Chapter III

ON THE GENERAL MODES OF ACTION OF THERAPEUTIC AGENTS INTRODUCED INTO THE STOMACH.

The principal affirmations which I have to make on this subject are divisible into Ten Propositions, as seen in the Table of Contents.

The first four of these concern the general conduct of medicines after their introduction into the stomach, and before their passage into the blood. Some broad rules are laid down by which the course which they take must be determined. The action of some few on the mucous membrane is also defined.

The remaining six propositions treat of the subsequent behaviour of those medicines which pass into the blood and fluids of the body. Of these, the fifth specifies their general course. The sixth states that they may undergo certain changes in the system. And the concluding four treat of the various modes in which these agents may operate in the cure of disease.

The first proposition lays down the great fundamental rule of the action of medicines through the medium of the blood and fluids.

Prop. I.—That the great majority of medicines must obtain entry into the blood, or internal fluids of the body, before their action can be manifested.

This is to say, that the mere contact of a medicine with the stomach is not in general sufficient for the production of its peculiar action. It will be seen that the only apparent exception to this rule consists of agents having a mere local action on the mucous membrane, for which simple contact is all that is required.

Even when acting on any part of the system removed from this mucous surface, as when applied to the skin, it is necessary that the medicine pass away from it to enter the blood or internal fluids. In the great majority of instances it enters the blood directly. But we know that it would be sufficient for its operation if it were to enter through the chyle, or into the serous fluid which exists in the interstices of the tissues throughout the body. For by these it might at length be conducted to distant parts. This is what is meant by internal fluids.

We are not just now concerned with the way in which this passage into the blood and fluids is obtained. It is by the process of absorption. The question of passage by absorption is treated in the second and third propositions. What we have now to decide is, whether a medicine acts by mere contact with the stomach, its influence being propagated to distant parts by means of the nerves; or by passage thence into the system, acting through the medium of the blood and fluids. I affirm that it operates in this latter way; and this is to be proved by four considerations, which we will consider in succession.

A medicine introduced into the system elsewhere acts in the same way as when introduced into the stomach.

This proves at least that contact with the mucous surface is not an essential requisite for the operation of a remedy. We may cause a medicine to be absorbed by the skin, or inject it directly into an opened vein. The result of this latter experiment proves not only that entry into a distant part of the system is sufficient for the action of a medicine, but that it will operate when introduced into the blood. Numberless proofs of this affirmation may be adduced. Tartar Emetic injected into the veins produces vomiting. Croton Oil rubbed on the surface of the abdomen causes purging. Mercurial ointment applied by friction to the skin will produce salivation. Extract of Belladonna applied to the temples causes dilatation of the pupil of the eye; and tincture of Opium dropped on the eyeball causes the pupil to contract. Ammonia inhaled as gas into the lungs will relieve fainting in the same way as when swallowed. The breathing of Prussic acid, causing its vapour to be applied to the pulmonary surface, is sufficient to kill. Prussic acid, dropped in a concentrated state into the eye of a dog, causes speedy death. Solution of Aconitina, applied to the skin, will produce numbness, and tingling of distant parts. Injection of Nux Vomica, or any powerful poison, into the veins, is rapidly followed by symptoms of poisoning, like those which would have followed its introduction into the stomach.[17] Thus contact with the stomach is not necessary, but introduction into the system any where is sufficient. But still, may not the poison in either case act by influencing the nerves? Even when it has entered the blood, it may not travel along in it, but act in a more direct way. So in the second part of the proof we must show that a remedy cannot act by an impression conducted from the surface of the stomach by means of the nerves.

The continuity of nerve is not necessary for the propagation of such effects; but vascular connexion is necessary.

This alone, if established, would be sufficient to prove that a medicine must be introduced into the circulation, in order to act on distant parts. When confined to a surface, it can operate on the remote part only by its contact with the superficial extremities of the nerves. For vascular connexion to be established, it must first enter the vessels. Many experiments have been made which demonstrate that the vessels are the only channel by which medicinal effects can be propagated.

M. Magendie introduced some Woorara poison into the limb of a dog, which was only connected with the trunk by means of quills uniting the divided ends of the main vessels. It rapidly took effect. Having divided all the nerves and lymphatics in the intestine of another dog, he introduced into it some Nux Vomica, beyond the division. It quickly acted, and must again have done so through the vessels. Sir B. Brodie cut all the nerves of the anterior extremity of a rabbit, near the axilla, and then introduced Woorara into the foot. It rapidly acted.[18] Thus we see that vascular connexion is sufficient, and that nervous connexion is not necessary. By other similar trials it is found that vascular connexion is absolutely necessary, for when it is interrupted, the action cannot be propagated along a nerve. If, on introducing poison into an extremity, a cord be tightened round the limb above it so as to intercept the flow of blood, no effect is produced. It takes effect after the ligature is relaxed. Sir B. Brodie introduced Woorara into the leg of a dog, which was connected with the trunk only by means of the principal nerve, carefully dissected out. No effect followed. M. Ehbert found that poison would not act when applied to an amputated limb connected with the trunk by a nerve only. Thus vascular connexion is necessary; whereas continuity of nerve is not necessary, neither is it sufficient by itself.[19] Woorara poison is a substance which acts with great rapidity on the nervous system; and if its action cannot be propagated by means of the nerves, à fortiori would it seem that slower poisons must act through the circulation. But, granting that it has been shown that introduction into the stomach is not necessary for the action of a medicine, and that when in the stomach medicines do not act by influencing the nerves, still it may be objected that the rule cannot possibly be universal. It may be urged that some poisons and medicines, as Hydrocyanic acid and Ammonia, act with such great rapidity, that we can only suppose their influence to be transmitted directly along a nerve-fibre to the nervous centre, because the process of passage in the blood to this distant part would be far too slow. This argument requires us to prove a third thing.

