Mode of Action of the Saline Cathartics.
Since the discovery of sodium sulphate by Glauber in the middle of the
seventeenth century, and the preparation of the double tartrate of
sodium and potassium at Rochelle some fifteen years later, the saline
cathartics have been in constant use among physicians. Attempts have
been made also from the first to explain in some way their mode of
action; but it was not until the discovery of the osmotic property
of salts that any explanation which seemed satisfactory was made.
Poiseuille[76] and Liebig[77] both advanced the theory that the
purgative action of salts was due to their power of attracting water
into the lumen of the intestine, i.e., to their power of endosmosis.
This seemed at first sight to be very satisfactory and to account
well for the increased amount of fluid in the faeces following the
administration of a saline cathartic. The theory did not, however,
take into consideration other substances whose osmotic power is as
great as that of the purgative salts, but which have no purgative
action whatever. It was later, however, supported by Rabuteau[78] in
an experiment in which he claimed to have found that the intravenous
injection of a large quantity of sodium sulphate produced constipation,
while the same salt given by mouth causes purgation. This he ascribed
to the flow of fluid towards the salt in each case due to its osmotic
pressure. This experiment lacks confirmation, and indeed it has been
shown above that sodium sulphate and other saline cathartics produce
increased peristalsis and in some cases increase of fluid in the
intestine when introduced intravenously or applied on the serous
surfaces of the intestine. And these evidences of a purgative action
appear much more rapidly and with smaller doses than when the salt is
placed in the lumen of the intestine. Claude Bernard[79] states in
his criticism of this theory that the intravenous injection of sodium
sulphate causes purgation, and further draws attention to the fact that
on this theory of the endosmotic action of cathartics, sugar, which has
a high osmotic power, should be among the more powerful purgatives.
It was further shown by other investigators that of several purgative
salts, the most powerful was not the one with the highest osmotic power.
Headland,[80] believing that all medicines must first pass into the
circulation before they act, claimed that the saline purgatives are
absorbed from the intestine and are again excreted lower down in the
intestine, and in being excreted they stimulate the glands to secrete.
A little later than this it was shown by Moreau[81] and others that
solutions of purgative salts placed in loops of intestine which
had been tied off caused an increased secretion of fluid into the
intestine. Brieger[82] further confirmed this with better methods and
showed that the fluid was a real secretion, and not an inflammatory
exudate, or a transudation.
Thiry in a series of experiments was unable to produce increased
secretion of fluid from a Thiry-Vella fistula by the introduction of
sulphate of magnesia. He therefore concludes that the action of saline
cathartics is due solely to an increase in peristaltic activity.
Radziejewski[83] held a similar theory and made many experiments in
an attempt to prove that an increase in peristaltic activity was the
main result of the administration of a saline purgative. In connection
with this it may be noted that van Braam-Houckgeest[84] concluded from
his experiments that saline purgatives do not increase the peristaltic
activity of the intestine. It is difficult to imagine how these results
could be obtained.
Hay[85] quotes Aubert, Buchheim, and Wagner as holding the theory
that in addition to causing an increased peristalsis, the salt is
slowly absorbed, and tends to prevent the absorption of fluid from the
intestine. This theory was held also by Schmiedeberg,[86] who claimed
that the purgative salts were absorbed with difficulty and reached the
lower parts of the intestine unchanged. In the large intestine the
salts, according to this hypothesis, prevent the faeces from becoming
compact by inhibiting the absorption of water from the lumen. This
explanation of the action of cathartic salts has been widely accepted
and has been supported by Wallace and Cushny,[87] who claim in addition
that the salts of acids which form insoluble compounds with calcium
are especially active in inhibiting the absorption of fluids from the
intestine.
Loeb in studying the action of salts in the production of muscular
twitchings in voluntary muscles, and of hypersensitiveness of the skin
and nervous elements, recognized the fact that the salts which had
these actions included those commonly known as saline purgatives. He
says in this connection: “I will not deny the effect of these salts
upon the phenomena of absorption of water from the intestine, but it
is obvious from our experiments that the same salts must increase the
irritability of the nerves and muscles of the intestine, and that this
must facilitate the production of peristaltic motions, possibly through
the mechanical or contact stimuli of the faeces upon the nerve endings
or the muscular wall of the intestine.”[88]
My own experiments which I have described above support this suggestion
of Loeb’s. In the first place it was found that the subcutaneous
or intravenous injection of one of these salts, especially sodium
citrate, caused muscular twitchings in the living rabbit. This had
already been done by Loeb in the frog. In both cases the injection of
calcium chloride inhibits the twitchings. As shown above, there are
produced in a rabbit by such an injection of a purgative salt not only
muscular twitchings, but also increased peristaltic movements, and an
increased flow of fluid into the intestine. The subsequent injection
of calcium chloride was shown to inhibit both the increased secretion
and the increased movements of the intestine. There thus seems to be a
very distinct analogy between the action of these salts in producing
twitchings in voluntary muscles and the production of their purgative
effect; and a similar analogy between the suppression of the former
and the suppression of the latter by calcium chloride. One is tempted
to suppose that these purgative salts act by removing calcium from
the tissues, as suggested by Loeb, in the production of muscular
twitchings, since they are all calcium precipitants. There is, however,
no direct proof of this, and other saline purgatives such as BaCl_{2}
and Hg_{2}Cl_{2} certainly have an action which is independent of
calcium.
