Experimental Pharmacology

Physiology teaches that the functional activities of the cells which compose the tissues of the body are dependent on the chemical reactions occurring in the living protoplasm.

It is probable that most drugs produce changes in the tissues by modifying these chemical reactions. Chemical changes may be brought about by a drug precipitating proteid, as metals do albumin, or by causing such changes in a proteid molecule that it reacts abnormally to the other cell constituents, or a drug being absorbed into a cell or tissue may change the osmotic condition of the protoplasm of that cell or tissue. It is now recognized that it takes but slight change in the molecular concentration or in the plasma constituency of a cell to greatly alter its chemical relation to the surrounding cells or fluids.

A drug in minute doses may cause no noticeable effect, though if long continued, even if the whole amount taken be very small, positive effects on the system may occur, especially on the various glands of the body, on the blood, or on metabolism. A slightly larger dose given for some time would cause this physiologic change sooner. The minimum dose of a drug that will produce physiologic symptoms is said to show pharmacologic action, and such action represents the primary physiologic effect of the drug, and this action can be demonstrated on living tissues. Such doses are physiologic doses, and if not too long continued or too frequently administered do no harm.

Doses larger than that which will produce a primary physiologic action cause more marked symptoms and finally poisoning, in the broad sense of the term, and the results are more or less toxic, depending upon the drug. The results of such large poisonous doses are sometimes apparently directly opposite to the action of small doses of the same drug, though careful investigation of the physiologic action of the drug will often show that it has stimulated other activities that overwhelm those caused by smaller doses rather than that there is an actual contrary action.

The physiologic study of toxic doses discloses the power of some drugs to prevent the poisonous action of others, i. e., antidotal action. An antidote to a toxic dose of a drug may be a chemical, physical or physiologic opponent. Hence, a drug or preparation that could by chemical reaction with a poison render the resulting combination inert, or by mechanical obstruction prevent the poison from acting, or being absorbed, or by physiologic action either could rapidly expel the poison from the body or could actually oppose the poison in the tissues of the body is an antidote.

By the local action of a drug is meant the action upon the part to which it is applied, i. e., an action that takes place without absorption into the blood.

Many drugs cannot be absorbed, and, therefore, have local action only. Other drugs not only have positive local action, but are also absorbed and thus reach through the circulation the organs of the body upon which they have specific action. Still other drugs have no local action, and act only after absorption. Drugs that have local action exert it on the skin and on the mucous membranes, and if taken into the stomach may aid or interfere with digestion.

Drugs that are absorbed into the blood may modify it, act upon the heart, blood-vessels, nerve-centers, nerves, muscles, lungs, liver, on the genito-urinary system, or on the organs of secretion. A drug may therefore act after absorption upon any one or upon all parts of the body, and the determination and localization of the action of the drug is the object of experimental pharmacology.

In investigating a drug it is of importance to note the length of time it takes for the drug to act, i. e., the rate of absorption, and this varies with the part of the body into which the drug is introduced.

The action of a drug is most rapid when it is injected into a vein, next when introduced into a serous cavity, next when injected deeply into the muscles, next when injected subcutaneously, next when absorbed from a mucous membrane (as from the mouth, empty stomach or rectum), next when given on a full stomach, and least rapidly when rubbed into the skin.

The liver retards and modifies the action of many drugs and most alkaloids, hence the doses of such drugs required to produce physiologic effects are greater when they are given by the mouth than when they are given hypoderniatically.

It is next of importance to note where and in what form the drug is excreted, and how long before it is all excreted.

What is termed the primary and secondary action of a drug should be noted. The primary action is that for which the drug is used and for which its action is sought. The secondary action is a late effect of a drug, which may not be desired. For instance, the primary action of mor phine is to stop pain and produce sleep, and the secondary action may be to cause loss of appetite and constipation.

Some few drugs when given for a certain length of time in small physiologic doses, i. e., doses that produce certain positive effects, tend to accumulate in the system, and there may later be definite signs of too great an effect from the drug, though the symptoms will not be exactly toxic. This is generally caused by a too frequent administration of the drug to allow complete excretion of the previous doses. This cumulative action as it is called can occur only with drugs which are excreted slowly, such as digitalis. Other drugs tend to accumulate in the system, notably the metallic, which are deposited in the various organs of the body. Such drugs do not cause what is termed cumulative action, but if a considerable amount is taken of another drug which acts as a solvent to them, or if such a solvent be suddenly developed in the system, large enough quantities of the deposited metals can be liberated to cause marked physiologic symptoms.

The amount of a drug that will cause definite symptoms or signs of its physiologic activity will vary, not only with the solubility of the drug and the manner in which it is administered, but also with the species of animal, with its size and age, and with individuals of the same class. This last variation is termed idiosyncrasy, which we generally recognize as an increased susceptibility, though frequent instances occur of diminished sensibility to a drug.

Other factors that modify the activity of a given dose are climate, temperature of the body, chemistry of foods and minerals that may be in the stomach when the medicine is given by the mouth, and what is termed tolerance. Tolerance to a certain drug or class of drugs may be inherent in races or certain animal species, or it may be individual, a kind of idiosyncrasy, or it may be acquired by individuals, especially for certain drugs of the narcotic class. In such individuals a much larger dose than ordinarily should produce physiologic symptoms will be needed to cause such action.

Certain diseased conditions may also modify the susceptibility of an individual to a drug, in some instances requiring the dose to produce physiologic symptoms to be larger, and in other instances smaller than the ordinary dose.