. In truth, the anticholinergic bronchodilators appear to offer a similar amount of bronchodilatation in all varieties of obstructive airways disease. As has been noted previously, when studies examine two patient populations, asthma and COPD, the two groups enjoy very similar FEV1 responses to anticholinergic administration [10, 26]. Typically, the FEV1 increases by 0.2-0.3 L. Indeed, normal subjects show similar improvement in indices of airflow. By contrast, the response to sympathomimetics differs markedly among diagnostic groups; remarkably effective in asthmatic patients, the sympathomimetics may produce little or no improvement in COPD. This lack of acute adrenergic responsiveness has led to the widespread use of the term "irreversible" chronic obstructive lung disease. This concept is being discarded as COPD patients unresponsive to other bronchodilators display useful improvements in airflow in response to anticholinergic compounds [24, 27, 28]. Although anticholinergic agents alone offer maximum achievable airflow in many COPD patients, some appear to benefit from the combination approach [29, 30]. When assessing the need for combination bronchodilator therapy, it would be appropriate to note that the commonly prescribed 2 puffs (40/zg) of ipratropium may be undertreatment. Greater bronchodilator effect is often achieved with 3-4 puffs, making the addition of other agents unnecessary. Again, individual therapeutic trials will be helpful. The role of the anticholinergic drugs in acute exacerbations of COPD remains to be established although published studies suggest that nebulized ipratropium is at least as effective and is perhaps more effective than sympathomimetics [17, 31].
Side Effects
The side effects of adrenergic and theophylline bronchodilators are wellknown. Nonselective adrenergic agents can produce significant adverse cardio-
Anticholinergic Bronchodilators
301
vascular consequences; selective adrenergic compounds are safer but not devoid of hemodynamic effects. Frequent tremor and metabolic side effects have been noted and in some clinical contexts may be troublesome. Theophylline is also beset by side effect problems--minor caffeine-like effects in therapeutic dosages and potentially lethal complications in overdosage. By contrast, the quaternary anticholinergic compounds are remarkably free of side effects. So little of the quaternary anticholinergic compounds are absorbed from the airway mucosa that radiolabeled tracers must be used to perform pharmacokinetic studies. As a result, there are essentially no systemic sequelae of quaternary anticholinergic inhalation. The side effects are local; dryness of mouth and a metallic taste noted by a minority of patients. Problems with increased sputum viscosity or reduced tracheobronchial clearance have been sought but none has been identified [32]. We have been particularly interested in examining the hemodynamic consequences of bronchodilator inhalation. We have found that fl2-selective adrenergic agents produce significant cardiovascular effects. Two puffs of fl2-agonist given by metered-dose inhaler have produced 25%-35% increases in cardiac output in our laboratory. In some healthy subjects, cardiac output may double [33]. By contrast, 8 puffs of ipratropium bromide (4 times the usual recommended therapeutic dose) produces no change in cardiac output [34]. Gross and Bankwala have extended these observations [35]. They have shown that vasodilatation and increased cardiac output produced by adrenergic agents causes a drop in PaO2 in COPD patients, the mechanism being presumably the uncoupling of ventilation/perfusion matching by dilatation of the pulmonary vasculature. They found quaternary ammonium compounds did not produce significant worsening of oxygenation in such patients.
Summary New quaternary anticholinergic compounds produce useful bronchodilatation in adult patients with asthma or with COPD. In asthmatics, anticholinergic compounds are useful adjuncts in a comprehensive bronchodilator regimen. In COPD, anticholinergic compounds generally produce better bronchodilatation than other available agents and do so with fewer side effects.
