Division of Clinical Pharmacology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202-5124
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ABSTRACT |
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The diuretic response to loop diuretics in various disease states has consistently been found to be subnormal. One of the key determinants of the degree of diuretic response is the functional integrity of the sodium-potassium-chloride transporter in the loop of Henle. Studies in animal models suggest that expression/activity of the transporter may be affected by factors such as altered natural splicing events of NKCC2 (the gene encoding for the renal transporter), renal prostanoids, vasopressin, and other autacoids. We have reviewed the pharmacokinetics and pharmacodynamics of loop diuretics in health and in edematous disorders for which they are used. On the basis of evidence reviewed in this paper, we propose that altered expression or activity of the sodium-potassium-chloride transporter in the loop of Henle, in conjunction with events occurring in other segments of the nephron, possibly accounts for the altered diuretic response to these agents. Thus the modulators of this altered expression/activity could serve as important therapeutic targets for alternative diuretic regimens in these conditions.
edematous disorders; furosemide
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INTRODUCTION |
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OPTIMAL THERAPEUTIC USE of loop diuretics requires an understanding of their basic pharmacology and how that translates to clinical pharmacology. As will be emphasized, the two complement one another in that discoveries in the domain of pharmacology lead to testable hypotheses as to clinical application. Similarly, clinical observations logically lead to studies best performed at the bench. For example, studies of the pharmacodynamics of loop diuretics in patients with heart failure consistently show that there is a subnormal response to amounts of diuretic reaching the site of action. There are several potential explanations for this observation, each of which dictates a different therapeutic strategy. The possible explanations would be difficult to dissect through clinical studies. For example, one possible explanation is altered expression or activity of the Na-K-2Cl transporter at the loop of Henle. It goes without saying that one could never measure such expression in a clinical study. In contrast, one can imagine addressing such a question in an appropriate animal model. If such a model showed that there was no difference in expression of the transporter, then alternative mechanisms should be explored. If, on the other hand, there were substantial changes in expression or activity of the transporter in heart failure, one would then need to ponder appropriate therapeutic strategies and test them in controlled clinical trials.
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PHARMACOLOGY OF LOOP DIURETICS |
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Loop diuretics act principally by blocking the luminal Na-K-2Cl transporter in the thick ascending limb of the loop of Henle; in other words, this transporter is the receptor for loop diuretics (15, 31, 40, 42, 64, 69, 78, 80). This transporter has been cloned and sequenced, and its expression has been mapped to different segments of the nephron as well as other tissues (66, 69, 70). It is a protein with a core molecular mass of 121 kDa, having 12 putative membrane-spanning domains (42, 70). Loop diuretics bind to portions of transmembrane domains 11 and 12, whereas portions of domains 2, 4, and 7 transport Na, K, and/or Cl. It is encoded for by the type 1 bumetanide-sensitive Na-Cl cotransporter (BSC-1)/NKCC2 gene on chromosome 2, and rat BSC-1 protein is localized to the apical membrane of epithelial cells in both medullary and cortical segments of the thick ascending limb of the loop of Henle (66, 69, 70). Several investigators have shown that it is expressed throughout the thick ascending limb of the loop of Henle, including the macula densa (66, 69, 70). Interestingly, nitric oxide (NO) synthase is coexpressed in the macula densa, suggesting that the Na-K-2Cl transporter may serve as the sensor of luminal chloride delivery to the macula densa and that NO is a mediator or modulator of subsequent effects in concert with or through locally synthesized prostanoids (77). Expression of Na-K-2Cl is at the luminal membrane but also in cytoplasmic vesicles, suggesting a reservoir of transporters for insertion into the membrane (66, 69). In turn, these vesicles are more predominant in smooth- than rough-surfaced thick ascending limb cells; the former are mainly in the medullary portion of the thick limb. Thus the transporter that serves as the receptor for loop diuretics is expressed at the apical surface of both the medullary and the cortical sections of the thick ascending limb of the loop of Henle, including the macula densa. It resides in cytoplasmic vesicles, offering a mechanism for altered activity of the transporter by way of increasing or decreasing the numbers of transporters inserted into the membrane.
In addition to the renal Na-K-2Cl transporter, there is a ubiquitous Na-K-2Cl transporter encoded by BSC-2/NKCC1 that is expressed in many tissues. Loop diuretics have little if any effect on this latter transporter in vivo. In contrast, ex vivo they inhibit its activity. In vivo selectivity derives from three factors. First, the renal Na-K-2Cl transporter has about a fourfold greater affinity for bumetanide and presumably other loop diuetics (41, 49). Second, there are likely differences in access of the loop diuretic to the site of transporter expression. All loop diuretics are highly bound to serum albumin, and this binding restricts their access to many tissues, as might physicochemical properties such as their negative charge and poor lipid solubility. Access to renal Na-K-2Cl receptors occurs via active secretion. One must presume that such an avenue of access is not present at sites of expression of the ubiquitous Na-K-2Cl transporter. Third, once a loop diuretic is secreted into the proximal tubule, as it flows to its site of activity at the thick ascending limb of the loop of Henle, it becomes more concentrated.
Studies in animal models have explored ways in which expression of the
Na-K-2Cl transporter might be altered (Fig.
1). It is now abundantly clear that
vasopressin itself, either exogenously or endogenously, or its analogs
increase expression of the transporter (24, 55). It is
important to note that vasopressin might also cause increased insertion
of transporters over and above increasing their expression. Studies
with knockout mice (Gs knockout) indicate that this
effect of vasopressin is through Gs
, presumably to increase cAMP, which then increases transporter expression via a cAMP
regulatory element of the BSC-1/NKCC2 gene (24) (Fig. 1).
The net effect would be an increase in solute reabsorption at the thick
limb, contributing to sodium retention and also increasing the driving
force for water reabsorption (Fig. 1). It is intriguing to note that
vasopressin also causes increased aquaporin expression and insertion,
thereby increasing the channels available for water reabsorption
(2, 59, 97, 103). That effect, coupled with the increased
osmotic driving force for water reabsorption noted above and with
nonosmotically mediated increases in vasopressin in edematous disorders
(84, 85), can readily account for the inability to excrete
free water and the hyponatremia that is a characteristic of these
clinical conditions (Fig. 2). These data suggest that the vasopressin-mediated increase in expression of the
Na-K-2Cl transporter amplifies the defect in water excretion in
edematous disorders. Might it also be a factor in the changed pharmacodynamics of loop diuretics? As will be discussed subsequently, vasopressin-mediated increased transporter expression alone is an
overly simplistic explanation for an altered diuretic response.
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The expression of the Na-K-2Cl transporter may also be influenced by alternate natural splicing events of the BSC-1/NKCC2 gene, with various degrees of expression of the different exons (66). In turn, this alternative splicing results in different transporter capacities (36). Disease-induced changes in splicing or distribution of splice variants could conceivably contribute to an altered cumulative response to a loop diuretic.
