History of Diuretics

Garabed Eknoyan

Department of Medicine, Baylor College of Medicine, Houston, Texas 77030

Diuretics, as therapeutic agents that act on the kidney to increase salt and water excretion, have a relatively short history. On the other hand, the very reason for which diuretics were developed, i.e., mobilization of excess body fluids, has a long history which dates back to the beginnings of medicine. No history of diuretics would be complete without some consideration of this long prelude, which is particularly important for an appreciation of the wonders that diuretics have accomplished and the essential niche they now occupy in therapeutics.

The agonal picture of volume overloaded patients drowning in their dropsy, after prolonged suffering and invalidism, has been a matter of human sympathy and medical concern since the earliest days of recorded history. "Flooding of the heart," the ancient Egyptians termed it, and shrouded in the mist of antiquity are the first musings on its treatment [9]. Among the celestial cures recorded on the pillars of the Aesklepion at Epidaurus is that of a Spartan girl, Arete, who suffered from dropsy and asked the god for relief. Aesculapius cut off her head, turned her upside down until the fluid ran out, and then replaced her head [31]. A cure, the same records indicate, that could not be repeated! In reviewing the history of diuretics this chapter will center around measures to treat this very condition, i.e., dropsy, for that is the principal problem which mankind in general, and medicine in particular, have had to deal with.

Diuretic Agents: Clinical Physiology and Pharmacology

Copyright © 1997 by Academic Press. All rights of reproduction in any form reserved.

It is the recorded measures for treating dropsy that provide the beginnings of the history of diuretics, which, much like that used by Aesculapius, were not always strictly diuretic in nature. The use of drugs to induce an actual diuresis is also ancient, dating back to observations made from the effect of foods prepared for the sick, and preserved in folklore throughout the ages. Such knowledge became codified rather early. Egyptian concoctions for "causing one to urinate" and "to expel fluid accumulations from the body and heart" are recorded in the Hearst Medical Papyrus dating back to 1550 B.C.E. These complex mixtures of plants and minerals in beer and honey were administered with proper incantations that were typical of the religious overtones of Pharaonic medicine. Treatment became more pragmatic with the advent of the relatively more secular and definitely more rational Greek medicine [13, 16, 35]. This is illustrated in the section on the management of dropsical patients from On Regimen in Acute Diseases of the Hippocratic Corpus:

Laborious exertion, fomentations and abstinence are to be enjoined. The patient should eat dry and acrid things, for thus will he pass the more water, and his strength be kept up. If he labours under difficulty of breathing, if it is the summer season, and if he is in the prime of life, and is strong, blood should be abstracted from the arm, and then he should eat hot pieces of bread, dipped in dark wine and oil, drink very little, and labour much, and live on well-fed pork, boiled with vinegar, so that he may be able to endure hard exercises.

The text goes on to give:

A draught for a dropsical person. Take three cantharides, reving their head, feet, and wings, triturate their bodies in three cupfulls (cyathia) of water, and when the person who has drunk the draught complains of pain, let him have hot fomentations applied. The patient should be first anointed with oil, should take the draft fasting, and eat hot bread with oil.

While some relief must have been obtained by these modes of therapy, their effectiveness perhaps can be best gleaned from a recounting of the death of Heraclitus (540-480 B.C.E.) by Diogenes Laertius (3rd century C.E.) in his Lives of Famous Philosophers (Vitae philosophorum):

He became so misanthropic that he withdrew and went off to live on herbs and plants in the mountains. But when this diet made him dropsical, he returned to the city and consulted the doctors, asking them about his condition in the form of a riddle: Could they change the wet weather into a drought? Since they did not understand, he shut himself up in a stable, hoping to cure himself and dry up the water by the heat of manure, with which he covered himself. To no avail—he ended up dead of it at age sixty.

The recommendations of Hippocrates (460-377 B.C.E.) were to remain a mainstay of the treatment of dropsy well into the 20th century (sweating, catharsis, bleeding) until the advent of clinically effective diuretics, while others remain in use to this day (dietary restriction). The popular perception of their

Diuretic Cartoons
FIGURE 1. Aesculapius defending the tools of his trade against innovators (Honore Daumier, 1859).

merits also remained unchanged from those of Heraclitus, as graphically expressed in a cartoon (Fig. 1) by Honoré Daumier (1808-1879), a contemporary of Claude Bernard (1813-1878).