References 1. Gandevia B (1975) Historical view of the use of parasympatholytic agents in the treatment of respiratory disorders. Postgrad J Med Sl(SuppI 7):13-20 2. Gross NJ, Skorodin MS (1984) Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 129:856-870 3. Pakes GE, Brogden RN, Heel RC, Speight TM, Avergy GS (1980) Ipratropium bromide: a review of its pharmacologic properties and therapeutic efficacy in asthma and chronic bronchitis. Drugs 20:237-266
302
K . R . Chapman
4. Ruffin RE, Fitzgerald JD, Rebuck AS (1977) A comparison of the bronchodilator activity of SCH 1000 and salbutamol. J Allergy Clin Immunol 59:136-141 5. Elwood RK, Abboud RT (1982) The short-term bronchodilator effects of fenoterol and ipratropium in asthma. J Allergy Clin Immunol 69:467-473 6. Lightbody IM, Ingrain CG, Legger JS, Johnston RN (1978) Ipratropium bromide, salbutamol and prednisolone in bronchial asthma and chronic bronchitis. Br J Dis Chest 72:181-186 7. Pierce RJ, Allen CJ, Campbell AH (1979) A comparative study of atropine methonitrate, salbutamol and their combination in airways obstruction. Thorax 34:45-50 8. Rnffm RE, Mclntyre E, Crockett AJ, Zeilonka K, Alpers JH (1982) Combination bronchodilator therapy in asthma. J Allergy Clin Immunol 69:60-65 9. Kreisman H, Frank H, Wolkove N, Gent M (1981) Synergism between ipratropium and theophylline in asthma. Thorax 36:387-391 10. Lefcoe NM, Toogood JH, Blennerhassett G, Baskerville J, Patterson NAM (1982) The addition of an aerosol anticholinergic to an oral beta agonist plus theophyUine in asthma and bronchitis. Chest 82:300-305 11. Rebuck AS, Gent M, Chapman KR (1983) Anticholinergic and sympathomimetic combination therapy of asthma. J Allergy Clin Immunol 71:317-323 12. Smith CM, Anderson SD, Scale JP (1988) The duration of action of the combination of fenoterol hydrobromide and ipratropium bromide in protecting against asthma provoked by hyperpnea. Chest 94:709-717 13. UUahMI, Newman GB, Saunders KB (1981) Influence of age on response to ipratropium and salbutamol in asthma. Thorax 36:523-529 14. Rebuck AS, Marcus HI (1979) SCH 1000 in psychogenic asthma. Scand J Resp Dis 103(Suppl): 186-190 15. Ward MJ, Fentem PH, Smith WHR, Davies D (1981) Ipratropium bromide in acute asthma. Br Med J 282:598-600 16. Ward MJ, MacFarlane JT, Davies D (1982) Treatment of acute severe asthma with intravenous aminophylline and nebulized ipratropium bromide after salbutamol (Abstract). Thorax 37:785 17. Leahy BC, Gomm SA, Allen SC (1983) Comparison of nebulized salbutamol with nebulized ipratropium bromide in acute asthma. Br J Dis Chest 77:159-163 18. Rebuck AS, Chapman KR, Abboud R, ¢t al. (1987) Nebulized anticholinergic and sympathomimetic treatment of asthma and chronic obstructive airways disease in the emergency room. Am J Med 82:59-64 19. Higgins RM, Stradling JR, Lane DJ (1988) Should ipratropium bromide be added to betaagonists in treatment of acute severe asthma? Chest 94:718-722 20. Bryant DH (1985) Nebulized ipratropium bromide in the treatment of acute asthma. Chest 88:24-29 21. Beck R, Robertson C, Galdes-Sebaldt M, Levison H (1985) Combined salbutamol and ipratropium by inhalation in the treatment of acute severe asthma. J Pediatr 107:605-608 22. Poppius H, Salorinne Y (1973) Comparative trial of a new anticholinergic bronchodilator, Sch 1000, and salbutamol in chronic bronchitis. Br Med Clin Res 4:134-136 23. Tashkin DP, Ashutosh K, Bleecker ER, et al. (1986) Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. Am J Med 81(Suppl 5A):59-67 24. Braun SR, McKenzie WN, Copeland C, Knight L, Ellersieck M (1989) A comparison of the effect of ipratropium and albuterol in the treatment of chronic obstructive airway disease. American Medical Association. Arch intern Med 149:544-547 25. Bleecker ER, Johns M, Britt EJ (1988) Greater bronchodilator effects of ipratropium compared to theophylline in chronic airflow obstruction. Chest 94(1 suppl):3S 26. Gross NJ (1987) Anticholinergic agents in chronic bronchitis and emphysema. Postgrad Med J 63(Suppl 1):29-34 27. Marini J J, Lakshminirayan S (1980) The effect of atropine inhalation in "irreversible" chronic bronchitis. Chest 77:591-596
Anticholinergic Bronchodilators
303
