The utilization of elementary nitrogen is also impossible for green plants and the derivation of simply bound nitrogen from mineral is made difficult by its inaccessibility (NO is formed through atmospheric discharges and is carried to the earth with rain; ammonium chloride is formed in traces in the lithosphere and ammonia may arise out of the decomposition of organic material). Here of assistance are the lower organisms, the bacteria which are able to carry out the inert nitrogen to NH3 unions. The plant protein on which the animal organism lives likewise for the most part has the presumption of a preliminary work of other organisms. And where the slow work of nitrification of the soil bacteria is not sufficient to cover the requirement for bound nitrogen, there the artificial nitrogen synthesis occurs as a supplement. Reversely, through the life of higher organisms and also many lower organisms, a part of the bound nitrogen again becomes free and with it life on earth is again lost.
Plants can at least utilize the oxidized nitrogen, in the NO3 form through reduction while this is not possible to any great extent in animals; it is found already reduced in plants in the amino form (-NH2) of reduced nitrogen.
So to animal metabolism the mineral nitrogen, as well as the ammonium and the nitrate form, remains essentially foreign. But both forms have their actions on the organisms which make them poisons and drugs. The regulatory equimolecular mass action of the ammonium cations at the end of the metabolic processes, when it is involved, spares the fixed alkalies in the neutralization of excessive acid excretions but still is not to be imitated medically. But on the way to detoxification to urea, NH3 or the cation NH4 unfolds irritant actions which can be used medically, and the nitrate form goes through the body without a trace. However, according to all appearances, they also do not remain entirely untouched. The animal organism obviously shows a residue of reduction ability for nitrates, for example, through the enzyme of milk (perihydridase) or the tissues (xanthinoxydase) it reduces nitrates to nitrites, nitrates becoming hydrogen acceptors. This more or less rapid passage into nitrites from the various nitrates occurs distinctly in the medicinal action of these preparations (nitroglycerine, alkali nitrates, nitric acid).
THE METABOLIC OR COMBUSTION ELEMENTS
While the four basic elements discussed compose the energy spending organic combustion material, we now pass to four other elements which to a certain extent represent the combustion apparatus in this burning process in vertebrate organisms, phosphorus, sulphur, iron and iodine. They can be designated as combustion elements in contradistinction to the organic basic elements. I know of nothing better to employ for an example than the match with wood as the burning material, phosphorus and sulphur as easily inflammable acceptors of oxygen which is made available by potassium chlorate. Phosphorus and sulphur are also biologic intermediator; the carrier of oxygen in the vertebrate organism is iron. And the regulator of this combustion system- in the match the release of the necessary warmth is brought about by rubbing- is represented in the animal organism by iodine.
In contradistinction to the crude example from daily life, the biologic combustion mechanism proceeds entirely on an interlocking and fine harmony through complicated chemical circuits so that for this process a labile dynamic equilibrium is also maintained. Therefore no extreme temperatures need appear. Of the interlocking of enzymatic and nervous regulation we need not speak in this connection. The sulphur containing building stone appears in all proteins down to peptones and protamines, and phosphorus in nucleoproteins and many lipoids. Iron and iodine fulfill their tasks in special organic compounds (hemin and thyroxin). There must be ascribed to each of these four materials a special physiologic rule in metabolism. Because of the manner in which they normally regulate organic chemistry, we also recognize their paths of disturbance in metabolism. And as always we are forced to a general supposition of an artificial regulations: that the disturbance circle of a material also shows orderliness; a supposition which is expressed in physiologic materials as follows; the medicinal action of a substance natural to the body presumes a disarrangement in the physiologic functions and paths of this material. When we repeatedly enter into the possibility of medicinal action of these physiologic materials, then it is always seen that these irregularities or regulations are in no way dependent on quantitative proportions, on excess or defect, but that the local and temporal siftings and the state of alteration are just as significant.
The four metabolic substances which we designate as combustion elements have entirely different functions in the preparation of the cells for oxygen in take and in the intermediation for oxygen itself, but common to them is the fact that they are originally and basically involved in dissimulation. They influence the body constitution from the metabolic side and here the relation to oxygen and to oxidation is decisive. The position of these four metabolic elements in the periodic system of element is certainly not inappropriate for their task. We see sulphur, phosphorus and iodine as anion formers, as representatives of Groups V, VI, VII, and iron which may vary between cation and anion building, as the representative of the accessory Group VIII, the heavy metals which serve in the special capacity of a catalysor.