The expression of the Na-K-2Cl transporter is also influenced by renal prostanoids, wherein PGE2 decreases its expression (29) (Fig. 1). PGE2 activates the EP3 receptor, causing decreases in cAMP via Gi; through the cAMP regulatory element, expression of the transporter decreases. Such an effect would decrease the driving force for water reabsorption and thereby diminish the hydrosmotic response to vasopressin, a well-known effect of PGE2 (44). This role of PGE2 could also explain the effect of nonsteroidal anti-inflammatory drugs in causing sodium and water retention, an effect that has been shown in clinical studies to occur anatomically at the thick ascending limb (51). It is interesting to note that administration of vasopressin and also edematous disorders are characterized by increases in renal prostanoids. Presumably, this represents a negative-feedback loop to ameliorate the sodium- and water-retentive effects of the edematous disorders. This pathophysiology also likely accounts for the sometimes devastating clinical effects of acute renal failure (16, 20, 83) or decompensation of heart failure (45, 65) that can occur when such patients are administered nonsteroidal anti-inflammatory drugs.
Vasopressin and other autacoids could also affect activity of the transporter in addition to its expression. Extensive studies have been performed with NKCC1 showing numerous fashions by which activity could be modified, including phosphorylation by any of a number of kinases (42). Presumably, the same potential applies to the renal Na-K-2Cl transporter.
From the foregoing, one would predict that increased expression of the Na-K-2Cl transporter occurs in the common clinical conditions treated with loop diuretics. In turn, might increased expression account, at least in part, for the diminished response to loop diuretics that occurs in the edematous disorders? This mechanism is likely overly simplistic. As will be discussed, the response to loop diuretics in the edematous disorders is characterized by a decrease in response to a maximally effective dose. If vasopressin simply caused more transporters to be present in the thick ascending limb of the loop of Henle, one would expect that administration of a dose of loop diuretic sufficient to block all of them would result in an increased maximal response. Thus one must postulate a more complicated scenario of altered activity and/or of events occurring at other segments of the nephron that obviate this manifestation of increased expression. For example, increased proximal and/or distal reabsorption of sodium could contribute. The answers to these questions are open and not only represent scientific opportunities for the future but are also important for the design of future therapeutic diuretic regimens. Importantly, the anticipated availability of vasopressin antagonists for clinical use will allow logical exploration of these different possibilities in parallel with studies at the bench that unravel this undoubtedly complicated pathophysiology.
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PHARMACOKINETCS OF LOOP DIURETICS |
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Loop diuretics reach the Na-K-2Cl transporters that are inserted into the luminal membrane by being actively secreted from the blood into the urine at the proximal tubule (71). High albumin binding (>95%) minimizes glomerular filtration. Binding to albumin traps the diuretic in the plasma and transports it to organic acid secretory sites at the proximal tubule. These secretory pumps have such avidity for the loop diuretic that the diuretic is in effect "stripped" from the albumin and transported across the cell into the lumen, where it gains access to the Na-K-2Cl transporters that are downstream of the secretory sites.
Fifty percent of a dose of furosemide is excreted as active, unchanged
drug into the urine (7, 10); the remainder is conjugated
to glucuronic acid in the kidney itself (76). In patients
with renal insufficiency, the plasma half-life of furosemide is
prolonged because both urinary excretion and renal conjugation are
decreased (7, 8, 10, 21, 47, 89) (Table
1). Bumetanide and torsemide have
substantial metabolism (50 and 80%, respectively), but with these loop
diuretics metabolism is hepatic rather than renal (11, 14, 22,
46). Therefore, their half-lives are not prolonged in patients
with renal insufficiency, because the liver provides an alternative
route for elimination (Table 1). Just as occurs with furosemide, with
these two loop diuretics renal disease impairs delivery into the
tubular fluid. In patients with hepatic disease, the plasma half-lives
of bumetanide and torsemide are prolonged, allowing more to reach the
tubular fluid, an effect that can paradoxically enhance response
(10, 86) (Table 1).
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Ethacrynic acid is another loop diuretic; there are no data concerning its pharmacokinetics. Its ototoxic effects have seemed to be greater than that of other loop diuretics, causing its use to be relegated to patients who have allergic reactions to other loop diuretics. It will not be discussed.
Other pharmacokinetic features of diuretics that are clinically important are bioavailability and half-life. On average, half a dose of furosemide is absorbed but with a large range (10-100%) (10, 68). This variability makes it difficult to predict how much furosemide will be absorbed in an individual patient. Clinically, this means that one may need to explore a wide range of doses in an individual patient to determine the appropriate oral dose. Absorption of bumetanide and torsemide is essentially complete (34, 68, 86, 94) (Table 1). The variability in furosemide absorption appears to be clinically important. A recent study from our laboratory reports fewer hospitalizations and better quality of life in patients with heart failure treated with a completely absorbed loop diuretic as represented by torsemide compared with furosemide (67). Edematous disorders do not cause malabsorption of loop diuretics (6, 13, 18, 34, 86, 91, 94, 95). Absorption is slowed, particularly in patients with decompensated heart failure (95), but the total amount absorbed is the same as in healthy individuals. The clinical implications of slowed absorption are unclear.
The plasma half-lives of loop diuretics range from ~1 h for bumetanide to 3-4 h for torsemide; that for furosemide is intermediate (10). Neither a truly long-acting loop diuretic nor a sustained-release preparation is available. The traditional dosing intervals of all loop diuretics exceed the duration of time when effective amounts of drug are at the site of action. This means that at the end of the dosing interval there is considerable time during which there are inadequate amounts of diuretic at the site of action. During this time, the nephron avidly reabsorbs sodium, causing so-called "rebound" sodium retention or "braking" (102). This sodium retention can be of sufficient extent as to nullify the prior natriuresis. This is particularly the case if the response is modest, if the time of no drug effect is long (for example, a short half-life coupled with a long dosing interval), and/or if dietary sodium is high relative to response. Dietary intake is particularly a problem if salt indiscretion occurs at the end of a dosing interval wherein most of the sodium is retained (28). As a consequence, it may be wise for patients to take their doses of loop diuretics at times that correspond to sodium ingestion.
In summary, excepting the infrequently used ethacrynic acid, the pharmacokinetic characteristics of loop diuretics are well defined. These data allow logical choices, depending on the needs of individual patients, of which loop diuretic to use. Choice of dose and the frequency of dosing are driven not only by these pharmacokinetic characteristics but also by the pharmacodynamics of loop diuretics in the different clinical conditions in which they are used.
