patient should go to sleep for the night, while for others to act but little time is needed. In order to cause a morning evacuation of the bowels, slowly acting purgatives must be taken the evening before, but promptly acting ones before breakfast. Drugs which are readily decomposed by the contents of the stomach should be given when that viscus is empty, preferably a half hour before the meal time. Experience has shown that the body is generally more resistant in the morning than in the evening, especially in the case of narcotic drugs.

6. Mode of Administration.-Drugs being absorbed much more rapidly from the subcutaneous tissue than from the stomach and upper portion of the intestinal canal, smaller doses are required when they are administered hypodermatically than by the mouth. On the other hand, their absorption is slower from the rectum; therefore to produce the desired effect, the rectal dose must be larger. The tendency of modern therapeutics is towards smaller and more frequently repeated doses.

7. Mental Influences.-The mental condition of the patient sometimes has more or less influence on the effectiveness of drugs. Thus, if his mind is particularly fixed on the action of a hypnotic, so that he feels convinced that he will sleep, quite a small dose may answer the purpose, but if, on the contrary, he is laboring under considerable mental excitement and feels that it is quite impossible for him to sleep, an unusually large dose may be required.

8. Other Temporary Conditions. Various other temporary conditions may influence the activity of drugs. As the drug is diluted by the stomach contents, absorption takes place more slowly after a meal than when the stomach is empty, and any local irritant action is less marked. Irritation of the stomach or intestine may also modify the effects of drugs, and vomiting and diarrhoea naturally tend to diminish their activity by quickly removing them from the alimentary canal. During pregnancy drugs must be used with great care. Purgatives may induce pelvic congestion, and thus lead to abortion, while drugs causing a marked fall of blood-pressure may have the result of asphyxiation of the fœtus. Drugs acting directly directly upon the uterus are naturally to be avoided, and also those whose effects may be transmitted from the mother to the child and injure the latter. During lactation certain drugs are excreted in the milk, and these may either act upon the child or render the milk distasteful to it. At the time of menstruation all very active drugs must either be given with great caution or temporarily intermitted, and purgatives should generally be avoided.

9. Temperature.-The action of drugs often being in part chemical, the temperature may be a factor of some importance in determing their effects in the case of cold-blooded animals and excised structures, but as in man the temperature range is so limited, this element may be practically disregarded.

10. Preparation of a Drug.-As a rule, a smaller dose of a soluble preparation, as a tincture, will be required than of a solid preparation, as a pill, which may be only slowly dissolved before absorption can occur, although in the latter instance much depends upon the process of manufacture. Pills which have been manufactured for a long time may be entirely insoluble.

11. Rate of Excretion. In order to produce a prompt effect, a smaller dose (other things being equal) will naturally be required of a drug that is excreted rapidly than of one the excretion of which is slow. It is also true that, in order to

maintain a continuous effect from drugs which are rapidly excreted, the doses must be repeated at shorter intervals.

12. Cumulative Action.-It sometimes occurs that in a person who has been taking a drug for some time, without the manifestation of any untoward effects, symptoms of poisoning suddenly make their appearance, or, at all events, that small doses of certain drugs taken repeatedly for a considerable period eventually give rise to symptoms which are more marked than those caused by a single dose. Such a result is attributed to the cumulative action of the drug, causing an acquired susceptibility, in consequence of which a given dose will produce more pronounced effects than it did originally. This is the opposite of habituation, and it may be due to any one of the following causes: (a) Greater capacity for absorption than excretion, as in the case of lead and mercury. (b) Inconstant absorption, successive doses of the drug being unabsorbed from the alimentary canal until such time as the conditions, in consequence of some alteration in the intestinal contents, may become favorable to absorption, when the whole amount is taken into the system at once. This is sometimes met with in the case of digitalis. (c) Summation of effects, the effect of the preceding dose not having disappeared when the succeeding dose is given. (d) Sudden arrest in the excretion of the drug. For instance, it is thought probable that from the use of digitalis the renal vessels become contracted when the quantity of the drug in the tissues has reached a certain amount, so that excretion can no longer take place. It has been suggested also that the organism is subject to what may be called an education to the effects of drugs, particularly in the use of certain ones acting upon the central nervous system. Under this hypothesis the fact that the susceptibility to strychnine increases with its administration would be explained by the central nervous system becoming educated to the stimulating actions and responding more readily to them. Cumulative action, it should be noted, may occur along with tolerance. Thus it is found that the tolerance of certain tissues for nicotine does not protect others from the effects of the abuse of tobacco. 13. Disease.—The action of drugs is liable to be greatly modified by disease. This is seen, for instance, in the use of antipyretics, which have little or no influence upon normal temperature, but have a pronounced effect in reducing pyrexia. The dose must sometimes be varied because of the conditions produced by disease. Thus, in peritonitis, and in many instances of hepatic, renal and other very severe forms of colic, enormous doses of opium may be borne perfectly well.