THE TONIC ELEMENTS
On the other side of the periodic system, in Groups I and II, we find again four physiologic elements, sodium, potassium, magnesium and calcium, with an entirely different function. We designate them as tension elements, as tonic elements. These four substances also have a common labor. As builders of cations they work together in order to guarantee the state of organic material, as structures on which the living processes play. As they are physiologic, that is, destined for the maintenance of labile equilibrium powers, their electrochemical and electrophysical reactions are reversible to a high degree, while the cations of higher (for example 3) valence and higher atomic weight have few or no reversible actions. Through their positive charges the four physiologic cations are the counterbalance to the anions (HCO3, HPO4, SO4) which are constantly arising from metabolism and which moreover through another anion, chloride, are held in equilibrium and regulated. The tonic work of the cations represents the limit, because tension depends upon limit. The relation of differentiated organic materials to their milieu, for the most part water, underlies the regulation through the electrolytes in general. And this is brought about in that they owe the electric discharge of atoms or atom complices to ions by separation by water. Their reciprocal relation to water makes it possible to create tensions and to balance them. And of the electrolytes the anions necessarily furnished in the course of life, in turn, are dependent upon other types of intermediary processes giving their counterbalances, the cation, the independent, indeed, the controlling role in the regulation of tension in and on the cells. The action of the charged ions proceeds on the surface of the body colloids. Colloids ar proteins or better said the organic structures are in a colloidal state as proteins, and, in consequence to the size of their molecules, not in a true solution in water. But thereby the relation of a colloid to water is decisive for its maintenance in a colloidal state. Colloids can incorporate and bind (hydration) water in their molecular complex; they can swell or shrink remarkably and owe their stability chiefly to their adaptability to their milieu, especially to water. One calls them lyophile or, since the swelling agent is generally water, hydrophile colloids. Hydrophobe colloids, on the other hand, maintaining their molecular complexes in a colloidal state independently of water, owe their stability to strong electric charges. We will encounter them especially in the metals, which in finest subdivision (high dispersion) with a distributing medium (dispergen) furnish the so-called metal sols. In the organism the hydrophobe colloids are rare (cholesterin, etc.). They are precipitated by ions of opposite charge (Hardy’s rule). Indeed the hydrophile colloids also carry an electric charge but the relation to water is decisive for the state of aggregation whether as fluids or sols semi-fluid or ‘gels, or as solids, coagulated. But the electrolytes act on the hydrophile colloids through loading or unloading, they influence the state of swelling and the surface tension. Now since most of the hydrophile colloids of the organism have a negative charge so the carriers of a positive charge, the cations, come to have an important role in influencing the colloidal cellular constituents. The actions of these physiologic cations can be best read off from the state of swelling and tension of the organic structure. Na, K, Mg, Ca, are the elements which primarily control the constitution of organic structure, indeed the organism, from the structural side and thereby is the relation of organic materials (proteins and lipoids) to water of special significance. One can also designate these tension elements as form-determining elements.
Within this common labor again each of the four cations has its special task. This becomes gradually and partly accessible to our knowledge through the alterations in colloids, cells, or organs, which we observe in one-sided disturbances of ion equilibrium. One must avoid rash generalizing on the equal or opposing relation of ions from single effects on the total way of action of these ions. This is frequently noted in regard to the cations and thereby much error has entered this scientific field. This holds especially for the apparent general antagonism of potassium and calcium, which is paralleled by the antagonism of the vagus and sympathetic. We shall see later that this hypothesis is not sufficiently justified. Indeed we will observe opposing effects many times within cation interrelationship entirely synergistic, whereas, when two cations as potassium and calcium or magnesium and calcium neutralize the effect of each, this is characteristic only for the usual effect. On this account one should not speak universally of antagonism. Closely related ions which follow as chemical elements in allied groups, as potassium and sodium, magnesium and calcium may appear as exactly similarly working agents for many purposes, but in respect to other actions their effects are not additive but subtractive and they seem then to be antidotal.
For this there is a simple physical and chemical example: cations as Na, K, Ca each increase by themselves the surface tension of lecithin solutions. But if sodium and potassium or sodium and calcium are employed at the same time in definite proportions, then the surface tension of lecithin remains unchanged (Neuschloss). Another example: cane sugar splitting through invertase becomes prolonged as much when one employs a magnesium salt as when he adds a calcium salt by itself; indeed the calcium salt acts stronger than the magnesium salt. But if one adds the two at the same time and in the same concentration, the one completely removes the depressing influence of the other.