The diuretic properties of various plants and minerals were also codified. Dioscorides (40-90 C.E.), whose De Materia Medica was to become the supreme authority on medicinal substances for over 1500 years, commented on the diuretic properties of several plants (juniper, radishes, cassia, cinnamon, dill, wormwood, periwinkle, squill). Arabic medicine expanded on this, monastic medicine nurtured it, and throughout the Renaissance information continued to accrue on the diuretic properties of medicinal plants. As a rule plants considered to have diuretic properties were introduced for the elimination of the spirits or humors that caused disease. Their utility in dropsy was a coincidental finding. A father figure of modern pharmacology is considered by some to be Aureolus Theophrastus Bombastus von Hohenheim (1493-1541), commonly known as Paracelsus. A man of many interests and a pioneer chemist, Paracelsus can be regarded as the originator of chemical pharmacology and therapeutics that began the march away from herbals [25]. He is certainly a key figure in the history of diuretics as will be detailed in the section on mercurials.

The purgative, and to a lesser extent emetic, property of herbs or their extracts was the basis for their successful use in the treatment of dropsy. Hippocrates commented on the use of purgatives in one of his aphorisms (Section VI, No. 14): "In a case of dropsy, when the water runs by the veins into the belly, it removes the disease." As with diuretic plants, purgatives were an integral component of the general materia medica used to treat a multitude of diseases (other than dropsy) to restore altered humoral balances that were considered the cause of illnesses. Over time, mixtures of plants, with varying properties, were developed specifically for the treatment of dropsy. One example of these from the Materia Medica for the Use of Students, published in Philadelphia in 1880, lists the following for the management of dropsy under the name "cider mixture":

A compound infusion is used in dropsy, of which the following formula: Juniper berries, mustard seeds, and ginger, each half an ounce; horseradish, parsley root, each an ounce; cider, two pints—dose, a wineglassful two or three times a day.

Mechanical means of removing blood (leeches, bloodletting, cupping, lancing), also came to be used in the therapy of dropsical patients (Fig. 2). Once again, their use stemmed from the notion that diseases resulted from humors generated by inflammation in the system and that blood removed from the proximity of the site that was painful or the organ considered to cause the disease would remove the noxious humors and provide cure. Neither Hippocrates nor Caelius Aurelianus (c. 400 C.E.) mention leeches, although Galen (129200 C.E.) and Pliny (23-79 C.E.) discussed them. Of interest is the recommendation of Areteus (30-90 C.E.) to use leeches in angina accompanied by dyspnea. Avicenna (980-1037) commented on their advantage over cupping. Leeches were especially in vogue during the latter part of the 18th and early 19th centuries [1, 7, 13]. The most sanguinary physician in history is said to have been F.J. V. Broussais (1772-1838), a pupil ofBichat (1771-1802), surgeon of the armies of France, and from 1831 Professor of General Pathology at Paris [16]. He believed that the physician should dominate nature and not merely try to assist it as Hippocrates had maintained. He was in the custom of ordering hundreds of leeches daily. The last of the great bloodletters was J. B. Bouillaud (1796-1881), who considered Broussais the "Messiah of Medicine." Bouillaud was a skillful and learned physician who played an important role in establishing the connection between rheumatic fever and heart disease and in 1835 came to recognize the merits of digitalis as the "opium of the heart" [8]. To appreciate how much blood could be removed one needs to consider the number of leeches applied (usually 10-30) and that when fully gorged each leech could contain about one-half to one ounce of blood. To increase the quantity of blood removed the tail was snipped or salt and vinegar sprinkled on the

Leech Therapy 17th Century
FIGURE 2. Seventeenth century woodcut showing scarification by lancing (Wellcome Institute Library, London).

leech. Leeches were considered particularly useful in children or the physically weak, who could not stand the harsher bloodletting [ 18].

