.

4- ___

EXPECTORANTS

V. E. HENDERSON AND A. H. TAYLOR

From the Laboratory of Pharmacology of the University of Toronto

Received for publication September 9, 1910

No therapeutic group of drug-stuffs suffers so greatly perhaps

from lack of exact methods of examination and careful observa-
tion as the expectorants. Consequently the few facts which the
authors have gathered are presented, though they feel that they
have by no means exhausted the subject and hope to continue
their investigation, which force of circumstances has for the time
interrupted.
There seem to be only two papers which deal experimentally
with this subject. The first is by Rossbach (5) published 1882.
The method he employed was the observation with the naked
eye of the exposed tracheal mucous membrane in cats and dogs.
The surface of the epithelium was dried with blotting paper and
the time noted before it again became covered with mucus. The
conclusions that he draws from his experiments may be sum-
marised as follows: 1st, The intravenous administration of sodium
carbonate led to a decrease in mucus production: the same seemed
to be true of ammonium carbonate. 2nd, Local application of a
0.5 per cent solution of sodium carbonate produced no noticeable
effect, while dilute solutions of ammonia or of acetic acid similarly
applied brought about marked secretion. 3rd, Pilocarpine given
intravenously caused a marked secretion; less marked but still
abundant secretion was brought about by the intravenous admin-
istration of apomorphine and emetine. Rossbach considers the
action of these three latter drugs to be peripheral either on local
ganglia, nerve endings or the gland cells themselves. The second
paper is by Calvert, (2) whose attention was drawn to the dis-
 4SS44 S #4 “‘ SS4 S
55 #{149} S 44 , ; 4 S 4 , 4 S S 55 S 4SS
.5#{231}w555

154 v. E. HENDERSON AND A. H. TAYLOR

crepancy between the experimental results of Rossbach and the

successful clinical use of alkalies as expectorants in medicine.
In consequence using the same method as Rossbach he repeated
with great care some of the former’s experiments. He concluded
that intravenous administration of sodium carbonate does cause
an increase in secretion, thus contradicting Rossbach. The first
of the three experiments considered by him to be positive would
seem to an unbiased observer to be at the least doubtful. In
other experiments he finds that intravenous injection of iodides
increases tracheal secretion. Intravenous administration of em-
etine increases the secretion ; while saponin in small doses does not
increase and in large doses decreases owing to its deleterious
heart action.
Neither of these papers were known to us until wj had concluded
our experiments. The method that they employed we had, how-
ever, tested and abandoned for two reasons. Firstly, because the
liability to subjective error was so great and secondly because the
appearance of secretion on any area of trachea is due to two fac-
tors, the secretion of the glands in that area and the secretion
brought to the area by the cilia of the areas below. The obser-
vations on the movements of mucus by the cilia, reported in a
subsequent paragraph, establish how irregular this may be under
the experimental conditions employed by these observers and
make it quite impossible to judge of the rate of secretion by the
method they employ. The point in dispute between these two
observers seems to us to be one of not great importance as sodium
carbonate is never given intravenously as an expectorant and
we have no reason for assuming that the small doses used as expec-
torants could have any marked effect upon the alkalinity of the
blood. The experiments reported in this paper on ammonium
carbonate, taken in conjunction with those in a previous paper by
one of us upon salivary secretion (4) show how much more impor-
tant the reflex secretion is than that produced by direct action
upon the centres. The experiments reported in this paper and in
the previous paper just alluded to show also that emetic drugs
even in doses insufficient to cause vomiting do cause a marked
reflex secretion. The emetic effect of sodium carbonate is so
 Th” S S5 4 , 55 r ‘ S S

