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Mechanisms and management of intractable heart failure
J. chron. Dis. 1965, Vol. 18, pp. 879-890.
MECHANISMS
Pergamon Press Ltd. Printed in Great Britain
AND MANAGEMENT OF INTRACTABLE HEART FAILURE JOHN H.
Associate
Professor
LARAGH,
M.D.
of Clinical Medicine, Columbia University Surgeons, New York, N.Y., U.S.A.
FOR several
College
of Physicians
and
centuries the study of the mechanisms involved in the causation and maintenance of congestive heart failure have intrigued perhaps more investigators than any other single subject in the field of investigative medicine. Within recent decades great advances have been made in our understanding of the mechanisms that are involved in causing and sustaining the state of salt and water retention. Heart failure begins with the failure of the heart as a pump. As a result of this failure the mean arterial pressure tends to fall, and the hydrostatic pressure transmitted to the glomerular capillaries falls. This induces renal hemodynamic changes which favor retention of sodium and water. It is now generally accepted that a state of congestive heart failure can neither be induced nor sustained without the presence of abnormal renal retention of sodium and water. Thus, while the condition may begin in the heart, changes that occur in the kidney support and sustain the condition. I would like first to review something of what is known about the renal function in heart failure. With this background I shall then consider the mechanism of action of various of the newer diuretic agents that are so effective in relieving patients suffering from this condition. A study of the physiologic changes induced by the different types of diuretic agents available allows not only a more rational basis for their use but also,-and perhaps this is more important-a much better understanding of the basic physiologic mechanisms that are disturbed in congestive heart failure. The major mechanisms involved in renal regulation of salt and water balance, both in normal subjects and in patients with heart failure, are the following: The glomerular filtration rate is determined in part by the hydrostatic pressure in the glomerular capillaries. This is determined by the mean arterial pressure generated by heart action. When the cardiac output falls, the glomerular filtration rate tends to fall. Renal blood flow falls perhaps even more, and a form of compensatory vasoconstriction occurs within the kidney. These hemodynamic changes in themselves lead to definable defect in the capacity to eliminate ingested sodium and water and thereby participate in the development of a progressive state of edema. It follows that when further stresses such as exercise or emotion are imposed, the myocardium and the hemodynamic state of the kidneys may be further embarrassed. In addition to these hemodynamic factors associated with heart failure we now know that sodium balance is regulated perhaps to even a greater extent by changes in the rate of renal tubular reabsorption of the filtered plasma. The kidney is constructed so that normally about 180 1. of plasma are filtered through the glomerular capillaries every day, and normally 99 per cent of this ultrafiltrate of plasma is reclaimed into the circulation by reabsorptive processes along the course 879
880
JOHNH. LARAGH
of each renal tubule. There is a good deal of experimental and clinical evidence to indicate that the tubular reabsorption of sodium is abnormally increased in congestive heart failure. We now know that these reabsorptive processes are accomplished by active transport mechanisms involving the expenditure of energy by renal tubular cells and that there are many different transport mechanisms and many different steps in each of the transport processes that participates in sodium reabsorption. Time does not permit a detailed description of these mechanisms. However, it is important to bear in mind that while the bulk of the sodium is reabsorbed with chloride ions, other types of sodium reabsorption occur which also serve to regulate both acid-base and potassium balance. Knowledge of these systems has proved of practical value. For example the sodium bicarbonate reabsorptive process occurring in exchange for secreted hydrogen ions can be inhibited by carbonic anhydrase inhibitors that interfere with the generation of hydrogen ions by the renal tubular cells. Also, the sodium ions that are reabsorbed in exchange for the tubular cell potassium ions can be blocked by aldosterone antagonists. The processes for tubular sodium reabsorption are also intimately involved in regulating both the amount of water in the body and the tonicity of body fluids. A fundamental tenet of renal physiology, which has been placed on a firm basis by micropuncture studies, is that some 80 to 85 per cent of the filtered salt is normally reabsorbed in the proximal tubule along with isosmotic amounts of water. The remaining 15 to 20 per cent of the glomerular filtrate is reabsorbed in the more distal portions of the nephron. This distal reabsorption differs in that it may or may not be isosmotic; thus, in water diuresis the distal reabsorption of sodium chloride may occur without isosmotic amounts of water, leading to the maintenance of a very dilute urine. This difference in proximal and distal tubular function also allows one to study selectively the distal and proximal transport mechanisms in normal subjects and in patients with congestive heart failure. This is because drugs which act to interfere with concentration or dilution of the urine are presumably interfering with distal tubular functions. With this brief and cursory review of some of the major renal tubular processes I would like now to turn to pharmacologic agents now in wide usage, which, as we learn about their mechanisms of action, can teach us something about the physiology of the kidney in heart failure. Figure 1 shows the chemical structures of six major types of diuretics. Many, many interesting derivatives of some of these types have been developed, partly for commercial reasons, by various companies. The oldest and probably still among the most useful types of diuretics are the organomercurials, which ordinarily require intramuscular injection. These are substituted mercury propyl compounds of the general structure shown. A major advance was made in the field of diuretic therapy when it was found that sulfanilamide, because of its ability to inhibit carbonic anhydrase, could promote diuresis in patients in congestive heart failure. This discovery led to the development of more powerful carbonic anhydrase inhibitors. Two that are now commonly used are acetazolamide (Diamox) and dichlorphenamide (Daranide) (Fig. 1). These compounds inhibit the generation of hydrogen ions by renal tubule cells and thereby promote a sodium bicarbonate diuresis.
Mechanisms
and Management
of Intractable
DIURETIC
ANTI-CARBONIC
ANYHYDRASE
CHLORURETIC
Heart Failure
881
SPECIES:
SULFONAYIDES
SULFONAMIDES
ITo
ANT;b&LD;,~ERONE FIG.
1.
PTERIDINE
Chemical structures
ETHACRYNIC
ACID
of six species of diuretics.