There thus seems to be produced by saline purgatives a condition of
increased irritability in the intestine analogous to the increased
irritability produced in the voluntary muscles. As a result of this
the two main activities of the intestine are increased, namely, the
peristaltic activity and the secretory activity. The action of the
saline purgative, then, as far as we know, consists of two main parts.
The peristaltic movements are greatly increased in rapidity and force,
and the faeces are carried rapidly from the upper to the lower parts of
the intestine. They are thus passed through the large intestine in so
short a time that the fluid they already contain has not time in which
to be reabsorbed, a process which apparently takes place normally in
the large intestine. At the same time there is a much larger quantity
of fluid secreted into the lumen of the intestine than takes place in
the normal animal. The faeces which are thus forced rapidly through the
gut by the increased peristaltic movements are more fluid than normal.
This together with the rapid passage of the faeces accounts for their
fluid character when a saline purgative is given.
Whether or not the saline purgatives also inhibit the absorption
of fluid from the intestine cannot be stated with certainty. The
experiments of Wallace and Cushny leave out of account the increased
secretion of fluid into the intestine caused by the purgative, a
process which undoubtedly takes place. Thus in comparing the amount of
NaCl, and the amount of a saline purgative absorbed in a given time
from separate loops under the same conditions, it is not surprising
that the amount of NaCl solution found in the loop after the experiment
is less than the amount of purgative solution left. If the quantities
of the two salts were equal in the beginning and an equal amount were
absorbed, there would still be more fluid left in the loop containing
the purgative on account of the secretion of fluid into the loop which
was caused by the purgative, and not by the NaCl.
With regard to the mode in which the salt must be administered it is
quite clear that it is not necessary to place it in the stomach or the
lumen of the intestine. As shown above, the action is more rapid and
more powerful when the solution is injected into the blood, or applied
locally to the peritoneal surface of the intestine. Nor is the action
due to its being secreted again into the lumen of the intestine,
because the action is almost immediate when the solution is poured on
the outside of the loops, and only takes place after several minutes
when placed in the lumen. If injected into the blood the action is
slower than when the solution is applied to the serous surfaces of the
intestine. In the former case every opportunity would be afforded for
its rapid excretion into the intestine if that were a factor. It is
evident that the solution must be absorbed into the blood and bathe the
tissues just as a solution surrounds a muscle which is immersed in it.
As to the tissues in the intestine which are primarily affected, it
is impossible to make a definite statement. The muscle and glands
cannot be at all separated from the complex nervous mechanism of the
intestine, and it is necessary to take the whole as an organ made up of
many tissues and affected in definite ways by certain solutions.
It is interesting in this connection to again note the effect of these
salts on the secretion of urine. It is well known that practically all
of them are diuretics, when introduced with a considerable amount of
fluid. And even when the flow of urine has been greatly increased by
the injection of m/6 NaCl solution, it can be still further augmented
by the addition of, _e.g._, sodium citrate to the injection fluid.
These salts constitute the well known class of saline diuretics. All
salts do not, however, belong to this class, as is often stated.
Calcium chloride, magnesium chloride, and to some extent strontium
chloride exert exactly the opposite effect, inhibiting the action of
the diuretics and diminishing the flow of urine. These salts might
be termed antidiuretics. There is thus an entire analogy between the
action of the saline diuretics on the kidney and that of the saline
purgatives on the intestine, and also the action of calcium and
magnesium is the same in both cases. And the analogy can be traced
farther back to the production and inhibition of muscular twitchings in
voluntary muscles, which was demonstrated by Loeb.
The actual mechanism of the secretion of fluid into the intestine is
difficult to determine. It seems improbable that a change in blood
pressure plays any very important rôle, if indeed it has an influence
at all. There is much evidence to show that many glands consisting
of cells resembling those of the intestine roughly, secrete their
characteristic fluids quite independently of blood pressure. In _Sida
crystallina_, a small fresh-water crustacean, it was found[89] that
if a small quantity of one of the saline purgatives or of BaCl_{2} or
pilocarpine be added to the water in which these crustaceans are lying,
there is not only a rapid increase of intestinal movement and a rapid
evacuation of faeces, but there is also an increased secretion of fluid
into the intestine, so that the whole lumen becomes filled with a pale
greenish fluid. It was pointed out further that in this organism there
is no closed blood vascular system, the blood simply running in wide
channels in more or less definite directions. There can therefore exist
nothing here comparable with the blood pressure of higher animals, and
yet secretion normally takes place without changes in blood pressure.
