NationalLibraryOfScotland/medical-history-of-british-india huggingface dataset:
17
ing to my calculation, Quinine alkaloid is about nine times as soluble in ox bile
as in water, and according to that of Giemsa and Schaumann5 about twenty
times. Further, the glycocholate of Quinine is soluble in excess of bile
and is easily decomposed by carbon dioxide and alkaline carbonates. Lastly, as
pointed out by Kerner, 2 Q u i n i n e s a l t s a r e m u c h m o r e s o l u b l e i n æ r a t e d t h a n i n
ordinary water, and carbon dioxide is possibly of importance in the process of
absorption of Quinine from the intestine.
From the large intestine probably little Quinine is absorbed. The results
of recent workers show a great falling off in the amount of Quinine eliminated
subsequent to a period of twelve hours after administration. Peristalsis, more-
over, being less active and the contents of the bowel having acquired greater
consistence, there is less contact between alkaloid and mucous membrane.
Lastly, the elimination of Quinine after administration in the form of an
enema is relatively small. Kleine 12 after administering two grammes of
Quinine hydrochloride in 100 cubic centimetres of water as an enema found
only 17.55 per cent. eliminated in the urine in the first 24 hours, as compared
with 25 per cent. in the same period when the same salt in the same dose was
administered by the mouth.
Kobert2 5
r e l a t e s a c a s e o f s u i c i d e o n t h e p a r t o f a s c h o o l m i s t r e s s w h o
swallowed four drachms of Quinine followed by the juice of two lemons.
Unfortunately, the interval of time between her last meal and her taking the
Quinine is not mentioned; but the periods at which the different toxic
symptoms appeared are interesting from two points of view. In the first
place, the minimum lethal dose for man being about four drachms, 25 the
correspondence between the periods at which the various symptoms in this
case of suicide and in the minimum-lethal dose experiments in guinea-pigs
is striking: secondly, if in the case of suicide the stomach was empty at the time
of swallowing the Quinine, then absorption was chiefly from the small intestines.
The mimimum-lethal dose experiments were carried out for testing the relative
absorption after oral and hypodermic administration and not for determining
the seat of absorption of Quinine. For the latter purpose such experiments
are of limited value until it is known how long food usually remains in the
guinea-pig's stomach. But this much can confidently be said—that the
Quinine could not have reached beyond the small intestine when toxic symp-
toms were fully developed. Two series of feeding experiments were carried out
with guinea-pigs, (1) after fasting 24 hours, and (2) immediately after food.
The guinea-pigs were fed by passing the Quinine solution (Quinine bi-hy-
drochloride 1 in 30) through a No. 3 gum male catheter into the stomach.
As gravity was insufficient to pass the solution into the stomach, a
Record syringe was used instead of a reservoir to hold the solution and
18
force it through the catheter into the stomach. The sequence of events is
given in the accompanying table alongside that in the case of suicide—
Table IV.
Time after
ingestion.
GUINEA-PIGS, MINIMUM-LETHAL OR SUB -
LETHAL DOSE OF QUININE BI-HYDROCHLOR-
IDE 1-30 BY MOUTH.
Case of suicide. Quinine
4 drachms + 2 lemons
swallowed.
After meal.
Fasting (24 hours).
2½ hrs.
...
Giddiness
(unsteadiness).
Giddiness and pallor.
3 „
Giddiness
(unsteadiness).
......
......
3½ „
...
Twitchings
......
4 „
Twitchings
......
Unconsciousness and convulsions.
4½ „
. . .
Convulsions
Convulsions.
6 „
...
Convulsions
Convulsions and death.
6½ „
Convulsions
Death if lethal dose;
signs of recovery if
sub-lethal.
There is therefore reason to believe that, under ordinary circumstances,
most of the Quinine administered by the mouth is absorbed from the small
intestine; a small amount possibly from the stomach, especially if adminis
tered while fasting and in the form of a salt easily soluble in water; and also
a relatively small amount from the large intestine. As already mentioned, the
absorption of Quinine is normally very complete, very little being passed with
the fæces after medium doses.
FACTORS INFLUENCING ABSORPTION FROM THE GASTRO-INTESTINAL TRACT.
