The bronchodilator effects of chlorpheniramine in childhood asthma

Br.

J. Dis.

Chest

(1979)

73, 297

THE BRONCHODILATOR EFFECTS OF CHLORPHENIRAMINE IN CHILDHOOD ASTHMA R. C. Department

GROGGINS,

of

A. D. MILNER

Child Health, Nottingham Queen’s Medical Centre,

AND

G. M.

University Nottingham

STOKES

Medical

School,

Summary Significant improvement in lung function has been demonstrated following the inhalation of chlorpheniramine. The doses which were used caused local irritation and are probably unsuitable for routine clinical use. Nevertheless, we believe that antihistamines deserve further investigation in the treatment of childhood asthma.

Although histamine is widely regarded as playing a central role in the genesis of bronchoconstriction in asthma (Schild et al. 1951), antihistamines have not found a place in the treatment of this condition and are generally considered to be inactive (Lancet 1955). Their failure to produce bronchodilation may be due to inadequate local concentrations of antihistamine or even to a histamine-releasing action (Hawkins 1955). Popa (1977) showed that large intravenous doses of chlorpheniramine produce bronchodilation in adult asthmatics. This drug is an HI-blocker with little atropinic or antiserotonin activity (Tozzi et al. 1976). Apart from causing drowsiness, it is safe and free of side effects. As ,6z-adrenergic stimulants may be very effectively administered as a nebulized solution with fewer side effects than equivalent oral or intravenous therapy, we conducted a pilot study to determine whether chlorpheniramine was an effective bronchodilator in childhood asthma when inhaled in this way. Patients and Methods Ten children, aged eight years seven months to 14 years two months (mean age 11 years), requiring regular treatment for chronic severe asthma, were studied. They had suffered from asthma for one to 12: years (mean 6.3 years) with the onset of symptoms between the ages of six months and 13 years (mean 4.5 years). Heights ranged from 117 to 163 cm (mean 140.9 cm) and weights from 19.95 to 49.5 kg (mean 31.3 kg). Six children had a family history of atopy and the three children on whom skin tests had been performed showed positive reactions to multiple antigens. Seven children had required hospital admissions (range one to six) and eight had been treated with courses of oral steroids. No child was receiving oral steroids at the time of testing. Their routine medication included salbutamol by inhalation (ten), beclomethasone diproprionate (eight), sodium cromoglycate (two) and theophylline (one). All children had previously undergone lung function testing and were accustomed to the procedures employed. Patients were asked to stop routine medication at least 12 hours before testing. On arrival in the

298

R. C. Groggins, A. D. Milner and G. M. Stokes

respiratory function laboratory they were questioned about their recent health and a clinical examination was performed. Base-line measurements of peak expiratory flow rate (PEFR) (best of three attempts using a Wright’s peak flow meter), forced vital capacity (FVC) and forced expiratory volume in 0.75 seconds (FEVs.75) (best of two satisfactory attempts using a Morgan water-filled spirometer) were recorded. The measurements were repeated after a 1.5-minute rest. The children then inhaled a solution of chlorpheniramine in sterile water using a commercially available face mask and nebulizer (Pari). Respiratory function tests were repeated 2, 5, 10, 15, 20, 30, 45, 60, 75, 90 and 120 minutes following inhalation. Finally, they inhaled 1 ml of nebulized 0.5% salbutamol respirator solution made up to 2 ml with water. Respiratory function tests were repeated 15 minutes later. The children were studied on three occasions (whenever possible on three consecutive days), when they were treated respectively with 2,4 and 8 mg of chlorpheniramine maleate made up to 2 ml by dilution of the standard intravenous preparation with water. These doses were selected as less than 25% of the solution is inhaled and available for systemic absorption, making the maximum nebulized dose approximately equal to the usual oral dose. The spirometry readings were corrected to BTPS. The project was approved by the local Ethical Committee and informed parental consent was obtained on all occasions.