28. Passamonte PM, Martinez AJ (1984) Effect of inhaled atropine or metaproterenol in patients with chronic airway obstruction and therapeutic serum theophylline levels. Chest 85:610-615 29. Brown IG, Chan CS, Kelly CA, Dent AG, Zimmerman PV (1984) Assessment of the clinical usefulness of nebulized ipratropium bromide in patients with chronic airflow limitation. Thnrax 39:272-276 30. Chart CS, Brown IG, Kelly CA, Dent AG, Zimmerman PV (1984) Bronchodllator responses to nebulized ipratropium and salbutamol singly and in combination in chronic bronchitis. Br J Clin Pharmacol 17:103-105 31. Backman R, Hellstrom PE (1985) Fenoterol and ipratropium bromide in respirator treatment of patients with chronic bronchitis. Curr Ther Res 38:135-140 32. Gross NJ (1988) Ipratropium bromide. N Engl J Med 319:485-494 33. Chapman KR, Smith DL, Rebuck AS, Leenen FHH (1984) Hemodynamic effects of an inhaled beta2 agonist. Clin Pharmacol Ther 35(6):762-767 34. Chapman KR, Smith DL, Rebuck AS, Leenen FHH (1985) Hemodynamic effects of inhaled ipratropium bromide; alone and combined with an inhaled B2 agonist. Am Rev Respir Dis 132:845-847 35. Gross J, Bankwala Z (1987) Effects of an anticholinergic bronchodilator on arterial blood gases of hypoxemic patients with chronic obstructive pulmonary disease: comparison with a beta adrenergic agent. Am Rev Respir Dis 136:1091-1984
The Role of Anticholinergic Bronchodilators in Adult Asthma and Chronic Obstructive Pulmonary Disease K. R. Chapman Division of Respiratory Medicine, Toronto Western Hospital and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
Abstract. Our renewed interest in anticholinergic bronchodilator therapy has been sparked by the development of safe yet effective quaternary anticholinergic compounds including ipratropium bromide, oxitropium and atropine methonitrate. These agents offer gradual and sustained bronchodilatation to patients with asthma and to patients with COPD. However, their role in the maintenance treatment of these two diseases differs significantly. In asthma, the anticholinergic drugs have useful additive properties when used with adrenergic drugs or theophylline. They may be a particularly useful component of combination regimens in patients with disease of more than mild severity and in older patients. The combination of inhaled adrenergic and anticholinergic drugs is also useful in the acute setting for acute exacerbations of asthma. In chronic obstructive lung disease, the anticholinergic compounds offer greater bronchodilatation than adrenergic drugs for the majority of patients. Thus, the inhaled anticholinergic drugs may be considered as useful initial choices in the chronic maintenance therapy of COPD.
Key words: Quaternary anticholinergic--Asthma--COPD. Introduction
Our present interest in antichohnergic bronchodilators represents the rediscovery and refinement of a form of therapy that is centuries old. Ayurvedic medical literature confirms that atropine-containing botanicals such as Datura stramonium were smoked for centuries in India for a variety of medicinal purposes including the relief of dyspnea [1]. Stramonium therapy was introduced to
Offprint requests to: Dr. K. R. Chapman, Suite 4-011, Edith Cavell Wing, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada.
296
K.R. Chapman
Western medicine at the turn of the nineteenth century and by mid-century, Salter's Treatise on A s t h m a listed stramonium as one of the truly effective remedies in this disorder. However, stramonium was not without hazard. Salter noted potent anticholinergic systemic side effects following the unpredictable absorption of the active alkaloid, atropine. Although atropine cigarettes and atropine-containing asthma powders were available well into the middle of the twentieth century, their use became infrequent after the introduction of adrenergic agents. Our renewed interest in anticholinergic bronchodilator therapy has been sparked by the development of safe yet effective quaternary anticholinergic compounds including ipratropium bromide, oxitropium, flutropium, atropine methonitrate and others [2]. These quaternary derivatives of atropine retain the bronchodilator properties of the parent compound atropine but are dissimilar in that they are poorly absorbed across biologic membranes. Thus, these agents are effective bronchodilators when given by inhalation but are essentially free of significant extrapulmonary side effects. This combination of safety and efficacy has prompted us to review our treatment strategies for asthma and chronic obstructive lung disease. Most of the data reviewed below concern the most widely studied and widely available of these compounds, ipratropium bromide.