More recently, largely due to the work of Ekeyer and his associates, a most significant contribution to treatment of patients was made with the development of chlorothiazide, a chloruretic sulfonamide, which, unlike the older carbonic anhydrase inhibitors, mainly promoted sodium chloride excretion. Some others of the many derivatives of chlorothiazide are shown in Fig. 1. Three other types of diuretic agents that each appear to have entirely different types of actions are shown at the bottom of Fig. 1. The first is the aldosteroneinhibiting agent, a 17+pirolactone, Aldactone, a steroid vaguely resembling aldosterone in chemical structure. A large body of evidence indicates that it specifically interferes with the sodium-retaining and kaluretic activity of the patient’s own aldosterone. Therefore it is of unique interest from a physiologic standpoint. Practically, it allows one to evaluate and inhibit the activity of aldosterone in patients with heart failure. The pteridine compound, triamterene, shown in Fig. 1, is interesting because it also causes potassium retention and appears to oppose some of the actions of aldosterone. However, unlike spirolactone, it is effective in the total absence of aldosterone. Finally, let us consider the recently developed compound, ethacrynic acid. It is a derivative of phenoxyacetic acid, with an unsaturated ketone radical shown on the left. It seems to be the most powerful diuretic agent yet developed. Its actions, as will be shown, are still different from those of the other species appearing in Fig. 1. HOW do these various diuretic agents act in patients? Figure 2 presents the mean values from 15 paired clearance studies of normal subjects. We injected intravenously either chlorothiazide (Diuril) or merallut-ide (Mercuhydrin), a mercurial diuretic, on different mornings, under the same condi-
JOHN H.
882
CHLOROTHIAZIDE CONTROL 1C.T.500 mg
LARACH
MERALLURIDE CONTROL II-@ 2ml
SPIROLACTONE CONTROL I250mg
I30c
IN mlhin
110;
n
_
IOOOb!$Rn
5oo-
-I
FIG. 2. Clearance studies in 15 normal subjects (average values) following administration during water diuresis of 500 mg of chlorothiazide or 2 ml meralluride. Reprinted through the courtesy of Charles C. Thomas, Publisher, Springfield, Illinois, from LARAGH, J. H. : Pharmacology of diuretic agents and electrolyte problems encountered with their use, in BARTTER, F. C., Ed. : The Clinical Use of Aldosterone Antagonists. Charles C. Thomas, Springfield, Illinois, 1960.
tions. The major differences in the action of thiazides and organomercurial agents can be seen in the figure and are compared with control values from three similar studies using spirolactone. Chlorothiazide (500 mg) increased sodium excretion considerably more than did 2 ml of meralluride. However, chlorothiazide also the mercurial diuretic actually suppressed produced the characteristic kaluresis; potassium excretion. Finally, mercurial agents produced a more dilute diuresis, as shown by the large increase in free water excretion. With chlorothiazide, during diuresis, the urine actually becomes more concentrated. How can these differences be interpreted in terms of the known mechanisms involved in sodium reabsorption? Figure 3 presents data from a single study that highlight the difference in urinary dilution produced by the two agents. The black circles represent the data obtained from a patient given chlorothiazide and the open circles data from a patient given meralluride. This normal subject was in water diuresis, and each diuretic was given at the same hour on different mornings. With meralluride, the urine flow increased to about the same extent as it did with chlorothiazide. However, with the latter, the urine became much more concentrated during diuresis, that is to say, chlorothiazide appears to promote proportionally more solute excretion, while mercurial agents promote more water excretion. Figure 4 shows how these data can be interpreted. As I have said, during normal water diuresis the urine is diluted by virtue of distal tubular reabsorption of solute,
Mechanisms
and Management
of Intractable
Heart Failure
883
Pt. P.C. 20
-
._ ? z E
IO-
8 0
I
I
IO
20
I
30
V ml/min FIG. 3. Osmotic clearance and urine flow during diuresis in normal subject given 500 mg of chlorothiazide or 2 ml meralluride intravenously on different mornings. Reprinted, by permission of the Editor of the Journal of the American Medical Association, from LARAGH,J. H., HEINEMANN,H. 0. and DEMARTINI,F. E.: Effect of chlorothiazide on electrolyte transport in man: its use in the treatment of edema of congestive heart failure, J. Amer. med. Ass. 166, 145, 1958.
without commensurate amounts of water, thus producing dilute urine. If an agent acted only proximally, that is, merely blocked isosmotic reabsorption, one would expect that the urine would become more dilute during the exhibition of the agent, because of the diversion of more solute to the diluting apparatus, the function of which remains uninhibited. The only way we feel that the action of meralluride can be explained is to say that it almost exclusively blocks the proximal reabsorptive mechanism, because the urine remains relatively dilute during diuresis. On the other hand, findings with respect to chlorothiazide and its derivatives indicate that chlorothiazide acts not only in the proximal tubule but also in the distal tubule, thereby interfering with urinary dilution, leading to a solute-rich diuresis. These differences in the action of thiazides and mercurial agents allow us to use them selectively in clinical situations that require one or the other of these effects. Furthermore, because these agents differ in their locus of action, they are, indeed, additive in their diuretic effects, a point worth remembering in treating more refractory patients. In fact, when chlorothiazide is given during a mercurial diuresis, as might be predicted, the natriuretic effects are additive. Furthermore, since mercurial agents block potassium secretion, the kaluresis of chlorothiazide is blocked by meralluride. Therefore, the diuresis that results from this combined use is actually more satisfactory than with one preparation alone. Finally, meralluride
884
JOHN H. LARAGH
e5q-d WATER DIURESIS
MERALLuRlDE
4. Schema showing mechanisms of solute and water reabsorption. Reprinted, by permission, from HEINEMANN, H. O., DEMARTINI, F. E. and LARAGH, J. H.: Effect of chlorothiazide on renal excretion of electrolytes and free water, Amer. J. Med. 31, 853, 1959. FIG.