The circulation of the blood is sufficiently quick to account even for the operation of those poisons which act most rapidly by influencing the nerve-centres.

There is no poison whatever which acts so quickly on distant parts that the circulation cannot previously have had time to conduct it to them. By means of an instrument invented by M. Poisseuille, Dr. Blake found that a chemical substance traversed the whole circulation of a dog in nine seconds, and of a horse in twenty seconds.[20] The results of Hering were similar. M. Volkmann, in the tenth chapter of his work on Hæmadynamics, states, as the result of several experiments, that the whole circulation in an adult man occupies exactly 65.76 seconds.

Now a poison that operated by nervous connexion would probably operate directly when it touched the stomach. This is not the case even with Hydrocyanic acid. This, the most sudden of all poisons, before it takes effect, allows sufficient time to elapse for the blood to conduct it to the brain. Blake made an interesting experiment upon it. He placed some on the tongue of a dog, having first fitted a tube into the larynx, so as to prevent the vapour from passing into the lungs. The effect did not commence until sixteen seconds had elapsed, and forty-five were required for its completion. This allowed of time for absorption.

Thus it is proved that poisons act when introduced into the system at any point; that vascular connexion is required for this action; and that the rapidity of the circulation is in all cases quick enough to account for it.

But this last is only a proof of possibility, and does not by itself show that a substance may not nevertheless act through the nerves. And to the experiments on nervous connexion some may object that no conclusions on this point can be drawn from trials made on isolated and exposed nerves. So we may imagine a person to be still incredulous as to the truth of the Proposition, that medicines must pass into the blood before they can act. But a fourth consideration will suffice to bring this probability as close as possible to a certainty.

The great majority of medicines have been detected in the blood, and found in the secretions formed out of it.

Having tried to prove that they must pass into the blood, if we find that they actually do so, we shall establish a stronger case. Isolated observations on this subject have been frequently made. Thus in 1847 Mr. Allen detected Daturia in the urine of a man poisoned by Stramonium. In 1824 M. Runge had discovered in the same way the principles of Henbane and Belladonna. M. Ragsky has lately detected Chloroform in the blood. (Journal für Prakt. Chem. 1849.) Dr. Golding Bird observes that Indigo, when given for Epilepsy, has turned the urine blue; that Logwood also passes into it, and causes it to give a dark precipitate with solutions containing iron; and that during a course of Copaiba or Cubebs, a resin may be precipitated from it on the addition of Nitric Acid. If a medicine cannot be proved to pass into the blood or secretions, we cannot so certainly affirm that it does not act through the nerves. But the experiments of Tiedemann and Gmelin, and since then of Wöhler, have definitively settled this point. The former two have found the great majority of mineral, and many vegetable substances, in the blood of animals to which they had been administered.

Thus, from these four considerations, we are strictly justified in concluding that a medicine must pass from the stomach into the blood before its action can be manifested. This action cannot then be conducted from the surface of the stomach through the agency of the nerves. Some experiments made by Dr. Garrod and others on the action of animal charcoal as an antidote, furnish again an additional confirmation of this fact. He finds that if a sufficient quantity of this absorbing agent be introduced into the stomach before time has been allowed for the passage of a medicine through the mucous membrane, then even such powerful nerve-medicines as Morphia and Strychnia, in very large doses, are prevented from taking effect. Yet before the contact of the charcoal they would have had time to act through the nerves, had they been capable of any such action.

In the fifth Proposition the rule here laid down will have to be further extended. It will be shown that medicines, having already passed into the blood, must travel along in it so far as to reach the part of the system on which they act.

Before concluding this question, a few remarks must be made on a subject which will be again referred to in the discussion of the Fourth Proposition.

The proper and peculiar action of a medicine, by which I mean that action on the system which is immediately recognised as distinct from that of any other agent, cannot be exerted on distant parts from the stomach-surface, but requires the passage of the medicine into the circulation. But can any other action on distant parts be produced by the remedy while in the stomach? This is a different question, and must be answered in the affirmative. Suppose a Cantharides plaster be applied to the surface of the chest in a case of Pericarditis, so as to redden or blister the skin, absorption of the fluid in the pericardium may follow this application. But any other irritant would have done this. It is not the proper or peculiar action of Cantharides, but an operation of the nervous system which follows the local change. Such agents are said to act by Counter-irritation or Revulsion, because it appears that, as a consequence of their action, the attention of the nervous system may be drawn off from a morbid process going on at some other part of the body. But it is only a consequence, and not a direct operation. Such an effect is no more the action of Cantharides than the healthy functions following recovery from sickness can be ascribed to the remedy which has cured the latter.

Now some few medicines have a marked local action on the mucous surface of the stomach and intestines. (Vide Prop. IV.) These, and these only, may, without passing into the blood, produce on distant parts an action of this kind by counter-irritation. Thus the operation of an irritant emetic may be followed by the arrest of some incipient inflammation, e.g. Ophthalmia. This revulsive action, when carried to an extreme, so powerfully impresses the nervous system, that it puts a stop to all other actions, and produces Syncope or Death. This extreme action is called Shock. Powerful corrosive poisons may effect this by a sudden destruction of the mucous surface, operating like a surgical injury. But such actions, not being the proper and characteristic operations of medicines, but rather attributable to a change in the relations of the nervous system, following a local impression, are not to be considered as exceptions to the above rule, that medicines cannot from the surface of the stomach or intestines propagate their influence to remote parts.

Prop. II.—That the great majority of medicines are capable of solution in the gastric or intestinal secretions, and pass without material change, by a process of absorption, through the coats of the stomach and intestines, to enter the capillaries of the Portal system of veins.

