Chemical reactions, as a rule, go on more rapidly the higher the temperature, excepting when very high temperatures are reached and dissociation occurs. The effect of drugs upon living organisms may be regarded as being to a great extent due to chemical union between the drugs and the organism, and therefore we should expect that alterations in temperature would greatly affect the action of drugs and that, as a rule, we should find that they would act with greater quickness when the temperature is high unless some other factor should be brought into operation by the increasing temperature. Experience confirms this expectation, and, as a matter of fact, the effect of temperature on the action of drugs is very great. At different temperatures the administration of the same drug may be followed by different results, and it is probable that a great number of the contradictory observations which we find in works on Pharmacology are due to this most important factor having been neglected in making the experiments. It is of the greatest importance to the physician also, as many of the cases of disease which he has to treat are accompanied by a rise in temperature which may have a very important effect upon the action of the drugs which he administers.

The alteration produced in the effect of drugs by warmth was first noticed by Alexander von Humboldt, who observed that warmth not only acted as a stimulant to the heart in increasing the power and rapidity of its contractions, but noticed that warmth increased the rapidity with which alcohol destroyed the irritability of a nerve, and potassium sulphide that of a muscle. Bernard observes generally that poisons act slightly on frogs when cooled down, and become more active the higher the temperature. The effect of warmth in stimulating the movements of protoplasmic structures, such as amoebae and cilia, was investigated by Kuhne; and, in an important research, Luchsinger experimented on the influence of warmth on the action of poisons on many organs, and found that the ciliary motion in the pharynx of the frog became paralysed by chloral, potassium carbonate, and tartrate of copper and sodium more and more quickly in proportion to the rise in temperature. On cooling down the ciliary movement again returned.

Dr. Cash and I have found that the action of veratrine or barium on muscle is very much altered by heat and cold. At ordinary temperatures contraction is greatly prolonged, but under the influence of either great heat or great cold the contraction again becomes nearly or quite normal.

Many, if not all, muscular poisons act more quickly with increased temperature; and frogs poisoned with chloral, copper, manganese, potash, and zinc are paralysed more quickly when the temperature is high, than when it is low, whether the alterations be produced artificially, or be due to differences in the season at which the experiments are made.

Rabbits poisoned with copper or potash also die more quickly when placed in a warm chamber than when left at the ordinary temperature.

The terminations of motor nerves in the muscles are also greatly affected by temperature.

Guanidine produces in the frog fibrillary twitchings of the muscles, which persist even in excised muscles, but are removed by curare, and are therefore in all probability dependent on an affection of the terminal ends of the motor nerves in the muscle. Luchsinger found that when four frogs are poisoned in this way, and one is placed in ice-water, another in water at 18°, a third at 25°, and a fourth at 32°, the fibrillary twitchings soon disappear from the muscles of the frog at 0°, and only return when its temperature is raised to about 18°. In the one at 18° convulsions occur, which are still greater in the one at 25°. In the frog at 32°, on the other hand, no abnormal appearance is to be remarked, and five times the dose may be given without doing it any harm.

This poison then resembles veratrine in acting only at ordinary temperatures, and in its action being abolished by excess of heat or cold.

The effect of temperature on secreting nerves is well marked. "When the sciatic is stimulated in an animal, the corresponding foot usually begins to sweat, but the sweating is very much less if the foot is cooled down than if it is warm. A similar action is exerted by temperature upon the sweating produced by pilocarpine - a drug which appears to act by stimulating the ends of the secreting nerves. When the animal is cooled, this drug is much less powerful than when it is warm.

Overheating appears to have an opposite action, and when the foot is heated up to a certain temperature it does not secrete nearly so readily, even though the glands themselves are not injured, and secretion may commence after the lapse of a little time.

The influence of poisons on the heart of the frog is also modified by temperature. Kronecker found that its beats were arrested by ether easily and quickly when the temperature was high, but with great difficulty when it was low. Ringer found that a small dose of veratrine greatly affects the ventricle at a moderate or high temperature, but at a low temperature produces no effect.1

Luchsinger noticed that when the frog's heart had been arrested by passing dilute solutions of chloral, copper, or potassium carbonate through at 25° C, the pulsations again began when the temperature was reduced to 15° C. When, on the contrary, the heart had been arrested in a similar manner, at a temperature of 5° C, pulsations could then be induced by warming it to 15°.

