The relief of airways obstruction by deptropine citrate and isoprenaline

Brit. o7. Dis. Chest Q968) 62, 8i.

The Relief of Airways Obstruction by Deptropine Citrate and Isoprenaline F. J. PRIME Department of Medicine, Brompton Hospital, London THF following account consists of work done in assessing the possibilities of using a bronchodilator drug, deptropine citrate, which was introduced into this country from the continent in 196 i. It had already received some attention from the continental workers but this was by no means complete from the clinical point of view and lacked the backing of objective measurements. New work was therefore initiated in this country by the manufacturers who wished to confirm and extend the continental work. Much of this new work has already been published and confirms its bronchodilator activity and gives some indications of its limitations. The pharmacology of deptropine has been fully worked out and reported by Funcke, de Jonge, Tersteege, Mulder, Harms and Nauta (I962). The best clinical trials have also been reported by van Ufford and Bruens (i962), Schmidt (i962), McNicol and Bruyns (I964) , and Kennedy (I965). The present report is complementary to these papers in that it was to some extent a basis for them, since it was carried out at about the same time and provided some of the basic data as to dosage and presentation of the drug. No reference is given in this paper to the extensive trials which have now been conducted on the use of deptropine in the field of anesthesia where it has been used as a premedicating drug in place of atropine. The possibility of using it in combination with isoprenaline was suggested by the work of Chamberlain, Muir and Kennedy (i 962) who tested a mixture of isoprenaline and atropine; they found that the prompt action of the former drug could be usefully prolonged by the atropine.

Pharmacology Deptropine is the name given to the compound 3-[Io, I i-dihydro(5H)dibenzo(a,d) cyclohepten-5-yloxy]tropane, which is used in the form of the citrate. This compound was found to have strong anticholinergic, antiserotonin and antihistaminic properties. It was found to be particularly effective in preventing experimental bronchospasm in guinea pigs, whether this was induced by histamine, acetylcholine, or by 2 per cent. egg albumen given to sensitized animals. Its action was many times more effective than atropine or diphenylhydramine. Dosage to these animals was at the rate of 5 mg/kg orally or 0.75 mg/kg subcutaneously. It had no action on the cardiovascular system except in extremely large doses; nor was there any evidence of antiadrenergic (Receivedfor publication, December x967)

82

PRIME

properties as far as could be judged from the effect on the changes in blood pressure following noradrenaline administration intravenously in anaesthetized cats. Its central effects are similar to those of atropine but are much weaker. The acute toxicity is low, as evidenced by the LDs0 in rats which is 445 mg/kg and in dogs 75 mg/kg given orally. The chronic toxicity measured over a period of six months in dogs was also low, a dose of 32 mg/kg having little effect on growth. The drug was used in the present work in the form of a 2 per cent. solution inhaled as a spray from a metered dose device. During the course of the initial investigation it became apparent that deptropine took some time to exert its action; for this reason it was decided to investigate the possibility of combining it with a shorter acting bronchodilator such as isoprenaline in order to hasten the bronchodilation and possibly make use of the longer activity of the deptropine. What follows, therefore, is divided into three main sections. First an assessment of the strength and duration of the action of deptropine; secondly, some experiments designed to indicate a range of dosage which could usefully be combined with isoprenaline and thirdly an assessment of the action of the combined drugs.

x. An assessment of the bronchodilator action of deptropine alone As a standard of comparison it was decided to compare the action of deptropine with that ofisoprenaline given in a similar way, i.e. as an aerosol from a metered dose apparatus. Twenty patients were invited to take part in the trial of whom I I were patients suffering from allergic asthma and nine from mild chronic bronchitis. All of them were known to have labile airways obstruction which was relieved promptly by isoprenaline itself. Both drugs were administered to all the patients on successive days when it had been established that the patients were in as stable a state as possible from the point of view of their bronchospasm. The action of the drugs was estimated by their effect on: (I) Forced Expiratory Volume at one second (F.E.V.I.o) (2) Forced Vital Capacity (F.V.C.) (3) Specific Airways Conductance (Sp.C.) The first of these was measured from direct recordings made with a light spirometer using a rapidly moving kymograph. The whole body plethysmograph was used for estimating airways conductance and this was expressed as the specific airways conductance by dividing it by the lung volume at the instant of measurement. Five estimates were made at a time and the average of the last three of these was used in assessing the results. Each patient was examined in the sitting position before the drug was administered and at intervals of 5, I5, 3 ° and 60 minutes thereafter and further measurements were made at hourly intervals up to six hours. Two "blasts" of the metered dose apparatus each containing I m g of deptropine or 1.5 mg of isoprenaline were administered. Care was taken to ensure that the patient used the apparatus properly