It has already been shown of medicines in general, that it is necessary for them to pass away from the mucous surface into the circulation. Mention has been made of their discovery in the blood by chemical means; and as we proceed it will be shown more particularly of different sets of medicines that each of them has been found in that fluid. Now, to gain entrance there, the medicine must first pass through the soft mucous membrane lining the stomach and intestine. This passage is performed by a process to which the names of Absorption and Endosmosis have been applied. Immediately outside this membrane, and between the tubes and cells which are formed by its involution, is a close net-work of very small veins, having thin and delicate walls. Now the same forces, whatever they be, which conduct the medicinal solution through the mucous membrane, cause it to pass on through the fine walls of these vessels. The two membranes, lying in such juxtaposition, are to all intents the same as one. Thus the medicine passes into the blood, and this is the only direct way by which it can gain entrance into it. These small veins, or capillaries, lead at length to the Mesenteric veins, which pour into the Portal vein, by which the blood proceeding from them is conducted into the Liver. The process of Absorption is the only mode by which remedies can thus enter the blood; we have now to consider what it is, and to show in what manner and by what agents different medicines are fitted to undergo it.

The subject of this Proposition divides itself naturally into three parts. We shall have to consider—1. What is the nature, and what the function, of the gastric and intestinal secretions. 2. The laws of this process of Endosmotic absorption, and how they are fulfilled in this case; and, 3. The mode in which the great majority of medicines are reduced to a state of solution, which is necessary before they can be absorbed.

The process of stomach-digestion has been cleared up of late years by the decisive experiments of Spallanzani and Réaumur, of Tiedemann and Gmelin, and of Dr. Beaumont of Canada.

Immediately that a substance touches the mucous surface of the stomach it causes the copious outpouring of a thin fluid, which is secreted by a glandular apparatus. This gastric juice is highly acid, and contains besides a peculiar nitrogenous substance called Pepsin. Dr. Prout thought that the reaction was due to free Hydrochloric acid. But it seems more likely that it is due to Lactic acid. Such at least is the opinion entertained both by Liebig and Lehmann. Now the result of the action of this fluid is to dissolve down the solid materials of the food, or other substances presented to it, reducing them to a thin watery pulp. This pulp is then mainly absorbed; and that which is not taken up through the coat of the stomach is absorbed in the earlier portion of the intestinal canal. I shall have to treat of Aliments as one of the orders of Restorative Hæmatics.

We are now concerned with medicines in general. The same juice is poured out to receive them. Such as are dissolved by it are immediately absorbed. Some other matters may be rendered soluble by the agency of the Bile and Pancreatic juice which are poured out into the middle of the Duodenum. The former is an alkaline fluid, containing carbonate of Soda. The Pancreatic juice is also said to be alkaline. That the stomach is absorbent may be proved by the experiment of placing a ligature round the intestine of a dog, just below the pylorus. It is then found that soluble substances placed in the stomach pass rapidly from it into the circulation. It is probable that all substances which are easily dissolved pass through the coats of the stomach. That the surface of the intestines is absorbent may be proved by the disappearance of enemata thrown into them. Liebig states that a solution of common salt, in the proportion of one part to eighty of water, disappeared so completely in the rectum that an evacuation one hour afterwards was found to contain no more than the usual proportion of salt. (Animal Chemistry, p. 77.)

On the mucous surface of the small intestines are a number of small projections, called Villi. Within these are the origins of the Lacteals, a peculiar set of Lymphatic vessels, which are engaged in the absorption of chyle. This chyle is a thick fluid which is formed by the meeting of the Bile and Pancreatic juice with that part of the digested food which passes into the Duodenum. It is generally white, from the presence of fat. Now these lacteal vessels are no doubt absorbent, but are they ever engaged in the absorption of medicinal solutions? It seems that they are not in ordinary cases at all concerned in this; for three chief reasons. In the first place it appears from the researches of Bernard and others that the lacteal system is a special arrangement for the absorption of fatty substances, and that other matters, such as albuminous compounds, pass generally into the veins, and thence to the liver. Besides, it seems that these lacteal absorbents are only in action during the digestion of food, when the epithelium on the surface of each villus becomes loosened, in order to allow to the chyle an easier access to the lacteal within it.[21] So that it is likely that a small portion of a fluid or soluble substance would be insufficient to rouse them to action. And, inthe third place, direct experiments of a decisive kind have been made on this point. Magendie has found that the ligature of the lacteal trunks does not prevent the occurrence of poisoning from agents introduced into the bowels. And Tiedemann and Gmelin have carefully sought in the chyle for a number of different medicines administered to animals in their food, and have been unable to detect any of them there. So that, with the exception perhaps of fats and fixed oils, we may reasonably conclude that no medicinal substances pass into the system through the lacteals, but that all are absorbed by the veins or capillary vessels.[22]

It seems probable that the Bile and Pancreatic juice may be engaged in reducing to a soluble state certain medicines that are insoluble in the Gastric secretion, and may thus procure the absorption of these substances by the veins of the intestinal canal.

Having briefly considered the secretions which meet the medicine on its first entrance into the system, we are next to inquire into the manner in which this medicine gains admission into the blood. In the first place, it must be in a fluid state, or it cannot be absorbed at all. It will be most convenient to consider afterwards how different remedies are to be reduced to this condition.

Now the force or process by which fluids are enabled to pass and repass through an animal membrane, has been named by Dutrochet Endosmose and Exosmose, according as the current tends inwards or outwards.

