The administration of Quinine, although so old and well tried a remedy,
is still beset with many difficulties and feelings of uncertainty on the
part of the physician regarding the rapidity and certainty of action of a given
dose of the alkaloid, by whichever channel that dose is administered. This is
due mainly to our want of knowledge regarding the physical, chemical and, in
particular, physiologico-chemical peculiarities of Quinine and its salts. The
factors influencing the absorption of Quinine from the gastro-intestinal tract
have been neglected ; and even the relative therapeutic or prophylactic value
of the various methods of administration of Quinine is still unsettled.
By many it is assumed that Quinine is absorbed chiefly from the stomach,
the intestines taking little or no part in the absorption. Malanin, in 1868,
pointed out the insolubility of the compound formed by Quinine and bile acids,
and took for granted that, when this alkaloid was administered by the mouth, as
much of it as was not absorbed from the stomach became inert on coming in
contact with bile in the intestines and was thus eliminated in the faeces. A
similar action was ascribed to bile acids by Kerner. Lauder Brunton, on
account of the precipitation from a mixture of Quinine and bile acids of this
salt, which is sparingly soluble, except in an excess of bile, recommended clearing
out the liver by administering an emetic and a cholagotrue purgative before
giving Quinine in the treatment of malaria. According to Sollmann, Quinine
is fairly readily absorbed from the stomach: Giemsa and Schaumann, however,
have come to the conclusion that most of the Quinine given by the mouth is
absorbed from the small intestine. Marshall states that most of the Quinine
passes into the duodenum: and Dixon is of the opinion that after entering the
duodenum Quinine is under ordinary circumstances absorbed rapidly; but, if
there is excess of alkali in the duodenum, Quinine is precipitated, forming with
the bile acids insoluble salts which are passed unchanged in the faeces.
When there is so little agreement regarding the fate of Quinine in the
gastro-intestinal tract, it is not surprising to find an explanation of the marked
variations in the absorption of Quinine—so often encountered in clinical
practice, sometimes even in the same individual and when using the same salt
of this alkaloid—wanting, and the reason of the efficacy of a preparation like
Warburg’s tincture still shrouded in mystery. Warburg’s tincture has been
described as “ merely Quinine concealed in a farrago of inert substances.”
To this description Maclean’s (Netley) reply was—“I have never seen a single
dose of Quinine given alone to the extent of 9.5 grains sufficient to arrest an
exacerbation of remittent fever, much less prevent its recurrence; while nothing
is more common than to seethe same quantity of the alkaloid in Warburg’s
tincture bring about such results.” According to Sollmann the substances—
aloes, rhubarb, camphor, gentian and aromatic substances which are combined
with the alkaloid in Warburg’s tincture, “probably aid in the absorption of the
Quinine;” and Cushny states that they promote Quinine absorption by acting
on the stomach and that capsicum and piperine have a similar reputation as adjuvants
in Quinine treatment. The view expressed in the National Dispensatory
is that Quinine absorption is hastened by the previous administration of
purgatives, of which a combination of rhubarb and aloes acts best.
Regarding the relative value of the various methods of Quinine administration,
it will suffice in these introductory remarks to refer to only two—oral
and hypodermic. Most authors of text-books of pharmacology and therapeutics
assume that Quinine given by the hypodermic method is rapidly and effectively
absorbed. Cushny recommends this mode of administration in cases of emergency; Sollmann states that by hypodermic injections, deep into the gluteal
muscles, rapid action is secured; Binz is of the opinion that absorption is
thorough and quick. Many clinicians have expressed similar views. Recent
experiments and clinical observations, however, have cast doubt upon the orthodox
belief that hypodermic injections of Quinine, as of other medicinal
agents, mean more rapid and more concentrated action than is possible with administration
by the mouth. In Italy and Germany attempts have been made
to solve this problem by laboratory methods. Kleine, on finding a smaller
percentage of Quinine eliminated in the mine when the alkaloid was injected
subcutaneously than when given by the mouth, came to the conclusion that
absorption was less in the former instance and that the hypodermic method was
therefore of less therapeutic value than the oral. Mariani made an intramuscular
injection into the leg of a rabbit, with a solution of .201 gramme of the
bi-hydrochloride of Quinine in one cubic centimetre of water, and from the
muscle of the rabbit which was killed seventeen hours after the injection he
recovered .1 gramme of anhydrous Quinine or 66.5 percent, of the amount
injected. The results of Giemsa and Schaumann agree with those of Kleine
they found that after oral administration the amount of Quinine eliminated in
the urine was 38.5 per cent, of the dose administered and that after hypodermic
injection the amount eliminated was only 19.2 per cent; but they
regard this difference in the elimination of Quinine as due not to less absorption,
but to a greater destruction of Quinine in the body when administered by hypodermic
injection than when given by the mouth. Krom the clinical aspect, the
subject has been investigated principally in India. Smythe states that
Quinine injected hypodermically is slowly absorbed and is eliminated in the urine for many weeks after administration; and that 20 grains injected into
the flanks will protect an individual from malaria for the following month at
least. According to Megaw the temperature of patients suffering from
malaria takes about twelve hours longer in coming to normal when treatment
is by hypodermic injections (bi-hydrochloride of Quinine in doses of
10 grains) than when Quinine is given by the mouth, and consequently that
absorption is slower from the subcutaneous connective tissue than from the
mucous membrane of the stomach. Scott regards the hypodermic method
(intramuscular) as of no special value in the treatment of acute cases of
malarial fever, owing to slowness of absorption; but he considers this method
particularly useful as a preventive of frequently recurring attacks of ague.
The authors of the National Dispensatory acknowledge that the tendency
of hypodermic injections to produce “pain, inflammation, gangrene and even
fatal tetanus more than counterbalances the advantages of facility of administration
and promptness of effect” and recommend that this method of administration
should be restricted to cases in which delay would be dangerous. The
importance of determining whether or not this “promptness of effect” is really
obtained by the hypodermic method is obvious.
In an endeavour to throw some light on these debated points regarding the
absorption of Quinine, this work has been undertaken. The alkaloid and its
salts employed in the various experiments were obtained direct from Merck
(Darmstadt) and therefore in unopened bottles.
