Comparative Bronchodilator Responses to Atropine and Terbutaline in Asthma and Chronic Bronchitis

Com,parative Bronchodilator Responses to Atropine and Terbutaline in Asthma and Chronic Br·onchitis· ThomasW. Chick, M.D.,·· and John W. Jenne, M.D.t

We have compared broncbodllator responses to atropine and terbutaline in 39 chronic bronchitics and 16 stable asthmatics. Fasting subjects were given either 1.05 mg atropine or 5.0 mg terbutaline orally. Pulmonary function was 8S8essed using the peak responses, namely: three 6O-minute intervals for terbutaline and three 3O-minute intervals for atropine. A subgroup of five reactive bronchitis patients was given a placebo with no response. Areas UIICIer the percent response-time interval curve were cOlllpared. Both patient groups responded to the

G old and associates

have demonstrated in the dog that antigen-induced bronchoconstriction can be abolished by administration of atropine. This single observation has important implications and has been said to indicate that the parasympathetic nervous system is of major importance in the causation of airway obstruction in asthma. However, in human asthma, many studies2--i have shown that atropine is less effective than adrenergic agents in bringing about bronchodilation. Obviously, these may be only dose-related diHerences. However, several investigators2 »S»8 have shown that patients with chronic bronchitis respond at least as well to atropine as to adrenergic agents. In view of the uncertainty of the role of the parasympathetic nervous system in asthma and chronic bronchitis, we undertook the present study to compare the airway responses of patients with chronic bronchitis and asthma to atropine and terbutaline. The use of either a vagal stimulant or a beta blocker was held to be too hazardous. We used tests reflecting both large and small airway dynamics. The small oral dose of atropine was held to be valid for these studies after preliminary trials in chronic bronchitis demonstrated its efficacy 1

·From the Research Service, Veterans Adminstration Hospital, Albuquerque. ···Chief, Pulinonary Function Laboratory; Assistant Professor of Medicine, University of New Mexico School of Medicine. tChief, Pulmonary Disease Section; Associate Professor of Medicine, University of New Mexico School of Medicine. Manuscript received December 22; revision accepted Aprtl 7. Reprint requests: Dr. ]enne:l VA Hoapital:l 2100 Ridgecrest Drloo:l SE:I Albuquerque 87108

CHEST, 72: 6, DECEMBER, 1977

same degree to atropine and terbutaliDe with respect to reduction of airway resistaDce. However, the FEV1 and V50 respooses to terbutaline were markedly enhanced compared to atropine in the II8tbmatia whOe equal to the atropiDe response in the bronchitis patients. Thus, atr0pine appean to exert its etfect upon both large and small airways in bronchitis, but predomiDantly 011 large airways in 8sthma. The results are couistent with a state of e.... hanced vagal tone in small airways Ia bronchitis compared to asthma, but other explanatlo.. are conceivable.

as a bronchodilator. The terbutaline response was considered to be the index of reversible bronchospasm present against which the atropine response could be compared. METHODS

The study group consisted of 39 patients with chronic bronchitis and 16 patients with asthma. The chronic bronchitis group ha~ chronic cough with sputum production by history, conBrmed by the British Medical Research Council questionnaire, and airflow obstruction by the forced expiratory flow maneuver. They did not have eosinophilia of sputum or peripheral blood. The asthmatic patients, of both the extrinsic and intrinsic variety, had variability in the degree of airflow obstruction when tested on repeated occasions and!or a response of 0.4 liters or more to an eight-minute inhalation of 1 ml of a 1:200 isoproterenol solution in 4 ml of water from a Maximyst aerosol generator and the presence of over 15 percent eosinophils in their sputum or 300 eosinophils/mm3 in the majority of peripheral blood samples. The bronchitis patients were average age 53 years (± 6 years) and the asthmatic patients averaged 49 years (± 6 years) . Airway resistance (Raw) and specific airway resistance (airway resistance time lung volume, SRaw) were measured by the panting technique using constant volume body plethysmograph (Cardiopulmonary Instruments, Inc, Houston). Maximum expiratory flow volume (MEFV) curves were measured by using a dry seal spirometer (model 5300 Pulmo . Lab, Cardiopulmonary Instruments, Inc). From the (MEFV) curves the following parameters were obtained: forced expiratory volume in the first second ( FEV 1 ), flow at 50 percent exhaled volume (\150); and vital capacity (VC). Peripheral pulse was measured by palpation. The patients reported to the Pulmonary Function Laboratory at 8 AM after an overnight fast and cessation of oral theophylline-containing compounds for 12-18 hours, although inhalers could be used until four hours before testing. On one

COMPARAnYE BRONCHODILATOR RESPONSES TO ATROPINE AND TERBUTAUNE 718

PERCENT CHANGE X TIME INTERVAL = 40+45+~=105

-

2 .

