If a substance be injected into the veins, the whole of it mixes with the blood and becomes active immediately, and the maximum effect is thus at once obtained and will again diminish as the substance is excreted. But the case is different if it be injected subcutaneously, and if it be given by the stomach or any other mucous cavity the difference is still greater; for as soon as some of it is absorbed excretion begins, and thus one portion of the drug is passing out of the blood while another portion is being taken in. The amount in the blood is, then, only the difference between that absorbed and that excreted in a given time (Fig. 6). Absorption may be so slow, or excretion so quick, that there is never a sufficient amount of the substance in the blood to produce any effect. Thus Bernard found that a dose of curare which would certainly paralyse an animal when injected into the veins, or even subcutaneously, would have no effect when introduced into the stomach;1 and showed that this was due to the kidneys excreting the poison as fast as it was absorbed from the stomach, by extirpating the kidneys,2 when the animal became paralysed as surely as if the poison had been introduced at once into the veins, though not so quickly. Hermann also discovered, without being acquainted with Bernard's observations, that curare taken into the stomach would produce paralysis if excretion were prevented by ligature of the renal vessels.

1 Bernard, Lecons sur les Effets des Substances Toxigues, p. 282.

2 Bernard, Revue des Cours Scientifiques, 1865.

Fig. 5.   Diagram to illustrate absorption and excretion

Fig. 5. - Diagram to illustrate absorption and excretion. The arrows show the direction of the currents. The absorbents from which the blood passes directly into the general circulation are represented diagrammatically by the veins of the lungs and of the general body surface in the figure. The absorbents by which the drug must pass through the liver, and possibly be partly excreted or destroyed, are represented by the veins of the stomach and intestine. The excreting Channels by which the drug may pass directly from the body without re-absorption occurring are represented by the vessels of the lung and by the ureter. Those by which excretion takes place into cavities from which much re-absorption may occur are represented by the arteries to the intestine and the stomach.

The absorption of drugs from the stomach and intestines may be considerably retarded, and their action diminished, by the liver. Before reaching the general circulation, drugs absorbed from the intestinal canal must all pass through the liver (Fig. 5). In their passage they may be partly arrested and excreted again into the intestine along with the bile. They may be also partially destroyed. A larger quantity of a drug may thus be necessary to produce similar effects when introduced by the stomach than when injected directly into the circulation or under the skin - (1) because it may be absorbed more slowly by the vessels of the gastric or intestinal mucous membrane; (2) because a part of it may be arrested in the liver and excreted into the intestine along with the bile; (3) because a part of it may be actually destroyed in the liver.

The more rapid the absorption, or the slower the excretion, of any drug, the greater will be its effect. Thus the effect produced by the same dose of a medicine will be in proportion to the rapidity of its absorption from the different parts to which it has been applied, unless the differences be so slight that there has not been time for the excretion of any considerable quantity from the blood during the process. On this account we must diminish the dose of a medicine in order to obtain the same effect, according to the rapidity of absorption from the place to which we apply it. Absorption is quickest from serous membranes, next from intercellular tissue, and slowest from mucous membranes. The vascularity and rate of absorption from intercellular tissue is greater on the temples, breast, and inner side of the arms and legs than on their outer surfaces, or on the back.1 It should not be forgotten that any drug introduced into the stomach, but not absorbed into the blood, is as much outside the body as if it were in the hand, for any effect it will have on the system, provided always it have no local action on the gastric walls. But if it act directly on the walls of the stomach, it may have an effect which it would not have when held in the hand or applied to the skin. Thus mustard, which would produce redness and burning of the skin, will cause vomiting when swallowed; but opium, which does not act on the stomach itself, except by diminishing its sensibility, produces no apparent effect until after it has been absorbed.

Fig. 6.   Diagram to illustrate the differences produced in the amount of a drug present in the organism by alterations in the rate of absorption and excretion

Fig. 6. - Diagram to illustrate the differences produced in the amount of a drug present in the organism by alterations in the rate of absorption and excretion. The lower funnel represents the organism. A represents the condition when a drug is rapidly introduced, as by injection into a vein. In this case the drug, e.g. curare, comes to be present in large quantities in the organism, and produces its full physiological effect. This is represented by the fulness of the lower funnel. And it does this notwithstanding the rapidity of excretion, which causes the drug to be quickly eliminated and to appear copiously in the urine, as represented by the fulness of the beaker into which the fluid flows from the lower funnel. B represents the condition when a drug is slowly absorbed and rapidly excreted, as when curare is given by the stomach. In this case the quantity present in the blood at any one time is very minute, as represented by the empty condition of the lower funnel. C represents the condition when absorption is rather quicker than excretion, as when a dose of morphine is given by the stomach. D represents the condition where absorption is moderate but excretion is interfered with, leading to accumulation in the blood, as where an active drug is given by the mouth and the kidneys are much degenerated.

Fig. 7.   Diagrammatic representation of the body

Fig. 7. - Diagrammatic representation of the body. A is a box to represent the tissues. B is an inner tube to represent the intestinal canal. It is obvious that anything which is merely in the inner tube is outside the box, and, similarly, anything which is merely in the intestinal canal is outside the body.

1 Eulenburg, Hypodermatische Injection der Arzneimittel, 3rd edit. p. 65.

By the difference between absorption and excretion under different circumstances or in different individuals,1 the cumulative action of drugs, the effect of idiosyncrasy, habit, climate, condition of body, as fasting, etc, disease, and form of administration, can, to a certain extent, though not entirely, be explained; but experiments on some of these points are deficient, and the explanations now given are to some extent theoretical.