Diuretics

DIURETICS (remedia diuretica, diuretic agents), a large group of pharmacological agents, quite different in their chemical properties, capable of increasing urine output (see Diuresis). The mechanism of action of diuretics can be different depending on their influence on one or another factor of diuresis, and it should be borne in mind that this influence often turns out to be quite multifaceted. Understanding the mode of action when using diuretics at the patient's bedside is of great practical importance, as the therapeutic effect will depend (unlike in a healthy organism) on the correct choice of the appropriate diuretic. It is most expedient to consider the action of diuretics on renal and extra-renal factors of diuresis separately. As studies of recent years have shown, in the normal state, the simultaneous functioning of all renal glomeruli usually does not occur: while some are in an active state, others turn out to be collapsed, and blood does not circulate through them. Therefore, all agents that promote the dilation of renal vessels attract a larger number of glomeruli to work and lead to an increase in the urine-secreting surface, and thereby to an increase in the amount of urine. Substances that dilate the vessels of the kidneys, when given in doses that do not lead to a drop in blood pressure, also contribute to an increase and acceleration of blood flow in the kidneys, which also favors urine output. In the case of a strong increase in the amount of renal filtrate (or secretion), one can expect its faster passage through the tubules and, as a result, correspondingly less reabsorption of water. Therefore, the resulting urine turns out to be less concentrated in comparison with normal urine. This is one of the actions of the caffeine group. Dilation of renal vessels is also caused by the group of nitrites, alcohol, digitalis, etc. In addition to substances that increase the urine-secreting surface due to improved blood circulation in the kidneys, a number of substances are attributed the ability to increase the very process of separating the components of urine through the endothelium of the Malpighian glomeruli and the epithelium of Bowman's capsule. Depending on the two main theories of urine output, one has to speak here about the strengthening of the process of filtration or secretion of urine. Proponents of the secretion theory also attribute the ability to secrete certain components of urine to the epithelium of the convoluted tubules. These substances primarily include substances of the caffeine group, which are also characterized by increasing the permeability of the vascular wall, which is of essential importance for the process of filtration. Furthermore, this includes all substances capable of irritating the vascular endothelium of the glomeruli and the renal epithelium. Such is the action of heavy metals, mainly mercury preparations, and the action of many essential oils and balsamic substances, cantharidin, etc. At high doses, these irritating substances lead to glomerulonephritis. Further, in the mechanism of action of diuretics on the kidneys, one should note their effect on the already mentioned process of reabsorption in the tubules of the liquid parts of the glomerular filtrate (or secretion). According to a number of authors, the caffeine group retards this process due to the inhibition of the absorptive capacity of the epithelium of the convoluted tubules. It should be noted that due to this, an increased excretion of solid substances can also be caused; thus, with caffeine diuresis, the excretion of salts is increased; it is very likely that a similar process plays a role in atophan diuresis in relation to uric acid, and in phlorizin diuresis in relation to sugar, since it is assumed that these "pharmaka" hinder their reabsorption (Cushny). A decrease in the reabsorption of water in the tubules can occur in the presence of substances in the glomerular filtrate (or secretion) that increase osmotic pressure (urea, milk sugar, acetic acid salts, etc.). Therefore, these substances, if they have been absorbed through the intestinal mucosa in sufficient quantity when administered per os, being excreted through the glomeruli, will hinder reabsorption, retain water, and thus increase the amount of urine. Such is the mechanism of diuresis occurring due to pharmacological action on the kidneys themselves. However, an increase in urine output can occur not only in this way. The presence of hydremia is of extremely essential importance in predisposing the organism to diuresis. Therefore, the following factors will act as diuretics. 1) Abundant drinking of liquids, especially those saturated with CO₂ and therefore quickly absorbed, such as various mineral waters, artificially carbonated drinks (lemonade, kvass, etc.), etc. Due to the rapid onset of diuresis in these cases, some authors (Kobert) classify them into the group of tachiuretica. Milk, kumis, fruits and vegetables rich in water (grapes, pumpkin, etc.) also cause diuresis, in the onset of which the content of sugar and salts in these "dietetic" diuretics is also of importance. 2) The appearance in the blood (after absorption from the gastrointestinal tract) of substances that increase the osmotic pressure of the blood and therefore cause an influx of tissue fluid into the blood. An excess content of all soluble solid substances in the blood regularly increases diuresis, as they are excreted by the kidneys with a correspondingly large amount of water. A significant increase in the solid substances of the blood is possible without harm to the organism only at the expense of indifferent salts and some other indifferent substances, and these substances must be absorbed from the digestive tract sufficiently quickly. This includes mainly acetic acid and nitric acid salts, urea, sugar, etc., in short, the same substances that inhibit reabsorption in the tubules. 