EXPECTORANTS 155

well known, that the entire explanation of its expectorant action

can be deduced from it.
The trachea and the bronchi are very richly supplied with
mucous glands. In the cat these are found even when the carti-
lage has almost completely disappeared from the bronchi. Mu-
cous epithelial cells seem also to occur. When we examine a series
of sections of tracheae and bronchi and realize the wealth of
glandular material, it seems remarkable that persons in normal
health do not notice more the activity of these glands. They must
produce but a small quantity of mucus, as normal persons do not
find it necessary to cough or hawk to get rid in the morning of
mucus which has accumulated in the pharynx.
Mucus excreted by the bronchial glands is carried very rapidly
upwards by the actionofthecilia. BeforevonGebhardt’s (3) inter-
esting paper appeared we had carried out a series of experiments
to ascertain how quickly mucus might be expected to be carried
up the bronchi and trachea to the larynx. In experiment XVI of
Gebhardt, undertaken 2 minutes after the dog’s death, powder
placed upon the opened trachea travelled at the rate of 5.3 cm.
per minute (320 cm. in 60 minutes). In this case the trachea
was moistened with Ringer’s solution through which air had been
passed. In other observations a rate of about 1-2.2-3.2 cm. per
minute seemed more common. Our observations were also made
on the trachea but during the life of the animal. It was observed
that dust, even if fine, did not travel so rapidly as mucus which
was stained by dropping into the trachea fine droplets of a solution
of indigo-carmine. In several experiments the indigo-carmine was
injected through the trachea by means of a fine syringe needle
and the time noted when it appeared at the larynx. A fine canula
inserted low down through the wall of the trachea served to deliver
air from a respiration pump when necessary. The fastest rate
observed was 4 cm. in 65 seconds (experiment XVI); the average
seemed to be 1.5-2 cm. per minute. Judged by the movements
of dust or stained mucus, the cilia appeared to be greatly affected
by the thickness and viscosity of the layer of mucus covering them.
We noted also that dust or stained mucus very frequently did
not travel in a straight line but tended to curve to one side or the
S 55 5 #{149} S 4 S#{231}4 ,w

156 v. E. HENDERSON AND A. H. TAYLOR

other. Streaks of stain were very commonly seen and Gebhardt

seems correct in his conclusion that not all the cilia in the trachea
or on any ring are working at the same rate. The data furnished
by these experiments showed that mucus due to any stimulation
should reach the larynx within 10-20 minutes. Several experi-
ments were made on the effects of moistening the surface of the
trachea with saliva to which had been addedvarious expectorants.
In no case could a definite action of the expectorant be detected
The most extensive series is reported in experiment XLII.
Several methods of collecting the secretion from the bronchi
and trachea were tried. The one most extensively used was the
following. The animal (cats were almost exclusively used) was
anaesthetised with chloroform (C) or ether (E), or both, which
were followed by urethane for the period of observation. One
short limb of a thin-walled glass Y-piece was tied into the upper
end of the trachea, the second short limb connected by a short
piece of rubber tubing to one side of a calcium chloride U-tube or
was inserted directly through the cork in the top of the U-tube.
The third limb of the Y-piece was connected to the blast side of a
Meyer’s respiration pump, to the exhaust cylinder of which the
other side of the U-tube was attached. The animal was placed
upon its belly with its body on an incline, so that there was a
sharp slope in the trachea and in its connections to the U-tube,
so that gravity aided the flow of the mucus after it passed into
the canula. With this method not only the fluid mucus but any
water evaporated from the mucus and also the water evaporated
from the lungs was estimated. The water from this latter source
varied greatly with the temperature of the animal, the amount
of air passing into the lung and also probably with changes in the
animal’s circulation. In consequence it was found necessary to
observe carefully the animal’s temperature, to place an accurate
governor on the pump and note that no marked changes took
place in the animal’s circulation. This imposed very great diffi-
culties which were not in every case overcome: only successful
cases are reported. Errors from these sources were also in part
avoided by the considerable length of time (10-20 minutes) over
which each observation was extended.
 55545