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PHARMACODYNAMICS OF LOOP DIURETICS |
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The urinary excretion rate of a loop diuretic has been shown to be a reliable measure of amounts of diuretic reaching the site of action and can be used as a surrogate for concentration in a typical concentration-response analysis of diuretic action (10, 19). Urinary concentration has not proven to be a useful measure because the concentration of diuretic in the final urine does not represent that at the site of action. Simplistically, the more diuretic reaching its site of action, the greater the response so that the net result is that diuretic concentration in the final urine is constant. Therein, the diuretic excretion rate is a better reflection of the amount of diuretic that is able to interact with the Na-K-2Cl transporter. The relationship between diuretic delivery and response, measured as urinary sodium excretion, chloride excretion, or fractional excretion of either, is characterized by a sigmoidally shaped curve, a so-called sigmoid Emax model (9). This relationship holds for all loop diuretics, although the position of each on the x-axis differs, because of differences in potency; namely, the excretion rate that causes a half-maximal response being least for bumetanide (~2.5 µg/min), greatest for furosemide (~100 µg/min), and intermediate for torsemide (~50 µg/min). Importantly, efficacy (maximal effect) is the same for all and amounts to a fractional excretion rate of sodium of ~20-25% in a healthy volunteer. This value is important, because it implies that a maximally effective dose of a loop diuretic is capable of completely blocking sodium reabsorption in the thick limb. In turn, once a maximally effective dose is administered, the only way to increase response is to block other segments of the nephron.
Several features of the sigmoidal shape of the pharmacodynamic relationship are important clinically. First, there is a threshold quantity of drug that must be achieved at the active site to elicit a response. Because of individual differences in sensitivity of the nephron and individual differences in pharmacokinetic characteristics, the dose that attains this threshold differs among patients. Clinically, this means patients should have doses tailored to their individual needs and that physicians should realize that a process of dose titration needs to occur in each patient. As noted above, the second feature of this pharmacodynamic relationship is that a maximal response can be identified, allowing definition of the ceiling dose of a diuretic, namely, the smallest dose of a diuretic that elicits a maximal response and therefore the dose that should not be exceeded.
In healthy volunteers, an intravenous dose of 40 mg of furosemide, 20 mg of torsemide, or 1 mg of bumetanide causes a maximal response, which is the excretion of 200-250 meq of sodium in a urine volume of 3-4 liters over a time interval of 3-4 h (10). In other words, loop diuretics cause excretion of urine with a sodium content resembling 0.5 normal saline. Knowing this fact can be helpful to clinicians in predicting the amount of sodium excreted based on simple measures of urine volume.
Tolerance to Loop Diuretics
There are two forms of tolerance to loop diuretics. Acute tolerance, or braking, refers to a decrease in response to a loop diuretic early in its use, in fact, within the duration of effect of the first dose. This type of tolerance can be prevented by restoring diuretic-induced loss of volume, implying that volume loss per se is the stimulus for whatever effectors are responsible (4, 43, 100). The mechanism by which acute tolerance occurs is unclear. Potential mediators include angiotensin II, sympathetic nervous system activation, or both. However, neither converting enzyme inhibition nor adrenergic blockade, separately and together, consistently prevents it (54, 75, 101). Thus other as yet unidentified mechanisms must also be involved. Acute tolerance is an important factor in the timing of doses of a loop diuretic and in the frequency of dosing. Because of the short half-lives of loop diuretics relative to their usual dosing interval, there can be a substantial period of time at the end of a dosing interval where amounts of diuretic are below the threshold needed to cause an effect. During this time, when homeostatic mechanisms have been triggered, avid sodium retention can occur. If the patient ingests sodium during these times, most or all of it will be retained, potentially obviating the diuretic effect (28). Several strategies can be used to counter this effect, including more frequent dosing, decreasing overall sodium intake, and/or coordinating diuretic and food ingestion so that the latter occurs at a time when sufficient amounts of diuretic are at the site of action, as, for example, ingestion within 2 h of administration of the diuretic (28). This problem could be most readily overcome by having a truly long-acting loop diuretic or a sustained-release preparation of one of them. Unfortunately, the chemical characteristics of all available loop diuretics have withstood substantial efforts to formulate such a product.The second type of loop diuretic tolerance occurs with chronic administration. When a loop diuretic is administered, the solute rejected from the loop of Henle floods more distal nephron sites. Increased exposure to solute causes hypertrophy of collecting and connecting duct segments of the nephron, with concomitant increases in reabsorption of sodium (25, 50, 60, 63, 88). Therein, sodium rejected from the loop of Henle is then reclaimed at these sites, decreasing overall diuresis. Thiazide diuretics block the nephron sites at which hypertrophy occurs, accounting for the synergistic response to the combination of a thiazide and a loop diuretic (26, 27, 72, 87). This phenomenon reinforces the logic of using combinations of loop and thiazide diuretics in patients who do not respond adequately to maximally effective doses of a loop diuretic.
Pharmacodynamics of Loop Diuretics in Edematous Disorders
Renal insufficiency.
Patients with a creatinine clearance of 15 ml/min deliver one-fifth to
one-tenth as much loop diuretic into the tubular fluid as a healthy
volunteer (7, 10). Thus a large dose must be given to
attain an effective amount of diuretic in the tubule (Table
2). When sufficient doses are
administered to attain effective amounts of the loop diuretic in the
urine, the relationship between excretion rate of diuretic and response
measured as fractional excretion of sodium is the same in patients with
renal insufficiency as in healthy volunteers (93, 99).
Thus remnant nephrons in patients with renal insufficiency retain their
responsiveness. That having been said, a response in terms of total
urinary sodium excretion never reaches that for a healthy volunteer
because the decrease in renal function limits filtered sodium (Fig.
3). Clinically, this means that a
maximally effective dose of a loop diuretic in a patient with renal
insufficiency may not result in the needed overall diuresis and that
other measures including frequent dosing, combining diuretics, and/or
restricting dietary sodium may also need to be employed.
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Nephrotic syndrome. Several changes occur in nephrotic syndrome that can affect the pharmacokinetics of loop diuretics. Two factors can affect delivery of the diuretic to its site of action, namely, inadequate secretion from blood to lumen of the nephron or alternatively binding of the loop diuretic to albumin in the tubular lumen. In terms of the former, studies in analbuminemic rats show that hypoalbuminemia may result in insufficient delivery of drug into the tubular fluid (48). As noted previously, the high degree of binding of loop diuretics to plasma albumin traps the diuretic in the vascular space and carries it to secretory sites in the kidney. In the absence of circulating albumin, loop diuretics are no longer restricted to the plasma (as reflected by a 10-fold increase in volume of distribution in the analbuminemic rat) and reach the secretory sites to a substantially diminished degree; therefore, less diuretic is secreted into the lumen, resulting in inadequate natriuresis (48). In analbuminemic rats, administration of a mixture of albumin and a loop diuretic restores bound diuretic to the animal. This results in a normalization of the volume of distribution and increased delivery of diuretic into the urine, restoring the response (48). That this mechanism might be operative in humans was suggested by a report that administration of 30 mg of furosemide mixed ex vivo with 25 g of albumin enhanced diuresis in several patients with nephrotic syndrome (48).