There are fluids on both sides of the membrane. The circumstances which determine their passage are mainly five. 1. The densities of the liquids: other things being equal, the lighter of the two tends to pass through to the heavier, more than the heavier to the lighter. 2. Their attraction for the intervening membrane.—That one passes through most which has the greatest affinity for the membrane. 3. The affinity of the fluids for each other.—A fluid passes through more rapidly when it is readily taken up and dissolved by that on the opposite side. By virtue of the last two laws, but contrary to the first, water passes through to alcohol more rapidly than alcohol to water. 4. The motion of the fluid on one side promotes the passage through of that on the other, because it is carried off as fast as it permeates the membrane. This also will cause endosmosis in defiance of the first law. This may be proved by a simple experiment. Let a large vein, cleanly dissected, be attached at one end to the stopcock of a vessel containing pure water. Let it then pass through a basin containing a strong solution of Ferrocyanide of Potassium, and let the other end hang over a jar filled with a solution of the Sesquichloride of Iron. If the cock be now turned, and water be allowed to pass through the vein into the vessel beyond, the solution of Iron will quickly acquire the tint of Prussian blue; for the heavy solution in the central vessel has passed through to the simple water of the vein, mainly by virtue of the motion of the latter. It will be seen directly that this is a matter of considerable importance. 5. The last law is, that any pressure on the fluid on one side of the membrane has a powerful influence in determining the passage of the current from that side. (Vide Liebig's Animal Chemistry, p. 72; Liebig on the Motion of the Juices; and the Lectures of Professor Matteucci of Pisa.)

The mucous membrane and the coat of the capillary vessel beyond it are probably subject to about the same physical conditions of absorption as those which are thus found by experiment to regulate the passage of fluids through dead animal membranes.

As to the first condition, it is probable that the aliment or medicine which is digested, however solid and dense, may be diluted down by the gastric juice until the solution is of less specific gravity than the serum of the blood. With the second law we are not so much concerned, as the medicine after solution has generally no repulsion for the animal membrane. So also with the third, as the serum of the blood mixes readily with all watery fluids. The fourth, viz. the condition of motion, is of great importance; for by it the motion of the contents of the capillary vessels will tend powerfully to determine the passage through of the liquid on the other side. Fifthly, the influence of pressure on endosmosis is one which is certainly exerted in the case of the stomach and intestines, which are muscular, and during the process of digestion contract on their contents with considerable force. This contraction, together with the circulation of the blood in the capillaries, would doubtless be sufficient to determine the passage of the digested matters inwards, even in opposition to the first law.[23]

Under the first proposition I have shown that the majority of medicines are absorbed into the system. It is now seen where and how they are absorbed. But it still remains to be seen what particular substances or classes of medicaments are thus taken into the blood, and whether while so passing they undergo any modifications.

The following, then, are the chief classes which I believe to undergo solution and absorption in the intestinal canal. They comprise the great majority of all substances used either as food or medicine:—

1. All soluble mineral substances—acids, alkalies, salts, and soluble compounds of the earths and metals—are absorbed in the stomach and intestines. The conditions and the process of absorption have been already stated. When solid they are first dissolved, when in a dense solution diluted down by the gastric fluid before they are absorbed. Thin watery liquids are quickly taken up. Motion on one side, and pressure on the other, hasten the process. I am not inclined to make any exception to this rule. This leads me to make some remarks on the Endosmotic theory of the action of saline purgatives.

M. Poisseuille found that the serum of the blood would pass through an animal membrane to a solution of Sulphate of Soda of greater specific gravity. He thus concluded that an ordinary saline purgative of greater specific gravity than serum (1.028) acted by causing the passage of this serum outwards into the intestine, producing a watery evacuation. The theory was taken up by Liebig and Matteucci, and by Laveran and Millon. Dr. Pereira and Dr. Golding Bird have drawn some practical inferences from it.

It is said that when a saline is absorbed it produces diuresis, and no purging; that when it purges it is not absorbed; that when given to act on the kidneys, the solution should be so diluted as to contain less than five per cent. of the solid; and when administered as a purgative, the specific gravity should be considerably above 1.028. Now I do not deny that a weak solution is more likely to pass off by the kidneys, and a dense one by the bowels; but I consider this due to the fact, that the kidneys are the proper emunctories of water, and of such matters as are soluble in it. But I believe that these solutions are equally absorbed, both heavy and weak, and that the purging or diuretic effect depends mainly on the quantity of the salt, as the kidneys will not eliminate beyond a certain amount of it. I must allege, to support this view of the question, firstly, some arguments à priori; and secondly, some experiments which I have made to satisfy myself. To consider first the former. Analogy is certainly against this theory. Other purgatives from the vegetable kingdom produce their effect when injected into the blood, and are yet often powerfully hydragogue. What effect on the process of endosmosis can be exerted by Castor or Croton oils, or by calcined Magnesia? On turning to what we know of the theory of digestive endosmosis, we find that the solid parts of the food are diluted down so as to be absorbed, and that the influence of pressure is to be taken into calculation. It was laid down by the great Boerhaave that a necessary requisite for the formation and absorption of chyle was the contractile force of the viscera. (Van Sweiten's Comment, vol. i. p. 290.) This, in fact, would press the fluid into the absorbent vessels, even if against the other endosmotic forces. Further, a fundamental principle was insisted on by Dutrochet—that even when the liquids on the two sides varied in density, they would both pass through to each other, though in different proportions. The ultimate result of this would be, that a heavy saline solution would be diluted down to the specific gravity of the serum, and would then pass through. This point I have illustrated in my first experiment. Thus it seems that my view is favoured by these physical laws. But even if it were not so, I should not be inclined to admit that all the endosmotic processes in the living body were regulated by merely physical tendencies. This cannot be the case with some of the secretions. The bile is of higher specific gravity than the serum of blood. Urine in health is lower, but in diabetes often much higher. The production of these secretions, differing in density from the serum of blood, would be inconsistent with the first law of endosmosis. Lastly, we find that in many known cases the theory which I am contesting does not hold good. Seidlitz water and sea-water are both known to be purgative. In both the specific gravity is below that of the serum of blood.