The injudicious use of bloodletting, which had been extensively used as a general therapeutic measure, was condemned by Hippocrates. By far the most extensive account of bloodletting in antiquity is that of Galen (129-199), who devoted three lengthy works to venesection in which he criticized Hippocrates for not including it in his Aphorisms and for not having laid down with sufficient precision the rules of venesection for dropsy. In the Middle Ages, the directions for phlebotomy and its techniques were minutely detailed and often determined by astrological considerations, being permitted only on favorable days and at propitious hours. Discussion on whether bleeding should be practiced at the start of the disease or later in its course and at a site close to or distant from the disease dominated Arabic therapeutics and extended well into the Renaissance. Leonardo Botallo (b. 1530), physician to the French kings Charles IX and Henry III, was a fervent advocate of frequent and copious bloodletting. Lorenzo Bellini (1643-1704), known for his contributions to renal anatomy, studied phlebotomy and wrote on its utility in clinical medicine. Throughout history bloodletting had its advocates and opponents. By the beginning of the 18th century the detrimental effects of phlebotomy led to increased criticism of its use. Bernardino Ramazzini (1633-1717), professor at Padua, who in a period when phlebotomy was much in favor, wrote "it seems as if the phlebotomist grasped the Delphic sword in his hand to exterminate the innocent victims rather than destroy the disease." By the first half of the 19th century, as experimental medicine began to assert itself, bloodletting fell in gradual disfavor but remained in use in the treatment of pulmonary edema well into the first half of the 20th century [1, 7-9].

Measures to combat dropsy continued to include considerable superstition and ritual best illustrated in the description of one Athanasius Kircher in 1646 of a wooden cup sent him by the Jesuits in Mexico which would color water poured into it a deep fluorescent blue. This was the celebrated lignum nephriti-cum, first noted in 1545 by Nicolas Monardes and Francisco Hernandes as a remarkable diuretic for renal and dropsical troubles. In the 17th century these cups became esteemed gifts fit for royalty [16]. Their mechanism of action remains a mystery. Their disappearance from the materia medica best speaks to their merit as a diuretic or lack thereof.

A sense of how information accrued through the centuries came to be used in the therapy of dropsy during the pre-Richard Bright era can be gleaned from the writings of the period. Thomas Sydenham (1624-1689), the great reformer of clinical medicine in England, writes in his Treatise on Gout and the Dropsy (1675):

With respect to the evacuation of the water it is well worth observing, that weak purgatives do more mischief than good in dropsical cases ... of all diseases the dropsy requires the roughest and quickest purgatives ... With respect to purging for the cure of dropsy, great care must be had to carry off the water as speedily as the strength will permit; it being proper to purge every day, unless great weakness, or the too violent operation of the purgative, should require a day or two to be interposed. For if purging be used only at distant intervals (though the last purge brought away plenty of water) we shall allow time for the fresh collection of water and by such a delay instead of accomplishing the cure, leave it unfinished. . . . There are other cases, likewise where the waters are not to be discharged by vomiting or purging; for instance in weak constitutions and hysteric subjects, they cannot be evacuated by purgatives, and much less by vomitives, but are to be carried off by diuretics. Several of this kind are extolled in the writings of physicians, but the most, if not the only efficacious ones, in my opinion, are those prepared from lixivial salts ... in two quarts of Rhemish wine, with one to two pugils of common wormwood, and prescribe four ounces of filtered liquor to be taken constantly every morning and at five in the afternoon, and at night until the swelling disappears.

He then gives a list of mixtures of mustard seed, seneca, juniper berries, winter's bark, and horseradish, which alongside with other herbal medicines (celery, parsley, asparagus, and cucumber seeds) were exalted as diuretics beginning with the Hippocratic Materia Medica. Relevant to the changes that were occurring is an added annotation on digitalis by George Wallis, editor of the 1863 edition of Sydenham's text:

I was convinced of the superior efficacy of this medicine over any other in the present practice, in a dropsical case at Hampstead; a lady had long laboured under visceral obstruction, which at last brought on a dropsy, an anasarca united with ascites, and tympany; squills, pariera brava, alkaline salts, etc. were tried in vain; at last the digitalis purpurea was given two grains twice a day, for 3 days she passed considerably more water than she had done for 10 or 14 days before, notwithstanding the different diuretics which had been tried to produce this effect, and I am persuaded that the digitalis purpurea is amongst the first and most certain of the class of diuretics.