THE RELIEF

OF A I R W A Y S O B S T t ~ U C T I O N B Y D E P T R O P I N E

83

CITRATE

a n d in particular to be certain that the c h a n n e l t h r o u g h w h i c h the aerosol is delivered to the m o u t h p i e c e w a s unobstructed. T h e nature o f the p r o c e d u r e and its object was in every case explained to the patient w h o w a s asked to n o t e particularly a n y side effects he m i g h t experience. Results. T h e s e are s u m m a r i z e d in T a b l e I w h i c h s h o w s differences at corresponding times b e t w e e n the m e a s u r e m e n t s m a d e after deptropine a n d after isoprenaline. A graph (Fig. x) o f the m e a n values indicates clearly the general T A B L E I . S H O W I N G MEAN VALUES FOR F O R C E D V I T A L C A P A C I T Y ( F . V . C . ) , F O R C E D E X P I R A T O R Y V O L U M E A T ONE SECOND ( F . E . V . : t . 0 ) AND S P E C I F I C A I R W A Y S C O N D U C T ANCE ( S p . C ) BEFORE AND A F T E R T H E A D M I N I S T R A T I O N OF I S O P R E N A L I N E ( I ) AND D E P T R O P I N E ( D ) T O 2 0 P A T I E N T S SUFFERING FROM REVERSIBLE A I R W A Y S OBSTRUCTION, S I G N I F I C A N T DIFFERENCES B E T W E E N T H E VALUES MARKED W I T H ASTERISKS* H A V E A P R O B A B I L I T Y OF OCCURRING BY CHANCE NO MORE T H A N ONCE IN 2 0 T R I A L S

F.V.C. Time hr. rain.

-

(I)

5

1.75 °.24

--

15

i 2 3 4 5

3° -

-

F.E.V.l.o

(D) S.E.

(I)

i-63 1.7I

0.204 0.293

I.Oi i-5o

o'43*

I'80*

O'3OI

2.56* 2"50 2.31 2.06 1"83" 1"69"

2.oi* 2"4° 2.51 2"49 2"47* 0"39*

o.2~2 0"342 0-371 o.212 o.3II o'321

Sp.C

(1)) S.E.

(I) 0.080 0.096*

(D) 0.080 0.084

&E.

0-92 i.! i

0.25 ° o.21o

0.0063 o.oo5i

I'6I*

I'I3"

0"212

O'I20"

O'O90** O'OIo2

1.72 i "55 1.3o 1-o6" I.OI* o.98*

1.33 i "43 I-51 1.44" 1.47" 1.42"

o'224 0"253 0"232 o.i9o 0"241 o.2o 9

o.iio* 0.098 o'o96 0"087** 0"082* o.o81"

o.o96* 0.096 o'o98 0.096** 0"095* o.o89*

o.oio 4 o-o138 o.o125 0.0042 0.0058 o-oo35

difference in the pattern o f responses and shows the i m m e d i a t e effect o f isoprenaline contrasted w i t h the slower, m o r e p r o l o n g e d effect o f deptropine. All the asthmatic patients responded well to both drugs but the response w a s less striking in t w o o f the bronchitics b o t h o f w h o m were recovering f r o m acute attacks.

>I--

< r, 0 ._] 2'0( t.-

N hJ O tic O tu I-0

~ 5

15

/o "--~--®----°~[ 50

(min)

i

2

hours

3

4

TIME

FIG. I. Graph of the mean values given in Table I for Forced Vital Capacity before and after the administration of Isoprenaline and Deptropine.