1. Food contents of the gastro-intestinal tract. —There seems no doubt
that, if Quinine is administered with or soon after a meal, absorption and elimi-
nation are retarded (Kleine, 22 Mariani,13 Giemsa and Schaumann 5). When ad-
ministered with a meal, Giemsa and Schaumann found traces of Quinine in
the urine only after two hours; when given fasting, they could detect traces in
20 to 30 minutes. Regarding total Quinine elimination see under (4) below.
2. Affections of the gastro-intestinal tract. —The frequency with which
purgatives (not necessarily cholagogue) are administered before Quinine is
evidence that experience has taught physicians that a sluggish or loaded bowel
is not favourable to Quinine absorption. Marshall 6 r e p o r t s t h a t i n d i s e a s e d
conditions of the heart or kidney absorption is delayed: this no doubt is due
19
to a catarrhal condition or chronic venous congestion of the gastro-intestinal
tract and liver.
3. Affections of the liver. —The probable adjuvant action of bile in Quinine
absorption has already been discussed. Carrive 26h a s r e p o r t e d a c a s e o f h e p a t i c
insufficiency in malaria (diagnosed by blood examination), and supposed to be
due to malaria, in which there was complete cessation of bile secretion and
diminished liver dulness. Under such circumstances Quinine by the mouth
would probably have very little therapeutic effect.
4. The solubility of the Quinine salt employed. —Mariani,1 3
w h o h a s m a d e a
thorough investigation of the effects on elimination of Quinine of the solubility
of the salt administered and of the food contents of the gastro-intestinal tract,
came to the conclusions that the total Quinine elimination is greater after
administering insoluble than after administering easily soluble salts; and that the
total Quinine elimination is also greater when Quinine is administered with a
meal than when fasting. Giemsa and Schaumann,5 using Quinine hydrochloride
and Quinine alkaloid, likewise conclude from the urine analyses that the less
soluble preparations of Quinine are at least as energetically absorbed from the
gastro-intestinal tract as are Quinine salts easily soluble in water.
As it seemed reasonable to doubt the validity of inferring more energetic
absorption from the fact of the total Quinine elimination being greater, I
determined the minimum-lethal dose of Quinine bi-hydrochloride for guinea
-pigs (1) after fasting 24 hours and (2) immediately after food.
Table V.
MINIMUM-LETHAL DOSE OF QUININE BI-HYDROCHLORIDE FOR GUINEA-PIGS
BY ORAL ADMINISTRATION.
A.—After fasting 24 hours.
Weight of
animal in
grammes.
Actual
dose in
grammes.
Dose per
kilogramme of
animal weight in
grammes.
Result.
550
0.165
0.3
Recovery. Distinct effects.
620
0.217
0.35
Recovery. Distinct effects.
510
0.204
0.4
Recovery. Very severe effects.
610
0.244
0.4
Recovery. Very severe effects.
600
0.240
0.4
Died in 6 —7½ hrs.
470
0.2115
0.45
Died in 8 hrs.
520
0.234
0.45
Died in 6 hrs.
500
0.25
0.5
Died in 21 hrs.
20
B.—Immediately after food.
Weight of
animal in
grammes.
A c t u a l
dose in
grammes.
Dose per
kilogramme of
animal weight in
grammes.
Result.
630
0.252
0.4
Recovery. Slight effects.
630
0.2835
0.45
Recovery. Slight effects.
660
0.295
0.45
Died in 11 hrs.
500
0.25
0.5
Died in 6¼ hrs.
500
0.25
0.5
Died in 6—7 hrs.
The minimum-lethal dose per kilogramme when Quinine is given with food
is larger (about .5 gramme) than when given after a fast of 24 hours (about .45
gramme). We must conclude, therefore, that, so far at least as guinea-pigs are
concerned, absorption is more energetic when the animal is fasting. The same
most probably holds for man, the reason for the greater total elimination of
Quinine in the urine when Quinine is administered with food being a
slower and more gradual absorption of Quinine, with a consequent smaller
amount of cleavage of the alkaloid. When Quinine is administered during a
fast, there is probably an early abrupt and energetic absorption with pro-
portionate cleavage of the alkaloid. Rapid and energetic absorption is most
likely best obtained, therefore, by giving a soluble Quinine salt during a fast ;
a slow, gradual but persistent action by giving insoluble salts of Quinine with
meals.
Soluble salts of Quinine, if given in capsules, are apt to form temporarily
local concentrated solutions in the stomach and cause gastric discomfort and
even serious injury to that organ. It is also worth noting that, where the
ordinary salts of Quinine cause gastric irritation, the difficulty may be overcome
by administering one of the insoluble salts, e.g., the tannate, which is
practically insoluble till it reaches the intestine.
