The idea that one drug might be made to counteract the deadly effects of another is a very old one, and in the middle ages alexipharmics and mithridates were used as antidotes. Of late years, however, the subject has been investigated experimentally, and a more accurate knowledge of it obtained. Amongst the first of these experimental researches were those of Preyer, on the antagonism of atropine and hydrocyanic acid; of Schmiedeberg and Koppe on the antagonism of muscarine and atropine; and of Fraser on the antagonism between physostigma and atropine.

Although the fact is undisputed that we are occasionally able by the administration of one drug, to prevent the appearance of certain symptoms which would otherwise have certainly been produced by another previously administered, it is by no means certain that the one simply counteracts the effect of the other.

Some regard the effect of one drug in counteracting another as a case of chemical combination or substitution, the second drug either becoming added on to a compound of the first with some of the tissues, or else displacing it from such a compound with the tissues. Others, again, think that no chemical action of this sort takes place, but that each drug acts upon the tissue or tissues by itself - one, for example, exciting, and the other paralysing.

In favour of the first view may be mentioned the analogy between the action of poisons and the formation of acid-albumin and alkali-albumin, either of which can be changed into the other by excess of alkali or of acid respectively.

The objection is a very natural one that the doses of alkaloids required to produce marked physiological action are so extremely small that one can hardly fancy any chemical action being the cause of their physiological action. I have, however, on one occasion, by the addition of a single drop of liquor potassa3, converted a milky-looking fluid, consisting of the nuclei of fowl's blood-corpuscles suspended in water and measuring 90 cc, into a solid jelly-like mass - a result more striking than if a similar quantity injected into a frog had induced rigor in every muscle. Even such a result is infinitely less delicate than the colour reactions by which alkaloids are detected.

Some of the best-marked examples of antagonism in regard to involuntary muscular fibre are those observed by Ringer in the frog's heart, and they strongly support the view which he advocates of chemical substitution. As already mentioned, calcium salts and veratrine greatly prolong the cardiac systole; but this prolongation is at once removed, and the systole rendered normal by a small quantity of a potassium salt. The salts of potassium alone render the systole short and weaker, and then normal, but this action again is neutralised by calcium.

A similar condition has been observed by Cash and myself in the voluntary muscles of the frog. The contraction of the gastrocnemius is prolonged to a slight extent by calcium, and to a great extent by veratrine, and also by barium salts. This contraction is quickly reduced to the normal by the addition of a small quantity of potash.

There is no very well-marked case of antagonism, in which one drug is able to restore power to motor nerves which have been paralysed by another drug; such antagonism, however, has been observed in regard to the vagus. By small doses of atropine this may be paralysed; by a dose of physostigma administered afterwards the inhibitory power may again be restored; and by a further dose of atropine it may be again paralysed. This action has been denied by Rossbach, but in experiments on the subject by myself, I have obtained this effect in such a marked degree that I have no doubt regarding it. It is possible that the different results obtained may be due partly to the animal employed, partly to the dose, partly to the preparations of the drug, and partly to the temperature at which the experiments are made.1 In my experiments the vagus was irritated, and I ascertained that the stimulation was strong enough to stop the heart. A very small quantity of atropine was then injected, and the same stimulus was repeated. After enough atropine had been gradually injected to abolish the inhibitory action of the vagus completely, some physostigma was injected into the jugular vein, and the irritation again repeated with the effect of stopping the heart as at first.

The antagonism of certain drugs upon the frog's heart has received much attention. In considering this subject care must be taken to distinguish between experiments made with the ventricle alone, containing involuntary muscular fibres but no ganglia, and the whole heart, in which both muscle and ganglia are contained. The experiments on veratrine, calcium, and potassium, already alluded to, were made with the ventricle alone; those which are now to be considered have reference to the whole heart. Atropine appears to have the power not only of destroying the inhibitory action of the vagus upon the heart, but of antagonising those drugs which inhibit the heart and render its beats slower, or stop them altogether, such as muscarine, physostigma, pilocarpine, and phytolacca. Digitalin and saponin have a mutually antagonistic power, so that when the frog's heart has been stopped by either of them, the other will restore its pulsations. A limited antagonism also exists between muscarine, aconitine, and digitalin; when the heart has been stopped by digitalis, muscarine and aconite will restore its movements. Digitalin will also restore the pulsations in a heart which has been arrested by aconite. Physostigmine, camphor, and other drugs which stimulate the muscular fibre of the heart will remove the still-stand caused by muscarine.

1 My experiments were made on rabbits during the summer. The preparation of physostigma employed was a glycerin extract of the bean, and the preparation of atropine used was the Liquor Atrophias, B.P. (1875).