Appraisal and reappraisal of cardiac therapy Edited by Arthur C. DeGraff and Alan F. Lyon

Diuretic therapy. Part I

Arthur C. DeGraff, M.D.* Alan F. Lyon, M.D.**

New York, N. Y.

T he use of diuretics to control the retention of salt and water in cases of

congestive heart failure is an essential part of treatment after digitalis and the dietary restriction of salt have become in- adequate. Considerable advances in di- uretic therapy in the past decade have greatly increased the ease and efficacy of treatment, but have also introduced new complications.

With the great increase in the number of diuretic agents a multiplication of trade names has evolved, not only of the single drugs but also of combinations of drugs. This all leads to confusion. Because of this, it is thought to be desirable to review and re-evaluate these agents, their modes of action in so far as they are known, their differences, and especially their clinical value.

We will consider first the diuretics of minor natriuretic capability which now have only a limited or specialized role in cardiac therapy. Mercurial diuretics, thia- zides, aldosterone antagonists, and re- cently developed new potent diuretics will be discussed in future articles.

establish osmotic equilibrium. Mannitol can only be given intravenously. Urea is available for both oral and intravenous use and is an effective osmotic diuretic in either case. Both substances are filtered by the glomerulus. Mannitol is not me- tabolized, nor is it reabsorbed or secreted by the renal tubules. At low rates of urine flow, some endogenous urea is reabsorbed, but when urea in large quantities is used as a diuretic, it may be considered to be essentially unreabsorbed. Thus, both agents add a large quantity of osmotically active material to the glomerular filtrate and prevent the tubular reabsorption of water while the water is held in the filtrate to maintain osmotic balance. Because of this retention of water in the filtrate, con- centration gradients of electrolytes develop while they are absorbed partially without water. This limits their reabsorption and causes a urinary loss of some electrolyte.

Osmotic diuretics. Nonionic osmotic diu- retics, such as urea or mannitol, are now rarely used in the treatment of congestive heart failure. When given intravenously they produce intracellular dehydration by drawing water from the cells to re-

Although this prominent water diuresis and modest natriuresis are not generally used now in the treatment of congestive heart failure, either urea or mannitol is occasionally used to provoke a water diu- resis in a patient with dilutional hypo- natremia. Either drug is used more fre- quently diagnostically in split renal func- tion tests or in the late washout modifica- tion of the intravenous pyelogram. In either case, the water diuresis produced

Received for publication Feb. 13, 1964. *Department of Therapeutics, New York University School of Medicine, 550 First Avenue, New York 16. N. Y. HCardiac Therapy Research Unit. Bronx Veterans Administration Hospital, 130 West Kingsbridge Road, Bronx

68, N. Y.

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Diuretic therapy. Part I 841

serves to exaggerate the difference in the water reabsorbing characteristics of the two kidneys in renovascular hypertension. The major clinical use of urea is in neuro- surgery, where its effect, intracellular de- hydration, is used to reduce cerebral edema. Mannitol has recently been recom- mended as an osmotic diuretic to increase barbiturate clearance in barbiturate in- toxication and to prevent renal failure after a hemolytic transfusion reaction by reducing the formation of hemoglobin casts. It has also been shown that the prompt institution of a mannitol osmotic diuresis can protect against acute renal failure in patients who are already oliguric from other causes, such as surgical shock or burns. How the osmotic diuresis affords protection in this situation is not known. Furthermore, when used with bicarbonate to maintain an alkaline pH, osmotic diu- resis with mannitol may afford some pro- tection against the renal shutdown which is associated with acute uric acid load after chemotherapy of lymphoma. (See Table I.)