From this one sees that an antagonism in effect can appear, when to judge according to the individual effects of two agents, a synergism, an addition of actions, would be expected; and this, even in a simple reaction mixture. But with increasing complication the possibility of reversal or removal of equal single effects becomes correspondingly complex. In a reactive substrate so many-sided as a cell, an organ, and an organism- where all processes strive to a state of equilibrium, of self- maintenance – the possibility of balancing of and by itself with equally directed powers is completely beyond the limits with drugs. The narcotic cell action of magnesium ions can be removed with calcium ions. But it would be false on this account to ascribe a universally cell-stimulating action to calcium ions. It is exactly the task to study the conditions under which individually similar or opposing effects can occur through the ions.
For the influence of cations on the state of body colloids one must always proceed from their physiologic equilibrium in the body fluids. The optimal concentrations of the vital ions in the fluids perfusing the cells of plants and animals correspond in a remarkable way to that of sea water. One can take this correspondence exactly as a basic fact of the telluric confederacy of the biosphere. Further details, as the corresponding distribution of sodium and potassium between the fluid and colloidal parts of the earth and body, are also available. The individuality which is demonstrated through the enrichment of definite ions in the various organs and organ systems allows many deductive conclusions on the role of single types of ions.
COLLOIDAL ACTION OF IONS
The reverse experimental way to demonstration of the action of single ions goes laboriously from one station to another. The point of departure is the influence of ions on the colloid state in general which goes back to the charges and valences of the ions. The influence of swelling of the colloids goes parallel with their water combining (hydration), and this again is dependent on the nuclear charge and the atom radius (Fajans). For the cations in alkaline reaction as they are found in the body fluids, the following series of effect on swelling or flocculation of hydrophile colloids can be arranged: Li< Na< K< Rb< Cs< Mg< Ca, whereby from left to right the swelling to shrinking or flocculating action of single cations is designated. This so-called Hofmeistr series or lyotrope series also proceeds in harmony with the ordinal number.
Proceeding from this basic series of general colloid effects of the cations by many experimental alterations one has demonstrated the influence on definite organ cells. From the position of the cations which are given in the form of the so-called transition series, the preferable action of this or that cation on the definite organ or function can be read off under certain conditions. (The same holds for the anions, only for reasons already mentioned, the influence of the body colloids through the cations is of greater significance.) What is worthwhile for a knowledge of effects of single cations from these reports, will later be discussed in detail in regard to the single compounds.
Outside of the nuclear charge of the cation, the valence is of general significance for its colloid action, the divalent act damaging in much less concentration than the univalent, and the trivalent more than the divalent, so that they hardly come into consideration in physiologic relationships. In physiologic equilibrium these ratios of ion concentration of Na, K, Mg, and Ca come distinctly into expression. In the serum Na: K: Mg: Ca approximately as 100: 1.7: 1.0: 0.5. Moreover, for the interpretation of experimental findings these quantitative ratios are to be regarded seriously. If for example, the disturbing action in a one-sided increase on time of potassium ions, at another time of calcium ions is to be compared, then correct conclusions are to be drawn only in case the concentration increases occur each time in the physiologic ratio of K: Ca. If, in order to ascertain calcium actions, one would increase the calcium ions just as much as in the corresponding potassium study, then the results would not be comparable. Because with a nonproportionate overdose of calcium a reversal of effect may appear. The consideration of these quantitative relationships is important whereby a premature one-sided conclusion on cation influences (for example, vagus or sympathetic stimulation) is avoided.
The damaging action of a definite ion excess on the living cells and tissues occurs apparently in that the normal permeability ratio of the plasma envelope is altered. The ions themselves are able to influence the conditions of their permeability. The normal task of ions- which is to guarantee the structure, and thereby the function of the cells, through tension differences (potential differences) on the surface- is to a great extent dependent upon the fact that the ions are distributed correctly at their sites. The inside or outside, the direction of the stream between the colloid and watery phase, is just as important for ion action as the quantitative ratios. Site of action and quantity can influence in opposing directions. Frequently the reversal of a false direction of the stream is decisive for the regulation, and for this it needs no greater amounts than are employed in the isolated organ. Here a central regulation through the vegetative nerves can be easily demonstrated.
Likewise the already mentioned chlorine, Cl, is vital as an anion. United with Na as a neutral salt, it participates in the regulation of water movement. Moreover, chlorine is an ever- available, easily movable reserve which can exchange itself for the anions occurring in metabolism and therefore markedly varies. Through this, chlorine is a regulatory factor in acid-base equilibrium on the side of the anions. It can also separate from sodium, for example as HCl in the gastric juice, introducing a decided change in the pH, which forms an optimum for a partial process in digestion. As chlorine intervenes in a regulatory manner in the dissimilative part of metabolism, so it can condition disturbances there. In this sense the chlorine fraction can become valuable in medicinal materials.