It is important to emphasize that this therapeutic strategy is aimed at increasing amounts of diuretic in the urine in hypoalbuminemic patients; it is not a strategy to alter the pharmacodynamics of the loop diuretic. Therein, it should be noted that pharmacokinetic studies in patients with both nephrotic syndrome (53, 79) and cirrhosis (32, 52, 90, 96, 98) show that normal excretion rates of furosemide reach the tubular fluid unless the patient also has renal insufficiency. These observations therefore raise the question of why a strategy of administering albumin should even be considered. Several recent studies, including one from our laboratory, have assessed the efficacy of albumin-furosemide mixtures in hypoalbuminemic patients and shown no increase in response over the loop diuretic alone (3, 17, 30). A caveat is that most of the patients in the reported studies had serum albumin concentrations of 2 g/100 ml or higher, suggesting that this level of circulating albumin is sufficient to deliver adequate excretion rates of diuretic. As such, there are sufficient data to reject use of loop diuretic plus albumin mixtures in patients with serum albumin concentrations above this value. In patients with more severe hypoalbuminemia, there are no clinical data. Consequently, it would seem reasonable that such a strategy can be considered but only after adequate doses of loop diuretic alone have been attempted and with the understanding that this therapy is experimental. As noted above, loop diuretics could theoretically bind to filtered albumin, rendering them inactive. In this scenario, although adequate amounts of total diuretic reach the site of action, the amount of unbound, active diuretic is insufficient to reach the threshold for response (37, 38, 56, 57). In animal models where the tubule is made "nephrotic" by including albumin in the tubular perfusate, the response is subnormal, and it can be restored by displacing the diuretic from urinary albumin (56, 57). It appears that nephrotic range proteinuria is able to bind one-half to two-thirds of the diuretic that reaches the tubular fluid. Consequently, diuretic doses two to three times greater than normal are needed to deliver adequate amounts of unbound, active drug to the site of action (Table 2). Another logical strategy to enhance the response in patients with albuminuria would be to administer another drug that could displace the loop diuretic from binding, thereby restoring amounts of unbound, pharmacologically active drug. A clinical study from our laboratory has tested this hypothesis and found that no benefit accrued, suggesting that other factors are more important in determining overall response in nephrotic patients (1). Because the delivery of diuretic into the urine is satisfactory and because urinary albumin binding is of minor quantitative importance, it is clear that pharmacodynamic factors are the major cause of a decreased response to loop diuretics in patients with nephrotic syndrome (53, 79) (Table 2). The mechanism of this altered response is unknown. Increased proximal and/or distal reabsorption of sodium may contribute (10). Interestingly, in a rodent model of nephrotic syndrome, a component of the changed response occurs within the loop of Henle itself (58). Might increased expression or altered activity of the Na-K-2Cl transporter occur and how might it influence response? Studies of such expression and activity in animal models would be interesting, as would assessment of the effect of vasopressin antagonists on response to a loop diuretic. In summary, patients with nephrotic syndrome have at least a pharmacokinetic plus a pharmacodynamic mechanism for decreased loop diuretic response (Table 2). Overcoming binding of diuretic to urinary albumin requires a sufficient dose to attain normal excretion rates of unbound diuretic in the urine. This amount defines the ceiling dose listed in Table 2. The diminished pharmacodynamics of response mandates frequent dosing and often addition of a thiazide diuretic. If these strategies fail and the patient is severely hypoalbuminemic, a mixture of loop diuretic and albumin can be attempted. We recommend mixing a ceiling dose with 25 g of albumin. This strategy should be conducted in a fashion such that response can be closely monitored to allow a definitive conclusion as to whether the combination was effective and should or should not be continued.Cirrhosis. Patients with cirrhosis receive loop diuretics only if their disease is so severe that spironolactone and thiazides are not effective; even then, loop diuretics are added to a regimen of spironolactone. The pharmacokinetics and pharmacodynamics of loop diuretics have been amply quantified in patients with cirrhosis. Unless patients have diminished renal function, they deliver normal amounts of diuretic into the urine (32, 34, 52, 90, 96, 98). Thus a diminished response in patients with cirrhosis occurs by pharmacodynamic mechanisms, wherein the relationship between excretion rates of diuretic and natriuretic response is shifted downward and to the right so that the response to a maximally effective dose is substantially less than occurs normally (32, 34, 52, 90, 96, 98). As was discussed above with nephrotic syndrome, the cause of this shift is unknown. It may entail increased solute reabsorption more proximal and/or more distal to the loop of Henle but also may imply changes at the loop itself.
Congestive heart failure. In patients with congestive heart failure and preserved renal function, delivery of loop diuretics to the tubular fluid is normal (5, 39, 74). Historically, the possibility has been raised that patients with overt heart failure likely have gut wall edema causing diuretic malabsorption; studies have shown that the same quantity of loop diuretic is absorbed in such patients as occurs in healthy control subjects (6, 13, 92, 95). Thus malabsorption does not occur. However, the rate of absorption is slowed, particularly in patients with decompensated heart failure; therefore, the time of maximal response is delayed to 4 h or more (95). Whether this change is important clinically has not been studied.
Because the pharmacokinetics of loop diuretics are essentially normal in patients with heart failure, it is pharmacodynamic mechanisms that account for diminished response (12, 94). In fact, patients with heart failure have a pattern of response that is similar to that of patients with nephrotic syndrome or those with cirrhosis, with a shift in the relationship between diuretic excretion rate and response downward and to the right (12). In patients with mild-to-moderate heart failure, this results in a natriuretic response in these patients that is one-fourth to one-third that which occurs normally to maximally effective doses of loop diuretics (12, 94). The response in patients with more severe disease is smaller yet. The response is not improved by large doses of loop diuretic; the therapeutic strategy is to administer modest doses more frequently (Table 2). Many patients with heart failure do not respond adequately to a loop diuretic alone even if accompanied by dietary sodium restriction. In such patients, a thiazide diuretic is often added, wherein it is not uncommon for patients to have a synergistic response with a profound diuresis (26, 27, 73, 87). The mechanism of this synergy is that discussed above in terms of the pathophysiology of chronic tolerance to loop diuretics. The hypertrophied distal nephrons are the site of action of thiazide diuretics so that their blockade results in substantial natriuresis (25-27, 50, 60, 63, 87, 88). In summary, patients with congestive heart failure have normal delivery of loop diuretics into the urine and do not require large doses; rather, doses must be given more frequently (Table 2). The possible mechanisms of the altered pharmacodynamics are as were discussed previously; particularly intriguing is the possibility of altered expression and/or activity of Na-K-2Cl transporters and the potential role of vasopressin therein. ![]() |
SUMMARY |
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The pharmacokinetics and clinical pharmcodynamics of loop diuretics have been well characterized in all the edematous disorders in which they are used. Such data allow more rational designs of therapeutic regimens than was possible in the past. More recent data on the receptor for loop diuretics, namely, the Na-K-2Cl transporter, offer the exciting prospect of linking changes in expression and/or function of this transporter to pharmacodynamic observations. Doing so should allow even better therapeutic strategies in the future. More specifically, questions that are highly pertinent are whether altered expression and activity of the transporter occur in models of heart failure, cirrhosis, and nephrotic syndrome and by which mechanism(s) that increase occurs. In particular, what is the role of nonosmotically released vasopressin? Is the function of the transporter altered? If so, what are the mediators of such changes and the implications therein for therapeutic strategies? Most importantly, the tools are now in hand to dissect these mechanisms and attack these common clinical conditions from a mechanism-based strategy as opposed to the more empirical approaches that have heretofore characterized this area.