EXPECTORANTS 157

The bronchial-gland centre seems to be almost as easily dis-

turbed as the salivary centre, and as the action of many of the
expectorants are reflex this again caused much trouble. Our
experiments seemed to show a parallelism between the activity
of the bronchial centre and that for the salivary glands.
The experiments carried out with potassium iodide yielded
results similar to those on the submaxillary gland. The presence
of this drug in the blood stream was not sufficient in itself to set
up bronchial secretion. It is excreted by the bronchial glands,
experiments VI, XI, XV. If it acts as an expectorant, its action
must be reflex from the stomach or mouth as in experiment 27
in the paper in Salivary “ Secretion.” (4) No action was detected
upon the cilia. Our results are directly opposed to those of Cal-
vert, who thought that intravenous administration of iodides
increased the bronchial secretion.
If the centre was depressed as in experiment XXXVIII am-
monium salts even in large doses failed to bring about increased
secretion. If, however, the centre was active, secretion was
brought about. In experiment XXXVI a dose equivalent to 184
gr. of ammonium carbonate for a man of 132 lbs., given intrave-
nously, induced a marked increase of secretion. It is to be remem-
bered that the animal was under an anaesthetic which must
have greatly decreased the irritability of the gland-centre. A very
good flow was caused by two and one half times this dose per os.
and when it is recalled that according to Saleski and Biedi and
Winterberg (1) one-half to four-fifths of the ammonium absorbed
from the intestine will disappear in the liver, the effectiveness of
this dose must be ascribed in part at least to a reflex action. A
relatively smaller dose given intravenously caused an equally
marked effect in experiment XV. Biedi and Winterberg showed
that in unanaesthetised dogs symptoms referable to the central
action of ammonium, occurred when enough ammonium was in-
jected to increase its amount in the blood from a normal of about
1.5 mgm. per 100 g. of blood to 2-2.5 mgm. In a dog weighing
8.7 k. this required, in their experiment 8, 0.15 g. NH3 (approxi-
mately 0.45 g. of ammonium chloride), the injection lasted eight
minutes. Man has normally about 0.9 mgm. NH3 per 100 g.
 555 4 45 5

158 V. E. HENDERSON AND A. H. TAYLOR

5 blood and if it had to be increased by the same amount 0.5 mgm.

per 100 g. to produce a central effect then a man of 65 kilos would

54 require 3.49 g. Now the therapeutic dose recommended is much
S smaller than this and as a part of that absorbed disappears in the
S liver, it can hardly be suggested that any action can occur on the
centres. Its action must be reflex. In only one case where
anunonium salts were given per os, experiment XXXIX, did we
obtain a result which was slow in developing as though due to an
action of the ammonium after absorption. In all other cases
the rise occurred promptly, if it occurred at all. One would not
expect that the reflex action of ammonium salts could be long
sustained.
Ammonium chloride was found by Biedi and Winterberg to be
less toxic than the carbonate when given intravenously and it is
odd that experiment XXXVI so closely confirms this. Experi-
ment XXXIX shows an action which may in part be reflex or may
be on the centre.
Ipecacuanha, given as either the wine or the fluid extract
(experiments XV, XXXVII and XXXVIII) was found to bring
about secretion, when given per os, if the centre was active. If
it was depressed (the lack of salivary flow was taken as an evi-
dence of this), no effect was obtained. When given intravenously
as emetine for example, experiment XL, a flow was at times
obtained, but as a rule the disturbance of the circulation was so
marked as completely to obscure this action.
Antimony was also found an effective reflex agent as may be
seen in such a protocol as that of experiment XLI.
Apomorphine acts on the bronchial centre and has probably no
action on the glands, as was stated by Rossbach. (5) In no experi-
ment was an action obtained when the centre was depressed,
and it was difficult to obtain striking results even with the centre
intact, as disturbances in circulation were so common. However,
thick bronchial mucus in some cases appeared in the canula
and this was taken as an indication of the action of apomorphine
although the increase in weight of the absorption tube was not
much greater than that of its controls. In no case when the
center was depressed did mucus appear in the canula in the way
 T-545;45 S #{149}
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EXPECTORANTS 159

just referred to. In the paper upon Salivary Secretion”