Following Richard Bright's report on dropsy (1827), the disease came to be classified as renal or cardiac in origin. Insight into how limited the options remained can be gleaned from the treatment of "acute renal dropsy" in the 1859 edition of Clinical Lectures by Robert Bentley Todd of London [34]:

The great thing is to promote free sweating, and this may be best done by the hot-air bath; or if you fear its debilitating effects (which are to be taken into account in weakly subjects), you may substitute the warm bath.

You should next, endeavour to obtain relief to the congestion of the kidneys. This is in part effected by restoring the function of the skin. Local bleeding by leeches and cupping will do much in some cases, but little in others. Now and then when your patient is plethoric and robust, you may save time and trouble, take some blood from the arm, but these, you must remember, are exceptional cases. As a rule, general bleeding is better avoided.

Purgatives, as indirect means of relieving the congestion of the kidneys are of great value; they eliminate water and the various morbid matters. Sudorifics may also be employed, and of this the best is the liquor ammoniae acetatis . . .

When the congestion of the kidney has been relieved diuretics may be given with advantage. Of all this large class, the best I can think, is the common cream of tartar . . . benzoate of ammonia is often very efficacious. Digitalis, with due precaution, is also very useful.

Irritative diuretics (as cantharides, squills) must be avoided, for obvious reasons, although they are very serviceable in other forms of dropsy. Broom tea is also useful; and the latter derives some advantage from the taraxacum which it contains.

I must caution you against the use of mercury. This mineral, so valuable in some diseases, is in these cases useless and even mischievous; at any rate, I have failed to observe any benefit from it.

For the treatment of "cardiac dropsy" Todd describes his treatment of one patient:

For the relief of the dropsy, a great deal can be done by attention to the position of the patient, and by the administration of diuretics. With the view of supporting his powers we gave our patient tonics and iron; and finding his kidneys acting imperfectly, we gave him digitalis. But in such cases it is desirable to be careful in administering this medicine, and it is good to combine it with some tonic. I frequently combine it with ammonia, or give the tincture of digitalis with the tincture of sesquichloride of iron.

There was much difficulty in getting the kidneys to act, and the greatest benefit was from the bicarbonate of potassium, either alone or in combination with the powder of jalap.

The dropsy has been kept down best by means of acupuncture: the quantity of water that has oozed away from him, and the relief that he has obtained is surprising. There is another method of relieving anasarcous legs, lately revived on the continent, incision instead of pricking the leg at various points . . . Each is apt to become the center of an erysipelatous inflammation.

Drainage of subcutaneous edema fluid by incision (Fig. 2), and later by the insertion of Southey's tubes (Fig. 3), were terminal drastic measures fraught with danger. Hippocrates had warned of the problem in one of his aphorisms (Section VI, No. 8): "In dropsical persons, ulcers forming on the body are not easily healed." With the advent of lancing time proved him right. Many an unfortunate patient succumbed to the complications of incisions to relieve edema, none so famous as Samuel Johnson (1709-1784). Johnson, who had been incapacitated for months by his terminal dropsy, had been lanced for the removal of edema. On the morning of December 13,1784, he lanced himself and cutting very deep bled to death that night. His autopsy revealed an enlarged heart, an atrophic left kidney, and an enlarged right kidney. The latter was secondary to nephrolithiasis and the former to an aortic valve defect [32].

Looking back over this prelude to the history of diuretics, a history as ancient as the earliest civilizations, it is remarkable that hardly any of the diuretics used today are older than the First World War (Fig. 4). By the time that World War II started, only four drugs were accepted as effective agents to increase urine flow: caffeine, a mild diuretic at best; digitalis, a powerful agent but effective only in heart failure; mercury, which despite its improvement as an organo-mercurial, remained potentially a toxic one; and acidifying agents, whose utility was questioned by most.

lag.