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ACKNOWLEDGEMENTS |
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This work was supported by the General Clinical Research Center (MO1 RR-00750) and by National Institutes of Health Grants R01-DK-37994 and R01-AG-07631.
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FOOTNOTES |
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Address for reprint requests and other correspondence: D. C. Brater, Indiana Univ. School of Medicine, Fesler 302, 1120 South Dr., Indianapolis, IN 46202-5124 (E-mail: dbrater{at}iupui.edu).
10.1152/ajprenal.00119.2002
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REFERENCES |
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---|
1.
Agarwal, R,
Gorski JC,
Sundblad K,
and
Brater DC.
Urinary protein binding does not affect response to furosemide in patients with nephrotic syndrome.
J Am Soc Nephrol
11:
1100-1105,
2000
2.
Agre, P.
Homer W. Smith award lecture. Aquaporin water channels in kidney.
J Am Soc Nephrol
11:
764-777,
2000
3.
Akcicek, F,
Yalniz T,
Basci A,
Ok E,
and
Mees EJ.
Diuretic effect of frusemide in patients with nephrotic syndrome: is it potentiated by intravenous albumin?
BMJ
310:
162-163,
1995
4.
Almeshari, K,
Ahlstrom NG,
Capraro FE,
and
Wilcox CS.
A volume-independent component to postdiuretic sodium retention in humans.
J Am Soc Nephrol
3:
1878-1883,
1993[Abstract].
5.
Andreasen, F,
and
Mikkelsen E.
Distribution, elimination and effect of furosemide in normal subjects and in patients with heart failure.
Eur J Clin Pharmacol
12:
15-22,
1977[ISI][Medline].
6.
Bailie, GR,
Grennan A,
and
Waldek S.
Bioavailability of bumetanide in grossly oedematous patients.
Clin Pharmacokinet
12:
440-443,
1987[ISI][Medline].
7.
Beerman, B.
Aspects on pharmacokinetics of some diuretics.
Acta Pharmacol Toxicol
54:
17-32,
1984[Medline].
8.
Beerman, B,
Dalen E,
and
Lindström B.
Elimination of furosemide in healthy subjects and in those with renal failure.
Clin Pharmacol Ther
22:
70-78,
1977[ISI][Medline].
9.
Brater, DC.
Diuretic pharmacokinetics and pharmacodynamics.
In: The In Vivo Study of Drug Action. Principles and Applications of Kinetic-Dynamic Modelling. Amsterdam: Elsevier, 1992.
10.
Brater, DC.
Diuretic therapy.
N Engl J Med
339:
387-395,
1998
11.
Brater, DC,
Chennavasin P,
Day B,
Burdette A,
and
Anderson S.
Bumetanide and furosemide.
Clin Pharmacol Ther
34:
207-213,
1983[ISI][Medline].
12.
Brater, DC,
Chennavasin P,
and
Seiwell R.
Furosemide in patients with heart failure: shift in dose-response curves.
Clin Pharmacol Ther
28:
182-186,
1980[ISI][Medline].
13.
Brater, DC,
Day B,
Burdette A,
and
Anderson S.
Bumetanide and furosemide in heart failure.
Kidney Int
26:
183-189,
1984[ISI][Medline].
14.
Brater, DC,
Leinfelder J,
and
Anderson SA.
Clinical pharmacology of torsemide, a new loop diuretic.
Clin Pharmacol Ther
42:
187-192,
1987[ISI][Medline].
15.
Burg, MB.
Tubular chloride transport and the mode of action of some diuretics.
Kidney Int
9:
189-197,
1976[ISI][Medline].
16.
Carmichael, J,
and
Shankel SW.
Effects of nonsteroidal anti-inflammatory drugs on prostaglandins and renal function.
Am J Med
78:
992-1000,
1985[ISI][Medline].
17.
Chalasani, N,
Gorski JC,
Horlander JC, Sr,
Craven R,
Hoen H,
Maya J,
and
Brater DC.
Effects of albumin/furosemide mixtures on responses to furosemide in hypoalbuminemic patients.
J Am Soc Nephrol
12:
1010-1016,
2001
18.
Chaturvedi, PR,
O'Donnell JP,
Nicholas JM,
Shoenthal DR,
Waters DH,
and
Gwilt PR.
Steady state absorption kinetics and pharmacodynamics of furosemide in congestive heart failure.
Int J Clin Pharmacol Ther Toxicol
25:
123-128,
1987[Medline].
19.
Chennavasin, P,
Seiwell R,
Brater DC,
and
Liang WM.
Pharmacodynamic analysis of the furosemide-probenecid interaction in man.
Kidney Int
16:
187-195,
1979[ISI][Medline].
20.
Clive, DM,
and
Stoff JS.
Renal syndromes associated with nonsteroidal antiinflammatory drugs.
N Engl J Med
310:
563-572,
1984[ISI][Medline].
21.
Cutler, RE,
Forrey AW,
Christopher TG,
and
Kimpel BM.
Pharmacokinetics of furosemide in normal subjects and functionally anephric patients.
Clin Pharmacol Ther
15:
588-596,
1974[ISI][Medline].
22.
Davies, DL,
Lant AF,
Millard NR,
Smith AJ,
Ward JW,
and
Wilson GM.
Renal action, therapeutic use, and pharmacokinetics of the diuretic bumetanide.
Clin Pharmacol Ther
15:
141-155,
1974[ISI][Medline].
23.
Dormans, TP,
van Meyel JJ,
Gerlag PG,
Tan Y,
Russel FG,
and
Smits P.
Diuretic efficacy of high dose furosemide in severe heart failure: bolus injection versus continuous infusion.