5. Carbon dioxide ( CO 2).—It has been shown by Kerner2 that Quinine and
its salts* are much more soluble in ærated than in ordinary water. When
Quinine sulphate is dissolved in ærated water, no immediate precipitate is
produced by adding an equivalent amount of sodium carbonate ; and, no
precipitate is produced by adding a concentrated Quinine solution to a dilute
solution of sodium bicarbonate in ærated water. These results suggested to
* NOTE.—Water saturated with carbonic acid dissolves Quinine sulphate freely.
21
Kerner that carbonic acid probably plays an important part in dissolving
Quinine, both in the process of absorption and in the blood. The results of his
experiments also seem to show that ærated water, swallowed with Quinine or
injected with Quinine as an enema, facilitates the absorption of the alkaloid.
Further support is given to Kerner's idea of the importance of carbonic acid as
a solvent by the following experiment, reported by Wood. 27 The amount of
pure Quinine that 1,000 parts of blood defibrinated and deprived of its gases at
36°C. can dissolve is only .398 part, which gives a solubility of about 1 in 25,00.
It has been shown above that Quinine alkaloid is soluble 1 part in 625 of
ordinary ox blood-serum.
6. Single large doses of Quinine or the same amount in divided doses in the
course of the day. —Giemsa and Schaumann5 have shown that, with the daily
administration of one gramme of Quinine in one dose, 23.8 per cent. was
eliminated daily in the urine ; with the daily administration of .2 gramme
every two hours till five closes were given, the corresponding figure was 27.8
per cent. From this they conclude that Quinine in divided doses is of greater
therapeutic value than in single large doses, as in the former case less Quinine
is destroyed in the body. They therefore support the treatment of malaria by
fractional doses of Quinine, as recommended by Nocht28 and Ufer.2 9
With the single large dose the absorption of Quinine for a certain period
of time must have been much greater than could occur at any time after
administration in divided doses. With the abrupt accentuated absorption from
the single large dose, it is reasonable to expect greater cleavage of Quinine by
the protective forces of the body, hence the diminished elimination in the
urine. Further, there is no reason to suppose that the Quinine which under-
goes cleavage is of no therapeutic value before cleavage has occurred; so the
inference of Giemsa and Schaumann that greater elimination in the urine
connoted greater therapeutic value is unwarranted. With single large doses.
Quinine absorption is accentuated for certain intervals of time ; with the small
frequently repeated closes absorption is never accentuated, but continues evenly
at a moderate average. The only way to settle the relative therapeutic value
of these two methods of administration is by actual clinical results.
Nocht seems to have obtained good results by giving four grains of Quinine
every two hours, day and night (if awake), but the great majority of physicians
have by experience come to rely more on 15 grains three times daily : in the
former instance about 48 grains are given daily, in the latter 45 grains. Ac-
cording to Wood,2 7
l a r g e d o s e s a t i n t e r v a l s h a v e b e e n f o u n d i n p r a c t i c e b e t t e r
than small amounts frequently, and this conclusion is supported by observations
made by Councilman 3 0
t h a t l a r g e c l o s e s e n t i r e l y d e s t r o y t h e p a r a s i t e w h e r e a s
fractional doses do not.
E 2
22
Quinine in the form of Warburg's tincture has often been found efficient
when Quinine administered in the ordinary way has been unavailing. It will
be interesting, therefore, to examine its constitution in an attempt to explain the
secret of its efficacy. It is composed of Quinine sulphate with aloes, rhubarb,
gentian and aromatics digested with proof spirits. It is recommended that
the bowels be first evacuated by any convenient purge.31 This preliminary
purgation removes any obstacle to the progress of the Quinine along the
intestinal canal, prevents dilution of the Quinine by the previous contents of
the intestine, permits more ready contact between the Quinine and the
mucous membrane of the intestine, and increases the general tone of the whole
intestinal tract. It will be observed also that the tincture contains two
cholagogue purgatives—aloes and rhubarb. These can help absorption in two
ways, (1) by increasing the flow of bile, and (2) by increasing peristalsis which
favours contact of Quinine with the intestinal mucous membrane. To prevent
any griping, due to these two purgatives, aromatics are present in abundance.