84

PRIME

2. The bronchodilator action of isoprenalinefollowed by deptropine The contrast of the general pattern of results suggested the second part of this enquiry. The object was to see whether the use ofisoprenaline followed by deptropine would act in a similar way to the mixture of isoprenaline and atropine methonitrite used by Chamberlain et al. (op. cit.) who showed that the addition of atropine prolonged the immediate action of the isoprenaline. The choice of dosage for the drugs was made arbitrarily on the basis of previous experience with both drugs. Three different dose combinations were selected, these were: (A) (B) (C)

Is otJrenaline

D eptropine

o.I mg o'I 5 mg o.I 5 mg

0-5 mg o-I mg o.I 5 mg

Although there was no a priori reason to suppose that deptropine would act synergistically with isoprenaline, the possibility had to be borne in mind especially because deptropine has no antiadrenergic activity. The experimental procedures used were the same as those described above and the drugs were given in the form of an aerosol from a metered dose apparatus as before. Measurements were made on this occasion, however, before administration and at intervals of 15, 3 ° and 60 minutes but only once after that, at 4 hours. The three combinations of dosage were given in random order to four patients whose airway obstruction was more than usually stable before the administration of the bronchodilator. They all suffered from pollen asthma and were examined during the winter. They were not receiving any systematic bronchodilator treatment but all responded to isoprenaline with a considerable rise in vital capacity and F.E.V.1.0 T A B L E I I . S H O W I N G T H E D I F F E R E N C E S IN T H E E F F E C T S OF T H E T H R E E M I X T U R E S B A N D C ) o f I S O P R E N A L I N E A N D D E P T R O P I N E D E S C R I B E D IN T H E T E X T U P O N T H E MEAN V A L U E S OF F O R C E D V I T A L C A P A C I T Y (F.V.C.), F O R C E D E X P I R A T O R Y V O L U M E

(A,

AT ONE SECOND (F.E.V.z.0) AND SPECIFIC AIRWAYS CONDUCTANCE (Sp.C.) OBSERVED IN FOUR

PATIENTS AT

STATED INTERVALS AFTER RECEIVING THE CESSIVE DAYS IN R A N D O M O R D E R

F.V.C. Time hr. rain. i 4

5 15 3o -

A 2-313 2"51o 2"53 ° 2"518 2"423 2.363

B 2.313 2"553 2"613 2"635 2.628 2.61o

M I X T U R E S ON SUC-

F.E.V.vo C

A

B

2.27 ° 2"5°o 2"54o 2"567 2"478 2-463

I.X18 I'253 I'295 1"3o8 1"23o 1"175

1-18o 1"318 x'37 o 1"398 I'4O 5 I'375

Sp.C. C 1"235 1"398 1"45o I'435 1"448 1"363

A 0"0695 o.o8Io o-o958 o'o985 o.o9io 0"0833

B 0"0723 o'o995 o.Io58 o'1123 o.i143 o'II33

C 0"0775 o'o984 O.ILOO o'Iio2 o.io93 0"0965

After s u b t r a c t i n g the v a r i a t i o n d u e to patients, drugs a n d t h e days of administration, t h e residual m e a n squares are o-oo4I 1. for F.V.C., o'oo36 I. for F . E . V . v o a n d o.oool 3 units for Sp.C. These m e a n squares are used to estimate the significance of the differences between the m e a n s recorded above.