“ it was
shown that apomorphine had no peripheral action on the salivary
gland.
Senega, given per os as the tincture, causes a good flow, as is
shown by experiment XXXVIII.
Pilocarpine increases bronchial secretion, even if the centre is
depressed, and atropine inhibits the flow when thus produced.
Experiment XXXVI shows characteristically the pilocarpine
increase and also the effect of atropine.
With the exception of experiment XXXIX, all increases in
secretion which were observed after administering an expecto-
rant per os occurred within the first 10-20 minutes and in no
case did the increase continue for a long period. The animals
were of course anaesthetised and it is quite possible that more
prolonged reflex stimulation is obtained under normal conditions.
Even a temporary increase in secretion might therapeutically
be of service. In the light of our experiments it hardly seems
probable that iodides can after absorption increase bronchial
excretion even under normal conditions unless they do so reflexly.
In the paper on “Salivary Secretion” an experiment (number 27)
was reported in which iodides given per os brought about a prompt
flow evidently reflex in character. Nor does it seem probable that
ammonium salts act after absorption, their action in therapeutic
doses must be reflex. The protocol of experiment XLII is given
as an example of experiments which show that even were small
amounts of ammonium chloride or carbonate or potassium iodide
excreted they would have no effect upon ciliary movement and
the flow of mucus.
CONCLUSIONS

If iodides produce an increase in bronchial secretion, it must

be brought about reflexly.
Ammonium compounds increase secretion reflexly and possibly
to a limited extent by an action on the bronchial gland centre if
very large doses are given.
Antimony and ipecac and senega produce bronchial secretion
reflexly. Emetine has a central action as well.
 4S554#{149}5S.4

.,

160 V. E. HENDERSON AND A. H. TAYLOR

Apomorphine stimulates the bronchial gland centre.

Pilocarpine stimulates the bronchial glands peripherally and
atropine depresses them.

REFERENCES:

(1) BIEDL U. WINTERBERG: Arch. f. d. ges. Physiol., 1901, 88, p. 140.

(2) CALVERT: Jour. of Physiol., 1896, 20, p. 158.
(3) GEBHARDT: Arch. f. d. ges. Physiol., 1909, 130, p. 353.
(4) HENDERSON: Jour. Pharm and Exp. Ther., 1910, 2, p. 1.
(5) ROSSBACH: Berlin. lOin. Woch., 1882, 19, pp. 281 and 302.
(6) WINTERBERG: Zeit. f. Kim. Med., 1898, 35, p. 389.

Experiment VI. Cat, 2 K. urethane 2 g. and high pithed, observed 20 minutes

before beginning experiment.
12.22 p.m. 0.4380 g. in 20 minutes.

12 26 mgm. potassium iodide intravenously

to 12.42 0.4200 g. in 20 minutes,
a failure owing to a faulty junction.
1 . 19 20 mgm. ammonium chloride intravenously.
to 1 . 39 0.4142 g. no saliva noted.
to 1.59 0.4168g.
Centre depressed, neither potassium iodide intravenously nor ammonium
chloride produce a secretion.

Experimint XI. Cat, female, 4 K. , E. C. 5 g. urethane. Had been under observa-

tion for an hour, during which time ammonium chloride had been given intraven-
ously and had caused an increased secretion but the experiment was not. considered
satisfactory.
-o 2.37 p.m. 0.4458 in 20 minutes.
to 2.43 20 mgm. potassium iodide intravenously.
to 2.57 0.4168 the pump was at this time not regulated and ran during
this period a beat slower per minute than previously.
to 3.17 0.4164
to 3.27 0.4262
at 3.35 20mgm. potassium iodide intravenously.
to 3.57 0.4110
Potassium iodide intravenously without effect. Subsequently an increase in
the amount of secretion was obtained with pilocarpine.

Experiment XV. Cat, female 2.2K. Chloroform urethane 2.25 g. Cat had been
observed for nearly an hour during which difficulty with pump and absorption
apparatus prevented exact results.
to 11.05 p.m. 0.3096g.in2Ominutes.
11.12 40 mgm. potassium iodide intravenously.
to 11.25 0.2992
to 11.45 0.2964
at 11.46 40 mgm. ammonium chloride intravenously: saliva appeared.
to 12.05 0.4156
 .- S

- . S

EXPECTORANTS 161

to 1225p.m. 0.3400
to 12.45 0.3170
to 1.25 0.2718 in 20 minutes (suspected to be low).
to 1.45 0.3036
to 2.05 failure
at 2.06 tincture of squill 1 cc. per Os; saliva appeared.
to 2.25 0.5708
to 2.45 0.3168
to 3.05 0.3080
at 3.06 2cc. wine of ipecac peros.
to 3.25 0.3284
to 3.45 0.2634
to 4.05 0.3058
Potassium iodide without effect. Ammonium chloride intravenously gave good
increase as did tincture of squill per os. Slight effect from wine of ipecac per os.