PHARMACOLOGICAL AND THERAPEUTIC ACTIONS

By the action of a drug is ordinarily meant its physiological action.

The primary action is that due to the unaltered drug. The emetic action of such drugs as zinc sulphate is an illustration of this.

The secondary action is that due to compounds formed from the drug in the body. Thus, genito-urinary disinfectants like cubeb and copaiba owe their effects in this regard to a combination with glycuronic acid, in which form they are excreted by the kidneys.

The local action is that produced at the point of application before the drug enters the circulation.

The direct action is that produced upon organs and tissues with which it comes into immediate contact.

The indirect or remote action is that produced as a secondary result. The paralysis of the heart caused by chloroform is a direct effect, while the fall of blood-pressure which results from this is an indirect effect of the drug.

The general or systemic action is the effect produced by the drug after absorption, and is due to its elective affinity for certain organs to which it is carried by the blood. Most active drugs have a selective affinity for special organs, as the heart or the central nervous system or certain definite tissues. Among those which select the central nervous system, for example, some act primarily upon the cerebral cortex, some upon the medulla oblongata, and some upon the spinal cord. It is sometimes the fact that a drug has the effect of affecting different structures in directly opposite ways. Atropine depresses the peripheral terminations of the secretory nerves, but stimulates the brain. Different drugs show very great differences in the extent of the field of their activity, and with most poisons the scope of this depends largely on the quantity administered. Hence, one which in small doses affects the medulla oblongata only, in larger doses may extend its influence to the brain and spinal cord, and when given in still larger amount act also on the heart and other organs. It is to be noted that the local effects of a drug may be entirely different in character from its general action; so that while it acts as an irritant at the point of application, it may be a depressant to the brain when it is carried thence in the circulation. For the reason that they are not absorbed or are absorbed in inactive forms, some drugs have only local action. Others, again, have only a local action because they are excreted or deposited with such rapidity that there is not a sufficient quantity in the blood at any one time to produce any general effects. Many powerful poisons on the other hand, show only a selective affinity for some internal organ to which they are conveyed in the circulation, and have little or no local action. Relation between Chemical Constitution and Physiological Action.-While it is true that in a general way drugs closely resembling each other as to their chemical composition and properties produce similar effects upon the organism, as seen, for instance, in the use of the heavy metals, yet it is found that when their physiological action is carefully followed out, considerable differences in their effects are discovered. This is due to the circumstance that certain factors are met with which are apparently quite independent of their chemical constitution, or, at all events, which it is impossible to deduce from the latter. It is worthy of attention that the position of the radicals in the molecule is sometimes of great physiological importance. Thus, resorcinol (metadihydroxybenzene) has a very sweet taste, while pyrocatechin (orthodihydroxybenzene) is bitter. Moreover, substitution of one radical for another in organic compounds often greatly modifies the action. It can be stated then, that it may be inferred with some probability that any substance belonging to a chemical group of similar constitution will give rise to symptoms resembling in general character those of the other members of the group, provided that it does not contain some radical which renders it inactive or gives it a more powerful action in some other direction.

At the same time, the details of its action can be determined only by actual experiment. It is also equally true that the details of the chemical behavior of such substance can be ascertained only by performing the necessary reactions, and the point has therefore, been well taken that for many drugs of definite chemical formula, while there is little prospect at the present time of explaining the latter from its constitution, there is still hope that much advance will be made in the near future in formulating the laws governing the details of its pharmacological effects.