J Am Coll Cardiol
28:
376-382,
1996[ISI][Medline].
24.
Ecelbarger, CA,
Yu S,
Lee AJ,
Weinstein LS,
and
Knepper MA.
Decreased renal Na-K-2Cl cotransporter abundance in mice with heterozygous disruption of the Gs gene.
Am J Physiol Renal Physiol
277:
F235-F244,
1999
25.
Ellison, DH,
Velazquez H,
and
Wright FS.
Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietary salt intake and chronic diuretic infusion.
J Clin Invest
83:
113-126,
1989[ISI][Medline].
26.
Ellison, DH.
The physiologic basis of diuretic synergism: its role in treating diuretic resistance.
Ann Intern Med
114:
886-894,
1991[ISI][Medline].
27.
Epstein, M,
Lepp B,
Hoffman D,
and
Levinson R.
Potentiation of furosemide by metolazone in refractory edema.
Curr Ther Res
21:
656-667,
1977[ISI].
28.
Ferguson, JA,
Sundblad KJ,
Becker PK,
Gorski JC,
Rudy DW,
and
Brater DC.
Role of duration of diuretic effect in preventing sodium retention.
Clin Pharmacol Ther
62:
203-208,
1997[ISI][Medline].
29.
Fernandez-Llama, P,
Ecelbarger CA,
Ware JA,
Andrews P,
Lee AJ,
Turner R,
Nielsen S,
and
Knepper MA.
Cyclooxygenase inhibitors increase Na-K-2Cl cotransporter abundance in thick ascending limb of Henle's loop.
Am J Physiol Renal Physiol
277:
F219-F226,
1999
30.
Fliser, D,
Zurbruggen I,
Mutschler E,
Bischoff I,
Nussberger J,
Franek E,
and
Ritz E.
Coadministration of albumin and furosemide in patients with the nephrotic syndrome.
Kidney Int
55:
629-634,
1999[ISI][Medline].
31.
Forbush, B, III,
and
Palfrey HC.
[3H]bumetanide binding to membranes isolated from dog kidney outer medulla. Relationship to the Na,K,Cl co-transport system.
J Biol Chem
258:
11787-11792,
1983
32.
Fuller, R,
Hoppel C,
and
Ingalls ST.
Furosemide kinetics in patients with hepatic cirrhosis with ascites.
Clin Pharmacol Ther
30:
461-467,
1981[ISI][Medline].
33.
Gallagher, KL,
and
Jones JK.
Furosemide-induced ototoxicity.
Ann Intern Med
91:
744-745,
1979[ISI][Medline].
34.
Gehr, TW,
Rudy DW,
Matzke GR,
Kramer WG,
Sica DA,
and
Brater DC.
The pharmacokinetics of intravenous and oral torsemide in patients with chronic renal insufficiency.
Clin Pharmacol Ther
56:
31-38,
1994[ISI][Medline].
35.
Gerlag, PG,
and
van Meijel JJ.
High-dose furosemide in the treatment of refractory congestive heart failure.
Arch Intern Med
148:
286-291,
1988[Abstract].
36.
Gimenez, I,
Isenring P,
and
Forbush B.
Spatially distributed alternative splice variants of the renal Na-K-Cl cotransporter exhibit dramatically different affinities for the transported ions.
J Biol Chem
277:
8767-8770,
2002
37.
Green, TP,
and
Mirkin BL.
Resistance of proteinuric rats to furosemide: urinary drug protein binding as a determinant of drug effect.
Life Sci
26:
623-630,
1980[ISI][Medline].
38.
Green, TP,
and
Mirkin BL.
Furosemide disposition in normal and proteinuric rats: urinary drug-protein binding as a determinant of drug excretion.
J Pharmacol Exp Ther
218:
122-127,
1981[Abstract].
39.
Greither, A,
Goldman S,
Edelen JS,
Benet LZ,
and
Cohn K.
Pharmacokinetics of furosemide in patients with congestive heart failure.
Pharmacology
19:
121-131,
1979[ISI][Medline].
40.
Haas, M,
and
Forbush B, III.
Na,K,Cl-cotransport system: characterization by bumetanide binding and photolabelling.
Kidney Int Suppl
23:
S134-S143,
1987[Medline].
41.
Haas, M,
and
Forbush B, III.
The Na-K-Cl cotransporters.
J Bioenerg Biomembr
30:
161-172,
1998[ISI][Medline].
42.
Haas, M,
and
Forbush B, III.
The Na-K-Cl cotransporter of secretory epithelia.
Annu Rev Physiol
62:
515-534,
2000[ISI][Medline].
43.
Hammarlund, MM,
Odlind B,
and
Paalzow LK.
Acute tolerance to furosemide diuresis in humans. Pharmacokinetic-pharmacodynamic modeling.
J Pharmacol Exp Ther
233:
447-453,
1985[Abstract].
44.
Hebert, RL,
Jacobson HR,
and
Breyer MD.
PGE2 inhibits AVP-induced water flow in cortical collecting ducts by protein kinase C activation.
Am J Physiol Renal Fluid Electrolyte Physiol
259:
F318-F325,
1990
45.
Heerdink, ER,
Leufkens HG,
Herings RM,
Ottervanger JP,
Stricker BH,
and
Bakker A.
NSAIDs associated with increased risk of congestive heart failure in elderly patients taking diuretics.
Arch Intern Med
158:
1108-1112,
1998
46.
Holazo, AA,
Colburn WA,
Gustafson JH,
Young RL,
and
Parsonnet M.
Pharmacokinetics of bumetanide following intravenous, intramuscular, and oral administrations to normal subjects.
J Pharm Sci
73:
1108-1113,
1984[ISI][Medline].
47.
Huang, CM,
Atkinson AJ, Jr,
Levin M,
Levin NW,
and
Quintanilla A.
Pharmacokinetics of furosemide in advanced renal failure.
Clin Pharmacol Ther
16:
659-666,
1974[ISI][Medline].
48.
Inoue, M,
Okajima K,
Itoh K,
Ando Y,
Watanabe N,
Yasaka T,
Nagase S,
and
Morino Y.
Mechanism of furosemide resistance in analbuminemic rats and hypoalbuminemic patients.
Kidney Int
32:
198-203,
1987[ISI][Medline].
49.
Isenring, P,
Jacoby SC,
Payne JA,
and
Forbush B, III.
Comparison of Na-K-Cl cotransporters. NKCC1, NKCC2, and the HEK cell Na-L-Cl cotransporter.
J Biol Chem
273:
11295-11301,
1998
50.
Kaissling, B,
and
Stanton BA.
Adaptation of distal tubule and collecting duct to increased sodium delivery. I. Ultrastructure.
Am J Physiol Renal Fluid Electrolyte Physiol
255:
F1256-F1268,
1988
51.