RESULTS

There was considerable variation in the base-line measurements of lung function when calculated as a percentage of expected from height (Cogswell et al. 1975a, b). Initial PEFR and FEV0.75 were within 2.5% of expected on 14 of the 30 and nine of the 30 assessments respectively. The children tended to have more severe airways obstruction on the day they attended for the 4 mg dose (Figs 1, 2) but the differences between the base-line readings did not reach statistical significance. The inhalation of chlorpheniramine produced coughing on --2mg

------4w

-a

60

I

mg

I

Salbutamol

I

I

I

90

120 PS

Chlorpheniramine

50 I

I

I

I

I

I

I

I

-20 -10 0 10 20 30 40 50 60 Time Imin) Fig. and

2. Changes in PEFR 5 mg of salbutamol

after inhalation in ten children

of solutions with asthma

containing

2,4

and

8 mg

of chlorpheniramine

Chlorpheniramine

299

in Childhood Asthma

--Znmg

120

110

I I -20 -10

I 0

-----

4 mg

-

8 mg

I I 10 20

I 30

1 40

I I 50 60

I 120

I 90

I PS

Time (min)

Fig. 2. Changes and

5 mg

in FEVo.75 after of salbutamol in ten

inhalation children

of solutions with asthma

containing

2,4

and 8 mg of chlorpheniramme

13 of the 30 occasions. This occurred at all doses and on three occasions was associated with a fall in either PEFR or FEV 0.75 of between 5 and 15% at two minutes. Three of the children coughed at all doses. However, all three treatment groups showed an improvement in PEFR and FEV a.75 at two minutes which progressed over the next 30-45 minutes (Figs 1, 2). Further rises in PEFR and FEVa.75 were seen after the inhalation of salbutamol at two hours, so that the group means all finished within 8.2% of the expected. When expressed as a percentage change from the initial reading, most post-treatment results were significantly better than the base-line (Tables I, II). Although Table I. Mean

percentage

change

(min)

Post

Sal

“P
(+

Chlovpheniramine

Time

2 5 10 15 20 30 45 60 75 90 120

in PEFR

2mg

7.3rt15.3 19.0+22.4* 20.6k20.6” 21.7k24.0” 22.3k22.3 23.Ok26.7” 23.1128.7” 27.8k33.1 26.4k36.5 33.8k33.7 38.3i44.5

(8)” (5) (6) (4)

42.1540.3 1

compared

with

initial,

SD)

from

initial

value

dose

4mg

8mg

15.1 k22.6 22.5+22.8* 23.6k25.2” 25.5k25.2” 25.6123.7” 30.2k29.7” 29.4230.7s 27.6k31.6” 26.1k32.6” 30.4rt33.9”

11.5~20.2 17.7k22.1” 21.2522.4” 21.2221.4” 25.5+21.9-t 27.9+27.7t 32.8k33.1” 36.5k33.71 36.0+35.2-t 40.2+33.5-t 34.2k28.81

46.9k38.1

60.3k53.3

19.1

(9)”

1

using

k26.3”

Student’s

t-test.

300

R. C. Groggins, A. D. Milner and G. M. Stokes Table II. Mean percentage

change in FEVo.75 (+ 1 Chlorpheniramine

Time (min)

--2

2 5 10 15 20 30 45 60 75 90 120

ll.lk20.2 13.0f37.0 10.4k35.2 8.7k30.4 9.9f35.8 11.9f32.3 22.9k38.1 21.Ok26.4 9.2f7.8 12.Ok17.1 14.5rtr17.7

Post Sal

(9) (8)s (5) (6) (4)

38.9k29.9

“P
compared

Table 111. Number

with imtial,

of children

SD)

from initial

value

dose

4mg

8mg

9.8k23.9 12.4k30.0 13.5k26.9 18.1 f29.5 17.3k30.8 23.7k27.7” 29.4f31.2” 29.8f33.6 27.4+25.2? 28.3 +40.0 33.6238.8”

5.6k23.6 16.1f20.2” 18.0&14.7-t 24.5~16.8+ 25.5k22.4.f 28.3+25.2+ 30.6f30.0” 32.8+24.9-f 33.Ok33.1” 29.3+28.2-f 28.6+26.2-i-

44.4k47.5

48.9k46.3

using Student’s

with greater

t-test.

