To compare the various diuretics, Raphael (1894) placed him-self on a uniform diet for a long period, the daily allowance of fluid being 1180 c.c. His twenty-four-hour urine ranged between 750 and 960 c.c. When, in addition to his uniform diet, he took diuretics, his urine increased as follows:

Increase.

0.4 gm.

oil of turpentine.........................

11

per cent.

0.2 gm.

oil of juniper + 1000 c.c. water............

111

"

0.5 gm.

caffeine and sodium salicylate.............

42

"

0.5 gm.

theobromine and sodium salicylate (diuretin)

2

"

1.5 gm.

theobromine and sodium salicylate.........

14

"

3.0 gm.

theobromine and sodium salicylate.........

53

"

30.0 gm.

sugar of milk...........................

34

"

1000.0 c.c.

water..................................

100

"

1000.0 c.c.

carbonic water..........................

73

"

1000.0 c.c.

beer....................................

100

"

1000.0 c.c.

claret..................................

80

"

1000.0 c.c.

milk ...............................................................................

153

"

As a general rule, the following things are true about diuresis: 1. The filtered substances, urea and salts, are increased in proportionally greater amount than the secreted substances, uric acid, creatinin, pigment, etc., and there may be no increase in the latter substances at all. The excretion of phosphates is increased by water (Hawk), and that of uric acid by atophan.

2. Substances which are ordinarily partially reabsorbed are passed out in greater proportion to the other substances than normally, their proportional reabsorption being prevented either by the more rapid flow which takes place through the tubules, or by impairment of the reabsorbing power of the cells.

3. Frequently for the first day or two of diuresis there is a great increase in the amount of some of the solids excreted, as if there had been accumulation of these in the body and they were being washed out. Magnus says that for each salt (substance) there is a "secretion threshold," a certain degree of concentration in the blood, above which an increase leads to the elimination of the excess with an increased secretion of water. It may be that in diuresis the level of this "secretion threshold" is lowered. By atophan, for example, it is possible to reduce the uric acid of the blood away below normal.

Fig. 57.

Fig. 57. - Drawing made to scale from tracings taken from a dog by C. C. Lieb. Horizontal line of figures, time in minutes. Black line, arterial pressure; dotted line, urine flow. The close relation between general blood-pressure and urine flow is striking. The drugs, in the order used, with dose per kilo, are: Caffeine, 2 mg., urine little affected. Theophylline acet-sodium, 3 mg., urine much increased. Spirit of nitroglycerin, 0.3 c.c., urine decreased. Theobromine sodium salicylate, 3 mg., urine increased. Caffeine and sodium benzoate, 4 mg., continues theobromine effect. Animal bled, 20 c.c. per kilo, great fall in urine. Saline infusion, 25 c.c. per kilo, great increase. Camphor in oil, 20 mg., decided fall. Pituitary extract, 0.1 c.c., fall followed by rise. Epinephrine solution, 0.1 c.c., fall followed by rise. Tincture of cantharides was then given in amounts large enough to produce inflammation of the kidney.

4. Without abundant supply of water there is no diuresis.

5. The continued use of diuretics results in fatigue of the kidney cells.

Therapeutics Of Diuresis

The two great uses of diuresis are - (1) To promote the elimination of toxins, usually of bacterial or metabolic origin, and (2) to cause the removal of dropsy. In the first case copious amounts of water must be administered to serve as the medium of excretion; in the second, the ingestion of water is kept below normal. When the human kidneys are impaired, as in nephritis, there may be abnormal retention of various substances, i. e., the kidney loses its power to excrete to the full degree. Such substances may be water, chlorides, urea, creatinin, uric acid, etc. In such cases the application of this or that diuretic is purely experimental.

1. To Promote The Elimination Of Toxins

Assuming that the kidneys are functionally good, diuresis brought about in any manner tends to increase the excretion of any dialyzable substance in the blood; for the water in passing out must carry with it some of each of the filterable substances of the blood. If the poisons are not filterable, they pass out in the urine only if the tubule cells, or perhaps the cells of the glomeruli, can take them from the blood and excrete them. The tubules are exceedingly sensitive to foreign substances in the blood, and are probably competent to excrete many of the unusual deleterious substances of the body, such as toxins of disease or abnormal products of metabolism; but we have no satisfactory data to indicate just how much of a role they do play in such elimination. To promote the elimination of drug poisons, such as strychnine, a saline infusion or 2 per cent. sodium sulphate intravenously may be administered. For metallic poisons see the Lambert-Patterson treatment for mercuric bichloride poisoning. This is also a method for overcoming suppression of the urine in acute kidney cases.

By promoting absorption of tissue fluid, diuresis may have an additional value by getting the tissue toxins into the blood stream to be excreted.

2. To cause the removal of dropsy and edema - i. e., the removal of fluid from the potential tissue spaces. The treatment of dropsical or edematous conditions is of the greatest interest from a diuretic point of view. There are four great causes of edema, viz., venous engorgement from cardiac disease, kidney impermeability, tissue retention, and abnormal general capillary permeability.

As a rule, a combination of diuretics is advised, and a diminution of the water intake.

(a) Venous engorgement has been discussed at length under Digitalis. At times the best results are obtained with digitalis to activate the circulation, and diuretin or a saline such as potassium acetate to activate the kidney or dilate the kidney arterioles.

(b) Kidney impermeability is a difficult thing to overcome, because it depends on kidney disease. The impermeability for salts, urea, uric acid, water, etc., may depend largely on the type of affection of the kidney. Much experimental work has been done on forms of acute nephritis produced by poisons. Thus poisons affecting the tubular epithelium are uranium nitrate, mercuric chloride, and the alkaline chromates; poisons affecting the glomerular capillaries are arsenous acid, cantharidin, and rattlesnake venom; and a poison that will affect both capillaries and tubules is diphtheria toxin. The glomerular capillaries seem to be affected beyond all other capillaries, probably by a remote local action in the elimination of the poisons.

In the experimental acute tubular nephritis there is copious urination, increased by most diuretics. In the experimental acute glomerular nephritis there is no polyuria and deficient response to diuretics. In either case, after a few days' exposure to the poison, the lesions tend to extend and become combined; but when the poison is stopped, the kidneys heal and do not show the lesions of chronic nephritis (Pearce).

In acute or chronic nephritis with edema we have little information to guide us in our choice of diuretics, and our best plan is to use a saline diuretic with one of the caffeine series, such as theobromine sodio-salicylate. Because of the danger of producing kidney fatigue, Christian and others recommend large doses for only two or three days at a time. Pearce has shown that kidney injury alone is insufficient to cause edema. There must be, in addition, general capillary permeability and hydremic plethora.

(c) Tissue retention of water as a cause of edema is a subject not fully understood. In chronic edematous states it is customary to put the patient on a diet very low in sodium chloride, the so-called "salt-free" or "salt-poor" diet. This reduces the sodium chloride in the urine, but seems to make little alteration in the percentage of sodium chloride in the blood-plasma. It is, however, an effective measure in many cases. The author has seen cases in which the salt had been so reduced that diuresis occurred only after the administraton of sodium chloride.

(d) Abnormal permeability of the capillaries of the body may result from poisons, as in arsenic and food poisoning and uremia.

It is to be remembered that diuresis requires water as its medium, so that to promote the elimination of poisons copious drafts of water should be administered with the diuretic. If, however, there is edema or any degree of water retention, all fluids should be restricted. (See also Caffeine, Theobromine, and Theophyllin.)