produces a dilute urine. However, when chlorothiazide is added, although the diuresis may double, the urine becomes more concentrated, again showing that chlorothiazide adds to the effect of mercurials by acting on the distal diluting segment of the nephron. What about the role of aldosterone in congestive heart falure? We have made a large number of measurements of the secretion rate of this hormone and have found that while at times it is not markedly increased, in certain patients with congestive heart failure there is a marked increase that plays a critical role in leading to further progression of the edematous state. It is helpful, then, to understand how aldosterone acts in normal subjects and what changes it produces in the urinary electrolyte pattern. Figure 5 depicts graphically what happens when 500 mg of D-aldosterone are given intravenously to a normal human subject during a maintained water diuresis. The hormone produces no significant effects on glomerular filtration rate or renal blood flow. Hence all of the observed effects can be ascribed to alterations in tubular transport of electrolytes. Aldosterone increases potassium excretion and causes sodium chloride retention, but these two effects may not occur exactly simultaneously. Note that first there is a considerable delay of 30 to 60 min before the hormone begins to act on the kidney. This delay is reminiscent of that seen with other steroids such as digitalis or vitamin D. Note also that the action of the hormone lasts for many hours, even though its chemical half-life in blood is known to be of the order of only 40 min. The most remarkable thing about the action of aldosterone, perhaps, is that while it nroduced sodium chloride retention, it did not change the urine flow; free water
Mechanisms
mllmin
and Management
of Intractable
Heart Failure
885
OL
14 -
%J mllmin
12 ,.
-100
0
100
200
300
400
500
600
Minutes FilG. 5. Effect of aldosterone in normal subject iu water diuresis. Reprinted, by permission, from SONNENBLICK, E. H., CA~W~N,P. J. and LARAGH, J. H.: Nature evidence for role of hormone in urinary of action of intravenous aldosterone: dilution, J. clin. Invesf. 40,903, 1961.
excretion actually rose as the urine became more dilute. This means that aldosterone acts beyond that proximal isosmotic segment I have mentioned and that it therefore acts in the portion of the nephron where the urine is diluted, thus producing a more dilute urine. In a study of the relationship between urinary dilution and aldosterone action in 7 normal subjects with various intakes of sodium, we found that in every instance when aldosterone was given, the induced fall in solute clearance (largely in sodium chloride) was accompanied by a commensurate rise in free water clearance. In other words, sodium chloride was abstracted from the urine virtually without water, so that the urine was made more dilute in proportion to the sodium chloride extraction. These data can only be interpreted, we feel, to mean that an important action of aldosterone is on the distal diluting segment, promoting the extraction of sodium chloride without water from the tubular urine. One might therefore be able to predict how a specific blocker of aldosterone would act and what pattern it would produce in the urinary excretion. The spirolactone which blocks aldosterone would be expected to inhibit sodium chloride transport in the distal nephron and to block potassium secretion, also a distal tubular function. Indeed, data on the effects of spirolactone in a normal subject (Fig. 2), as compared with those of the mercurials and chlorothiazide, show that spirolactone causes a more concentrated urine, because as does chlorothiazide, it has a distal action at the diluting segment of the nephron. Furthermore, spirolactone, unlike chlorothiazide, blocks potassium secretion in the distal portion of the nephron Because of the different characteristics of these three species of diuretic agents, the data suggest that they might be quite useful, both in combination or in selected
JOHN H. LARAGH
886
FIG. 6.
Body weight, plasma potassium, chloride, carbon dioxide, and sodium and urinary potassium, chloride, and sodium in a patient with heart failure. Reprinted, by permission of the Editor of the Journal of the American Medical Association, from LARAGH, J. H., HEINEMANN, H. 0. and DEMARTINI, F. E.: Effect of chlorothiazide on electrolyte transport in man: its use in the treatment of edema of congestive heart failure, J. Amer. med. Ass. 166, 145, 1958.
situations, to correct or modify the underlying electrolyte abnormalities of the patient. Next, we will consider some clinical instances in which we can apply these principles to the rational and effective diuresis of patients with refractory congestive heart failure. Figure 6 is the record of a patient in congestive heart failure whose problem had been difficult to manage in the outpatient department. As is shown on the bottom line, a mercurial diuretic produced a modest diuresis but not enough to cause any appreciable change in weight. When chlorothiazide alone was given, a marked increase in sodium excretion occurred. The effect, however, began to fade out. Then a mercurial diuretic, when added to the chlorothiazide, produced a marked augmentation of effect, and diuresis was reinstituted. Later on, the carbonic anhydrase inhibitor, acetazolamide, was given on two occasions; this, too, augmented the diuresis. Because both chlorothiazide and acetazolamide produced potassium depletion, potassium chloride supplements had to be given, as well as ammonium chloride supplements for the hypochloremia. The satisfactory mobilization of all the edema fluid in this desperately ill patient, by combined therapy when the use of single agents had failed, again illustrates the
Mechanisms
and Management
of Intractable
Heart Failure
887
Chlorothiazide 2 gm Meralluride 2 ml SC-81 09 400 mg Urip-y mEq /day
2 20 0 500
Urinary Nat
300
mEq /day 100 0
10
20
30 Days
40
50
60
FIG. 7. Effect of aldosterone inhibitor in patient with congestive heart failure on constant metabolic regimen. Reprinted, by permission, from LARAGH, J. H.: The use of diuretics in congestive heart-failure, Postgmd. Med. 25, 528, 1959.
practical aspects of rational combination therapy in difficult situations. It also suggests again the existence in different sites in the nephron of different transport mechanisms that can participate to a varying extent in the state of sodium retention. Experience with another patient demonstrates the advantages of spirolactone (Fig. 7). This patient had virtually no sodium diuresis with mercurial diuretics or chlorothiazide and was given spirolactone, with only a modest increase in salt excretion and with the characteristic potassium retention. The mercurial agent alone produced little effect, but when chlorothiazide and the mercurial agent were combined, a marked diuresis occurred. However, this diuresis faded out again. Finally, with the patient still quite waterlogged, the addition of the aldosterone antagonist produced a sustained diuresis and clearing of all edema fluid, along with the reversal of negative potassium balance. These two clinical experiences demonstrate how these agents can be used in combination. The findings suggest that spirolactone, which by itself has the most subtle and least dramatic effect on sodium excretion, is probably one of our most useful agents. It might be wise to use it as a basal medication on a day-to-day basis in all patients to prevent potassium loss and sustain mild sodium diuresis. Then, when more power is needed, a thiazide or mercurial diuretic can be added to the program. Finally, I would like to discuss the very exciting action of the new compound, ethacrynic acid, in congestive heart failure. This is the most powerful diuretic agent that we have yet studied. Table 1 presents a clearance study of a 44-year-old woman with rheumatic heart disease, who was in advanced heart failure that was refractory to mercurials and thiazides. Her urine flow was only 8 ml/min and her glomerular filtration rate was some 70 to 90 ml/min. When 50 mg of ethacrynic acid was given intravenously, the urine flow increased to 18 ml/min; the urine