Some extraordinary observations on the effect of temperature upon the action of drugs on the spinal cord have been made by Kunde and Foster, who have found that, in a number of frogs poisoned with strychnine and exposed to different temperatures, raising the temperature diminishes the convulsions, while cold increases them if small doses are employed. Raising the temperature, indeed, may not only diminish but entirely abolish the convulsions, while putting a frog in ice may bring them on when they would not otherwise appear, and cause them to last for no less than twenty-four hours. When large doses are employed the opposite effect is produced; raising the temperature then increases the convulsions, while cooling the frog down to 0° abolishes them.

An observation similar in some respects, though differing in others, has been made on the effect of temperature on the action of picrotoxin by Luchsinger.2 When this poison is given to three frogs, and they are then placed in water at 0°, 15°, and 32°, in a few minutes the convulsions occur in the one at 32°, shortly afterwards in that at 15°, while the one at 0° remains for a long time completely unaffected, and only exhibits signs of convulsion when the dose has been very great indeed, or when it is taken out of the cold bath.

1 Ringer, Archives of Medicine, vol. vii. Feb. 1882, p. 5.

2 Luchsinger, Physiologische Studien, Leipzig, 1882.

The effect of warmth in accelerating death from muscular poisons has already been mentioned.

The power of warmth to preserve life in narcotic poisoning was observed by Hermann in relation to alcohol, which rabbits bear better when they are somewhat warmed.1 Its extraordinary effect in preventing death in animals poisoned with chloral was noticed by Strieker, and more thoroughly worked out by myself at his suggestion.2 Death by chloral appeared from my experiments to be in a great measure due to continued loss of heat from the animal. This seems to be the case also in metallic poisoning by copper, manganese, mercury, platinum, potassium, thallium, tungsten, and zinc. Its cause appears to be twofold : (1) the poisons lessen combustion in the body, and the amount of heat produced, as is shown by their diminishing the amount of carbonic acid excreted; (2) besides disturbing the production they also disturb the regulation of heat, so that animals poisoned by them have less power of resisting the influence of external temperature, and therefore the temperature rises more quickly when they are put in a warm chamber, as well as sinks more quickly when they are exposed to cold.

All these observations show that the definition of the action of a drug, already given (p. 5), must be still further modified, and we must define it as the reaction between the drug and the various parts of the body at a certain temperature.

Thomas3 found that digitalis has sometimes no action on the pulse in pneumonia. As the slowing of the pulse produced by this drug is to some extent effected through the vagi, it occurred to me that its want of action in this disease might be due to the paralysis of these nerves by heat. On testing the action of heat, however, on the vagus, in rabbits deeply chloralised, I found that it was not paralysed at a temperature just sufficient to kill the animal.4 Cash and I, however, have found that though the peripheral ends of the vagi are not completely paralysed by high temperature, the roots of the vagus in the medulla appear to be so, and probably the want of action of digitalis, when the temperature is high, is due to this paralysis (vide Digitalis).

The abnormal effect which opium has in some cases of fever - causing excitement instead of sleep - is occasionally most distressing to the physician. It is possible that this may be partly due to the temperature, and that the combination of tartar emetic with the opium may owe some of its utility to its effect in lowering temperature, although not improbably both it and another useful combination with chloral also act more perfectly on account of the depressing action on the circulation. These are points, however, on which further observations are greatly needed.

1 Hermann, Arch.f. Anat. u. Physiol. 1867, p. 64.

2 Lauder Brunton, Journal of Anatomy and Physiology, vol. viii.

3 Arch. f. Heilk., vol. iv. 329, 1865.

4 St. Bartholomeiv's Hospital Reports, 1871, p. 216.

Climate

It is said that the action of narcotic drugs is greater in warm climates than in cold, and that smaller doses are therefore required to produce a similar effect. If this statement be true, it may be due to the higher temperature, for Crombie has shown that in India the average temperature of the body is about half a degree higher than in England. It may, however, be due to the slower elimination of the drug by the urine; because in hot climates the secretion of the skin is apt to be much greater, and the secretion of urine and elimination by it consequently less.

Time Of Day

In healthy persons fluctuations of the body-temperature occur. The lowest temperatures occur at night between 10 p.m. and 1 a.m., and in the early morning between 6 and 8 a.m. The highest temperature occurs between 4 and 5 in the afternoon.

The action of drugs may be partially altered by the slight variations in temperature which occur within the body, and perhaps still more by the variations in tissue-change, of which these fluctuations of temperature are the indication. Thus the necessity for great attention to the administration of stimulants in the early hours of the morning in cases of threatening collapse has long been recognised.