Asthma
Anticholinergic bronchodilators have taught us the importance of distinguishing between asthma and chronic obstructive lung disease when devising our treatment regimens. Anticholinergic and adrenergic bronchodilators have different relative potencies between these disease states. Stable A s t h m a
Numerous studies have examined the bronchodilator potency of quaternary anticholinergics given by metered-dose inhaler to stable ambulatory asthma sufferers and have reported similar results [2-5]. Typically, ipratropium bromide bronchodilates more gradually than fl2-adrenergic agents such as salbutamol, fenoterol, and terbutaline (see Fig. 1). It produces 50% of its bronchodilator effect in 3 rain, 80% in 30 min, and its maximal effect in 1-2 h [3]. The compound is bound more strongly to cholinergic receptors than atropine so that its bronchodilator effects are better sustained. When ipratropium is compared to fl2-adrenergics in asthma, the adrenergic agents show superior bronchodilatation in the first 2-3 h postadministration. The combination of ipratropium and various fl2-agonists has been studied extensively. The combination produces greater bronchodilatation than either agent used singly [4-7]. This additive effect is demonstrable even when supramaximal doses of the adrenergic are given. Anticholinergic bronchodilators may also be combined effectively with theophylline. In a double-blind trial, Wolkove et al. examined the bronchodila-
Anticholinergic Bronchodilators
297
SALBUTAMOL SchlO00. . . . -
8OO[ . ~ . ~
,/
-
Fig. 1. Legend represents mean values for increase in FEV~ above baseline in 25 asthmatic patients after administration of salbutamol and ipratropium. Vertical bars indicate --. SE. Asterisks indicate significant differences between treatment groups: p < 0.05 (reproduced with permission from [4, 18, 24]).
z
O
30
60
gO 120
180
240
300
360
T I M E (minutes)
420
480
200pg S~lbutamol
ASTHMATICS
~ I+F+T c~ E~
°,i
O6
r,1 ,
1 L, the combina-
Anticholinergic Bronchodilators
299
0.7
A
0.6 0.5 _1
,,=
0.4 0.3 0.2 0.1 I
0
45 TIME
9tO
Fig. 3. For 138 patients with acute exacerbations of asthma, mean increase in FEVt above baseline after inhalation of ipratropium (triangles), fenoterol (open circles), or the combination (solid circles). Bars represent plus or minus one standard error [18].
(MIN)
tion regimen was superior to either monotherapy within each group. The bronchodilator advantage of combination nebulizer therapy over monotherapy was more evident in the more severely ill subset of asthmatics, those with initial FEV1 - 1 L; that is, patients in greatest need benefited most from the combination anticholinergic/adrenergic approach. Higgins et al. have recently extended these observations by confirming the superiority of combined salbutamol and ipratropium inhalations when compared to salbutamol inhalations alone in the first 4 h of emergency room asthma therapy [19]. All patients in their study received intravenous corticosteroids. The additive effect of anticholinergic bronchodilators in acute asthma is not the result of suboptimal adrenergic dosing. Two studies of acute asthma, one in adults and one in children, have shown that nebulized ipratropium bromide produces improvements in airflow unobtainable with additional doses of sympathomimetic [20, 21].
Chronic Obstructive Pulmonary Disease The role of anticholinergic bronchodilators in COPD contrasts sharply with their role in asthma. In the former disease, the anticholinergic bronchodilators offer greater relief of airflow limitation and hyperinflation than adrenergic agents. Using an acute bronchodilator challenge, Poppius and Salorrine were among the first to demonstrate the bronchodilator superiority of ipratropium to salbutamol [22]. In a much larger multicenter trial of maintenance therapy in COPD, Tashkin et al. showed that ipratropium's bronchoditator advantage over metaproterienol was evident on the first day of therapy and was unchanged after 3 months of continuous treatment [23]. Contrasting the bronchodilator effects of ipratropium and salbutamol in COPD, Braun et al. confirmed the superiority of the anticholinergic agent and pointed out that ipratropium's superiority was most evident when FEVl was low and there was a long history
300
K. R. Chapman
1.325 -
1.225
- ....
..
: 1.1751.125-
..............
~___
1.0751.025-
...................
0.975
.
.
.
0.250.5 1
• ...............................