3) Hydremia occurring after taking calomel. The administration of calomel leads to an increase in the secretion of intestinal glands and to a delay in absorption in the small intestines, and therefore to a temporary thickening of the blood and a compensatory influx of water from the tissues. After the highly watery contents of the small intestines pass into the large intestines, part of the water (especially with the delay of bowel movements by opium) is absorbed into the blood, causing hydremia. 4) The release of water bound by both tissue colloids and plasma colloids. A whole range of substances can reduce the ability of proteins to swell, which leads to the release of the water previously bound by them. This takes place under the influence of potassium ions (which partly explains the diuretic effect of its salts), then under the influence of substances of the caffeine group, diuretics of the mercury group, under the influence of the thyroid hormone, etc. One should also take into account that the caffeine group is characterized by increasing the permeability of the capillary wall and thereby facilitating the transition of water and salts from the tissues into the blood. The diuresis occurring in all these cases is called extra-renal. It should be said that the conditions of its onset have not yet been studied sufficiently (for example, the extra-renal action of the caffeine group is linked by Fröhlich, Pick, and Molitor partly to their action on the central nervous system). In addition to the thyroid hormone, urine output is also subject to other hormonal influences. Thus, under certain conditions (anesthesia), diuresis occurs under the influence of hypophysin, which normally, as a rule, inhibits diuresis. Such are the physiological processes that can be influenced by pharmacological agents that cause a diuretic effect. To what has been said, it should be added that in case the decrease in diuresis is associated with a disturbance of cardiovascular activity, an extremely pronounced diuretic effect occurs from agents that eliminate this insufficiency. Such is, for example, the action of digitalis in congestions of cardiac origin. Digitalis also gives a certain diuretic effect in a healthy person, which is associated with the dilation of renal vessels. In case of congestion, it leads to an improvement in blood circulation throughout the body; the diuresis that appears as a result of this increases sharply after the absorption of edema due to the hydremia occurring during this. It should be noted that in reflexively arising anuria (renal colic, etc.), various nervina can play the role of substances capable of restoring urine output, partly due to the suppression of the pain reflex (morphine), partly due to the lowering of the tone of the vasomotor center, through which a reflex spasm of vessels can arise (chloral hydrate, etc.). Among the diuretics, the mode of action of which was briefly reviewed, one can distinguish the following pharmacological groups of substances. 1) The caffeine group, which possesses an extremely multifaceted effect on diuresis and is therefore a diuretic par excellence.

It should be noted that caffeine itself and its salts, which possess an undesirable stimulating effect on the central nervous system for diuretics (stimulation of the vasomotor center, which can lead to constriction of renal vessels and thereby hinder diuresis; restlessness and insomnia due to the effect on the brain, etc.), are used significantly less frequently than other xanthine bases (theobromine and its numerous preparations, theocin, theophylline, and others). 2) The mercury group (calomel, Novasurol, Salyrgan, Novurit), the preparations of which, with the exception of calomel, have entered the ranks of diuretics only in the very last years and are acquiring ever greater therapeutic significance. 3) The group of diuretics acting either by the water contained in them or by crystalloids easily absorbed from the digestive tract. This includes long-established classification subdivisions: a) diuretica aquosa (mineral waters containing CO₂ and poor in salts, etc.), b) diuretica aquoso-salina (alkaline mineral waters, milk, pumpkin, etc.), and c) diuretica salina (acetic and nitric acid salts of potassium and sodium, calcium salts, urea, milk sugar, etc.). The latter subgroup, like the caffeine and mercury groups, causes diuresis by enhancing water exchange between the blood and tissues, while the first subgroups lead to diuresis mainly due to water absorbed from the intestine. 4) The group of terpenes (various essential oils and balsamic substances: Ol. Petroselini, Ol. Juniperi, Ol. Levistici, etc., and herbal preparations containing them) and other substances capable of irritating the urinary organs (cantharidin, glycyrrhizin, etc.). According to old terminology, these are so-called diuretica acria; they are relatively rarely used in modern therapy and are contraindicated in inflammatory kidney lesions. 