Kaojarern, S,
Chennavasin P,
Anderson S,
and
Brater DC.
Nephron site of effect of nonsteroidal anti-inflammatory drugs on solute excretion in humans.
Am J Physiol Renal Fluid Electrolyte Physiol
244:
F134-F139,
1983
52.
Keller, E,
Hoppe-Seyler G,
Mumm R,
and
Schollmeyer P.
Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide.
Eur J Clin Pharmacol
20:
27-33,
1981[ISI][Medline].
53.
Keller, E,
Hoppe-Seyler G,
and
Schollmeyer P.
Disposition and diuretic effect of furosemide in the nephrotic syndrome.
Clin Pharmacol Ther
32:
442-449,
1982[ISI][Medline].
54.
Kelly, RA,
Wilcox CS,
Mitch WE,
Meyer TW,
Souney PF,
Rayment CM,
Friedman PA,
and
Swartz SL.
Response of the kidney to furosemide. II. Effect of captopril on sodium balance.
Kidney Int
24:
233-239,
1983[ISI][Medline].
55.
Kim, GH,
Ecelbarger CA,
Mitchell C,
Packer RK,
Wade JB,
and
Knepper MA.
Vasopressin increases Na-K-2Cl cotransporter expression in thick ascending limb of Henle's loop.
Am J Physiol Renal Physiol
276:
F96-F103,
1999
56.
Kirchner, KA,
Voelker JR,
and
Brater DC.
Intratubular albumin blunts the response to furosemide-A mechanism for diuretic resistance in the nephrotic syndrome.
J Pharmacol Exp Ther
252:
1097-1101,
1990[Abstract].
57.
Kirchner, KA,
Voelker JR,
and
Brater DC.
Binding inhibitors restore furosemide potency in tubule fluid containing albumin.
Kidney Int
40:
418-424,
1991[ISI][Medline].
58.
Kirchner, KA,
Voelker JR,
and
Brater DC.
Tubular resistance to furosemide contributes to the attenuated diuretic response in nephrotic rats.
J Am Soc Nephrol
2:
1201-1207,
1992[Abstract].
59.
Knepper, MA.
Molecular physiology of urinary concentrating mechanism: regulation of aquaporin water channels by vasopressin.
Am J Physiol Renal Physiol
272:
F3-F12,
1997
60.
Kobayashi, S,
Clemmons DR,
Nogami H,
Roy AK,
and
Venkatachalam MA.
Tubular hypertrophy due to work load induced by furosemide is associated with increases of IGF-1 and IGFBP-1.
Kidney Int
47:
818-828,
1995[ISI][Medline].
61.
Kramer, WG,
Smith WB,
Ferguson J,
Serpas T,
Grant AG, III,
Black PK,
and
Brater DC.
Pharmacodynamics of torsemide administered as an intravenous injection and as a continuous infusion to patients with congestive heart failure.
J Clin Pharmacol
36:
265-270,
1996
62.
Lahav, M,
Regev A,
Ra'anani P,
and
Theodor E.
Intermittent administration of furosemide vs. continuous infusion preceded by a loading dose for congestive heart failure.
Chest
102:
725-731,
1992[Abstract].
63.
Loon, NR,
Wilcox CS,
and
Unwin RJ.
Mechanism of impaired natriuretic response to furosemide during prolonged therapy.
Kidney Int
36:
682-689,
1989[ISI][Medline].
64.
Martinez-Maldonado, M,
and
Cordova HR.
Cellular and molecular aspects of the renal effects of diuretic agents.
Kidney Int
38:
632-641,
1990[ISI][Medline].
65.
Merlo, J,
Broms K,
Lindblad U,
Bjorck-Linne A,
Liedholm H,
Ostergren PO,
Erhardt L,
Rastam L,
and
Melander A.
Association of outpatient utilisation of non-steroidal anti-inflammatory drugs and hospitalised heart failure in the entire Swedish population.
Eur J Clin Pharmacol
57:
71-75,
2001[ISI][Medline].
66.
Mount, DB,
Baekgaard A,
Hall AE,
Plata C,
Xu J,
Beier DR,
Gamba G,
and
Hebert SC.
Isoforms of the Na-K-2Cl cotransporter in murine TAL. I. Molecular characterization and intrarenal localization.
Am J Physiol Renal Physiol
276:
F347-F358,
1999
67.
Murray, MD,
Deer MM,
Ferguson JA,
Dexter PR,
Bennett SJ,
Perkins SM,
Smith FE,
Lane KA,
Adams LD,
Tierney WM,
and
Brater DC.
Open-label randomized trial of torsemide compared with furosemide therapy for patients with heart failure.
Am J Med
111:
513-520,
2001[ISI][Medline].
68.
Murray, MD,
Haag KM,
Black PK,
Hall SD,
and
Brater DC.
Variable furosemide absorption and poor predictability of response in elderly patients.
Pharmacotherapy
17:
98-106,
1997[ISI][Medline].
69.
Nielsen, S,
Maunsbach AB,
Ecelbarger CA,
and
Knepper MA.
Ultrastructural localization of Na-K-2Cl cotransporter in thick ascending limb and macula densa of rat kidney.
Am J Physiol Renal Physiol
275:
F885-F893,
1998
70.
Obermuller, N,
Kunchaparty S,
Ellison DH,
and
Bachmann S.
Expression of the Na-K-2Cl cotransporter by macula densa and thick ascending limb cells of rat and rabbit nephron.
J Clin Invest
98:
635-640,
1996
71.
Odlind, B,
and
Beermann B.
Renal tubular secretion and effects of furosemide.
Clin Pharmacol Ther
27:
784-790,
1980[ISI][Medline].
72.
Olesen, KH,
and
Sigurd B.
The supra-additive natriuretic effect addition of quinethazone or bendroflumethiazide during long-term treatment with furosemide and spironolactone. Permutation trial tests in patients with congestive heart failure.
Acta Med Scand
190:
233-240,
1971[ISI][Medline].
73.
Oster, JR,
Epstein M,
and
Smoller S.
Combined therapy with thiazide-type and loop diuretic agents for resistant sodium retention.
Ann Intern Med
99:
405-406,
1983[ISI][Medline].
74.
Perez, J,
Sitar DS,
and
Ogilvie RI.
Kinetic disposition and diuretic effect of frusemide in acute pulmonary oedema.
Br J Clin Pharmacol
9:
471-478,
1980[ISI][Medline].
75.
Petersen, JS,
Shalmi M,
Abildgaard U,
Christensen NJ,
and
Christensen S.
Renal effects of alpha-adrenoceptor blockade during furosemide diuresis in conscious rats.
Pharmacol Toxicol
70:
3-12,
1992[ISI][Medline].
76.
Pichette, V,
and
du Souich P.
Role of the kidneys in the metabolism of furosemide: its inhibition by probenecid.