Acid.$f&.g SUMS. Ammonium chIoride, the acidifying salt used most commonly, is given by mouth. It is not an osmotrc diuretic. Although its only important use is the potentiation of the effect of mercurial diuretics, apparently by an increase in the serum chloride, it does have some inde- pendent diuretic activity. In the past, this has been thought to be due to a reduction in the ability of protein to bind water or

to an effect of acidosis on renal tubular enzymes. Ammonium chloride, which is converted in the liver to urea and chloride, increases the level of serum chloride and the amount of filtered chloride. The re- absorption of some of this excess chloride into renal tubular cells probably blocks the secretion of hydrogen ion in the hydro- gen-sodium exchange mechanism of the distal tubule, thus producing an increased excretion of sodium. This results in a mild diuresis, which is limited in 2 or 3 days by the development of acidosis and a com- pensatory increase in the tubular produc- tion and excretion of ammonia. Ammonium chloride frequently causes gastric irritation and even nausea and vomiting; this further limits its usefulness.

The use of enteric-coated tablets de- creases these gastrointestinal side effects but introduces the problem of variable absorption.

L-lysine monohydrochloride, originally marketed as a geriatric amino acid supple- ment, is another salt which produces chloruresis and systemic acidosis. When given as a liquid in milk or juice, it is fairly palatable and produces less gastro- intestinal irritation than does ammonium chloride. It has no independent diuretic activity but can potentiate the effect of mercurials.

Ammonium chloride can occasionally produce hepatic coma when used in pa- tients with severe liver disease; 1-lysine

Table I. Osmotic diuretics

Preparations Dosage forms

Urea (N.F.) Crystalline powder Mannitol (N.F.) 25 per cent, SO-ml. vial

Table II. Acidifying salts

Dose

Oral-g to 40 Gm. one to four times a day in fruit juice 50 to 100 Gm. as 25 per cent solution

Preparations

Ammonium chloride (N.F.)

I Dosage forms Dose

300-mg. tabtets Between 4 and 12 mg. a day, 300 and SOO-mg. enteric-coated usually 8 Gm.

tablets

L-lysine monohydrochloride Solution of 10 Gm. per 30 C.C. 10 Gm. three times a day

monohydrochloride, although contributing to the amino acid pool, does not produce hepatic coma.

Ammonium nitrate and calciunl chloride may also serve as acidifying salts but are little used. (See Table II.)

Xunthines. Although the santhines have been largely supplanted as diuretics, they still have other important actions, which include stimulation of the central nervous system and the heart, vasodilatation, and bronchodilatation. They produce an in- crease in cardiac output, in renal blood flow, and in glomerular filtration rate, but these effects cannot fully esplain the diu- resis and natriuresis produced especially by theophylline and theobrotnine. It is thought that, as diuretics, they also di- rectly interfere with the tubular reab- sorption of sodium. The total diuretic effect is minor, and tolerance develops in several days. Moreover, the oral prepa- rations of the xanthines are apt to cause gastric irritation. .

The only current use of xanthines in diuresis takes advantage of their ability to increase the glomerular filtration rate. In this application, aminophylline (theo-

phylline ethylenediamine) is given intra- venously 2 to 3 hours after the injection of a mercurial diuretic, potentiating the effect of the mercurial by increasing the filtered load of sodium on the tubules at the time when the mercurial can block its reabsorption. This has been recommended especially for patients in severe refractory congestive heart failure who may be pre- sumed to have a very low renal blood flow and glomerular filtration rate. (See Table III.)

Carbonic-anhydmse inhibitors. The ob- servation that sulfanilamide causes a diu- resis led to the discovery of a group of sulfa-like drugs with diuretic activity which operate by inhibition of carbonic anhydrase. By inhibiting this enzyme in the renal tubule, they prevent the forma- tion of carbonic acid from carbon dioxide and water. Thus, a diminished supply of hydrogen ion is available to the acidifica- tion mechanism in the distal tubule, where the hydrogen ion is ordinarily exchanged for tubular sodium. Interference with this produces a diuresis of sodium bicarbonate, an alkaline urine, and a systemic acidosis.