888 TABLE 1.
Period
JOHN H. LARAGH EFPECT OF ETHACRYNIC
ACID* ON RENAL HEMODYNAMICS AND ELECTROLYTE EXCRETION DURING WATER DILJRESISt
V (ml/ min)
&WV (mEq/ min)
UKV tmW min)
&IV (mEq/ min)
U,SIn (mOsm/ ml) Control
1
2 3
8.4 8.5 8.7
6.7 5.1 17.4
117 112 109
3 2 4
97 96 94
Values with Ethacrynic 4 5 6 7
14.4 18.6 18.0 17.7
1099 1652 1503 1347
471 432 369 324
1381 1834 1634 1466
*A total of 50 mg (1 mg/kg) administered tThe patient was a 44-year-old Negro heart failure.
249 247 227 210
U,,,V (mOsm/ min)
AND
WATER
C, (ml/ min)
C,,, (ml/ min)
$7 min)
C IX20
78 87 99
235 229 247
3.0 3.0 3.1
5.4 5.5 5.6
251 273 259 232
13.5 17.4 15.7 14.4
0.9 1.2 2.3 3.3
(ml/
min)
Values 815 816 818
Acid Administration 3586 4594 4086 3752
94 100 97 89
intravenously in 3 min. woman with rheumatic
heart
disease
and congestive
sodium excretion increased from 6 mEq/min to 1,650; and this patient lost 18 lb in the 24 hr following this single injection. Other patients receiving this diuretic agent have astounded us by at times producing a diversion of half of their glomerular filtration rate into the urine. The urine flow of one cardiac patient, for example, was 0.5 ml/min and went up to 40 ml/min. Figure 8 illustrates the effect of this agent in another patient with salt and water retention that had been refractory to mercurials and thiazides. Ethacrynic acid produced a marked diuresis, with the loss of huge amounts of sodium chloride in the urine. The patient’s weight dropped from 165 to 120 pounds. The clearing of the edema fluid produced negative potassium balance. However, other studies have shown that this, too, could be blocked by the addition of the aldosterone antagonist, spirolactone, which also augments the diuresis. These experiences illustrate the importance of renal tubular reabsorption of filtered sodium chloride in the regulation of salt and water balance. They indicate that the active transport processes occurring along the course of the proximal and distal nephron all can participate to a greater or lesser extent in the regulation of normal salt balance, as well as in the causation of the abnormal salt retention of heart failure. We know that aldosterone can modify and augment distal tubular sodium reabsorption in heart failure, and the ability to specifically block this hormone has been a major advance in both understanding and therapy. Having at our disposal a variety of pharmacologic agents that appear to interfere specifically with different transport operations in different portions of the nephron, we are in a position to all but eliminate the category of ‘refractory’ congestive heart failure from our medical practice. With the combined rational use of these agents with differing actions to modify and correct electrolyte imbalances in the plasma and in the urine, we can treat successfully an increasingly greater number of patients with congestive heart failure by selectively modifying renal tubular functions. However, for proper use, these powerful agents are a mandate for the physician to develop an increasing knowledge of pharmacology and renal physiology and then
Mechanisms
and Management
of Intractable
Heart Failure
889
FIG. 8. Effect of ethacrynic acid in patient with congestive heart failure refractory to mercurial and thiazide diuretics. Reprinted, by permission, from CANNON, P. J., AMMES,R. P. and LAUGH, J. H. : Methylenebutyryl phenoxyacetic acid : Novel and potent natriuretic and diuretic agent, J. Amer. med. Ass. 185, 854, 1963.
to keep a constant vigil on the evolving acid-base and fluid balance of each patient. This presentation has not attempted a fully detailed discussion of the pharmacology of the various diuretics. However, physicians should make every effort to become familiar with this information. To me, a most exciting facet of diuretic therapy is the varying responsiveness observed among individual patients. Thus, some edematous patients with heart failure, cirrhosis, or nephrosis respond brilliantly to one agent and not at all to another. Such results point to the operation of a number of different renal tubular transport mechanisms, each of which may participate to a greater or lesser extent in the patbogenesis of fluid retention of a given patient. The intelligent use of various pharmacological agents permits us to learn more about the basic nature of these discrete tubular transport systems and then to evaluate the role of these processes in causing the particular state of fluid retention. Perhaps we can look forward to a time when we will be able to characterize the edematous states of heart failure, nephrosis, or cirrhosis more precisely in terms of the specific renal biochemical lesion involved.
1. 2.
REFERENCES CANNON,P. J., AMES, R. P. and LAUGH, J. H. : Methylenebutyryl phenoxyacetic acid: Novel and potent natriuretic and diuretic agent, J. Amer. med. Ass. 185, 854, 1963. LNUGH, J. H.: The mode of action and use of chlorothiazide and related compounds, Circulation 26, 121, 1962.
890 3. 4. 5.
JOHN H. LARAGH LARAGH,J. H., HEINEMANN,H. 0. and DEMARTINI,F. E.: The effect of chlorothiazide on electrolyte transport in man and its use in the treatment of edema of congestive heart failure, nephrosis and cirrhosis, J. Amer. med. Ass. 166, 145, 1958. Prrrs, R. F. : The Physiological Basis of Diuretic Therapy. Charles C. Thomas, Springfield, Illinois, 1959. SONNENBLICK,E. H., CANNON, P. J. and LARAGH, J. H.: The nature of the action of intravenous aldosterone: Evidence for a role of the hormone in urinary dilution, 1. clin. Invest. 40, 903, 1961.