J Am Soc Nephrol
7:
345-349,
1996[Abstract].
77.
Plato, CF,
Stoos BA,
Wang D,
and
Garvin JL.
Endogenous nitric oxide inhibits chloride transport in the thick ascending limb.
Am J Physiol Renal Physiol
276:
F159-F163,
1999
78.
Popowicz, P,
and
Simmons NL.
[3H]bumetanide binding and inhibition of Na+ + K+ + Cl co-transport: demonstration of specificity by the use of MDCK cells deficient in co-transport activity.
Q J Exp Physiol
73:
193-202,
1988[ISI][Medline].
79.
Rane, A,
Villeneuve JP,
Stone WJ,
Nies AS,
Wilkinson GR,
and
Branch RA.
Plasma binding and disposition of furosemide in the nephrotic syndrome and in uremia.
Clin Pharmacol Ther
24:
199-207,
1978[ISI][Medline].
80.
Rose, BD.
Diuretics.
Kidney Int
39:
336-352,
1991[ISI][Medline].
81.
Rudy, DW,
Gehr TW,
Matzke GR,
Kramer WG,
Sica DA,
and
Brater DC.
The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency.
Clin Pharmacol Ther
56:
39-47,
1994[ISI][Medline].
82.
Rudy, DW,
Voelker JR,
Greene PK,
Esparza FA,
and
Brater DC.
Loop diuretics for chronic renal insufficiency: a continuous infusion is more efficacious than bolus therapy.
Ann Intern Med
115:
360-366,
1991[ISI][Medline].
83.
Schlondorff, D.
Renal complications of nonsteroidal anti-inflammatory drugs.
Kidney Int
44:
643-653,
1993[ISI][Medline].
84.
Schrier, RW,
and
Berl T.
Nonosmolar factors affecting renal water excretion (second of two parts).
N Engl J Med
292:
141-145,
1975[ISI][Medline].
85.
Schrier, RW,
and
Berl T.
Nonosmolar factors affecting renal water excretion (first of two parts).
N Engl J Med
292:
81-88,
1975[ISI][Medline].
86.
Schwartz, S,
Brater DC,
Pound D,
Green PK,
Kramer WG,
and
Rudy D.
Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide in patients with cirrhosis.
Clin Pharmacol Ther
54:
90-97,
1993[ISI][Medline].
87.
Sica, DA,
and
Gehr TW.
Diuretic combinations in refractory oedema states: pharmacokinetic-pharmacodynamic relationships.
Clin Pharmacokinet
30:
229-249,
1996[ISI][Medline].
88.
Stanton, BA,
and
Kaissling B.
Adaptation of distal tubule and collecting duct to increased Na delivery. II. Na+ and K+ transport.
Am J Physiol Renal Fluid Electrolyte Physiol
255:
F1269-F1275,
1988
89.
Tilstone, WJ,
and
Fine A.
Furosemide kinetics in renal failure.
Clin Pharmacol Ther
23:
644-650,
1978[ISI][Medline].
90.
Traeger, A,
Hantze R,
Penzlin M,
Krombholz B,
Reinhardt M,
Keil E,
and
Jorke D.
Pharmacokinetics and pharmacodynamic effects of furosemide in patients with liver cirrhosis.
Int J Clin Pharmacol Ther Toxicol
23:
129-133,
1985[Medline].
91.
Van Meyel, JJ,
Gerlag PG,
Smits P,
Russel FG,
Tan Y,
Van Ginneken CA,
and
Gribnau FW.
Absorption of high dose furosemide (frusemide) in congestive heart failure.
Clin Pharmacokinet
22:
308-318,
1992[ISI][Medline].
92.
Van Meyel, JJ,
Smits P,
Dormans T,
Gerlag PG,
Russel FG,
and
Gribnau FW.
Continuous infusion of furosemide in the treatment of patients with congestive heart failure and diuretic resistance.
J Intern Med
235:
329-334,
1994[ISI][Medline].
93.
Van Olden, RW,
van Meyel JJ,
and
Gerlag PG.
Sensitivity of residual nephrons to high dose furosemide described by diuretic efficiency.
Eur J Clin Pharmacol
47:
483-488,
1995[ISI][Medline].
94.
Vargo, DL,
Kramer WG,
Black PK,
Smith WB,
Serpas T,
and
Brater DC.
Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide and furosemide in patients with congestive heart failure.
Clin Pharmacol Ther
57:
601-609,
1995[ISI][Medline].
95.
Vasko, MR,
Cartwright DB,
Knochel JP,
Nixon JV,
and
Brater DC.
Furosemide absorption altered in decompensated congestive heart failure.
Ann Intern Med
102:
314-318,
1985[ISI][Medline].
96.
Verbeeck, RK,
Patwardhan RV,
Villeneuve JP,
Wilkinson GR,
and
Branch RA.
Furosemide disposition in cirrhosis.
Clin Pharmacol Ther
31:
719-725,
1982[ISI][Medline].
97.
Verkman, AS,
and
Mitra AK.
Structure and function of aquaporin water channels.
Am J Physiol Renal Physiol
278:
F13-F28,
2000
98.
Villeneuve, JP,
Verbeeck RK,
Wilkinson GR,
and
Branch RA.
Furosemide kinetics and dynamics in patients with cirrhosis.
Clin Pharmacol Ther
40:
14-20,
1986[ISI][Medline].
99.
Voelker, JR,
Cartwright-Brown D,
Anderson S,
Leinfelder J,
Sica DA,
Kokko JP,
and
Brater DC.
Comparison of loop diuretics in patients with chronic renal insufficiency.
Kidney Int
32:
572-578,
1987[ISI][Medline].
100.
Wakelkamp, M,
Alvan G,
Gabrielsson J,
and
Paintaud G.
Pharmacodynamic modeling of furosemide tolerance after multiple intravenous administration.
Clin Pharmacol Ther
60:
75-88,
1996[ISI][Medline].
101.
Wilcox, CS,
Guzman NJ,
Mitch WE,
Kelly RA,
Maroni BJ,
Souney PF,
Rayment CM,
Braun L,
Colucci R,
and
Loon NR.
Na+, K+, and BP homeostasis in man during furosemide: effects of prazosin and captopril.
Kidney Int
31:
135-141,
1987[ISI][Medline].
102.
Wilcox, CS,
Mitch WE,
Kelly RA,
Skorecki K,
Meyer TW,
Friedman PA,
and
Souney PF.
Response of the kidney to furosemide. I. Effects of salt intake and renal compensation.
J Lab Clin Med
102:
450-458,
1983[ISI][Medline].
103.
Yamamoto, T,
and
Sasaki S.
Aquaporins in the kidney: emerging new aspects.
Kidney Int
54:
1041-1051,
1998[ISI][Medline].