There is still another possible action of these two purgatives which has to be
guarded against besides griping. It is not desirable that the Quinine should
pass too rapidly along the intestinal tract. For this purpose prepared chalk
and a little opium are generally included in the composition of the tincture :
these tend to diminish the intestinal secretions, and so impede the progress of the
Quinine in the intestine. Two other recommendation13 generally accompany
the tincture : (1) it is to be taken alone without dilution, and (2) all drinks are
withheld after its administration : these precautions, besides preventing dilu-
tion, which would diminish contact of Quinine with intestinal mucous
membrane, probably help to retard the progress of the Quinine along the
intestinal tract. These latter effects are also favoured or aided indirectly by a
further recommendation—that the patient should be well covered after the
administration of the tincture and diaphoresis encouraged.
Subcutaneous (including Intramuscular) Administration.
Until quite recently no one ever doubted or questioned the alleged advan-
tages of the hypodermic injection of Quinine,—rapidity and accentuation of
action as in the case of other medicinal substances that are commonly adminis-
tered in this way. And, even now, all authoritative books on pharmacology
and therapeutics, while noting its drawbacks and dangers, recommend the
hypodermic administration of Quinine in malignant types of malaria. Binz1 1
states that the satisfactory results obtained by this method of treatment show
that the Quinine is thoroughly absorbed. Some medical officers would even go
the length of giving Quinine hypodermically as routine practice in preference
to oral administration. According to the National Dispensatory, 10 however, the
23
tendency to produce "pain, inflammation, gangrene and even fatal tetanus"
more than counterbalances the advantages of facility of administration and
promptness of effect, and the use of this method of administration should be
restricted to cases in which delay may be dangerous.
The behaviour of those Quinine salts that are used for hypodermic injec-
tion, in different strengths of solution, when mixed with ox blood-serum, has
already been described. It should be noted also that solutions of Quinine
hydrochloride prepared with the addition of antipyrine, urethane and sodium
chloride, respectively, as recommended by some for hypodermic and intravenous
use, were tested in the same way and showed no greater miscibility with ox
blood-serum than did simple solutions of Quinine hydrochloride itself. The
ordinary Quinine hypodermic injection, as recommended by Squire, 3 2
i s n o t
more dilute than 1 in 6; the strength of Burrough's and Wellcome's Quinine
bi-hydrochloride Vaporoles is 1 in 5 ; and the strength of extemporaneous
Quinine injections generally borders on 1 in 1½ Solutions of Quinine of such
strengths must of necessity result in a coagulum and precipitation of much
of the Quinine at the seat of injection. It has already been shown that the
addition of a 1 in 20 solution of Quinine hydrochloride to an equal volume
of ox blood-serum throws about half the Quinine, temporarily at least, out of
solution. An examination of Table II strongly suggests that the more con-
centrated the solution of Quinine salt, the more alkaloid will be precipitated in
the mixture with serum ; and the more dilute the solution of Quinine salt,
the less alkaloid will be thrown out of solution. One would expect therefore
from these serum experiments that much of the Quinine contained in the
ordinary Quinine hypodermic injection would be thrown out of solution at
the point of injection, but that, if the Quinine injection is sufficiently dilute
(1 in 150), little or no Quinine would be deposited in the tissues.
It will be remembered that the substance separated by adding dilute
sulphuric acid to the coagulum (formed by adding Quinine hydrochloride 1 in
20 to serum), after the latter had been washed free from all traces of Quinine,
gave a blue colour when treated with chlorine water and ammonia, and that
this blue colour changed to green rapidly on heating, but after a few days if
left at laboratory temperature. This substance is probably an oxidation product
of Quinine, and the ease with which it can be re-converted into Quinine sug-
gests that, although much Quinine is thrown out of solution at the seat of in-
jection apparently as a transformed product in combination with albumen
(compare with Rossbach's3 3
i n v e s t i g a t i o n s ) , Q u i n i n e m a y b e g r a d u a l l y l i b e r a t e d
from the coagulum for two or three days after injection. Reference will
again be made to this coagulum in connection with the occurrence of tetanus
after Quinine injections.
24
Giemsa and Schaumann5 state that a solution of one part of Quinine urea.
bi-hydrochloride in ten of water is particularly suited for subcutaneous use.
Table II shows that in this dilution Quinine urea forms a curdy mass only when
mixed with serum, and that, in the same dilution, quinine bi-hydrochloride
produces a gelatinous mass. The latter salt, however, contains considerably
more Quinine base than the former ; and, when solutions of both salts each
containing 1 in 80 of Quinine base were tested with serum, no difference in,
the behaviour of the two salts could be detected.