Experiment XVI Cat; high pithed; natural respiration. A minute drop of

indigo-carmine was placed upon the inner surface of the trachea with a hypoder-
mic needle. It reached the larynx in 4 minutes, distance 6 cm. 1.5 cm. per minute.
The trachea was then split. Chalk placed upon the trachea travelled in one case
4 cm. in 65 seconds, in another 2 cm. in 30 seconds; these were however, much faster
than what appeared to be normal, which was 2 cm. per minute.

Experiment XVII. Cat, urethane. Indigo-carmine injected into the trachea

reached the larynx, 5 cm. distant, in 3 minutes. It was distributed in two long
streaks when the trachea was opened.

Experiment XXXVI. Cat, female, 2K. Ether and chloroform during the opera-
tion, subsequently urethane. Stomach tube inserted. Artificial respiration for
20 minutes before beginning experiment. Temperature 98.4#{176}F.
10.50-11.10 am. 0.8158g.
to 10.30 0.8346 g.
11.32 50 mgm ammonium chloride intravenously.
to 11.50 0.8842 g.
to 12.10 0.7994g.
to 12.17 40 mgm. am.monium carbonate intravenously, one or two
slight twitches. Salivary flow.
to 12.30 0.9502 g.
to 12.50 0.7890 in 20 minutes.
This increase would be equivalent to 0.3945 in 10
minutes.
12.53 100 mgm ammonium carbonate per os.
to 1.00 0.5506 in lOminutes.
to 1.10 0.4600 in 10 minutes.

to 1.20 0.4170 The thick saliva which has been flowing from the
mouth since the carbonate was given per os now
ceased.
to 1.30 0.4006
1.32 2 mgm. pilocarpine intravenously.
to 1.40 0. 6954 saliva abundant.
 162 v. E. HENDERSON AND A. H. TAYLOR

I . 42 am. Atropine was injected but as saliva was still flowing

at 1.47 p.m. more was given.
to 1.50 0.4700
to 2.00 0.3926 Temperature 98.6#{176}it has not increased above this
point nor fallen below that taken at the beginning of
the experiment.
Ammonium chloride and carbonate both act when given intravenously; the
carbonate more strongly. The carbonate has a greater action per os than intra-
venously. Pilocarpine increases and atropine inhibits the flow.

F. ExperimentXXX VII. Cat, male 2.1 K. Ether and Chloroform during operation,
55 urethane subsequently. Artificial respirationfor 2Ominutes before beginning
observations. Stomach tube inserted.
3: 1 .55-2.05 p.m. 0.4401 Temperature 98.8#{176}.
S. to 2.15 0.4224 at 2.13 p.m. 2 cc. wine of ipecac were given per os.
, no sign of vomiting but salivation.

F:, to 2.25 0.4830

IC to 2.35 0.5846
S to 2.45 0.4190
to 2.55 0.4256
to 3.05 0.4140
to 3 15 0.4052
to 3.21 1 cc. fluid extract. of ipecac given slowly intravenously.
t.o 3.25 0.4460
to 3.35 0.4716
to 3.45 0.4180 Ipecac acts reflexly and also when given intravenously.