Because potassium exchange increases

Table III. Xanthines

Preparations Dosage jams I Dose

Aminophylline (theophylline Injection-USP 250 mg./ml. Intravenously 250 to 500 mg. ethylenediamine) Infiltration-USP 25 mg./ml.

Tablets--USP 100 and 200 mg. Enteric-coated-100 and 200 mg. Suppository-250 and 500 mg.

Theobromine calcium salicylate (N.F.) Tablets-300 and 500 mg. 100 to 200 my. after meals (Theocalcin)

Table IV. Carbonic-anhydrase inhibitors

I Preparations Dosage fo~wzs Dose

Acetazolamide (Diamox) Tablets-250 mg. 250 to 375 mg. a day Injection-sodium salt

Ethoxyzolamide (Cardrase) Tablets-62.5 and 125 my. 62.5 to 250 mg. a day

Methazolamide (Neptazane) Tablets-50 mg. 100 to 300 mg. a day

Dichlorphenamide (Daranide) Tablets-50 mg. 25 to 150 mg. a da)

Diuretic therapy. Part I 843

when hydrogen ion is unavailable, an in- creased kaliuresis also occurs. The effect of the carbonic-anhydrase inhibitors lasts for 3 or 4 days; then the development of systemic acidosis blocks the effect. Because of the mild effect with prominent kaliuresis and acidosis, these agents have been gener- ally supplanted. Like acidifying salts, they can be used to potentiate or restore the effect of mercurial diuretics by reversing hypochloremic alkalosis. Unlike the acid- ifying salts, they must be discontinued 24 hours prior to the administration of the mercurial, because, if the carbonic-an- hydrase inhibitor is still acting when the mercurial is given, it may interfere with the effect of the mercurial.

The carbonic-anhydrase inhibitors have also been suggested for and tried in cases of pulmonary insufficiency with CO2 re- tention, with and without edema, in the hope that the bicarbonate diuresis pro- duced might, by increasing acidosis, stimu- late respiration, Iower the pCOz, and thus produce further stimulation of the respira- tory center. The results have been gener- ally disappointing. Although some authors have reported good short-term effects, long-term use has not been satisfactory. One author found no effect from acetazol- amide alone, but did find that acetazolamide potentiates the stimulating effect of amino- phylline.

The present major uses of carbonic- anhydrase inhibitors are in certain con- vulsive states which can be ameliorated by acidosis, and in glaucoma, especially acute narrow-angle congestive glaucoma.

The effect is a reduction in the intraocular pressure by decreasing the secretion of aqueous humor.

Of the drugs presently available, aceta- zolamide, ethoxyzolamide, and methazol- amide have essentially the Same action, differing only in dose and to a lesser estent in duration of action. Acetazolamide has the briefest action, methazolamide the longest (about 12 hours).

Another drug, dichlorphenamide, is somewhat different from the others, in that, although it is an effective carbonic- anhydrase inhibitor, it also produces a chloruresis so that acidosis does not occur. It must, therefore, produce diuresis by an additional mechanism. This is quantita- tively not important. Because of their hypokalemic effect, all these drugs may induce hepatic coma in susceptible indi- viduals. Drowsiness, dizziness, paresthesia, and headache can occur with high dosage. Gastrointestinal and allergic skin reactions are also seen. (See Table IV.)

REFERENCES Galdston, M., and Geller, J.: Effect of amino- phylline and Diamox alone and together on respiration and acid-base balance and on re- spiratory response to carbon dioxide in pul- monary emphysema, Am J. Med. 23:183, 1957. Gilman, A.: The mechanism of diuretic action of carbonic anhydrase inhibitors, Ann. New York Acad. SC. 7:355, 1958. Lasser, R., Schoenfeld, W., and Friedberg, C.: L-lysine monohydrochloride, New England J. Med. 263:728, 1960. Mudge, G. H., and Weiner, I. RI.: The mecha- nism of action of mercurial and xanthine diu- retics, Ann. New York Acad. SC. 71:344, 1958.