I~ .s

f j

FIGURE

see text.

T.tJutaIine 1. Calculation of area under the percent response-time interval curve. For explanation

day, the patients underwent baseline pulmonary function testing and received the te.rbutaline dose consisting of a 5.0 mg tablet by mouth. Pulmonary function tests were repeated at 1.0, 2.0, and 3.0 hours after drug administration. On another day, the patients received atropine, 1.05 mg by mouth and pulmonary function was tested at 0, 0.5, 1.0 and 1.5 hours after the drug was administered. A subgroup of 11 bronchitis and ten asthmatic patients received 0.6 mg atropine subcutaneously rather than by mouth, and five bronchitis patients with strong bronchodilator responses to atropine were given an oral placebo for comparison. Responses of pulmonary function are expressed as the area under the percent response-time inte",al curve by the trapezoidal technique. As an example ( Fig 1) , the percent responses are 40, 45 and 40 percent at time intervals 1, 2, and 3; the area under the curve-is 40 45 40 or 105 percent response X time interval units. It is to be emphasized that the time intervals were one hour for terbutaline and 30 minutes for atropine; these time intervals were chosen because previous trials demonstrated that they encompassed peak drug effects. The comparisons of the drug responses for each group of patients were analyzed for statistical significance by the Student's t test for paired data. Nonparametric statistical comparisons were also carried out, but are not cited, since the oral and subcutaneous responses to atropine were combined in the analysis. Despite this, the results with the nonparametric analyses were completely consistent with the t-test re-

+

+

and Raw for the two drug tests in either group. Table 2 displays the percent-time interval responses of the MEFV curve and plethysmographic airway resistance for each patient group to terbutaline and oral atropine. It can be seen that, in terms of FEV1 and V50, the patients with chronic bronchitis had bronchodilation after atropine equal to that after terbutaline. This pattern also held true for the plethysmographic measures of airway resistance ( Raw, SRaw ). In the patient with asthma, the FEV1 and V50 showed much greater responses after administration of terbutaline than after atropine. Thus, the FEV1 response to atropine was only 42 percent response-time interval units compared to 99 units for terbutaline (P < 0.(01), whereas the responses were equal in the chronic bronchitis group (66 vs 62 units, respectively). Similarly, the 'Iso response to atropine in asthma was 119 units compared to 353 units for terbutaline (P < 0.(01), whereas responses were equal in chronic bronchitis Table I-Baeline PrdmoRGry Funedora (J'alae. are MetUU and Slandard DeI1iadou) Asthma Chronic Bronchitis (n == 16) (n == 39) Terbutaline Atropine Terbutaline Atropine

sults.-

REsuLTS Terbutaline side-effects were tremor in the majority of patients and, occasionally, a sensation of weakness. Atropine caused only mouth· dryness in most patients. Table 1 shows baseline pulmonary function. There were no differences in baseline FEV 1, '150 720 CHICK, JENNE

FEVl,liters

1.94 .70

2.09 .76

1.65 .63

1.69

V50, liters/sec

1.33 1.13

1.52 1.07

.98 .68

1.00

Raw, cmH2O/L/sec

2.22 .83

2.46 1.22

1.97

1.90

.96

.68

.66

.88

CHEST, 72: 6, DECEMBER, 1977

Table 2--AinDCIY Raporue.

'0 A'ropine and Terbu'aline *

Asthma

(n == 16)

Terbutaline VC

FEV1

V. Raw

BRaw

SD

51 80

SD

99 112

SD

353 436

SD

-91 50

SD

Atropine

NS p
p
34 34

SD

42 47

SD

119 146

SD

-84 61

NS

-93

-108

53

Chronic Bronchitis (n-39) Terbutaline

NS

80

SD 8D

42 32

NS

62 66

199 168

N8 N8

-58 59

N8

-72

58

N8

Atropine 46 34

66 48 200 178

-72 48 -87 49

·Responses represent areas under the percent response vs. time interval curves. Values are mean and standard deviations

(200 vs 199 units, respectively). Airway resistance responses were roughly similar with atropine and terbutaline for both the asthmatic and the bronchitis patients. . Comparison of the atropine response to a placebo in five bronchitis patients suggested a marked difference. The mean response of FEV1 to atropine was 72 area units compared to only 10.6 area units for the placebo response. In the ten asthmatic and 11 bronchitis patients in whom terbutaline and 0.6 mg subcutaneous atropine were compared, the patterns of response were qualitatively very similar to the oral results. For example, the atropine FEV1 response was 39 percent of the terbutaline response in the asthmatic group. The differences did not reach statistical significance in these smaller groups. DIscuSSION