MECHANISMS
Pergamon Press Ltd. Printed in Great Britain
AND MANAGEMENT OF INTRACTABLE HEART FAILURE JOHN H.
Associate
Professor
LARAGH,
M.D.
of Clinical Medicine, Columbia University Surgeons, New York, N.Y., U.S.A.
FOR several
College
of Physicians
and
centuries the study of the mechanisms involved in the causation and maintenance of congestive heart failure have intrigued perhaps more investigators than any other single subject in the field of investigative medicine. Within recent decades great advances have been made in our understanding of the mechanisms that are involved in causing and sustaining the state of salt and water retention. Heart failure begins with the failure of the heart as a pump. As a result of this failure the mean arterial pressure tends to fall, and the hydrostatic pressure transmitted to the glomerular capillaries falls. This induces renal hemodynamic changes which favor retention of sodium and water. It is now generally accepted that a state of congestive heart failure can neither be induced nor sustained without the presence of abnormal renal retention of sodium and water. Thus, while the condition may begin in the heart, changes that occur in the kidney support and sustain the condition. I would like first to review something of what is known about the renal function in heart failure. With this background I shall then consider the mechanism of action of various of the newer diuretic agents that are so effective in relieving patients suffering from this condition. A study of the physiologic changes induced by the different types of diuretic agents available allows not only a more rational basis for their use but also,-and perhaps this is more important-a much better understanding of the basic physiologic mechanisms that are disturbed in congestive heart failure. The major mechanisms involved in renal regulation of salt and water balance, both in normal subjects and in patients with heart failure, are the following: The glomerular filtration rate is determined in part by the hydrostatic pressure in the glomerular capillaries. This is determined by the mean arterial pressure generated by heart action. When the cardiac output falls, the glomerular filtration rate tends to fall. Renal blood flow falls perhaps even more, and a form of compensatory vasoconstriction occurs within the kidney. These hemodynamic changes in themselves lead to definable defect in the capacity to eliminate ingested sodium and water and thereby participate in the development of a progressive state of edema. It follows that when further stresses such as exercise or emotion are imposed, the myocardium and the hemodynamic state of the kidneys may be further embarrassed. In addition to these hemodynamic factors associated with heart failure we now know that sodium balance is regulated perhaps to even a greater extent by changes in the rate of renal tubular reabsorption of the filtered plasma. The kidney is constructed so that normally about 180 1. of plasma are filtered through the glomerular capillaries every day, and normally 99 per cent of this ultrafiltrate of plasma is reclaimed into the circulation by reabsorptive processes along the course 879
880
JOHNH. LARAGH
of each renal tubule. There is a good deal of experimental and clinical evidence to indicate that the tubular reabsorption of sodium is abnormally increased in congestive heart failure. We now know that these reabsorptive processes are accomplished by active transport mechanisms involving the expenditure of energy by renal tubular cells and that there are many different transport mechanisms and many different steps in each of the transport processes that participates in sodium reabsorption. Time does not permit a detailed description of these mechanisms. However, it is important to bear in mind that while the bulk of the sodium is reabsorbed with chloride ions, other types of sodium reabsorption occur which also serve to regulate both acid-base and potassium balance. Knowledge of these systems has proved of practical value. For example the sodium bicarbonate reabsorptive process occurring in exchange for secreted hydrogen ions can be inhibited by carbonic anhydrase inhibitors that interfere with the generation of hydrogen ions by the renal tubular cells. Also, the sodium ions that are reabsorbed in exchange for the tubular cell potassium ions can be blocked by aldosterone antagonists. The processes for tubular sodium reabsorption are also intimately involved in regulating both the amount of water in the body and the tonicity of body fluids. A fundamental tenet of renal physiology, which has been placed on a firm basis by micropuncture studies, is that some 80 to 85 per cent of the filtered salt is normally reabsorbed in the proximal tubule along with isosmotic amounts of water. The remaining 15 to 20 per cent of the glomerular filtrate is reabsorbed in the more distal portions of the nephron. This distal reabsorption differs in that it may or may not be isosmotic; thus, in water diuresis the distal reabsorption of sodium chloride may occur without isosmotic amounts of water, leading to the maintenance of a very dilute urine. This difference in proximal and distal tubular function also allows one to study selectively the distal and proximal transport mechanisms in normal subjects and in patients with congestive heart failure. This is because drugs which act to interfere with concentration or dilution of the urine are presumably interfering with distal tubular functions. With this brief and cursory review of some of the major renal tubular processes I would like now to turn to pharmacologic agents now in wide usage, which, as we learn about their mechanisms of action, can teach us something about the physiology of the kidney in heart failure. Figure 1 shows the chemical structures of six major types of diuretics. Many, many interesting derivatives of some of these types have been developed, partly for commercial reasons, by various companies. The oldest and probably still among the most useful types of diuretics are the organomercurials, which ordinarily require intramuscular injection. These are substituted mercury propyl compounds of the general structure shown. A major advance was made in the field of diuretic therapy when it was found that sulfanilamide, because of its ability to inhibit carbonic anhydrase, could promote diuresis in patients in congestive heart failure. This discovery led to the development of more powerful carbonic anhydrase inhibitors. Two that are now commonly used are acetazolamide (Diamox) and dichlorphenamide (Daranide) (Fig. 1). These compounds inhibit the generation of hydrogen ions by renal tubule cells and thereby promote a sodium bicarbonate diuresis.
Mechanisms
and Management
of Intractable
DIURETIC
ANTI-CARBONIC
ANYHYDRASE
CHLORURETIC
Heart Failure
881
SPECIES:
SULFONAYIDES
SULFONAMIDES
ITo
ANT;b&LD;,~ERONE FIG.
1.
PTERIDINE
Chemical structures
ETHACRYNIC
ACID
of six species of diuretics.