Paracentesis Dropsy

FIGURE 3. A woman with dropsy treated by paracentesis from Frederik Dekker's Exercitationes Practicae Circa Mendendi Methodum (Practical Exercises in Methods of Treatment) (Leyden, 1694) (courtesy of the Blocker History of Medicine Collections, Moody Medical Library, The University of Texas Medical Branch at Galveston).

FIGURE 3. A woman with dropsy treated by paracentesis from Frederik Dekker's Exercitationes Practicae Circa Mendendi Methodum (Practical Exercises in Methods of Treatment) (Leyden, 1694) (courtesy of the Blocker History of Medicine Collections, Moody Medical Library, The University of Texas Medical Branch at Galveston).

30 Yr. War

MERCURY

1553 Paracelcus

1700

POTASSIUM NITRATE 1679 Willis yrfr®

CAFFEINE THEOBROMINE UREA 1864 1887 1892

Koshlakoff Schnieder Friedrich

WWI WWII

CAFFEINE THEOBROMINE UREA 1864 1887 1892

Koshlakoff Schnieder Friedrich yrfr®

Schult^

MERCURIALS 1919 Saxl Vogl

SULFANILAMIDE 1949 Schwartz

Schult^

MERCURIALS 1919 Saxl Vogl

CHLOROTHIAZIDE 1958 Beyer/Sprague

Vesalius

Sydenham

Pare

Harvey

Malphighi

Bellini

Benjamin Franklin

Morgagni

Richard Bright

Bichat

Claude Bernard

Laennec

Homer Smith John Peters

Cushny

Wm. Bowman

Wearn

Magendie

Carl Ludwig

Heidenhain

Van Slyke

Osier

R.F. Pitts

J. Oliver

" A.N. Richards

Shakespeare Galileo

Samuel Johnson

Newton

Goethe

Rousseau

Descartes

Bach

Mozart

Beethoven

Darwin

Zola

Einstein

Picasso

James Joyce

Nietzsche

Hemingway

FIGURE 4. Time-line of the discovery of diuretics presented alongside that of contemporary figures in medicine, nephrology, and the liberal arts.

The history of diuretics in earnest had to await an understanding of the functions of the kidney and its role in the regulation of urine volume. A decrease in urine output had been observed in dropsical patients but was considered a subordinate phenomenon. The painting of a physician examining the urine of a dropsical woman in the Louvre notwithstanding (Fig. 5), the role of the kidney

Dropsical Woman
FIGURE 5. The Dropsical Woman (La Femme Hydropique) by Gerard Dou (1613 (Louvre, Paris).

in edema formation was not appreciated. What the physician in the painting is performing is uroscopy (visual examination of the urine), long an integral component of the practice of medicine that was to be condemned in the 17th century. The earliest dissenting opinion that the kidney does play a role has been attributed to the French physician, P. Merklen, who in 1903 reported that edema preceded the onset of oliguria [23, 35]. He was led to this view because of the belief that tissues bound water, thereby causing secondary oliguria, and that the diuresis attributed to herbs and chemicals was due to direct interruption of the water binding properties of the tissues [ 17]. The appreciation of the relation between edema and oliguria was to await subsequent studies that were to elucidate renal function.

In his Body Water, published in 1935, John Peters (1887-1956) characterized knowledge of diuretic drugs as being in a "hopelessly chaotic state" [26]. This condition was soon changed drastically by the work of Peters, Alfred N. Richards (1876-1966), Homer Smith (1895-1962), and their associates. The subsequent understanding of the mechanisms underlying diuretic therapy paralleled the development of renal physiology and the role of the kidney in the accumulation of excess volume. By then, almost a century and a half had elapsed between the introduction of the first two effective diuretic agents to treat edema: digitalis in 1775 and the organic mercurials in 1919. Another 30 years elapsed before the introduction of sulfanilamide in 1949 (Fig. 4).

All three were discovered by serendipity. Another force that was to herald the beginning of the modern era of diuretics was increased understanding of organic and molecular chemistry that now allowed for involvement of the pharmaceutical industry directly in the development of new and more potent agents. It was the relationship between organic chemists and the new breed of renal physiologists that was to provide the basis for the development of new and effective diuretics. Diuretics, in turn, were to provide, initially renal physiologists and subsequently renal biochemists, powerful probes with which to explore renal function.

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