5) Cardiovascular agents (mainly substances of the digitalis group, inorganic and organic nitrites, etc.), which in most cases are diuretics in the indirect sense of the word; special mention should be made of sea squill (Bulbus scillae), which also possesses a direct diuretic effect of the diuretica acria type. 6) Preparations of endocrine glands, among which preparations of the thyroid gland are of primary importance, more often used for hormonal disorders of water metabolism (myxedematous states). Less studied and less consistent is the diuretic effect of organ preparations of the kidneys themselves, proposed at one time, possibly due to the low value of the preparations being made. In modern therapy, which makes wide use of the synergistic effect of medicinal substances, various diuretics are often used together. Such is, for example, the long-used combination of substances of the caffeine group and the digitalis group in cases of urinary disorders in cardiac patients, or the combination of the caffeine, mercury, and diuretica salina groups with each other. Upon repeated administration of the same diuretic, diuresis sometimes does not occur at all or is less pronounced than with its first doses. Such 'habituation' (explained by some authors as fatigue of the excretory apparatus) is clearly expressed in substances of the caffeine group. The use of the latter in large (especially repeated) doses can even lead to complete anuria, occurring due to sharp thickening of the blood in the capillaries of the glomeruli (Teplov). It must be assumed that to avoid these phenomena, one should either change the diuretic or use the just-mentioned synergistic effect of diuretics. Since the main effect of using diuretics is an increase in the liquid component of urine, their therapeutic significance, expressed in the 'flushing' of the urinary tract, is most clear. An increased flow of urine can lead to the washing out of solid parts from the renal tubules, e.g., 'casts' and urinary sand. Furthermore, diuretics are resorted to for the purpose of washing the urinary tract of inflammatory secretions (in pyelitis, cystitis, and urethritis). The dilution of urine caused by the use of diuretics, by reducing the concentration of acids in it, leads to a decrease in the acidity of the urine and thereby reduces its irritating effect, which is also significant in inflammatory conditions of the urinary tract. In all such cases, one should use mainly diuretica aquosa or aquoso-salina. It should be added that by prolonged use of diuretica aquosa, one also strives to prevent the accumulation of urinary sand and the formation of stones in cases of predisposition to the corresponding diseases (in this case, for better dissolution of phosphates, one should take care of the acidic reaction of the urine, and for the dissolution of urates, of its alkaline reaction). It is significantly more difficult to achieve the use of diuretics for the purpose of 'flushing' the organism. Thus, in various kinds of acute poisoning (as in exogenous, and sometimes in endogenous intoxications, as well as in acute infections), by prescribing the same diuretica aquosa, one strives to lower the concentration of the poison in the blood in order to reduce the harmful effect of the poison on tissues and especially on the kidneys, since it is here, due to the concentrating activity of this organ, that the effect of the poison is especially sharply expressed. Diuretics are also used in chronic poisoning (mainly for the purpose of removing the poison from the tissues), as well as in metabolic disorders accompanied by the appearance of abnormal and harmful metabolic products in the tissues and blood; in this case, diuretics are combined with preparations that can facilitate the removal of these products from the tissues into the blood (e.g., with iodide salts in chronic lead poisoning, anti-gout agents in uric acid diathesis, etc.). The excretion of a large amount of fluid by the kidneys leads to a decrease in the liquid part of the blood, which is quickly replenished from the tissues, leading to their greater or lesser dehydration, and in the presence of pathological fluid accumulation in the body, to its rapid absorption. Therefore, the third important indication for the use of diuretics is the removal of fluid accumulated in the body. Here, mainly substances of the first two groups are used, usually in combination with cardiovascular agents if these fluid accumulations are associated with congestive phenomena. In the presence of inflammatory effusions in the body, diuretics do not directly stimulate their resorption, but accelerate it if resorption has already occurred spontaneously or under the influence of anti-inflammatory treatment. The use of diuretics is most difficult in kidney diseases, since here two tasks simultaneously confront the physician: the preservation of normal diuresis (or even its increase in case of insufficient excretion of metabolic products), and at the same time, providing the diseased excretory organ with possible rest. When choosing diuretics in these cases, especially in acute inflammatory diseases, one should avoid prescribing diuretica acria and mercury preparations, and also limit the intake of water and salts. The most effective, and at the same time harmless, are substances of the caffeine group here, especially with their cautious dosing. In non-inflammatory lesions of the vascular system of the kidneys (arteriosclerosis, congestive phenomena, vascular spasm), cardiovascular agents (digitalis, nitrites, etc.) are of particular importance. For more detailed instructions on the use of diuretics in nephritis, nephrosis, etc., see the corresponding articles.