More recently, largely due to the work of Ekeyer and his associates, a most significant contribution to treatment of patients was made with the development of chlorothiazide, a chloruretic sulfonamide, which, unlike the older carbonic anhydrase inhibitors, mainly promoted sodium chloride excretion. Some others of the many derivatives of chlorothiazide are shown in Fig. 1. Three other types of diuretic agents that each appear to have entirely different types of actions are shown at the bottom of Fig. 1. The first is the aldosteroneinhibiting agent, a 17+pirolactone, Aldactone, a steroid vaguely resembling aldosterone in chemical structure. A large body of evidence indicates that it specifically interferes with the sodium-retaining and kaluretic activity of the patient’s own aldosterone. Therefore it is of unique interest from a physiologic standpoint. Practically, it allows one to evaluate and inhibit the activity of aldosterone in patients with heart failure. The pteridine compound, triamterene, shown in Fig. 1, is interesting because it also causes potassium retention and appears to oppose some of the actions of aldosterone. However, unlike spirolactone, it is effective in the total absence of aldosterone. Finally, let us consider the recently developed compound, ethacrynic acid. It is a derivative of phenoxyacetic acid, with an unsaturated ketone radical shown on the left. It seems to be the most powerful diuretic agent yet developed. Its actions, as will be shown, are still different from those of the other species appearing in Fig. 1. HOW do these various diuretic agents act in patients? Figure 2 presents the mean values from 15 paired clearance studies of normal subjects. We injected intravenously either chlorothiazide (Diuril) or merallut-ide (Mercuhydrin), a mercurial diuretic, on different mornings, under the same condi-
JOHN H.
882
CHLOROTHIAZIDE CONTROL 1C.T.500 mg
LARACH
MERALLURIDE CONTROL II-@ 2ml
SPIROLACTONE CONTROL I250mg
I30c
IN mlhin
110;
n
_
IOOOb!$Rn
5oo-
-I
FIG. 2. Clearance studies in 15 normal subjects (average values) following administration during water diuresis of 500 mg of chlorothiazide or 2 ml meralluride. Reprinted through the courtesy of Charles C. Thomas, Publisher, Springfield, Illinois, from LARAGH, J. H. : Pharmacology of diuretic agents and electrolyte problems encountered with their use, in BARTTER, F. C., Ed. : The Clinical Use of Aldosterone Antagonists. Charles C. Thomas, Springfield, Illinois, 1960.
tions. The major differences in the action of thiazides and organomercurial agents can be seen in the figure and are compared with control values from three similar studies using spirolactone. Chlorothiazide (500 mg) increased sodium excretion considerably more than did 2 ml of meralluride. However, chlorothiazide also the mercurial diuretic actually suppressed produced the characteristic kaluresis; potassium excretion. Finally, mercurial agents produced a more dilute diuresis, as shown by the large increase in free water excretion. With chlorothiazide, during diuresis, the urine actually becomes more concentrated. How can these differences be interpreted in terms of the known mechanisms involved in sodium reabsorption? Figure 3 presents data from a single study that highlight the difference in urinary dilution produced by the two agents. The black circles represent the data obtained from a patient given chlorothiazide and the open circles data from a patient given meralluride. This normal subject was in water diuresis, and each diuretic was given at the same hour on different mornings. With meralluride, the urine flow increased to about the same extent as it did with chlorothiazide. However, with the latter, the urine became much more concentrated during diuresis, that is to say, chlorothiazide appears to promote proportionally more solute excretion, while mercurial agents promote more water excretion. Figure 4 shows how these data can be interpreted. As I have said, during normal water diuresis the urine is diluted by virtue of distal tubular reabsorption of solute,
Mechanisms
and Management
of Intractable
Heart Failure
883
Pt. P.C. 20
-
._ ? z E
IO-
8 0
I
I
IO
20
I
30
V ml/min FIG. 3. Osmotic clearance and urine flow during diuresis in normal subject given 500 mg of chlorothiazide or 2 ml meralluride intravenously on different mornings. Reprinted, by permission of the Editor of the Journal of the American Medical Association, from LARAGH,J. H., HEINEMANN,H. 0. and DEMARTINI,F. E.: Effect of chlorothiazide on electrolyte transport in man: its use in the treatment of edema of congestive heart failure, J. Amer. med. Ass. 166, 145, 1958.
without commensurate amounts of water, thus producing dilute urine. If an agent acted only proximally, that is, merely blocked isosmotic reabsorption, one would expect that the urine would become more dilute during the exhibition of the agent, because of the diversion of more solute to the diluting apparatus, the function of which remains uninhibited. The only way we feel that the action of meralluride can be explained is to say that it almost exclusively blocks the proximal reabsorptive mechanism, because the urine remains relatively dilute during diuresis. On the other hand, findings with respect to chlorothiazide and its derivatives indicate that chlorothiazide acts not only in the proximal tubule but also in the distal tubule, thereby interfering with urinary dilution, leading to a solute-rich diuresis. These differences in the action of thiazides and mercurial agents allow us to use them selectively in clinical situations that require one or the other of these effects. Furthermore, because these agents differ in their locus of action, they are, indeed, additive in their diuretic effects, a point worth remembering in treating more refractory patients. In fact, when chlorothiazide is given during a mercurial diuresis, as might be predicted, the natriuretic effects are additive. Furthermore, since mercurial agents block potassium secretion, the kaluresis of chlorothiazide is blocked by meralluride. Therefore, the diuresis that results from this combined use is actually more satisfactory than with one preparation alone. Finally, meralluride
884
JOHN H. LARAGH
e5q-d WATER DIURESIS
MERALLuRlDE
4. Schema showing mechanisms of solute and water reabsorption. Reprinted, by permission, from HEINEMANN, H. O., DEMARTINI, F. E. and LARAGH, J. H.: Effect of chlorothiazide on renal excretion of electrolytes and free water, Amer. J. Med. 31, 853, 1959. FIG.