The first, according to Bergmann, has a density of 1.006. It contains in each pint 192.8 grains of solid matter. Out of this, 180 grains consist of Sulphate of Magnesia.

Sea-water has a specific gravity of 1.026, and its solid contents are about 3.5 per cent. But Dr. G. Bird says that less than five per cent. of saline matter constitutes a liquid diuretic.

These, then, are strong reasons against this idea considered merely as a theory. But it can readily be put to the proof. With this purpose I have made the following experiments. As far as they are concerned, they seem to show that salines are in all cases absorbed, and that whether they are subsequently excreted through the kidneys or by the bowels depends more on the quantity administered than on the degree of dilution of the dose.

Exp. 1.—A sufficient quantity of white sugar was dissolved in four ounces of water to raise its specific gravity to 1.028, that of the serum of the blood. Two drachms of sulphate of magnesia were dissolved in another ounce of water, so that the solution measured nine fluid drachms, and had a density of 1.060. This heavier solution was introduced into an open wide tube, closed completely below by a clean piece of bladder. It was introduced into a small vessel containing the solution of sugar, and arranged so that the height of the two liquids should correspond. After three days, the inner solution measured two drachms more, and the specific gravity had sunk to 1.050. The outer solution, after making up exactly the loss by evaporation, was found to have risen in density to 1.040. On adding a small quantity each of the solutions of phosphate of soda and carbonate of ammonia, a copious precipitate took place, indicating the presence of magnesia. Thus it appeared that the fluids passed both ways, some of the heavy solution of magnesia finding its way through to the lighter solution of sugar. The tendency of this process was evidently to an equalization of their densities, both by endosmose one way and by exosmose the other. Thus, apparently, would it be with a saline purgative, and with the serum of the blood.

Exp. 2.—Three drachms of Sulphate of Magnesia (a very mild purgative dose) were dissolved in ten ounces of water, and thus administered to a healthy young man. It produced, after some time, slight purging, and some diuresis. The urine, when tested, contained only a very little more than the usual quantity of magnesia. The quantity in the dose was less than five per cent. of the solution, and thus, according to the endosmotic theory, should have produced no purging.

Exp. 3.—Six drachms of the same salt were given in eighteen ounces of water to the same patient. After a few hours, it caused very copious and long-continued watery purging. The urine did not seem to be increased, and contained no excess of magnesia. It seemed, that in spite of the dilution, the quantity of the salt was so large, that it could not pass off by the kidneys, and so was eliminated from the blood by the bowels, in the same way as other purgative medicines. (Vide Chap. IV.)

Exp. 4.—This trial was the reverse of the last. Two scruples of Acetate of Potash were dissolved in three drachms of water, and thus administered. The solution then contained about twenty per cent. of the salt. According to the endosmotic theory, it should have caused only slight purging, on account of its density. It did not do so, but produced diuresis. The dose was so small, that after absorption it was easily eliminated by the kidneys.

These experiments are in favour of my views, and seem, as far as they go, to cast discredit on the theory of Poisseuille. It will be very easy to multiply them, so as to place the fact beyond a doubt.[24]

This point being so far settled, and there being no physical reason why any other soluble mineral substance should not be absorbed—it being, moreover, proved, by repeated experiments, that they all pass into the blood, we therefore proceed to the second class of bodies capable of absorption.

2. Mineral substances soluble in acids.—It is apparent that if any insoluble substance will admit of easy solution in the fluids of the stomach and intestines, it may be brought to the condition of a soluble one and thus absorbed. Now the gastric juice is acid. This secretion has been variously ascribed to free hydrochloric, acetic, phosphoric, and lactic acids; also to an acid phosphate or lactate of magnesia. There seems to be most reason to conclude that it is lactic acid, which would be easily formed out of the constituents of the food.[25]

But we have now only to regard the gastric juice as containing a free acid. This would reduce to solution the carbonates and oxides of all the metals; less perfectly when anhydrous, more easily when in the hydrated form. In this manner are absorbed the oxides of Iron and Silver, the carbonates of Lime and Magnesia, and other medicines of the same kind. They would be slightly modified, being absorbed in combination with the (lactic) acid of the stomach. In this they would differ somewhat from the substances already soluble, which would probably be absorbed unchanged, unless we except the alkalies and their carbonates, which might be similarly decomposed. Even these, if given in solution, would probably be absorbed faster than the gastric acid could be secreted to neutralize them.

Other insoluble substances, such as calomel and metallic sulphurets, would be more or less dissolved by the action of this acid. But as a great part would necessarily escape its influence, being propelled onwards by the muscular contraction of the stomach, it follows that insoluble substances of this kind are much less active as medicines than similar compounds introduced in a soluble state. It is also likely that a certain quantity would be sufficient to exhaust for a time the acid gastric secretion.

We now pass on to a third class of mineral products, which, though insoluble both in water and in acid, yet, being soluble in alkalies, appear to be in this way prepared by absorption.

3. Mineral bodies insoluble in water and in acid, but soluble in alkalies.—These remain unaffected by the action of the gastric juice, but on passing on as far as the centre of the duodenum, they meet with two alkaline fluids. These are the bile and the pancreatic juice. We know that some such insoluble bodies pass into the blood. It will be shown in the proof of the next Proposition, that they cannot do so without being first dissolved. Therefore, there must be in the intestinal canal something capable of thus dissolving them. For this purpose these two alkaline secretions are well adapted. As an example of such mineral bodies, of which there are not many, I may adduce sulphur. It unquestionably passes into the blood, and is found there in combination with alkalies, as a sulphuret or sulphate. It has been detected in the urine of those who were taking it, by Dr. Ronalds and others. It is possible that iodine, bromine, and some of the hydrated metallic oxides; may enter the blood in the same way.