Further, it can be greatly increased by chemicals without an increase
in blood pressure being possible. A similar secretion without blood
pressure as a causative factor is seen in the skin of the common slug
(Ariolimax). Here the secretion of the skin may be markedly increased
by the injection or local application of a solution of any of the
saline purgatives. This takes place equally well when the heart of the
animal is removed, and also in an isolated portion of the animal, or in
a piece of the skin cut off with the scissors. In these latter cases
there can be no possibility of blood pressure taking a part in the
secretion.
It has been further shown[90] that loops of intestine entirely removed
from the body may be caused to secrete a measurable quantity of fluid
by immersing them in certain purgative solutions, especially those
containing BaCl_{2}. Other solutions such as pure m/6 NaCl do not cause
this secretion, although active peristaltic movements go on in NaCl.
In this case the secretion must be entirely independent of the blood
pressure. Pilocarpine also in the salivary gland causes an enormous
increase in the secretion, without raising the blood pressure in the
carotid.
It is certain from these facts that in many glands secretion is quite
independent of any change in blood pressure; and it seems probable that
such changes must play a very subordinate part in the secretion of
fluid from the intestine.
On the other hand, it is to be noted that in many instances muscular
and secretory activities are controlled by the same conditions.
There seems to be a common factor in the production of the two
functions. Saline purgatives produce not only muscular activity, but
also increased secretion; and calcium and magnesium are capable of
inhibiting both. Atropin also quiets the movements of the intestine,
and at the same time is conspicuous in suppressing the secretion.
Section of the splanchnic nerves causes not only increased muscular
movements, but an increased secretion of fluid in the intestine. These
instances could be greatly increased in number. From them it seems
that something exists in common in muscular movements and in glandular
activity. What first suggests itself is that the gland cells themselves
are made to contract rhythmically by the various conditions which cause
rhythmical contractions in muscle. That the stimulus for this must
be greater in the case of secretion is shown by the fact that in the
intestine peristaltic movements may be maintained in a solution (m/6
NaCl) in which no secretion takes place. It seems not at all improbable
that one factor in the production of secretory activity is dependent on
a property of the gland cell closely related to muscular contractility.
A further factor is suggested by the action of certain diuretics.
In the kidney the changes in the quantity of blood flowing through
the organ and to some extent changes in blood pressure influence the
flow of urine. The diuresis produced by such substances, however, as
saponin, digitalin, potassium chlorate, etc., probably depends on
an increase in permeability of the capsule of Bowman. As shown[91]
recently, these substances produce haemolysis, and are also strong
diuretics. Calcium chloride, which inhibits the flow of urine produced
by them, inhibits also the haemolysis. Haemoglobinuria, which readily
appears with small doses of saponin or digitalin, is inhibited by
simultaneously injecting calcium chloride. There thus seems to be
something in common between haemolysis and diuresis; and what suggests
itself as most probable is that the permeability of the red blood
corpuscle, as well as that of the kidney cell is increased, so that on
the one hand haemoglobin escapes into the blood (is secreted into the
blood), and the amount of urine on the other hand passing through the
kidney cell is increased. Calcium, according to the same idea, would
decrease the permeability in both cases.
In secretion we have therefore among other things two factors which
probably play a rôle, namely, a property of the gland cell resembling
that of muscular contractility and controlled in many cases by the
same conditions, and a change in permeability of the cells which are
secreting. In the kidney there is a third factor dependent on the flow
of blood through the organ. A continuous supply of blood is of course
necessary in all glands for a continued secretion.
FOOTNOTES:
[76] Recherch. expériment. sur les mouvements des liquides dans les
tubes de petits diamètres, Paris, 1828. Quoted from Hay.
[77] Über die Saftbewegung, 1848.
[78] L’Union médicale, 1871, 50, 51. Gaz méd. de Paris, 1879.
[79] Substances toxiques et médicamenteuses, 1857.
[80] Action of Medicines, 1867.
[81] Archiv. général d. médicine, VI Série f. XVI, 1870. Centralbl. f.
d. medicin. Wiss., 1868, p. 209.
[82] Arch. f. exp. Path. u. Pharm., Bd. VIII, 1878, S. 355.
[83] Reichert’s u. DuBois-Reymond’s Archiv, 1870, S. 37.
[84] Pflüger’s Archiv, 1872, S. 266.
[85] _Loc. cit._
[86] Arzneimittellehre, Leipzig, 1883.
[87] Amer. Journ. Physiol., 1898, Vol. I, p. 411.
[88] LOEB: Decennial Publications, University of Chicago, Vol. X, 1902,
p. 10.
[89] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. II, 1905, p. 65.
[90] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. I, 1904, p. 115.
[91] MACCALLUM, J. B.: University of California Publications,
Physiology, Vol. II, 1905, p. 93.