The Theory of Ions has, for its fundamental or underlying basis, electrolytic dissociation. When acids, bases and salts, which, since they conduct the electric current, are termed electrolytes, are dissolved, either all or a part of the molecules are split up by the solvent into simpler substances, the electrically charged atoms or groups of atoms known as ions, constituent parts of the molecules which, under the directive influence of an electric current, travel in opposite directions through the solution. Those which take on a positive charge are called kations, and those assuming a negative charge, anions. A simple illustration is afforded in the instance of hydrochloric acid, a solution of which is made up not only of HCl molecules, but also of H ions and Cl ions. When such a solution is completely dissociated, it would be put down as H+ and Cl-. It is a fact, however, that while in a solution of hydrochloric acid there are dissociated chlorine ions, it does not contain free chlorine in the condition met with in a solution of chlorine gas. In solutions of a chloride the existence of chlorine cannot be demonstrated by its physical properties, but its presence can always be recognized by its reactions. The circumstance that all chlorides, by reason of their chlorine, yield a certain set of reactions which are precisely the same, whatever, the associated element may be, is regarded as proof of the correctness of the dissociation theory. Since all chlorides thus give off free chlorine-ions on solution, notwithstanding that each one in its solid condition is characterized by its own special properties, it becomes clear why they present a common set of reactions. The importance is insisted upon of the fact that only those portions of the substance which are ionized are chemically active, the ionized condition being necessary for the rapid reactions which electrolytes display. With the exception of hydrogen dioxide, water, the universal solvent of the body, seems to cause the best dissociation of molecules into ions. Formic acid comes next in this respect, then nitric acid; methyl alcohol is superior to ethyl alcohol, acetone and various ethereal salts follow, and hydrocarbons are of only feeble power. It has been found by experiment that only those substances which afford abnormal osmotic pressure in solution are capable of conducting the electric current, and if they are dissolved in other solvents in which they behave normally, they lose this power. The ions which conduct the current must always be present, i.e., they are not formed by the current. The ions naturally act as molecules, and so increase the osmotic pressure. The ions which are formed from a substance must necessarily be charged with electricity; otherwise they would not conduct the current. Furthermore, some ions are always charged with positive electricity, while others are charged with negative; but no ion is known which is at one time positive and at another negative.

The physiological as well as the chemical effect of the electrolytes have been

found to be entirely dependent upon their constituent ions, quite irrespective of the nature of their molecules. Thus, all acids are characterized by H-ions, and it is in consequence of this that they all have certain general properties, while the differences between the solutions of different acids containing the same number of H-ions depend upon the difference between their anions. The kation of acids is hydrogen; the anion of bases is the hydroxyl group (OH). The general conclusion is, then, that the physiological effects of an electrolyte are for the most part determined by the character of its ions. While the principal characteristics of most of the substances which are of importance in therapeutics are farily well known, it is a desideratum to understand why or how it is that they produce their special effects, and, so far as the exectrolytes are concerned, the theory of ions would seem to largely supply such knowledge. For instance, the longrecognized community of the reactions of the dissolved salts of a given metal (being the same with respect to that metal whether the chloride, sulphate, nitrate, or other salt is employed), received no adequate explanation until the promulgation of this theory. In the solid state, and when undissociated in solution, each salt has individual attributes; while in dilute solution, when dissociation is usually more or less complete, the properties of the salt are merely the sum of the properties of its ions. If, therefore, a series of salts contains a common ion, the properties of this will be common to all its members. As an illustration of this the behavior of iron salts may be cited. While all the simple salts exhibit common chemical reactions and have a very similar physiological action, compounds such as the ferrocyanides, for instance, neither yield the reactions of iron or exhibit the influence of the metal in their physiological effects. The explanation would seem to be that the simple salts yield metallic ions on dissociation, but the ferrocyanides yield the group ferrocyanogen, neither the chemical behavior nor the physiological action of which is identical with that of iron itself. It is plain that when a dissociable body is administered, not one, but two separate agents are put in action in the tissues, so that the effect of each of the ions must be taken into consideration. In the great majority of such substances in the organic materia medica, however, the action of one ion is so much more powerful than the other that the less important one may be practically disregarded. This is especially true of the more toxic bodies. In the instance of morphine sulphate, for instance, while this exists in the body as a morphine and a sulphate-ion, the action of the former ion is so much more powerful than the other that the sulphateion is of no consequence. Evidence of this is furnished by the fact that morphine hydrochloride, which in the body is dissociated into morphine and chlorine-ions, has practically the same action as morphine sulphate. With less poisonous substances, however, both the ions may exert a more or less powerful influence. Thus, we find that quite different symptoms are produced by potassium sulphate and potassium bromide, and this is because here larger amounts can be administered, and the SO4- and Br-ions are present in sufficient quantities to elicit their specific actions, which are quite as important as that of the K-ion. What are ordinarily called the strongest acids and the strongest bases are those which, in a given solution, are most ionized. The effects of an ion can be determined only by administering it along with another in the form of a salt, but certain ions, it has been pointed out, are so inactive in the tissues that, if any effect is noted after a com