THE RELIEF

OF

AIRWAYS

OBSTRUGTION

BY

DEPTROPINE

85

CITRATE

Results. A s u m m a r y o f the m e a s u r e m e n t s r e c o r d e d is given in T a b l e I I . This shows t h a t t h e r e is no a p p r e c i a b l e difference in the effects o f the two mixtures c o n t a i n i n g the larger dose levels o f d e p t r o p i n e whilst t h e r e was evidence t h a t the first m i x t u r e , w h i c h c o n t a i n e d the smallest dose of isoprenaline secured less t h a n a m a x i m u m response. T h e m i x t u r e c o n t a i n i n g the largest dose o f d e p t r o p i n e caused a n u n d e s i r a b l y h i g h incidence o f side effects including, in two cases, mydriasis w i t h t e m p o r a r y paralysis of a c c o m m o d a t i o n . A l t h o u g h these effects did n o t last long t h e y w e r e u n p l e a s a n t e n o u g h to w a r r a n t the a v o i d a n c e o f this m i x t u r e . I t was c o n c l u d e d t h a t the best m i x t u r e to use was the second. H a v i n g m a d e this selection the last p a r t o f this trial was started. 3. Testing the selected mixture I n this, the effects o f the selected m i x t u r e w e r e o b s e r v e d o n 12 patients t h r o u g h o u t the course o f one d a y c o n t r a s t i n g these w i t h the effects o f isop r e n a l i n e m e a s u r e d on a second day. O b s e r v a t i o n s using the s a m e m e t h o d s as before were a g a i n m a d e at intervals u p to five hours as in the first e x p e r i m e n t a n d the results are r e c o r d e d in T a b l e I I I t o g e t h e r w i t h notes o n the analysis o f TABLE

III.

S H O W I N G MEAN VALUES F O R F O R C E D V I T A L

CAPACITY

(F.V,C,),

FORCED

EXPIRATORY VOLUME DURING ONE SECOND (F.E.V.1.0) AND SPECIFIC AIRWAYS CONDUCTANCE (Sp.C.) MEASURED IN I 2 SUBJECTS W I T H A I R W A Y S O B S T R U C T I O N B E F O R E AND

AT STATED

Tim~ hr. min. -

I

2 3 4 5

5 15 3o -

-

INTERVALS AFTER THE INHALATION OF AN AEROSOL OR A MIXTURE OF ISOPRENALINE AND DEPTROPINE

F.V.C. q.)

OF ISOPRENALINE

(I)

(ID)

f . g . r . . o (z.)

sp.c.

(I)

(ID)

(I)

(ID)

(I)

(ID)

2.oo2 2"363 2"55° 2"593 2"49o 2"343 2-128 1"937 1"867

2-o5° 2"377 2"514 2"572 2"58o 2"585 2-418 2"46o 3"343

o'998 1"285 1"417 I'37-3 I'322 I"217 I.I53 x'o47 o'94o

I'O69 1"2o7 1"422 1"465 1"478 I"442 1.367 1"367 1"377

o'o7o8 o'o982 o'1152 o.II98 o'1o98 o.o788 o.o8o8 o'o738 o'o72o

o'o735 o'o955 o.Io82 O.ILOO o'Io65 o.I26O o.Io35 o'o993 o'o96o

An analysis of variance carried out on the original data from which the mean values were calculated showed that the variation due to the drugs was significant compared with the residual variance for all the measurements. The residual variance itself gives a measure of "error" from which the standard error of the differences between the means can be calculated. These were o-I23 for F.V.C., o'o25 for F.E.V.I.o and o'oo7 for Sp.C. variance. T h e findings confirm the m o r e p r o l o n g e d action o f the isoprenalined e p t r o p i n e m i x t u r e c o m p a r e d w i t h isoprenaline alone. N i n e o f the patients noticed t h a t the m i x t u r e g a v e rise to dryness o f the m o u t h b u t they were n o t p a r t i c u l a r l y distressed b y this. I t was r e m a r k a b l e t h a t n o n e c o m p l a i n e d o f u n u s u a l p a l p i t a t i o n after taking the m i x t u r e .