than 15% improvement

in PEFR

or

FEVo.m Chlorpheniramine dose 2mg 4mg 8mg Total sx Children

whose initial

Improvement

in PEFR

Improvement

in FEVo.75

All

Init. < 75 yO*

All

Init. < 75 %*

s/10 6110 6/10 17130

416 416 414 12/16

s/10 s/10 7110 17130

518 516 517 15/21

results were less than 75% of the expected

figure.

the improvement as measured by FEV 0.75 appeared to be dose related, only at 75 minutes did the difference between responses to the 8 mg and the 2 mg regimens reach statistical significance. The improvements in peak flow rate failed to show this trend. When the children were examined individually an improvement of at least 15% was seen on 17 occasions (Table III). Considering only those occasions when initial values were less than 75% of expected, a response was seen on 12 out of 16 occasions as determined by PEFR and 15 of 21 by FEV a.75 (Table III). Only 50% of those children who failed to respond to chlorpheniramine showed an improvement of 15% or more when treated with salbutamol.

DISCUSSION Recent work by Nogrady et al. (1978), following that of Popa (1977), suggests that the place of antihistamines in the management of adult asthma needs to be re-examined. Both these groups have shown that antihistamines, if given in appropriate doses by appropriate routes, will lead to appreciable bronchodilation. We used chlorpheniramine because of Popa’s encouraging findings and because it is a relatively pure antihistamine with few

Chlo+heniramine

in Childhood Asthma

301

antiserotonin and anticholinergic effects. The nebulized route was selected as this provides a simple means of producing high concentration in the lung without the need for injection and with little systemic absorption. This was a preliminary open trial attempting to determine whether chlorpheniramine was an effective bronchodilator when given by inhalation and to identify the most appropriate dose. The response to chlorpheniramine was often apparent within two minutes and reached a plateau by 3045 minutes, rather earlier than the 60 minutes observed in adults using inhaled clemastine or intravenous chlorpheniramine (Popa 1977; Nogrady et al. 1978). As the response to the three dose regimens was broadly similar, we consider it unlikely that higher concentrations would produce further improvements. Nevertheless, most children improved further after the inhalation of salbutamol. This may be related to the different modes of action of the two drugs. The coughing which sometimes led to a slight fall in lung function makes the concentrations used in this trial unsuitable for general clinical use. It may be that smaller concentrations can be tolerated without loss in therapeutic response. ACKNOWLEDGEMENTS

We wish to thank the children and their parents for helping us with the project. Financial support was gratefully received from the Asthma Research Council. Requests fog yepyints to: DY A. D. Milnev, Department Centre, Nottingham.

of Child Health, Queen’s Medical

REFERENCES ANNOTATION (1955) Anti-histamines and asthma. Lancet 2, 1182. COGWELL, J. J., HULL, D., MILNER, A. D., NORMAN, A. P. & TAYLOR, B. (1975~~) Lung function in childhood, I. BY. J. Dis. Chest 69, 40. COGSWELL, J. J., HULL, D., MILNER, A. D., NORMAN, A. P. & TAYLOR, B. (197.53) Lung function in childhood, II. Br. J. Dis. Chest 69, 118. HAWKINS, D. F. (1955) Bronchodilator actions of antihistamine drugs. BY. J. Phavmac. 10, 230. NOGRADY, S. G., HARTLEY, J. P. R., HANDSLIP, P. D. J. & HURST, N. P. (1978) Bronchodilation after inhalation of the andhistamine clemastine. Thorax 33, 479. POPA, V. P. (1977) Bronchodilator activity of an Hl blocker, chlorpheniramine. g. Allergy din. Immunol. 59, 54. SCHILD, H. O., HAWKINS, D. F., MONGAR, J. L. & HERXHEIMER, H. (1951) Reactions of isolated human asthmatic lung and bronchial tissue to specific antigen. Histamine release and muscular contractions. Lancet 2, 376. TOZZI, S., ROTH, F. E. & TABACHNICK, I. I. A. (1974) The pharmacology of azataclihe, a potential anti-allergy drug. Agents Actions 414, 264.