produces a dilute urine. However, when chlorothiazide is added, although the diuresis may double, the urine becomes more concentrated, again showing that chlorothiazide adds to the effect of mercurials by acting on the distal diluting segment of the nephron. What about the role of aldosterone in congestive heart falure? We have made a large number of measurements of the secretion rate of this hormone and have found that while at times it is not markedly increased, in certain patients with congestive heart failure there is a marked increase that plays a critical role in leading to further progression of the edematous state. It is helpful, then, to understand how aldosterone acts in normal subjects and what changes it produces in the urinary electrolyte pattern. Figure 5 depicts graphically what happens when 500 mg of D-aldosterone are given intravenously to a normal human subject during a maintained water diuresis. The hormone produces no significant effects on glomerular filtration rate or renal blood flow. Hence all of the observed effects can be ascribed to alterations in tubular transport of electrolytes. Aldosterone increases potassium excretion and causes sodium chloride retention, but these two effects may not occur exactly simultaneously. Note that first there is a considerable delay of 30 to 60 min before the hormone begins to act on the kidney. This delay is reminiscent of that seen with other steroids such as digitalis or vitamin D. Note also that the action of the hormone lasts for many hours, even though its chemical half-life in blood is known to be of the order of only 40 min. The most remarkable thing about the action of aldosterone, perhaps, is that while it nroduced sodium chloride retention, it did not change the urine flow; free water
Mechanisms
mllmin
and Management
of Intractable
Heart Failure
885
OL
14 -
%J mllmin
12 ,.
-100
0
100
200
300
400
500
600
Minutes FilG. 5. Effect of aldosterone in normal subject iu water diuresis. Reprinted, by permission, from SONNENBLICK, E. H., CA~W~N,P. J. and LARAGH, J. H.: Nature evidence for role of hormone in urinary of action of intravenous aldosterone: dilution, J. clin. Invesf. 40,903, 1961.
excretion actually rose as the urine became more dilute. This means that aldosterone acts beyond that proximal isosmotic segment I have mentioned and that it therefore acts in the portion of the nephron where the urine is diluted, thus producing a more dilute urine. In a study of the relationship between urinary dilution and aldosterone action in 7 normal subjects with various intakes of sodium, we found that in every instance when aldosterone was given, the induced fall in solute clearance (largely in sodium chloride) was accompanied by a commensurate rise in free water clearance. In other words, sodium chloride was abstracted from the urine virtually without water, so that the urine was made more dilute in proportion to the sodium chloride extraction. These data can only be interpreted, we feel, to mean that an important action of aldosterone is on the distal diluting segment, promoting the extraction of sodium chloride without water from the tubular urine. One might therefore be able to predict how a specific blocker of aldosterone would act and what pattern it would produce in the urinary excretion. The spirolactone which blocks aldosterone would be expected to inhibit sodium chloride transport in the distal nephron and to block potassium secretion, also a distal tubular function. Indeed, data on the effects of spirolactone in a normal subject (Fig. 2), as compared with those of the mercurials and chlorothiazide, show that spirolactone causes a more concentrated urine, because as does chlorothiazide, it has a distal action at the diluting segment of the nephron. Furthermore, spirolactone, unlike chlorothiazide, blocks potassium secretion in the distal portion of the nephron Because of the different characteristics of these three species of diuretic agents, the data suggest that they might be quite useful, both in combination or in selected
JOHN H. LARAGH
886
FIG. 6.
Body weight, plasma potassium, chloride, carbon dioxide, and sodium and urinary potassium, chloride, and sodium in a patient with heart failure. Reprinted, by permission of the Editor of the Journal of the American Medical Association, from LARAGH, J. H., HEINEMANN, H. 0. and DEMARTINI, F. E.: Effect of chlorothiazide on electrolyte transport in man: its use in the treatment of edema of congestive heart failure, J. Amer. med. Ass. 166, 145, 1958.
situations, to correct or modify the underlying electrolyte abnormalities of the patient. Next, we will consider some clinical instances in which we can apply these principles to the rational and effective diuresis of patients with refractory congestive heart failure. Figure 6 is the record of a patient in congestive heart failure whose problem had been difficult to manage in the outpatient department. As is shown on the bottom line, a mercurial diuretic produced a modest diuresis but not enough to cause any appreciable change in weight. When chlorothiazide alone was given, a marked increase in sodium excretion occurred. The effect, however, began to fade out. Then a mercurial diuretic, when added to the chlorothiazide, produced a marked augmentation of effect, and diuresis was reinstituted. Later on, the carbonic anhydrase inhibitor, acetazolamide, was given on two occasions; this, too, augmented the diuresis. Because both chlorothiazide and acetazolamide produced potassium depletion, potassium chloride supplements had to be given, as well as ammonium chloride supplements for the hypochloremia. The satisfactory mobilization of all the edema fluid in this desperately ill patient, by combined therapy when the use of single agents had failed, again illustrates the
Mechanisms
and Management
of Intractable
Heart Failure
887
Chlorothiazide 2 gm Meralluride 2 ml SC-81 09 400 mg Urip-y mEq /day
2 20 0 500
Urinary Nat
300
mEq /day 100 0
10
20
30 Days
40
50
60
FIG. 7. Effect of aldosterone inhibitor in patient with congestive heart failure on constant metabolic regimen. Reprinted, by permission, from LARAGH, J. H.: The use of diuretics in congestive heart-failure, Postgmd. Med. 25, 528, 1959.
practical aspects of rational combination therapy in difficult situations. It also suggests again the existence in different sites in the nephron of different transport mechanisms that can participate to a varying extent in the state of sodium retention. Experience with another patient demonstrates the advantages of spirolactone (Fig. 7). This patient had virtually no sodium diuresis with mercurial diuretics or chlorothiazide and was given spirolactone, with only a modest increase in salt excretion and with the characteristic potassium retention. The mercurial agent alone produced little effect, but when chlorothiazide and the mercurial agent were combined, a marked diuresis occurred. However, this diuresis faded out again. Finally, with the patient still quite waterlogged, the addition of the aldosterone antagonist produced a sustained diuresis and clearing of all edema fluid, along with the reversal of negative potassium balance. These two clinical experiences demonstrate how these agents can be used in combination. The findings suggest that spirolactone, which by itself has the most subtle and least dramatic effect on sodium excretion, is probably one of our most useful agents. It might be wise to use it as a basal medication on a day-to-day basis in all patients to prevent potassium loss and sustain mild sodium diuresis. Then, when more power is needed, a thiazide or mercurial diuretic can be added to the program. Finally, I would like to discuss the very exciting action of the new compound, ethacrynic acid, in congestive heart failure. This is the most powerful diuretic agent that we have yet studied. Table 1 presents a clearance study of a 44-year-old woman with rheumatic heart disease, who was in advanced heart failure that was refractory to mercurials and thiazides. Her urine flow was only 8 ml/min and her glomerular filtration rate was some 70 to 90 ml/min. When 50 mg of ethacrynic acid was given intravenously, the urine flow increased to 18 ml/min; the urine