Our data suggest that atropine exerts its bronchodilatory action on both large and small airways in the chronic bronchitis group, but predominantly on large airways in the group with asthma. This is evident from the plethysmographically determined-airway resistance which showed equal improvement after use of atropine and terbutaline in both groups; however, VIO, a test of small airway caliber, was seen to improve to a greater degree after use of terbutaline in patients with asthma. Relative to the effects of terbutaline, atropine was more effective on the small airways in chronic bronchitis than in asthma patients. These results supplement those of several other investigators. In a group with chronic bronchitis,

CHEST, 72: 6, DECEMBER, 1977

Klock et al6 found equal improvement in lung function during three-week periods of inhaled atropine or isoproterenol. Crompton2 studied the airway response in patients with both asthma and bronchitis to adrenaline by inhalation and by subcutaneous injection, aminophylline by intravenous injection (0.5 mg), isoproterenol by inhalation, and atropine sulfate (0.6 mg) subcutaneously. Among these drugs, atropine gave the weakest bronchodilatory response in the asthmatic, but the strongest response in the bronchitis group. Kennedy and Thursby-PelhamS compared inhaled adrenaline, isoproterenol, the combination of Isoproterenol and atropine, and atropine methonitrate alone in asthma patients. For the first 60 minutes of the study, the atropine compound gave less bronchodilation than isoproterenol and adrenaline. However, the effect of atropine was more prolonged so that at 120 minutes the bronchodilation was actually greater for atropine than for the catecholamines. One might criticize our failure to employ a placebo in all patients, since the placebo effect rather than the drug effect might be involved for either oral tablet. However, the oral dose of atropine, while small and ineffective in causing an increase in pulse rate, was as effective as terbutaline, a proven bronchodilator, in the chronic bronchitis patient. Furthermore, the subpopulation of five patients with bronchitis in whom a placebo was compared to atropine, showed no FEV1 response to placebo but a strong FEV l response to atropine. Finally, although a placebo effect may exist for both drugs, their comparison is qualitatively valid since the placebo effect probably cancels out

COMPARAnYE BRONCHODILATOR RESPONSES TO ATROPINE AND TERBUTAUHE 721

These findings support a major role for the para-:sympathetic nervous system in the large and small airway obstruction of chronic bronchitis. Possible cholinergic mechansims to consider are an effect on bronchial secretions and an effect on smooth muscle tone. Thus, 0.4 mg atropine has been shown by Annis and associates 7 to redu~ tracheal mu~us velocity in women undergoing general anesthesia. Blair and Woods8 demonstrated that topically applied atropine significantly retarded ciliary motility and mucous' How in anesthetized cats. However, Costello et al,9 using an amount of atropine sufficient to cause a dry mouth or a 10 percent increase in pulse rate, was unable to show an effect on sputum volume, viscosity or chemical composition in four patients with asthma, two with chronic bronchitis and two with bronchiectasis. It is probably safe to assume that any effects of atropine on airway dynamics that occur by virtue of the mucous content are minor, if indeed they occur at all. The rapid onset of atropine effect favors its well-recognized smooth muscle action as the principal factor. One can speculate that the enhanced eHect of atropine in chronic bronchitis results from a greater vagal tone in these structures secondary to the effect of inflammation decreasing the firing threshold for the irritant receptors with consequent increase in resting vagal tone. The role of the parasympathetic nervous system in the pathogenesis of asthma· is controversial. Obviously, parasympathetic tone is present and prominent, since its lysis by anticholingergic agents such as aerosolized SCH 1000 results in marked branchodilatation. I G-17 The dose of atropine used in our studies was small. Yet it was as effective as terbutaline in decreasing specific airway resistance in both the asthma and chronic bronchitis groups. The subcutaneous dose of 0.6 mg, sufficient to cause an increase in pulse rate, was similar in its effects. Yet, both doses of atropine were relatively less effective than terbutaline in asthma in those tests reflecting :small airway function, ie, the FEVI, and Vso. Lack of effect on small airways in asthma could be explained by several possible mechanisms. An obvious one, and perhaps the correct explanation, is that vagal tone to the small airways is relatively less in asthma than chronic bronchitis. A second possibility that must be considered is that vagal tone to the small airways in asthma is so pronounced that atro'pine shows little effect. A third possibility, even more intriguing, is that the cholinergic receptors in the small airways in asthma are altered so that acetylcholine has a higher intrinsic activity or that atropine is only a partial antagonist. The studies of Kessler and associates l8 in dogs are 722 CHICK, JENNE