From the small amount of Quinine eliminated in the urine after hypo-
dermic injections and from his findings at the point of injection Kleine 22 came
to the conclusion that Quinine was precipitated largely at the seat of injec-
tion, and that Quinine was very slowly absorbed from this depot by the lymph
stream. He was of opinion that absorption lasted for weeks, and that such a.
prolonged action would be useful in the treatment and prophylaxis of malaria.
Mariani,13 however, showed that this Quinine depôt at the point of injection
did not persist beyond five or six days, and so rejected the idea that subcutaneous
administration was particularly useful for the prophylaxis of malaria. That
Quinine was precipitated at the point of injection he settled by experiment.
He injected Quinine hi-hydrochloride (about 1 in 5) intramuscularly in the leg
of a rabbit and 17 hours thereafter killed the rabbit and recovered from the
muscles 66.5 per cent. of the amount injected. Kleine,1 2
on finding that elimi-
nation in the urine was so small in amount and that elimination did not
continue so long as he had formerly supposed, concluded that the subcutaneous
administration of Quinine was of less therapeutic value than the oral.
There is very little harmony in the results of experimenters who have
investigated the proportion of Quinine eliminated in the urine after hypoder-
mic injection. There is one point, however, on which they are all in agree-
ment, namely, that the proportion of Quinine eliminated, when administered
subcutaneously, is much less than when given by the mouth. The following
gives the proportions eliminated in the first twenty-four hours after adminis-
tration (1) by mouth and (2) subcutaneously :—
By mouth (fasting)
Subcutaneously
=
21.91%/
12.13% (Kleine).22
Do.
=
24.7% /
14.74% (Mariani).13
Do.
= 19.50%/
1 7 . 9 % (Schmitz). 21
Do.
= 25.8%/
121.6% (using dilute solution) (Giemsa and Schaumann).5
25
Kleine2 2
g a v e . 5 g r a m m e Q u i n i n e b i - h y d r o c h l o r i d e s u b c u t a n e o u s l y t o e a c h
of two patients and found the amount eliminated in the first 24 hours in one
case was 11.37 per cent. and in the other 9.70 per cent. To another patient he
gave .5 gramme Quinine hydrochloride, and the amount eliminated in the first
24 hours was 15.32 per. cent. The greater excretion in the last case probably
accompanied a greater absorption due to the greater dilution in which the
hydrochloride was probably given owing to its less solubility. Mariani13 tested
the effect of concentration of the Quinine injection on the elimination. In
the one case he injected one gramme of Quinine bi-hydrochloride in ten cubic
centimetres of water and in the other case the same salt and dose in two cubic
centimetres of water: in the former, 13.7 per cent. was eliminated in the first
24 hours; in the latter, 15.791: in the former, elimination was at its height
between the sixth and twelfth hours after injection; in the latter, between
the ninth and eighteeth hours after injection. It is worthy of note that
differences in dilution of 1 in 2 and 1 in 10 had no great influence on the
amount of Quinine excreted and probably absorbed. This agrees with the
results obtained by me in the minimum-lethal dose experiments. Giemsa and
Schaumann,5 h o w e v e r , u s i n g Q u i n i n e u r e a h a v e o b t a i n e d v e r y d i f f e r e n t
results. They carried out two sets of experiments: in one set they adminis-
tered one gramme of Quinine urea in ten cubic centimetres of water to each
patient daily, and in the other set one gramme of Quinine urea in one cubic
centimetre of water daily, with the following tabulated results :
—
Table VI.
A.—Daily subcutaneous injection of 1 gm.
Quinine urea in 10 c.c. of water.
B.—Daily subcutaneous injection of 1 gm.
Quinine urea in 1 c.c. of water.
No. 1. No. 2. No. 3.
No. 1.
No. 2.
per
cent.
per
cent.
per
cent.
per
cent.
per
cent.
1st day
.
. 21.0 24.1 19.8 1st day .
.
.
10.3
12.1
2nd day
.
. 26.2 24.9 22.0 2nd day .
.
.
16.3
15.1
3rd day
.
. ...
26.9
... 3rd day .
.
.
18.2
19.3
AVERAGE .
. 23.6 25.3 20.9
AVERAGE
.
.
14.9
15.5