888 TABLE 1.
Period
JOHN H. LARAGH EFPECT OF ETHACRYNIC
ACID* ON RENAL HEMODYNAMICS AND ELECTROLYTE EXCRETION DURING WATER DILJRESISt
V (ml/ min)
&WV (mEq/ min)
UKV tmW min)
&IV (mEq/ min)
U,SIn (mOsm/ ml) Control
1
2 3
8.4 8.5 8.7
6.7 5.1 17.4
117 112 109
3 2 4
97 96 94
Values with Ethacrynic 4 5 6 7
14.4 18.6 18.0 17.7
1099 1652 1503 1347
471 432 369 324
1381 1834 1634 1466
*A total of 50 mg (1 mg/kg) administered tThe patient was a 44-year-old Negro heart failure.
249 247 227 210
U,,,V (mOsm/ min)
AND
WATER
C, (ml/ min)
C,,, (ml/ min)
$7 min)
C IX20
78 87 99
235 229 247
3.0 3.0 3.1
5.4 5.5 5.6
251 273 259 232
13.5 17.4 15.7 14.4
0.9 1.2 2.3 3.3
(ml/
min)
Values 815 816 818
Acid Administration 3586 4594 4086 3752
94 100 97 89
intravenously in 3 min. woman with rheumatic
heart
disease
and congestive
sodium excretion increased from 6 mEq/min to 1,650; and this patient lost 18 lb in the 24 hr following this single injection. Other patients receiving this diuretic agent have astounded us by at times producing a diversion of half of their glomerular filtration rate into the urine. The urine flow of one cardiac patient, for example, was 0.5 ml/min and went up to 40 ml/min. Figure 8 illustrates the effect of this agent in another patient with salt and water retention that had been refractory to mercurials and thiazides. Ethacrynic acid produced a marked diuresis, with the loss of huge amounts of sodium chloride in the urine. The patient’s weight dropped from 165 to 120 pounds. The clearing of the edema fluid produced negative potassium balance. However, other studies have shown that this, too, could be blocked by the addition of the aldosterone antagonist, spirolactone, which also augments the diuresis. These experiences illustrate the importance of renal tubular reabsorption of filtered sodium chloride in the regulation of salt and water balance. They indicate that the active transport processes occurring along the course of the proximal and distal nephron all can participate to a greater or lesser extent in the regulation of normal salt balance, as well as in the causation of the abnormal salt retention of heart failure. We know that aldosterone can modify and augment distal tubular sodium reabsorption in heart failure, and the ability to specifically block this hormone has been a major advance in both understanding and therapy. Having at our disposal a variety of pharmacologic agents that appear to interfere specifically with different transport operations in different portions of the nephron, we are in a position to all but eliminate the category of ‘refractory’ congestive heart failure from our medical practice. With the combined rational use of these agents with differing actions to modify and correct electrolyte imbalances in the plasma and in the urine, we can treat successfully an increasingly greater number of patients with congestive heart failure by selectively modifying renal tubular functions. However, for proper use, these powerful agents are a mandate for the physician to develop an increasing knowledge of pharmacology and renal physiology and then
Mechanisms
and Management
of Intractable
Heart Failure
889
FIG. 8. Effect of ethacrynic acid in patient with congestive heart failure refractory to mercurial and thiazide diuretics. Reprinted, by permission, from CANNON, P. J., AMMES,R. P. and LAUGH, J. H. : Methylenebutyryl phenoxyacetic acid : Novel and potent natriuretic and diuretic agent, J. Amer. med. Ass. 185, 854, 1963.
to keep a constant vigil on the evolving acid-base and fluid balance of each patient. This presentation has not attempted a fully detailed discussion of the pharmacology of the various diuretics. However, physicians should make every effort to become familiar with this information. To me, a most exciting facet of diuretic therapy is the varying responsiveness observed among individual patients. Thus, some edematous patients with heart failure, cirrhosis, or nephrosis respond brilliantly to one agent and not at all to another. Such results point to the operation of a number of different renal tubular transport mechanisms, each of which may participate to a greater or lesser extent in the patbogenesis of fluid retention of a given patient. The intelligent use of various pharmacological agents permits us to learn more about the basic nature of these discrete tubular transport systems and then to evaluate the role of these processes in causing the particular state of fluid retention. Perhaps we can look forward to a time when we will be able to characterize the edematous states of heart failure, nephrosis, or cirrhosis more precisely in terms of the specific renal biochemical lesion involved.
1. 2.
REFERENCES CANNON,P. J., AMES, R. P. and LAUGH, J. H. : Methylenebutyryl phenoxyacetic acid: Novel and potent natriuretic and diuretic agent, J. Amer. med. Ass. 185, 854, 1963. LNUGH, J. H.: The mode of action and use of chlorothiazide and related compounds, Circulation 26, 121, 1962.
890 3. 4. 5.
JOHN H. LARAGH LARAGH,J. H., HEINEMANN,H. 0. and DEMARTINI,F. E.: The effect of chlorothiazide on electrolyte transport in man and its use in the treatment of edema of congestive heart failure, nephrosis and cirrhosis, J. Amer. med. Ass. 166, 145, 1958. Prrrs, R. F. : The Physiological Basis of Diuretic Therapy. Charles C. Thomas, Springfield, Illinois, 1959. SONNENBLICK,E. H., CANNON, P. J. and LARAGH, J. H.: The nature of the action of intravenous aldosterone: Evidence for a role of the hormone in urinary dilution, 1. clin. Invest. 40, 903, 1961.