4. Vegetable substances soluble in water.—These would be absorbed with more or less readiness according to their degree of solubility. They would probably be taken up in great part by the stomach. Some vegetable matters—as Lignine, or woody fibre, and Resins—are insoluble in water. Starch even is comparatively insoluble, and thus comes under another division, being probably one of those vegetable substances which are rendered soluble by the aid of the pepsin of the gastric juice.

These soluble vegetable matters are of several kinds. Cane-sugar and grape-sugar are readily soluble. So also are the various vegetable acids. There is another class of bodies which is highly important in a medical point of view. These are the natural salts of the vegetable alkaloids, of which are constituted so many of the active principles of plants. In pharmaceutical operations we are enabled, by the judicious employment of different menstrua, to extract from the crude and inert mass these vegetable active principles, and thus to obtain in a concentrated form the medicinal power for which each plant is esteemed. This process is also performed in the stomach. By digestion and concoction, with or without the aid of acid, it is enabled to dissolve out these soluble and potent matters from the ligneous and bulky tissues which surround them. For though the alkaloids themselves are in general almost insoluble in water, yet their natural salts which occur in the vegetable kingdom are mostly very soluble. The most important of these salts are as follow. In Cinchona bark, the Kinates of Quina and Cinchonia. In Opium, the Bimeconates of Morphia and Codeia. In Nux Vomica, the Igasaurate of Strychnia. In Aconite, the Aconitate of Aconitina. In Colchicum and Sabadilla, the Supergallates of Colchicia and Veratria. There are some neutral soluble substances, not partaking of the nature of Alkalies. Thus we find in Ipecacuanha and Ionidium, Emetine; in Tea and Coffee, Caffeine; in Willow-bark, Salicine; and the soluble active principles of Senna, Aloes, and Gentian, are probably of the same nature. Many other alkaloids are known. Atropia in Belladonna, Daturia in Stramonium, and Hyoscyamia in Hyoscyamus, occur in combination with Malic acid. Conia in Hemlock, and Nicotia in Tobacco, are peculiar volatile alkalies containing no Oxygen: thus in two respects they resemble Ammonia. They too are soluble in water.

Alcoholic and Ethereal fluids may be enumerated here as soluble products of the vegetable kingdom. Alcohol mixes with water to any extent; and one part of Ether is soluble in ten parts of water. Nitric Ether and Chloroform are also sufficiently soluble. So is Creosote, 1.25 parts of which dissolve in 100 of water. But this may be absorbed in another way, as will be seen presently. Volatile Oils and Turpentine come also under this head. They are all slightly soluble in water. The former, when given in small doses, are probably absorbed in this way. Turpentine, when given in large doses, may perhaps, by undergoing a change, come under the head of vegetable substances dissolved by alkalies. Camphor may be included here: one part is soluble in 1000 parts of water.

The soluble gummy matters of plants, when added to the substances enumerated above, constitute an aggregate which is called the watery extractive of a vegetable product: i.e. that part which is capable of being dissolved out of it by pure water.

But there are other active parts of vegetables, such as oily and resinous matters, and some neutral acrid principles, which, before they can be dissolved by water, require the aid of an alkali. These will be considered separately.

We now arrive at a fifth class of matters which are taken up by absorption.

5. Animal and vegetable products dissolved by the gastric juice.—The most important of these are the nitrogenous and nutritive constituents of the flesh of animals and of the parts of vegetables. Albumen, Glutine, Fibrine, and Caseine, are connected together as compounds of Proteine. Animal Fibrine, and the analogous Glutine of vegetables, are quite insoluble in water. Albumen and Caseine, though soluble, are immediately precipitated by acids. This is known to be at first effected by the gastric juice on their entry into the stomach. But the action of the gastric juice which contains an acid, and a peculiar nitrogenous material called Pepsin, —together with the temperature of the body, which is about 100°,—causes at length the gradual solution of these previously insoluble matters. This is found to take place out of the body when the above conditions are imitated with an artificial gastric fluid. The result of the process is a viscid fluid, which is then absorbed. The hard Gelatine of gristle and bone is not soluble in water at this temperature, but is readily soluble in the acid gastric juice. The Pepsine seems to be an important agent in this process, for an acid by itself is found to produce an imperfect solution. The nitrogenous matters thus digested and absorbed constitute that portion of the food which is of most use in the nutriment of the system; for the starchy compounds cannot be appropriated to the more solid tissues, although in some cases they may be converted into fat, as in herbivorous animals. (Liebig's Animal Chemistry, p. 113.)

Starch itself is one of this class. Tiedemann and Gmelin found that by the action of the gastric juice it was slowly converted into Dextrine, which afterwards changed into grape sugar. Both of these are very soluble. From the researches of Bouchardat and others, it appears that other fluids, as the Saliva, the secretion of Brunner's glands, and the Pancreatic juice, possess also this power of converting starch into a more soluble compound. So that if any of it escape the action of the stomach-secretion, it is probably reduced to solution and absorbed in the small intestine.

This change of starch is the first of a series of transformations, now ascertained, the ultimate result of which is its combustion and resolution into carbonic acid. Thus the nitrogenous compounds are called the nutritive, and the starchy materials the calorifacient elements of the food. Considered as medicines, these substances belong to the division of Aliments.

6. We have already considered some few mineral substances which are absorbed by the aid of the free alkali contained in the Biliary and Pancreatic secretions.[26] The sixth kind of absorbed matters consists of some vegetable and animal products which can only be rendered soluble by a similar agency. Fats and oils, resinous matters, and some principles resembling resins, come under this head. Fats and fixed oils consist of acids, as Stearic, Margaric, and Oleic, insoluble in water, in combination with a base, Glycerine, which, when isolated, is soluble. With a free alkali such a fat forms a soluble salt, called a soap, and the base Glycerine is set free.

