If a substance be naturally so slowly excreted from the body that the whole of the dose in ordinary use is not excreted before another is given, the amount present in the body will gradually increase, just like the curare in Hermann's experiment, and will produce an increasing or cumulative effect. Examples of this are to be found in metallic preparations,

1 Children absorb more quickly than adults, so opium is more dangerous to them. Marx, Lehre von den Giften, vol. ii. p. 117.

such as those of mercury or lead, which are excreted very slowly; or in some of the organic alkaloids, if given in sufficiently large and frequent doses. The sparingly soluble alkaloids which form stable compounds with the tissues and are thus slowly eliminated are more liable to prove cumulative. The size of the dose and the frequency with which it must be repeated in order to produce a cumulative effect will differ according to the rapidity with which the drug is excreted; for, if excretion be rapid, a larger dose or more frequent repetition will be required.

Sometimes the symptoms of the physiological action of a drug instead of increasing gradually may do so suddenly, and it is to this kind of action that the term cumulative action is most usually applied. This may sometimes be due to a sparingly soluble drug accumulating in the intestinal canal, and being suddenly dissolved and absorbed on account of some change occurring in the intestinal contents; at other times it may be due to arrest of excretion, as in the case of the two vegetable active principles, digitalin and strychnine, to which an especial cumulative action is ascribed. After moderate doses of these drugs have been taken for some time, it is found that instead of the effects they produce increasing gradually, as we would expect from a gradual accumulation in the blood, the symptoms of poisoning become suddenly developed, in somewhat the same way as if the dose had been suddenly increased. It is evident that a diminution in the quantity excreted will produce this effect as readily as an increase in the quantity taken, and this is probably the true cause of the phenomenon. When digitalin has been taken for some time and accumulated to a certain extent in the blood, it causes a diminution in the amount of urine excreted, and this diminution is either accompanied or quickly followed by the other symptoms of poisoning.1 The effect, indeed, seems exactly the same as Hermann would have obtained in his experiment if he had only partially compressed the renal arteries instead of ligaturing them completely. For digitalin appears to diminish the secretion of urine by causing a powerful contraction of the renal vessels,2 and in large doses may completely arrest the secretion of urine,3 and probably also the circulation through the kidneys. Strychnine has a similar action on the vessels.4

Effect Of Different Preparations

When a drug is given in a soluble form, and in small bulk, it is more quickly absorbed and will have greater effect than when given in a less soluble form or much diluted. Thus drugs given in solution as tinctures will act, as a rule, more quickly than when given in the form of pill or powder.

1 Brunton, On Digitalis, p. 39.

2 Brunton and Power, Proceedings of Royal Soc, 1874, No. 153, and Central-blatt f. d. Med. Wiss., 1874, p. 497.

3 Christison, Edin. Med. Journ., vii. 149.

4 Griitzner, Pflilger's Archiv, 1876, Bd. xi. p. 601. Gartner, Separat-Abdruck a. d. lxxx. Bd. d. k. Akad. d. Wiss. III. Abt., Dec. Heft, Jahrg. 1879.