2 Time
3 After Treatment,
,i
Fig. 4. In COPD, mean forced expiratory volume in 1 s (FEV0 in response to ipratropium (solid line), salbutamol (dashed line), and placebo (dotted line) [24].
i h
of cigarette smoking [24]. Anticholinergics have also been found more potent bronchodilators than oral theophylline in the treatment of COPD [25]. This bronchodilator superiority of anticholinergic versus adrenergic agents in COPD may lead to the erroneous impression that patients with chronic bronchitis and emphysema are uniquely sensitive to anticholinergic drugs. In truth, the anticholinergic bronchodilators appear to offer a similar amount of bronchodilatation in all varieties of obstructive airways disease. As has been noted previously, when studies examine two patient populations, asthma and COPD, the two groups enjoy very similar FEV1 responses to anticholinergic administration [10, 26]. Typically, the FEV1 increases by 0.2-0.3 L. Indeed, normal subjects show similar improvement in indices of airflow. By contrast, the response to sympathomimetics differs markedly among diagnostic groups; remarkably effective in asthmatic patients, the sympathomimetics may produce little or no improvement in COPD. This lack of acute adrenergic responsiveness has led to the widespread use of the term "irreversible" chronic obstructive lung disease. This concept is being discarded as COPD patients unresponsive to other bronchodilators display useful improvements in airflow in response to anticholinergic compounds [24, 27, 28]. Although anticholinergic agents alone offer maximum achievable airflow in many COPD patients, some appear to benefit from the combination approach [29, 30]. When assessing the need for combination bronchodilator therapy, it would be appropriate to note that the commonly prescribed 2 puffs (40/zg) of ipratropium may be undertreatment. Greater bronchodilator effect is often achieved with 3-4 puffs, making the addition of other agents unnecessary. Again, individual therapeutic trials will be helpful. The role of the anticholinergic drugs in acute exacerbations of COPD remains to be established although published studies suggest that nebulized ipratropium is at least as effective and is perhaps more effective than sympathomimetics [17, 31].
Side Effects
The side effects of adrenergic and theophylline bronchodilators are wellknown. Nonselective adrenergic agents can produce significant adverse cardio-
Anticholinergic Bronchodilators
301
vascular consequences; selective adrenergic compounds are safer but not devoid of hemodynamic effects. Frequent tremor and metabolic side effects have been noted and in some clinical contexts may be troublesome. Theophylline is also beset by side effect problems--minor caffeine-like effects in therapeutic dosages and potentially lethal complications in overdosage. By contrast, the quaternary anticholinergic compounds are remarkably free of side effects. So little of the quaternary anticholinergic compounds are absorbed from the airway mucosa that radiolabeled tracers must be used to perform pharmacokinetic studies. As a result, there are essentially no systemic sequelae of quaternary anticholinergic inhalation. The side effects are local; dryness of mouth and a metallic taste noted by a minority of patients. Problems with increased sputum viscosity or reduced tracheobronchial clearance have been sought but none has been identified [32]. We have been particularly interested in examining the hemodynamic consequences of bronchodilator inhalation. We have found that fl2-selective adrenergic agents produce significant cardiovascular effects. Two puffs of fl2-agonist given by metered-dose inhaler have produced 25%-35% increases in cardiac output in our laboratory. In some healthy subjects, cardiac output may double [33]. By contrast, 8 puffs of ipratropium bromide (4 times the usual recommended therapeutic dose) produces no change in cardiac output [34]. Gross and Bankwala have extended these observations [35]. They have shown that vasodilatation and increased cardiac output produced by adrenergic agents causes a drop in PaO2 in COPD patients, the mechanism being presumably the uncoupling of ventilation/perfusion matching by dilatation of the pulmonary vasculature. They found quaternary ammonium compounds did not produce significant worsening of oxygenation in such patients.
Summary New quaternary anticholinergic compounds produce useful bronchodilatation in adult patients with asthma or with COPD. In asthmatics, anticholinergic compounds are useful adjuncts in a comprehensive bronchodilator regimen. In COPD, anticholinergic compounds generally produce better bronchodilatation than other available agents and do so with fewer side effects.
References 1. Gandevia B (1975) Historical view of the use of parasympatholytic agents in the treatment of respiratory disorders. Postgrad J Med Sl(SuppI 7):13-20 2. Gross NJ, Skorodin MS (1984) Anticholinergic, antimuscarinic bronchodilators. Am Rev Respir Dis 129:856-870 3. Pakes GE, Brogden RN, Heel RC, Speight TM, Avergy GS (1980) Ipratropium bromide: a review of its pharmacologic properties and therapeutic efficacy in asthma and chronic bronchitis. Drugs 20:237-266
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