In Man the Bile and Pancreatic juice are discharged together into the middle of the Duodenum. The fatty matters of the food are not absorbed before they meet with these secretions. But, after they have mixed with them, a milky fluid, called chyle, is formed, which is then taken up by the lacteal absorbents. It passes thence into the Thoracic duct, meeting there with an albuminous lymph, and is discharged at length into the general circulation at the junction of the left jugular and subclavian veins.

M. Bernard, in some papers laid lately before the French Academy, states, as the result of his experiments, that the function of the Pancreatic juice is to reduce the fat to the condition of a white emulsion. He states that no milky chyle is formed when the Pancreatic ducts are tied in dogs. He considers it absolutely necessary that saccharine and albuminous matters should be absorbed by the capillaries of the Portal veins, and then pass through the liver; and believes that the sole function of the lacteals is to take up fat thus emulsified. His experiments and inferences have received the high sanction of M. Magendie.

M. Frerichs has since affirmed that, whatever be the function of the Pancreatic juice, the Bile, by virtue of the alkali which it contains, is an indispensable agent in the absorption of fats. But M. Bernard has also found that the Pancreatic juice is always alkaline in health.

Whatever be the particular function of the Bile, it may reasonably be concluded that the alkali contained in one or both of these fluids is engaged in the saponification and solution of the emulsified fats. If it were not for this, this alkali would seem without an object; and further, it is contrary to all we know of the process of absorption to suppose that oil could pass through to a watery fluid without the intervention of an alkali to reduce it to the soluble state.

Thus it would seem likely that by means of the Pancreatic juice, with or without the aid of the Bile, fatty matters are first emulsified, in order to undergo an increase of surface, and then again saponified before they can be absorbed by the lacteal villi.

The principal fixed oils which are used in medicine are Castor, Olive, Almond, Croton, and Cod oils. It is certainly to be regarded as a very beautiful arrangement in the animal economy, that those substances which are not acted upon by an acid fluid should be subsequently subjected to the action of a free alkali, so that by the successive action of these solvents, together with the peculiar process of stomach digestion, the great majority of substances taken into the system are dissolved and rendered fit for absorption.

There seem to be other vegetable substances which are rendered soluble by means of alkali in the way already described. Resins form an important class of remedial agents, in which are comprised many Diuretics, Diaphoretics, and Purgatives. They consist chemically of peculiar acids, which, though themselves insoluble in water, combine with alkalies to form salts which are soluble. They are certainly in most cases absorbed. They have been found in the blood, and detected when passing out in the urine. From this last they may be precipitated by an acid, indicating that they are held in solution by an alkali. In large doses they may not be absorbed, but by irritating the surface of the intestinal canal, may act externally as Cathartics, and be expelled by the peristaltic action which they excite. But in small doses they enter the circulation in solution, and affect remote organs. The only way in which they can be dissolved is by means of the alkali of the two intestinal fluids. Among resinous medicines I may mention Catechu, Kino, Benzoin, Storax, Peru and Tolu, Copaiba, Guaiacum, the fetid resins, etc. Many purgative drugs, as Jalap, Scammony, and Gamboge, owe their efficacy to resin.

There are moreover certain neutral acrid principles, similar in their nature to resins, which are soluble only in alkalies, and thus come under this head. Such are Cantharidin, Piperin, Pyrethrin, Colocynthin, Elaterin, and Capsicin, obtained from Cantharides, Pepper, Pyrethrum, Colocynth, Elaterium, and Capsicum. But it should be observed that some of these are soluble in Acetic acid; and if, as some have supposed, this acid exist in the gastric juice, then they might be dissolved in the stomach.

We may add here some medicines which were enumerated also in a former division. Creosote, not very soluble in water, is easily dissolved in a free alkali. This substance also, like the last, is soluble in Acetic acid.

Some volatile oils, especially Turpentine, display a marked tendency to oxidize into resins; and being themselves very sparingly soluble in water, may perhaps be dissolved after having undergone this change. Thus Turpentine changes into common Resin, which consists of two isomeric acids, Pinic and Sylvic.

and,

or, Oil of Turpentine, with the addition of three atoms of Oxygen, produces Pinic acid, i.e. Resin, and an atom of water.

Now Turpentine, when given in large quantities, irritates the surface of the intestinal canal in man, and is not absorbed. But in the horse very large doses are found to pass through the system into the urine. It is not likely that a large quantity should enter in solution in water. It seems more probable that it may first in some way become oxidized, and then dissolved as a resin. The action of turpentine resembles that of some other substances which contain resin, as Copaiba and Balsam of Peru.

The resins thus dissolved would pass, like other solutions, through the mucous membrane of the intestines into the Portal capillaries.

But of the fats and fixed oils it cannot be said to be proved that they are absorbed in a state of solution, although such a conclusion is almost forced upon us by a consideration of the laws of endosmosis. They do not pass into the veins, but are taken up by the lacteal absorbents. They are capable of solution, and are thus not in that sense an exception to the rule of Prop. II. But in another sense they are an exception to it; for they do not pass directly into the veins, but through the lacteal system. It seems that the sole purpose of these lacteal vessels is to absorb fats. Thus it appears that all soluble substances, whether in the food or given as medicine, and in whatever manner rendered soluble, whether by acid, by alkali, or by stomach digestion, are absorbed in the stomach and intestines. All of them, with the exception of fatty matters, pass directly into the blood, traversing the mesenteric and Portal veins, to reach the liver. From this organ they pass on into the heart through the Vena cava inferior. I have shown also that they are mostly absorbed without material change. Supposing the stomach acid to be lactic, it would be too weak to displace mineral acids. It would, however, decompose a few insoluble matters, and combine with alkalies and their carbonates, forming salts which in the blood would again change into carbonates. (Vide Prop. VI.)

