CHAPTER I

INTRODUCTION-THE THEORY OF THE ACTION OF SYNTHETIC DRUGS

IN bygone years Pharmacology was an empirical collection of recipes, hardly deserving the name of a science; but a new era was begun with the investigation of medicinal substances by chemists in the early years of the nineteenth century. These researches soon bore fruit in the isolation of the active principles of many vegetable drugs, and it was found in many cases that the active compound was a nitrogenous substance of basic character, and to this class of substance the name alkaloid was given.

Although all vegetable drugs do not contain alkaloids, nevertheless in the majority of cases definite chemical compounds, to the presence of which the action of the drug is due, have been isolated. These non-alkaloidal active principles include a large number of different types of chemical compound, but the class of substances known as glucosides (substances readily hydrolyzed by dilute acids or by ferments into a sugar and another constituent which is generally physiologically active) is especially well represented.

The isolation of the pure active compounds was of very great importance, as it opened up the possibility of an accurate study of the effect of dosage, and, as time went on, enabled quantitative measurements of the physiological effect of the drug to be made. Such progress was obviously impossible as long as investigators were compelled to deal with a crude drug of unknown strength and composition. By this means, also, secondary by-effects, often unpleasant and harmful, could be got rid of in those cases where they were due to the presence of substances other than the desired active principle.

B

The study of the constitution of the active principles led to attempts at their synthetic production. For a long time, however, synthetic chemistry was not far enough advanced to succeed in the synthesis of such complex substances, and efforts were therefore made to find which portion of the molecule gave rise to the physiological effect in order that simpler analogous compounds might be prepared possessing the characteristic action of the drug.

In this way it was found that the physiological action of the drug was in general dependent on its chemical nature, although naturally modified by differences in physical properties, such as solubility, volatility, etc. For instance, certain types of compounds often possess a characteristic action, e.g. the quaternary ammonium compounds have a paralytic action on the motor nerves. On the other hand, in the majority of cases the relation between chemical constitution and physiological action is extremely obscure, and is usually to be found only within very narrow limits, outside which any generalizations that may have been made are apt to break down. Thus a very small change in the chemical constitution of a compound is often accompanied by a complete change in its physiological action, as in the case of cocaine, a-cocaine, and a-eucaine,

the first of which has a strong local anesthetic action, whilst the second has no local anesthetic action whatever, and the third-which resembles a-cocaine in its chemical constitution more than it does cocaine-has a marked local anesthetic action, just like cocaine itself. In this connection mention should be made of the fact that a very considerable difference in physiological action is often shown by stereo-isomerides, as in the case of d- and l-nicotine, d- and l-hyoscyamine, pilocarpine, and isopilocarpine, etc.

At this point it may be advisable to indicate the relation between the chemical composition and the physical properties of a substance. It is held by some pharmacologists that the physiological action of a drug is conditioned solely by its physical properties, but even if this were always the case, it would not exclude a connection between the physiological action and the chemical constitution. It may be that the effect of some drugs is due to a subtle combination of various physical properties; these cannot, however, be readily ascertained in the majority of cases, but we can endeavour to correlate the chemical constitution-which is the foundation of these properties-with the physiological action. Another point on which misconception seems to have arisen, is the question of whether a difference in properties between two substances is to be attributed to chemical or purely physical causes. The following quotation from a leading text-book of pharmacology will serve to illustrate this: "Yellow phosphorus, given by the mouth, is a violent poison, but red phosphorus, which only differs from it in its physical properties, is comparatively innocuous. Yet were the two differently constituted chemically, the difference in their

action would, no doubt, be referred to this fact." Now, according to all modern views, there is a considerable difference in the chemical constitution of the molecules of the two different kinds of phosphorus, a difference which is manifested in the great difference of their reactivity and of their toxic action. There is probably as great a chemical difference between yellow and red phosphorus as between acetylene, (CH)2, and benzene, (CH)6, but at present we have no means of accurately investigating the molecular complexity of the two solid varieties of phosphorus.

Although the action of some drugs may be conditioned chiefly by their physical properties, yet there are others in which it is undoubtedly due to their chemical character (e.g. organic arsenic derivatives certainly owe their trypanocidal and anti-syphilitic action to the presence of the arsenic). The term chemical "character" rather than "constitution" is used deliberately, as in many cases the physiological action of a substance may be traced to some specific chemical property, which is not necessarily closely connected with its constitution. For example, the poisonous character of oxalic acid and its soluble salts could hardly be deduced from its structural formula, but its toxicity is sufficiently explained by the fact that it forms an insoluble calcium salt, a sufficient quantity of calcium in solution being essential for the welfare of the organism.* The higher members of this series of dibasic acids, having more soluble calcium salts, are proportionately less toxic. In other cases, however, some kind of relation has been traced between the presence of certain groupings in the molecule and the appearance of certain more or less characteristic physiological effects. These relations may be used in attempting to prepare new synthetic drugs, but it is impossible to forecast the action of any new substance with certainty, and careful pharmacological experiments must be made before a new compound can be introduced as a drug.

Guidance in our efforts to obtain synthetic drugs may also be obtained from a study of the changes undergone by compounds in the organism. These changes are usually in the

*This accounts for the toxicity of the salts and dilute solutions of the acid; strong solutions of the acid are poisonous in the same way as other acids; i.e. on account of their corrosive action.