Experiment XXXVIII. Cat, female, 2.7 K. E., C. and Urethane, under

artificial respiration for2O minutes before experiment began. Temperature 37#{176}C.
to 10.30 p.m. 0.3601 in 10 minutes
to 10.40 0.3614
to 10.50 0.3534
to 11.00 0.4432 during this time stomach tube was passed and blood pres-
sure 110 mm. was taken.
11 .04 1 .5 mgm. emetine intravenously.
to 11.10 0.3010 blood pressure fell to 80mm. Hg., no saliva appeared.
S to ii .20 0.3398 blood pressure rose again to 100 mm. temperature 36.6#{176}C.
to 11.30 0.3160(2minuteslost.)
11.32 2cc. tinctureofsenagaperos.
to 11.42 0.4110 saliva appeared but not abundantly.
S to 11.52 0.2800 temperature fell to 36.2#{176}warmth to body
to 12.12 0.8045 in 20 minutes, 0.4027 in 10 minutes T. 36.6#{176}
12.17 2 cc. tinct.ure of squill per Os..
to 12.22 0.4104
to 12.32 0.3578 temperature 36.8
to 12.42 0.3636
to 12.52 0.3632 temperature 36.8 blood pressure 95
12.52 40 mgm. ammonium carbonate intravenously
to 1.02 0.3432
to 1.12 0.3602
 55

EXPECTORANTS 163

Result for emetine questionable. Senega per os caused an increase, centre

subsequently depressed, squill per os, and ammonium carbonate intravenously
ineffective.

Experiment XXXIX. Cat, female, E. C. urethane.

to 12.44 p.m. 0.3462 in 10 minutes. Temperature 38.4#{176}C.
to 12.54 0.3390 in 10 minutes.
to 12 . 58 400 mgm. ammonium chloride as 20 per cent solution into stomach
12.02 saliva appeared.
to 12.04 0.3406 in lOminutes. Temperature 28.4#{176}C.
to 12.14 0.3506
to 12. 24 0. 3630 salivary flow more marked.
to 12.34 0.4494
to 12.44 0.3600 salivary flow ceased.
to 12.55 0.34O8Temperature 38.6#{176}C.
Secretion slow but marked due to ammoniun chloride per Os.

Experiment XL. Cat 2.4 K. E. C. Urethane.

to 2.34 p.m. 0.3784 in lOminutes. Temperature 38#{176}C.
2.34 emetine 1 mgm. intravenously.
to 2.44 0.3968in lOminutes nosaliva appeared.
to 2.54 0.4l90salivaryflow. Temperature 38#{176}C.
to 2.04 0.4162
to 2.14 0.3636.
Slight flow due to emetine intravenously.
Experiment XLI. Cat 3.9 K. E. C. urethane
to 940a.m. 1.1132 in2Ominutes. 0.5566for lOminutes. Temperature 39#{176}
to 9.50 0.537OinlOminutes.
to 10.00 0.4956inl0minutes.
10.00 2 cc. wine of antimony was given by the stomach tube but only
part reached the stomach, as part syphoned out of the
tube.
10.10 0.8207: salivary flow.
to 10.20 1.0052
to 10.30 0.8104
to 10.40 0.6495
to 10.50 0.6540
to 11.10 1.0040 in 20 minutes. = 0.5023 in 10.
Wine of antimony causes a flow of bronchial secretion.

Experiment XLII. Previously used for other purposes. Greyhound under

urethane anaesthesia. Owing to length of neck good observations could be carried
over a considerable length of trachea which of course preserved its normal blood
supply. Carefulobservations were made on the movements of particles of charcoal
in various parts immediately after opening. Average rate was found to he about
10 mm. per 60 seconds, but in small areas 2.4 cm. long the rate often reached 20 mm.
Human saliva dropped on the membrane also was moved at. the same rates. If
a very thick layer was placed on it, the movement was not so fast as when it was
thinner while a very thin layer rarely reached a rate of 10 mm. To samples of the
164 V. E. HENDERSON AND A. H. TAYLOR

same saliva, ammonium chloride and carbonate were added in solution to produce
solutions of the strength approximately of 0.007 per cent. With these solutions
the rate never exceeded 20 mm. per minute. Concentrations of ammonium car-
bonate up to 0.05 per cent were tried without greater effect. Potassium iodide was

also used but no effect was evident. Water mixed with saliva appeared as often
to increase the rate to amaximum as the salt solutions. Changes in viscosityseemed
of much more importance than the chemicals in solution.