86

PRIME

Discussion Some comments are in place with regard to the data published here. In the first place, it should be noted that the enquiry was not concerned with making any distinction between the effectiveness of this drug in treating the different diseases which m a y produce airways obstruction in man. McNicol and Bruyns (I 964) advert to this matter in their admirable account of a double-blind trial of deptropine in a group of patients some of whom were bronchitic and others asthmatic. T h e y make the point, supported by experimental evidence, that the use of the drug for patients with airways obstructions m a y not, in the long run, produce any different effect from that of isoprenaline or any other bronchodilator. The object of the work reported here was quite different from theirs in that here the only interest is in the effects of the drug in the immediate few hours after administration. From this point of view, the patients were to be regarded more as indicators of the effect than as subjects of an experimental therapeutic regimen. This fact must be clearly borne in mind if any comparison is contemplated between the results shown here and those shown in the paper quoted, in which the main emphasis was on long-term results. Isoprenaline was used in this work as a standard for reference of bronchodilator activity with which to compare the activity of deptropine; it was only after the initial investigations that it became apparent that the two drugs could be combined. Although there was some hesitation at first in accepting the combination on account of the lack of anfiadrenergic action of deptropine (which it was thought might enhance the risks of cardiac irregularity) extensive electrocardiographic data accumulated over the past eighteen months has failed to demonstrate any risk. It is proper, however, to mention some points of clinical importance in the use of deptropine. First, deptropine has unwanted effects which are often noticeable. The commonest of these is the tendency to produce dryness of the mouth. This is not an invariable occurrence and it has been found that it is evanescent; about 3° per cent. of the patients using an isoprenaline-deptropine combination noticed it, but they nearly all found that it disappeared within the course of a few days. A few found it intolerable. The other important unwanted effect is mydriasis and paralysis of accommodation; as a matter of experience, this has never been found in patients who have received reasonable dosage. It is recommended that no more than I.O m g of deptropine be given in one day and that no more than 0.2 mg should be given at any one time. The usual rate of dosage from the Brontisol metered dose inhaler is two puffs properly administered not more than five times a day. I n the individual case, this should give maximum bronchodilation throughout the day and at the same time avoid all unwanted effects other than occasional dryness of the mouth already mentioned. A question arises in the use of this drug in the chronic bronchitic patient, in whom it may be desirable to limit the amount of mucoid secretion. McNicol and Bruens (1964) noted a diminution of this, as might have been expected from the atropine-like properties of deptropine. Marshall Clarke (1964) also mentions this. Some clinicians m a y not agree that this action is desirable and it should be noted that in the past, atropine overdosage has been

THE RELIEF OF AIRWAYS OBSTRUCTION BY DEPTROPINE filTRATE

87

blamed for the ill-effects of sputum retention after surgical operations. In general, it would seem illogical to inhibit the production of sputum when this is purulent or when there is considerable risk of retaining infected sputum." On the other hand, there is justification for treating the really excessive volume of mucoid secretion which may be a feature of chronic bronchitis, especially in the elderly.

Summary An account is given of investigations into the short term effectiveness of deptropine citrate and a mixture of this drug with isoprenaline. Deptropine was found to have a longer period of action than isoprenaline; combined with isoprenaline the immediate effect of the latter was prolonged by the action of the deptropine.

Acknowledgements I am gratefuI to Brocades (Great Britain) Ltd for the opportunity to study this drug and for providing it by itself and in combination with isoprenaline in metered dose inhalers. My thanks are also due to the patients who generously volunteered to help me by being subjects for study. Finally, it is a great pleasure to thank my eldest daughter Jane for some help in the writing and my youngest, Sally, who drew Fig. I for me.

References CHAMBERLAIN, D. A., MUIR, D. C. F., • KENNEDY, K. P. (1962). Atropine methonitrate and isoprenaline in bronchial asthma. Lancet, 2, lO19. KENNEDY, IV[. C. S. (I 965). "Bronchodilator" action of deptropine citrate with and without isoprenaline by inhalation. Brit. med. o7, 2, 916. MARSHALL CLARKE, G. B. (I964). The symptomatic treatment of chronic bronchitis using dibenzheptropine citrate (Bronfina). Brit. 07. Dis. Chest, 58, x35. SCHMIDT, F. (1962). Lecture at Antwerp. VAN UFFORD, W . J . Q . . , & BRUENS, J. C. E. (1962). Mededeelingen Stichting Experimented Andersoek AUergologie, 7.