SILICIUM AND THE RARE STRUCTURAL MATERIALS
Finally silicium, Si, in its dioxide, the anhydride of silicic acid, SiO2, is a substance regularly appearing in the organism. SiO2, has its position and work especially in the connective tissue. As negatively charged colloids which can incorporate water are hydrophile, it is the opposite to the characteristic function carriers of the organism, in any case for negatively charged hydrophile organic colloids. This role in the organism forms the basis for the medicinal activity of SiO2 when it is made available in a suitable form. Then too, in its actions, it stands very close to the mineral carbon compounds from the same group of the periodic system.
These fourteen elements are the essential participants in the structure of the human organism. Indeed fluorine, F, also plays a role in its firm calcium compound in the bones and teeth; perhaps similarly traces of bromine, Br, a neighbor of iodine, but still with its own physiologic task: perhaps there will also be discovered a physiologic significance for aluminum, Al, in the animal organism as in the plant world; but the fourteen elements discussed remain the basic materials, the essential structural elements of the vertebrate organism.
With these elements we find ourselves at the limit of the cosmic and telluric weight frequency rule. One distinct exception is made by iodine as the sole representative of the fifth period. Its important task in the biosphere is counted in terms of minimal quantities, which are measured in millionths of gram.
That a general similarity in the composition between the earth crust and organism exists is, indeed, not remarkable. Materially considered, the organism is to a certain extent an outgrowth of the earth crust. But the selection among the elements and particularly their relative amounts shows a distinct and characteristic difference, an increasing differentiation from the inorganic milieu though the series of organisms.
CONSTITUTIONAL AGENTS AND STRUCTURAL ELEMENTS
We have recognized the physiologic materials as drugs of a special rank of constitutional agents and cited the reasons for this. We now present the question; in how far do the structural elements determine the character of the drugs formed by them as constitutional agents? If we answer this: through their position in the periodic system of elements, then we presume a knowledge of the drug pictures of these physiologic materials. But it enlightens the survey if we draw the rough outline now.
On the electronegative side of the system in the Groups, V, VI VII and the accessory Group VIII we have found the structural elements which originally and decisively participate in chemical metabolism. To these metabolic elements as medicinal substances the constitutions also correspond whereby the altered rhythm of the metabolic and energy exchange gives the impression. When the splitting processes are increased, it is concerned with an oxygenoid, warm, febrile tending erethistic constitution of accelerated rhythm. These persons are hyperesthetic, easily irritable and thin. From the endocrine side they correspond to an increased function of the glands associated with the sympathetic system under the leadership of the thyroid. They are basedowoid types. Iodine, chlorine (as a drug constituent), iron, nitrites and phosphorus show these trends distinctly. The position of sulphur on the other hand is dual, corresponding to its partly reducing, partly oxidizing functions in metabolism. In the sulphur constitution the stronger weight lies toward the side of oxidation depression, the incomplete oxidation.
On the electropositive side of the periodic system we found on the other hand in Groups I and II, the tonic, form-giving elements. If the alkali and earthy alkali metals, Na, K, Mg, Ca as cations determine the drug picture, then they shape it as hydrogenoid, cold, sensitive to cold, relaxed torpid lymphatic constitutional types stigmatized along the side of the parasympathetic system. Seen from an endocrine side, they tend toward the hypothyroid side, the function of the lymphocytic apparatus (thymus) is increased. The neuromuscular tension is altered in such a way that they show a generally prolonged way of reaction with paroxysmal discharges, tetanoid states.
Between these two chief directions stands silicium with the closely related mineralic carbon compounds in the middle as the amphoteric Group IV of the periodic system. These materials act as negatively charged colloids foreign to the body. They impede chemical metabolism, assimilation as well as dissimulation. Where silicium is form-giving, cell function is reduced to a minimum. The drug picture of these materials represents constitutional types which, to some extent but not universally, correspond to the carbonitrogenous constitution of Grauvogl. Defective metabolic exchange with the outer world, primarily failure of skin and intestinal function (in carbo vegetablis and animalis, especially defective gas exchange), and on this basis of stagnation, tendency to suppuration and septic processes characterize the special constitution picture when it can only imperfectly correct common assaults. The anoxybiotic metabolism seems to be predominant over the oxidative; thereby this drug picture seems to hang together with the tendency to carcinoma. Arthritism, venosity, carbonitrogenous constitution fit this type only in a limited way. Much more the conception applies to the sulphur type in which imperfect oxidation is a basic item.