consistent with the incomplete relaxation of small airways by atropine compared to the effect of sympatho~etic agents. After induction of airway consbiction by specific antigen challenge in sensitized dogs, bronchography using tantalum demonstrated bronchoconstriction down to airways as small as 0.5 mm diameter. A large dose of atropine (0.2 mg/kg IV) was effective in partially revers~g the large airway constriction and there was no addi.tional relaxation with subsequent isoproterenol infu. sions. However, although atropine also partially reversed the small airway constriction, further relaxation occurred with isoproterenol. Anatomic corroboration of parasympathetic innervation in small airways in man has not been demonstrated, but ElBermani and Grant l9 demonstrated acetylcholinesterase-positive fibers down to the terminal airways . in the Rhesus monkey. These provocative differences on small airway function in the two diseases, apart from their possible pathogenetic implications, introduce the therapeutic possibility that anticholinergic agents will particularly benefit small airway function in chronic bronchitis, provided that their delivery to these sites can be accomplished. ACKNOWLEDGMENTS: This study was supported by United States Public Health Services, Contract No. I-HR22943 and a grant from the Astra Pharmaceutical Products Incorporated, Worcester, Mass. We are indebted to Drs. R. J. Rosandich, B. H. Feldman and R. C. Fields for their kind referral of paatfents to the study, and to Rosemary Mitchell and Richard Hall, and to Mr. Kurt Bake of Astra for close support.

1 Gold WM, Kessler GF, Yu DYC: Role of the vagus nerves in experimental asthma in allergic dogs. J Appl Physio) 33:719-725, 1972 2 Crompton GK: A comparison of responses to bronchodilator drogs in chronic bronchitis and chronic asthma. Thorax 23:46-55, 1968 3 Kennedy NCS, Thursby-Pelham DC: Some adrenergic drugs and atropine methonitrate given by inhalation for asthma: A comparative study. Br Med J II: 1018-1021, 1964. 4 Yu DYC, Galant SP, Gold WM: Inhibition of antigen induced bronchoconsbiction by atropine in asthniatic patients. J Appl Physiol 32:823-828, 1972 5 Astin TW: Reversibility of airways obsbuction in chronic bronchitis. Clio Sci 42:725-733, 1972 6 Klock LE, Miller TD, Norris AH: A comparative study of atropine sulfate and isoproterenol hydrochloride in chronic bronchitis. Am Rev Respir Dis 112:371-376, 1975 7 Annis P, Landa J, Uchtiger M: Effects of atropine on velocity of tracheal mucous in anesthetized patients. Anesthesiology 44:74-77, 1976 8 Blair AMSN, Woods A: The effects of isoprenaline, atropine and disodium cromoglycate on ciliary motility and mucous flow measured in vivo in cats. Br J Pharmacal 35:379-380, 1969 9 Costello JF, Lopez-Vidiero MT, Charman J: The effects

CHEST, 72: 6, DECEMBER, 1977

10

11 12 13 14

of atropine sulfate on sputum production. Postgrad Med J 51( Suppl 7) 107, 1975 (abstr) Pappius H, Salorinne Y, Viljaenn AA: Inhalation of a new anticholinergic drug, scn 1000, in asthma and chronic bronchitis: Effect on airway resistance, thoracic gas volume, blood gases and exercise induced asthma. -Bull Physiopath Resp 8:643-652, 1972 Gunter W, Kamburoff PL: The bronchodilator effect of a new anticholinergic drug, SCH 1000. Cur Med Res Opin 2:282-287, 1974 Petrie CR, Palmer KNV: Comparison of aerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma. Br Med J I:~2, 1975 Emirgil C, Dwyer K, Baskett P: A new parasympatholytic bronchodilator: A study of its onset of effect after inhalation. Cur Therapeutic Res 17:215-224, 1975 Storms WW, DoPico GA, Reed CE: Aerosol scn 1000:

An anticholinergic bronchodilator. Am Rev Respir Dis

111:419-422, 1975 15 Gross NJ: SCH 1000: A new anticholingergic bronchodilator. Am Rev Resp Dis 112:823-828, 1975 16 SimoDSSon BG, Johnson B, Strom B: Bronchodilatory and circulatory effects of inhaling increasing doses of an anticholinergic drug, Ipratropium bromide (SCH 1(00). Scand J Resp Dis 56: 138-149, 1975 17 Chapman TT: The effect of scn 1000 MDI and salbutamol MDI on ventilatory function in patients with chronic bronchitis, assessed by spirometry. Postgrad Med J 51 (Suppl 7) 112, 1975 (abstr) 18 Kessler GF, Austin JHM, Graf PD: Airway constriction in experimental asthma in dogs: Tantalum bronchographic studies. J Appl Physiol 35:703-708, 1973 19 El-Bermani IA, Grant M: Acetylcholinesterase-positive nerves of the Rhesus monkey broncbial tree. Thorax 30: 162-170, 1975

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CHEST, 72: 6, DECEMBER, 1977

COMPAunVE BRONCHODILATOR RESPONSES TO ATROPINE AND TERBUTALINE 723