Prop. III.—That those medicines which are completely insoluble in water, and in the gastric and intestinal juices, cannot gain entrance into the circulation.

It may at first sight be objected to this proposition, that fatty matters may probably enter the lacteals in an undissolved state. But this is not proved; and besides, whether dissolved or not, we know that they are soluble in one at least of the intestinal juices—viz. the Bile. So that they do not come under the above definition.

We have just seen that many medicines which are given in the insoluble form are capable of being dissolved in the fluids of the intestinal canal. This so much reduces the list of perfectly insoluble medicines, that it is difficult to find any that come under such a definition. But Charcoal, the simple metals, woody fibre, and Nitrate of Bismuth, will serve as examples.

Sulphate of Lead is often quoted as perfectly insoluble; but this is not the case. It is soluble in a solution of acetate of ammonia. This salt is contained in the perspiration. Thus the sulphate, when substituted for the carbonate in some lead works at Paris, proved fatal to the foreman, who died of colic. M. Flandin found that it poisoned a dog when rubbed into the skin as ointment. Even some metals may possibly be brought within the influence of weak acids when in a fine state of subdivision, as Mercury in blue-pill. Gold in a very fine powder has been used successfully in syphilis.

Thus the list of insoluble substances is still further reduced. But there is no doubt that many substances which are slightly soluble in the intestinal fluids may in great part escape this solution, and pass out with the fæces just as they went in.

To assert that the particles of an insoluble substance cannot pass through the homogeneous wall of the capillary or absorbent vessels, is merely to state what follows from an absolute physical law, and is generally admitted by physiologists. But even this fundamental datum has been lately attacked.

Professor Œsterlen of Dorpat has been induced to affirm the possibility of the absorption of insoluble substances, from some experiments which he has made. Finely-powdered charcoal was administered to rabbits for some days. They were then killed, and globules of charcoal, measuring from 1/6000 to 1/3000 of an inch, were found in the blood of the Portal circulation. (Zeitschrift für Rationelle Medizin, 1847.) To obtain these results the microscope was used, a far less certain test in such matters than chemical analysis. Œsterlen reasonably concludes that, if charcoal can so pass, so also can any other insoluble substance. The necessity of solution could then at once be done away with, and the blood continually liable to admixture with all kinds of heterogeneous and crude materials. Œsterlen asserts further that he has found minute globules of mercury under the skin after rubbing in mercurial ointment. (Journal für Praktische Chem., No. IX. 1850.) Now, if these things were true, there could be no need to suppose the solution of insoluble active medicines, for they would be enabled without difficulty to pass through in an undissolved state.

To test for myself the accuracy of such statements, I have made some experiments, the object of which is to discover if some of the most insoluble of our known remedies, which are yet known to obtain entry somehow into the blood, could do so while yet in the insoluble state. They are as follow:—

Exp. 1.—Ten grains of calomel were given to a large dog. It was killed after three hours, allowing this time for digestion. A considerable quantity of blood was collected from the Portal vein, and submitted to analysis to determine whether it contained any compound of Mercury in an insoluble form. The blood was dried and pulverized. The result was boiled for some time in water, and the insoluble part collected. It was dissolved in a small quantity of aqua regia, and the clear acid solution placed in a test tube. A slip of zinc foil was folded round a narrow plate made of gold foil, and introduced into the solution. A galvanic current being thus set up, the minutest quantity of mercury, if present, would have been deposited on the gold, so as to tarnish it. But this did not take place, and when at last the zinc was completely dissolved, the gold remained as bright as before. Thus there was no Calomel, or compound of mercury, present in the insoluble form.

Exp. 2.—Ten grains of strong mercurial ointment (containing half its weight of metallic mercury, with some oxide) were given to another dog. He was killed after the same time, and the Portal blood analyzed carefully in the same way, but here also no mercurial compound was present in the insoluble form.

Exp. 3.—To a third dog five grains of Oxide of Silver were administered. After three hours he was killed. The Portal blood was dried in a water-bath, and reduced to powder. This was boiled for some time in water, which was separated by filtration. Aqua regia was then boiled on the insoluble part. This would convert any silver into chloride. The acid was evaporated off as much as possible, and the solid remainder heated in a small porcelain crucible to dull redness. The result was powdered, and digested in liquor ammoniæ. It was filtered, and excess of nitric acid was added. There was not any precipitate. Had chloride of silver been present, it would have been dissolved by the ammonia, and precipitated by the acid. Thus no insoluble silver compound was contained in the blood analyzed.

Exp. 4.—Ten grains of sulphur were administered in the same way to a fourth dog. On killing it and opening the body, the thoracic duct was found to be full. A considerable quantity of chyle was collected from it. Now, as it is asserted by some, that fat passes undissolved into the chyle, and as I believe that sulphur is digested in the neighbourhood of the bile duct, this chyle was chosen for analysis in preference to blood, as more likely to contain any insoluble sulphur. Besides, the blood would be less satisfactory, on account of the large quantity of albumen and fibrine contained in it, both of them also containing sulphur. The insoluble part of the chyle was obtained in the same manner as with the blood. It was then boiled in a small quantity of a weak solution of caustic potash. By this any free sulphur would be converted into a soluble sulphate of Potassium. The solution was filtered, and a few drops of a solution of the Nitro-prusside of Potassium added. (This is a salt lately discovered by Dr. Playfair. It is a delicate test for soluble sulphurets, with which it strikes a deep purple colour.) No change was produced. Therefore no insoluble sulphur was present in the chyle.

The results of these experiments are thus in direct opposition to those of M. Œsterlen, and support a view of the question which seems even à priori more philosophical and reasonable than that which he has adopted. I believe that no insoluble medicine can in any way gain entry into the blood without first undergoing solution in some way or another.